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Jackie Westaway-1

To: Barry Brand, Bonnie Rossello, Lionel D Houle, Jackie C Owens, Pascale Richetta, Beatrix Steffen, Luis DE LORENZO, Ken DiPangrazio, Roland Kaan, Eddy R Beke, Frank D Auton, B Srinivasan, Christophe Weber cc: Julie Wilson-1, Sarah Daniels-1, Jill Andrews-1, Margaret M Black, Keiron T Sparrowhawk, Graham Griffiths-1, Susanne Borrett-1, Fiona Barnard-1, Paul Jenner-1, Jane M Nicholass, Anne J Bell Subject: Seroxat/Paxil in Adolescent Depression

14-0ct-1998

13:04

Please find attached to this memo a position piece, prepared by Julie Wilson of CMAT, summarising the results of the clinical studies in Adolescent Depression. As you will know, the results of the studies were disappointing in that we did not reach statistical significance on the primary end points and thus the data do not support a label claim for the treatment of Adolescent Depression. The possibility of obtaining a safety statement from this data was considered but rejected. The best which could have been achieved was a statement that, although safety data was reassuring, efficacy had not been demonstrated. Consultation of the Marketing Teams via Regulatory confirmed that this would be unacceptable commercially and the decision to take no regulatory action was recently endorsed by the TAT. As you will see from the position piece the positive trends in efficacy which were seen in Study 329 are being published as a poster at ECNP this year and a full manuscript is in development. Published references will therefore be available for the study. There are no plans to publish data from Study 377. This report has been prepared for internal use only, Data on File summaries will be prepared and issued once the final reports from the studies have been approved. This position piece will also be available on The Seroxat/Paxilresource database Best wishes

Jackie Westaway

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SEROXAT/PAXIL ADOLESCENT DEPRESSION Position piece on the phase III clinical studies FOR INTERNAL USE ONLY SITUATION
2 SB sponsored, placebo-controlled, phase III clinical trials have been conducted, Study 329 (US) and Study 377 (Europe, South America, South Africa and Saudi Arabia), in order to assess the efficacy and safety of Seroxat/Paxil (up to 40mg/day) in the treatment of adolescents (aged between 13 and 18 years and 11 months) with unipolar major depressive disorder (diagnosed according to DSM IIIR, Study 329 or DSM IV criteria, Study 377). Study 329 was a placebo-controlled, imipramine comparator study with an 8 week acute treatment phase followed by a 6 month extension phase. The acute phase has completed and the extension phase is due to complete at the end of 1998. 275 patients were recruited to the study. Results from the acute phase of this study show that there were no statistically significant differences from placebo on either of the primary efficacy parameters (change from baseline in HAMD total scores and the proportion of responders-where response was defined as a ~50% reduction from baseline in HAMD score or a HAMD score :=:;8 at endpoint). However, trends in favour of paroxetine compared with placebo were seen across all the indices of depression (change from baseline in HAMD total [p=0.133], HAMD responders [p=0.112], CGI [p=0.094] and K-SADS [p=0.065] scores) and statistically significant differences from placebo were observed in the proportion of patients in remission (defined as a HAMD score of :=:;8 at endpoint). In general, the response to imipramine was similar to that for placebo. The 6 month extension phase is ongoing and is scheduled to complete at the end of 1998. Study 377 was a 12 week placebo-controlled study, conducted in 276 adolescents with major depression. There was a high placebo response rate in this study and no statistically or clinically significant differences from placebo were observed on either of the primary efficacy variables (proportion of patients achieving a _:::50% reduction from baseline in total MADRS scores and change from baseline in the K-SADS-L depressive subscale score). The only differences from placebo (secondary efficacy variables) were seen in a subgroup of patients who were _:: : 16 years of age.

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Possible explanations for the high placebo response include; 1) The large number of study visits 2) the duration of the assessments 3) The fact that concomitant psychotherapy was not excluded 4) Question marks about the adequacy of using currently available diagnostic criteria and rating scales in younger patients 5) Adolescents may be more susceptible to a placebo effect 6) Developmental issues. Children and adolescents may respond m a pharmacologically different manner due to quantitative and/or qualitative differences in neurotransmitter/receptor systems. Conclusions from these studies: There were no differences in the safety profile of Seroxat/Paxil in adolescents when compared to that already established in the adult population The efficacy data from the above clinical trials are insufficiently robust to support a regulatory submission and label change for this patient population.

OTHER DATA: Ongoing studies: SB France are conducting a locally funded double-blind, comparative study of Seroxat/Paxil with clomipramine in adolescents with major depression (Study 511). In addition, a study in adolescents with OCD (Study 453) is underway in the US. This study comprises a 16 week open label Seroxat/Paxil treatment phase, followed by double-blind, randomisation to paroxetine or placebo for a further 16 weeks of treatment. The regulatory acceptability of these 2 studies needs to be established. Published data: A review of the literature shows that 2 studies assessing the use of paroxetine in the treatment of 34 adolescents and children with depression have been published (Rey-Sanchez F and Gutierrez-Cesares, 1997; Findling et al; 1996). COMPETITOR ACTIVITIES: Lilly are believed to be in near to completing their phase III clinical trials in adolescent depression. One relatively large placebo-controlled 8 week study with an open 12

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month follow-up period conducted in 96 patients (aged 8-18 years) has recently been published (Emslie et al; 1997 and 1998). These data show that 56% (27/48) patients on fluoxetine (20mg/day) compared with 33% (16/48) patients on placebo were rated as much or very much improved on the CGI at Week 6 (p=0.02. In the 12 month follow-up period, 85% (n=74) patients recovered from the depressive episode (47 on fluoxetine, 22 on placebo and 5 on other antidepressants or lithium). Twenty nine (39%) of the patients (36% of those who had recovered on fluoxetine [17/47] and 41% of those who had recovered on placebo [9/22] had a recurrence of depression during the 12 month follow-up (a higher recurrence rate than seen in adults). Other published data on fluoxetine are from small open studies or individual case reports (Colle et al; 1994).
Pfizer already have positive data (including PK data) and are licenced in the US for the treatment of adolescent OCD. In addition, Pfizer are also believed to be conducting clinical trials in adolescent depression. Available published data are limited, derived from small open studies in adolescent depression (McConville et al; 1996; Tierney et al; 1995)

TARGET
To effectively manage the dissemination of these data m order to mmnruse any potential negative commercial impact.

PROPOSALS
Based on the current data, and following consultation with SB country regulatory and marketing groups, no regulatory submissions will be made for either efficacy or safety statements relating to adolescent depression. The rationale for not attempting to obtain a safety statement is as follows; i) regulatory agencies would not approve a statement indicating that there are no safety issues in adolescents, as this could be seen as promoting off-label use ii)it would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine. Positive data from Study 329 will be published in abstract form at the ECNP (Paris, November 1998) and a full manuscript of the 329 data will be progressed.

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The regulatory acceptability of Studies 511 and 453 and any other data in this patient population will continue to be investigated.

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REFERENCES
1. Rey-Sanchez F; Gutierrez-Cesares JR. Paroxetine in children with major depressive disorder: an open trial. JAm Acad Child Adolesc Psychiatry1997; 36 (10): 1443-1447. 2. Findling R Fiala S, Myers C et al. Putative determinants of paroxetine response in pediatric patients with major depression. Psychopharmacol Bull; 1996; 32 (3):446. 3. Emslie GJ, Rush AJ, Weinberg WA et al. A double-blind, randomized, placebocontrolled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry; 1997; 54 (11): 1031-1037. 4. Emslie GJ, Rush AJ, Weinberg WA et al. Fluoxetine in child and adolescent depression: acute and maintenance treatment. Depression and Anxiety (US); 1998; 7 (1): 32-39. 5. Colle LM, Belair JF, DiFeo M et al. Extended open label fluoxetine treatment of adolescents with major depression. J Child Adolesc Psychopharmacol. 1994; 4 (4): 225-232. 6. McConville BJ, Minnery RL, Sorter MT et al. An open study of the effects of sertraline on adolescent major depression. J Child Adolesc Psychopharmacol. 1996; 6 (1):41-51 7. Tierney E, Joshi PT, Llinas JF et al. Sertraline for major depression in children and adolescents: Preliminary clinical experience. J Child Adolesc Psychopharmacol; 1995; 5 (1): 13-27.

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Statement for the markets Summary of the Seroxat/Paxil clinical trials in Adolescent Depression
Results from the 2 placebo-controlled, phase III clinical trials designed to assess the efficacy and safety of Seroxat/Paxil in adolescents with major depression are now available. Study 329 (conducted in the US) showed trends in efficacy in favour of Seroxat/Paxil across all indices of depression. However, the study failed to demonstrate a statistically significant difference from placebo on the primary efficacy measures. The second study (study 377), which was conducted in Europe, South America, South Mrica and Saudia Arabia, showed a high placebo response rate and failed demonstrate any separation of Seroxat/Paxil from placebo. Data from these 2 studies are insufficiently robust to support a label change and will therefore not be submitted to the regulatory authorities. Results from Study 329 will be presented in abstract form at the ECNP meeting (Paris, November 1999) and a full manuscript will be progressed. There are no plans to publish data from Study 377.

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Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial
MARTIN B. KELLER, M.D., NEAL D. RYAN, M.D., MICHAEL STROBER, PH.D., RACHEL G. KLEIN, PH.D., STAN P. KUTCHER, M.D., BORIS BIRMAHER, M.D., OWEN R. HAGINO, M.D., HAROLD KOPLEWICZ, M.D., GABRIELLE A. CARLSON, M.D., GREGORY N. CLARKE, PH.D., GRAHAM J. EMSLIE, M.D., DAVID FEINBERG, M.D., BARBARA GELLER, M.D., VIVEK KUSUMAKAR, M.D., GEORGE PAPATHEODOROU, M.D., WILLIAM H. SACK, M.D., MICHAEL SWEENEY, PH.D., KAREN DINEEN WAGNER, M.D., PH.D., ELIZABETH B. WELLER, M.D., NANCY C. WINTERS, M.D., ROSEMARY OAKES, M.S., AND JAMES P. McCAFFERTY, B.S.

ABSTRACT Objective: To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. Method: After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score :>8 or ;::50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores. Results: Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score :>8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects. Conclusions: Paroxetine is generally well tolerated and effective for major depression in adolescents. J. Am. Acad. Child Ado/esc. Psychiatry, 2001, 40(7):762-772. Key Words: paroxetine, imipramine, major depression, adolescent.

Accepted Februaryl5, 2001. From the Department of Psychiatry and Human Behavior, Brown University, Providence, Rl (Dr. Keller); Department of Psychiatry, University of Pittsburgh School ~f Medicine (Drs. Ryan, Birmaher); UCLA Medical Center (Drs. Strober, Feinberg); New York UnitJersity Child Study Center {Drs. Klein, Koplewicz); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia (Dr. Kutcher); Department of Psychiatry, University of Pennsylvania, Philadelphia (Dr. Hagino); Department of Child and Adolescent Psychiatry, State University of New York at Stony Brook (Dr. Carlson); Center for Health Research, Portland, OR (D1: Clttrk,'); Dqttrtment of l'sycbitttl)\ Unioersity of Texas Southwestem lvfedical Center, Dallas (Dr. Emslie); Department of Psychiatry, Washington Unit1mity School of Medicine, St. Louis (Dr: Geller); Department of Psychiatry, G,ace-JWK Hospital, Haliftx, Nova Scotirl {Dr. Kusumakar); Department of Psychiatry, Sunnybrook Health Science Centre, University of Toronto (D>: Papatheodorou); Departrnent of Psychiatry, Oregon Health Sciences University, Portland (Drs. Sack, Winters); New York State Psychiatric Institute, New York (Dr. Sweeney); Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston (Dr. Wagner); Department of Psychiatry,

The treatment of depression in adolescents is an area of burgeoning interest. Unfortunately, few well-controlled, large-scale, randomized clinical trials have been conducted in this population. Data fiom the 1,769 adolescents and
Children! Hospital of Philadelphia (Dr. Weller); North America Medical Affairs, GlaxoSmithKline, Collegeville, PA (Ms. Oakes, Mr. McCafferty). This study wa.r supported by a grant ftom GlaxoSmithKline, Collcge11ille, PA. The authors acknowledg:e the contributions of the fvllowing indi11iduals: fill M AMott, Ellen Br~,,ir;n, Ph.D., Cr<ro(yn BouloJ, lvf.D., E(yse Du/Jo, Jvf.D., lvfaryA. Fristad, Ph.D., Joan Hebeler, M.D., Kevin Kelly, Ph.D., C.haron Reiter, M.D., and RonaldA. Weller, MD. Editorial assistance was provided by Sally K Laden, MS. Reprint requests to Dr. Keller, Department of Psychiatry and Human BehatJior, Brown University School ofMedicine, 345 Blackstone Blvd., Providence, Rl
02906. 0890-8567/01/4007-07622001 by the American Academy of Child and Adolescent Psychiatry.

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young adult participants in the National Comorbidity Survey (Kessler and Walters, 1998) indicate a lifetime prevalence rate of 15.3% for major depression, comparable with the 17% lifetime prevalence of depression in adults (Kessler eta!., 1994). As with adults, the course of major depression in adolescents is often characterized by protracted episodes, frequent recurrence, and impairment in social and academic domains (Rao eta!., 1995). Suicide is the third leading cause of death in adolescents, and depressive disorders are strongly correlated with suicide attempts (Eisenberg, 1984; Kovacs et a!., 1993). Depressed adolescents grow up to be depressed adults and, compared with healthy controls, have higher rates of suicide, psychiatric and medical hospitalizations, and impairment in work, family, and social lives (Weissman eta!., 1999). The efficacy of tricyclic antidepressants has been investigated in at least 11 double-blind, randomized studies (Dulcan eta!., 1998; Ryan and Varma, 1998), none demonstrating superiority of active treatment over placebo. However, methodological deficiencies in these studies, including very small sample sizes and diagnostic heterogeneity, limit statistical inference and generalizability of the findings. At the same time, cardiovascular effects and lethality in overdose associated with the tricyclic agents have greatly limited their use in clinical practice. Since the selective serotonin reuptake inhibitors (SSRis) became commercially available, the safety, tolerability, and efficacy of these agents in treating major depression in adolescents have been noted in several open-label reports (Ambrosini et a!., 1999; Apter et a!., 1994; Masi et a!., 1997; McConville et al., 1996; Rey-Sanchez and Gutierrez-Casares, 1997; Rodriguez-Ramos et a!., 1996; Simeon et a!., 1998). Placebo-controlled trials, which remain the standard against which efficacy is determined, number only two, both with fluoxetine (Emslie et a!., 1997; Simeon eta!., 1990). A small study by Simeon and associates (1990) was negative. In contrast, a large-scale trial by Emslie and colleagues (1997) showed a 23% drugplacebo difference in overall clinical improvement. The findings of a third study, which used a historical casecontrol design (Strober eta!., 1999), suggested greater efficacy of fluoxetine compared with imipramine in a severely ill, inpatient population of adolescents with major depression. We now report principal findings from the first double-blind, placebo-controlled comparison of an SSRI, paroxetine, and a placebo-controlled comparison with a tricyclic antidepressant, imipramine, in the treatment of adolescents with major depression.

METHOD Study Design


This was an 8-week, multicenter, double-blind, randomized, paralleldesign comparison of paroxetine with placebo and imipramine with placebo in adolescents with major depression. The trial was conducted at 10 centers in the United States and 2 in Canada. Four hundred twenty-five subjects were screened for eligibility, and 275 subjects were randomly assigned to experimental treatment. The trial was conducted in accordance with good clinical practices and the Helsinki Declaration. All subjects and their parent(s) provided written informed consent before entry into the study; the identity of all subjects is completely blinded in this report. Funding for this study was provided by GlaxoSmithKline; each author had access to data and signed off on the manuscript before it was submitted for publication.

Patient Eligibility
Male and female subjects, aged 12 through 18 years, fulfilling the DSM-IV (American Psychiatric Association, 1994) criteria for a current episode of major depression of at least 8 weeks in duration were enrolled. Major depression was diagnosed by a systematic clinical interview which used the juvenile version of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (KSADS-L) rating scale. The K-SADS-L was developed by one of the authors (R.G.K.) through modification of the adult SADS assessment technique (Endicott and Spitzer, 1978) by providing uniform anchors so that symptoms were specifically rated for clinical relevance and by adding items to generate DSM-IV diagnoses. The K-SADS-L uses separate patient and parent reports to assess lifetime presence of affective and schizophrenic disorders, as well as the full range of childhood and adolescent psychopathological conditions. In addition to fulfilling DSM-IV criteria for major depression, subjects were required to have a total score of at least 12 on the 17-item Hamilton Rating Scale for Depression (HAM-D), a score of less than 60 on the Children's Global Assessment Scale, and a score of at least 80 on the Peabody Picture Vocabulary Test. All subjects were medically healthy. Potential subjects in the study were screened initially by telephone, and candidates who were considered likely to meet diagnostic criteria were evaluated at the study site. Adolescents and parents were interviewed separately. For those cases in which there existed a significant discrepancy between information provided by the adolescent and information provided by the parent, the clinician met with both to discuss the information obtained and then rendered a rating. Eligible subjects and their parent(s) were required to reach agreement with the site investigator that the subject had a disorder requiring treatment. In cases in which the diagnosis was not certain, audiotapes of the screening interview were to be reviewed and the diagnosis was to be verified further by an independent expert from another participating site prior to certifYing study eligibility. Subjects with a current or lifetime DSM-IV diagnosis of bipolar disorder, schizoaffective disorder, eating disorder, alcohol or substance use disorder, obsessive-compulsive disorder, autism/pervasive developmental disorder, or organic brain disorder were excluded from consideration. A diagnosis of posttraumatic stress disorder within 12 months of recruitment was also exclusionary; as was current suicidal ideation with intent or specific plan, a history of suicide attempts by drug overdose, any medical condition in which the use of an antidepressant was contraindicated, current psychotropic drug use, an adequate trial of antidepressant medication within 6 months of study entry, or exposure to investigational drug use either within 30 days of

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study entry or within five half-lives of the drug. Females who were pregnant or breastfeeding and those who were sexually active and not using reliable contraception were also excluded.

Blinding, Randomization, and Treatment


All subjects underwent a 7- to 14-day screening phase to determine persistence and severiry of entry diagnostic and eligibility criteria and to obtain baseline global functioning scores, physical examination, and clinical laboratory studies. Placebo was not administered during the screening phase. By means of a computer-generated list, subjects who still met entry criteria were randomly assigned to an 8-week course of treatment with paroxetine, imipramine, or placebo in a 1:1:1 ratio. Tablets were overencapsulated in matching Supro B locking capsules to preserve medication blinding. Subjects assigned to paroxetine treatment received 20 mg/day in the morning for weeks 1 through 4. Optional dosage increases to 30 mg of paroxetine per day (divided dose) were allowed at week 5 and to 40 mg per day (divided dose) at weeks 6 through 8 if deemed necessary by the treating clinician. Imipramine treatment was initiated with a forced titration schedule in which subjects received daily doses of 50 mg during week 1, 100 mg during week 2, 150 mg during week 3, and 200 mg during week 4. Thereafter, optional dosage increases to 250 mg/day (during week 5) and to 300 mg/day (during weeks 6 through 8) were allowed if judged necessary by the research study clinician. Imipramine administration was divided between morning and evening for all daily doses of 100 mg or greater. Subjects were instructed to take their medication twice daily, once in the morning and again in the evening. The number of active drug or matched placebo capsules administered per day was identical for each treatment group during forced titration. During weeks 1 and 2, subjects in the paroxetine or imipramine groups received one active drug capsule in the morning and one active drug or matched placebo capsule in the evening. Subjects in the placebo group received one capsule in the morning and one in the evening. During week 3, subjects received one active drug capsule in the morning and two active drug or matched placebo capsules in the evening. At week 4, subjects received one active drug capsule plus one matched placebo capsule in the morning and two active drug or matched placebo capsules in the evening. Beginning at week 5, subjects either remained at the week 4 dose level (i.e., four capsules per day) or were titrated upward to five or six capsules per day. Subjects who completed the study were offered the option of continuing blinded treatment at the same dose for 6 additional months. If subjects withdrew from the study prematurely for any reason, the dose of medication was gradually tapered over a 7- to 17-day period. Supportive case management was provided to all subjects at each weekly clinic visit according to the method described by Fawcett et al. (1987). Such management was limited to psychosocial interaction that enabled observation of treatment effects. Interpersonal or cognitive-behavioral psychotherapeutic interventions were strictly prohibited.

K-SADS-L; (3) Clinical Global Impression (CGI) improvement scores of 1 (very much improved) or 2 (much improved); (4) change in the nine-item depression subscale of the K-SADS-L; and (5) mean CGI improvement scores. Assessment of multiple domains of functioning, general health, and behavior consisted of (1) Autonomous Function Checklist, completed by the parent, which assessed the subject's autonomy in performing daily activities (Sigafoos et al., 1988); (2) Self-Perception Profile, completed by the subject to measure self-esteem (Harter, 1988); and (3) Sickness Impact Scale, completed by the subject, to measure present health and quality of life (Bergner et al., 1981). Adverse events, heart rate, blood pressure, and body weight were determined at each weekly visit. Rhythm strip electrocardiograms (ECGs) were obtained at each visit, and 12-lead ECGs were obtained during the screening phase and at weeks 4 and 8. Routine clinical laboratory studies were conducted during the screening phase and at week 8, or upon study withdrawal. If changes in cardiovascular parameters occurred, then dosage reductions were required. Doses were reduced by 10 mg for paroxetine doses of 30 mg or 40 mg; subjects receiving 20 mg of paroxetine were withdrawn from the study. Similarly, imipramine doses of 250 mg or 300 mg per day were reduced by 50 mg, and subjects receiving ~200 mg of imipramine were withdrawn from the study. Cardiovascular parameters necessitating dosage reduction or study withdrawal were defined prospectively as heart rate ~llO beats per minute (bpm) at two consecutive visits or heart rate ~130 bpm at a single visit; systolic blood pressure >140 mm Hg or diastolic blood pressure >85 mm Hg; PR interval ~0.21 seconds; QRS interval ~0.12 seconds and ~150% of baseline; or QTc interval ~0.48 seconds. Blood samples were obtained from all patients at weeks 4 and 8 for determination of plasma concentrations of imipramine, desmethylimipramine (the major, pharmacologically active metabolite of imipramine), and paroxetine. Subjects were withdrawn from the study if the combined imipramine and desmethylimipramine concentration exceeded 500 ng/mL.

Statistical Methods
A sample size of 90 patients per arm was required to provide approximately 80% power to detect an effect size of 0.4 between an active regimen and placebo with an a level of 5% (two-tailed). The change from baseline in the HAM-D total score was used. The efficacy analyses were performed on the population of patiems who were randomized and had at least one postbaseline efficacy evaluation. Two datasets from this population were examined: (1) a last observation carried forward dataset in which the last observation on treatment was carried forward to estimate missing data for patients who withdrew prior to completing 8 weeks of treatment, and (2) a completer dataset that examined results in patients who received study medication for the full 8 weeks. Missing data were not estimated for the completer dataset. Cuutiuuuus variaGles, such as changes frurn baseline to endpoint in the HAM-D total score, CGI improvement scale, and K-SADS-L, were analyzed by a rwo-factor analysis of variance using the general linear model procedure of the Statistical Analysis System (SAS). The model included tenus fur treatment and investigator. Categorical variables, such as percentage of subjects responding to treatment, were analyzed with logistic analysis implemented in the categorical modeling procedure (CATMOD) of the SAS; the model included effects for investigator and treatment. Pairwise comparisons between each active treatment and placebo were two-tailed and performed at an a level of .05. Data are reported as least square means (SD or SE).

Efficacy and Safety Evaluation


After randomization, subjects were seen at weekly intervals and evaluated with standardized instruments and global assessments for efficacy. The protocol described two primary outcome measures: (1) response, which was de!lned as a HAM-D score of ~8 or a ~50% reduction in baseline HAM-D score at the end of treatment; and (2) change from baseline in HAM-D total score. Five other depressionrelated variables were declared a priori: (1) change in the depressed mood item of the HAM-D; (2) change in the depression item of the

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RESULTS

Treatment groups were similar with regard to demographic characteristics and psychiatric profile (Table 1). Most subjects had a first-degree relative with major depression and were experiencing their first episode of major depression. The mean duration of the current depressive episode was more than 1 year, with a mean baseline HAM-D total score between 18 and 19. Features of melancholic or endogenous depression were exhibited by 35% to 40% of patients, and 20% had features of atypical depression. Despite exclusion criteria that limited many comorbid conditions, psychiatric comorbidity was common. Comorbid anxiety disorders, such as separation anxiety and social anxiety disorder, and externalizing disorders were present at the time of screening in I9% to 28% of subjects.
Premature Discontinuation

40% for imipramine (p = .02 versus placebo). Premature study discontinuation due to adverse effects occurred at a rate of 6.9% in the placebo group. Study withdrawal due to adverse effects was the most common reason for discontinuation in the paroxetine (9.7%; p = .50 versus placebo) and imipramine (31.5%; p < .OI versus placebo) groups, respectively. Cardiac adverse effects consisting of tachycardia (8 patients), postural hypotension (2), prolonged QT intervals (2), arrhythmia (1), atrioventricular block (1), abnormal ECG (1), extrasystole (I), and hypertension (1) led to withdrawal among 14% of subjects in the imipramine group (13 subjects). Protocol violation, including lack of compliance, was the most common reason for withdrawal in the placebo group (8.0%).
Efficacy Results

A total of I90 subjects (69% of 275) completed the 8week study. Premature withdrawal rates were 24% for placebo, 28% for paroxetine (p = .60 versus placebo), and

Of the depression-related variables, paroxetine separated statistically from placebo at endpoint among four of the parameters: response (i.e., primary outcome measure), HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of I (very much

TABLE 1 Demographic Characteristics and Mean Baseline Depression Scores for 275 Randomized Subjects
Paroxetine Parameter Gender, M/F Age, mean SD (yr) Race, no. (%) White African American Asian American Other CGAS, mean SD Duration of current depressive episode, mean SD (months) No. of prior depressive episodes (%) 0 1 :?:2 First-degree relative with major depression (%) Age at onset of first episode, mean SD (yr) Mean baseline HAM-D total score Features of melancholic or endogenous depression Features of atypical depression (%) Current comorbid psychiatric diagnosis(%) Any diagnosis Anxiety disorder 4 Externalizing disorderb
4

Imipramine
(n = 95)

Placebo
(n = 87)

(n = 93)

35/58 14.8 1.6 77 (82.8) 5 (5.4) 1 (1.1) 10 (10.8) 42.7 7.5 14 18 81 12 7 86 13.1 2.8 18.98 0.43 36 25 41 19 25

39/56 14.9 1.6 83 (87.4) 3 (3.2) 2 (2.1) 7 (7.4) 42.5 7.4 14 18 79 14 6 90 13.2 2.7 18.11 0.43 35 16 50 26 26

30/57 15.1 1.6 70 (80.5) 6 (6.9) 2 (2.3) 9 (10.3) 42.8 8.3 13 17 77 14 8 95 13.5 2.3 18.97 0.44 40 9 45 28 20

Note: CGAS = Children's Global Assessment Scale; HAM-D = Hamilton Rating Scale for Depression.
b

Includes separation anxiety, panic agoraphobia, agoraphobia, social anxiety disorder, generalized anxiety disorder. Includes conduct disorder, oppositional defiant disorder, and attention-deficit/hyperactivity disorder.

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improved) or 2 (much improved) and trended toward statistical significance on two measures (K-SADS-L nine-item depression subscore and mean CGI score) (Table 2). The response to imipramine was not significantly different from that for placebo across any of the seven depression-related variables. A total of 63.3% of paroxetine subjects (57/90; p = .02 versus placebo), 50% of imipramine subjects (47/94;p = .57 versus placebo), and 46% of placebo subjects (40/87) achieved a HAM-D total score of ::::;3 at endpoint (Fig. 1). The time course of response in mean HAM-D total score is shown in Figure 2. Among patients who completed 8 weeks of treatment, 76.1 o/o of paroxetine subjects (51/67; p = .02 versus placebo), 64.3% of imipramine subjects (36/56; p = .44 versus placebo), and 57.6% of placebo subjects (38/66) achieved a mean HAM-D total score of ::::;8. In the paroxetine group, 65.6% of patients were considered very much or much improved on the CGI (p = .02 versus placebo); rates for the imipramine and placebo groups were 52.1 o/o (p = .64 versus placebo) and 48.3%, respectively. Improvement in baseline depressed mood as

measured by the HAM-D and the K-SADS-L depressed mood items was significantly greater than placebo in the paroxetine group, but not significantly greater than placebo in the imipramine group. Improvements in the K-SADS-L depression subscore (p = .07) and mean CGI score (p = .09) trended toward statistical significance in the paroxetine group, but not in the imipramine group (p = .98 and p = .90, respectively) (Table 2). Although neither paroxetine nor imipramine separated statistically from placebo across the nonsymptom measures of functioning, health, and behavior, improvements over baseline were achieved for each active treatment group. Placebo-treated subjects also improved along the behavioral measures, but to a lesser extent than patients in the active treatment groups.
Dosage Titration

Nearly half of subjects in the paroxetine group remained at the initial starting dose of 20 mg/day (48%). Mean dose at study endpoint for paroxetine was 28.0 mg (SD 8.54 mg) and for imipramine was 205.8 mg (SD

TABLE 2 Mean Scores of Depression-Related Variables in Adolescents With Major Depression Who Were Treated With Paroxetine, Imipramine, or Placebo Paroxetine Variable
HAM-D~8

Imipramine
n

Placebo
n

Mean 63.3% 66.7% 2.99 0.99 4.57 2.37 65.6% 28.25 16.59 2.37 18.98 8.24

(SE)
(-) (-)

pb
.02

Mean 50.0% 58.5% 2.79 1.17 4.29 2.52 52.1 o/o 27.54 17.99 2.70 18.11 9.2

(SE)
(-) (-)

pb
.57 .61

Mean 46.0% 55.2% 2.86 1.53 4.63 2.90 48.3% 28.84 19.27 2.73 18.97 9.88

(SE)
(-) (-)

Week 8 endpoint HAM-D ~8 or 50% reduction in baseline HAM-D Week 8 endpoint HAM-D depressed mood item Baseline Week 8 endpoint K-SADS-L depressed mood item Baseline Week 8 endpoint CGI score of 1 or 2c Week 8 endpoint K-SADS-L 9-item depression subscore Baseline Week 8 endpoint Mean CGI score Week 8 endpoint HAM-D total score Baseline Week 8 endpoint

90 90 90 9 83 83 90 83 83 90 90 90

94 94 94 94 87 87 94 88 88 94 94 94

87 87 87 87 85 85 87 85 85 87 87 87

.11

(0.08) (0.14) (0.09) (0.18)


(-)

.001

(0.08) (0.14) (0.09) (0.18)


(-)

.14

(0.08) (0.14) (0.09) (0.18)


(-)

.05 .02

.87 .64

(0.52) (0.84) (0.16) (0.43) (0.81)

.07 .09

(0.51) (0.83) (0.15) (0.43) (0.81)

.98 .90

(0.52) (0.83) (0.16) (0.44) (0.83)

.13

.87

Note: HAM-D = Hamilton Rating Scale for Depression; K-SADS-L = Schedule for Affective Disorders and Schizophrenia for AdolescentsLifetime version; CGI = Clinical Global Impression. The last evaluation during treatment for subjects who did not complete the entire study (i.e., the last observation carried forward) is reported. b The p values compare treatment difference in active versus placebo groups. c CGI score of 1 = very much improved; CGI score of 2 = much improved.

766

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 40:7, JULY 2001

PAROXETINE FOR ADOLESCENT DEPRESSION

n = 90 n = 94 n = 87

n = 67 n = 56 n = 66

LOCF

oc
Dataset

Dataset

Fig. 1 Percentage of subjects treated with paroxetine (.), imipramine (t21), and placebo (D) who achieved a HAM-D total score :<;;8 in the LOCF and completer (OC) subgroups at week 8. *p = .02; NS =p 2 .44. HAM-D = Hamilton Rating Scale for Depression; LOCF = last observation carried forward; OC = observed cases.

-2

en
]i
~
Cl
<(

E:1 0 u

-4

..... Placebo __,._ Imipramine ....., Paroxetine

-6

:I:

.
Ql

c:

0>

-8

.c

tO

()

c:

::2
-12

Ql

tO

-10

-14
0

4 Weeks of Treatment

LOCF

Fig. 2 Least square mean change HAM-D total score (SEM) during an 8-week course of paroxetine (n = 90), imipramine (n = 94), and placebo (n = 87) administration in adolescents with major depression. HAM-D = Hamilton Rating Scale for Depression; LOCF = last observation carried forward.

]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 40:7, JULY 2001

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KELLER ET AL.

63.94 mg). The most common "doses" of placebo (administered as divided doses) were four capsules per day (31.0%) and six capsules per day (41.4%).
Adverse Effects

Paroxetine was generally well tolerated in this adolescent population, and most adverse effects were not serious. The most common adverse effects reported during paroxetine therapy were headache, nausea, dizziness, dry mouth, and somnolence (Table 3). These occurred at rates that were similar to rates in the placebo group with the exception of somnolence, which occurred at rates of 17.2% for paroxetine and 3.4% for placebo. Dizziness, dry mouth, head-

ache, nausea, and tachycardia were most commonly reported during imipramine treatment. Tremor occurred in 10.8% of paroxetine-, 14.7% of imipramine-, and 2.3% of placebo-treated subjects. Adverse effects in all treatment groups occurred most often during the first week of therapy. Dosage reductions were most often required for somnolence, insomnia, and restlessness among paroxetine-treated subjects. Dry mouth, constipation, and tremor were the most common adverse effects leading to imipramine dose reductions. Premature withdrawal from the study because of adverse effects occurred at rates of 9. 7% for paroxetine, 31.5% for imipramine, and 6.9% for placebo. Clinically significant

TABLE 3 Adverse Effects Occurring in ~5% of Subjects in the Paroxetine, Imipramine, and Placebo Groups
Adverse Effect Cardiovascular system Tachycardia Postural hypotension Vasodilation Chest pain Digestive system Dry mouth Nausea Constipation Decreased appetite Diarrhea Dyspepsia Tooth disorder Vomiting Abdominal pain Nervous system Dizziness Emotional lability Hostility Insomnia Nervousness Somnolence Tremor Headache Respiratory system Cough increased Pharyngitis Respiratory disorder Rhinitis Sinusitis Other Sweating Abnormal vision Asthenia Back pain Infection Trauma
Note: Values represent no. (%).

Paroxetine (n

93)

Imipramine (n

95)

Placebo (n

87)

2 0 2 19 22 5 7 7 6 5 3 10 22 6 7 14 8 16 10 32 5 5 10 7 6 1 1 10 4 10 2

(2.2)
(1.1)

18

13
6 5 43 23 9 2 3 9 2 8 7 45 3 3

(0) (2.2) (20.4) (23.7) (5.4) (7.5) (7.5) (6.5) (5.4) (3.2) (10.8) (23.7) (6.5) (7.5) (15.1) (8.6) (17.2) (10.8) (34.4) (5.4) (5.4) (10.8) (7.5) (6.5)

(18.9) (13.7) (6.3) (5.3) (45.3) (24.2) (9.5) (2.1) (3.2) (9.5) (2.1) (8.4) (7.4) (47.4) (3.2) (3.2) (13.7) (6.3) (13.7) (14.7) (40.0) (3.2) (12.6) (7.4) (3.2) (2.1) (6.3) (7.4) (7.4) (2.1) (5.3) (3.2)

1 I 2 2 12 17 4 4 7 4 2 6 10 16 I 0 4 5 3 2 34 6 8 11 5 7

(1.1) (1.1)

(2.3) (2.3) (13.8) (19.5) (4.6) (4.6) (8.0) (4.6) (2.3) (6.9) (11.5) (18.4)

(1.1)
(O) (4.6) (5.7) (3.4) (2.3) (39.1)
(6.9) (9.2) (12.6) (5.7) (8.0)
(1.1)

13
6 13 14 38 3 12 7 3 2 6 7 7 2 5 3

(1.1) (1.1)
(10.8) (4.3) (10.8) (2.2)

2 10 10 9 6

(2.3) (11.5) (11.5) (10.3) (6.9)

768

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PAROXETINE FOR ADOLESCENT DEPRESSION

increases or decreases in body weight were not observed among any of the three treatment arms of this study. Serious adverse effects occurred in 11 patients in the paroxetine group, 5 in the imipramine group, and 2 in the placebo group. An event was defined as serious if it resulted in hospitalization, was associated with suicidal gestures, or was described by the treating physician as serious. The serious adverse effects in the paroxetine group consisted of headache during discontinuation taper (1 patient) and various psychiatric events (10 patients): worsening depression (2); emotional lability (e.g., suicidal ideation/ gestures [5]); conduct problems or hostility (e.g., aggressiveness, behavioral disturbance in school [2]); and euphoria! expansive mood (1). Seven patients were hospitalized: 2 with worsening depression, 2 with emotional lability, 2 with conduct problems, and 1 with euphoria. Of the 11 patients, only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment. The 5 serious adverse effects in the imipramine group consisted of maculopapular rash (1 patient), dyspnea/ chest pain (1), hostility (1), emotional lability (1), and visual hallucinations/abnormal dreams (1). Two of the adverse effects (i.e., hallucinations, rash) were considered related to imipramine. All 5 patients were withdrawn from the study, and the patients with hostility or emotional lability were hospitalized. In the placebo group, emotional lability (1 patient) and worsening depression (1) were considered serious. The placebo-treated patient with emotional lability, which was considered to be related to placebo, was withdrawn from the study. Of subjects in the imipramine group who stopped therapy because of adverse effects, nearly one third (13.7%) did so because of cardiovascular effects, including tachycardia, postural hypotension, and prolonged QT interval. Mean standing heart rate increased by 17 bpm over baseline among subjects treated with imipramine. Neither paroxetine nor placebo was associated with changes in heart rate.
DISCUSSION

This is the first study to compare efficacy of an SSRI and a tricyclic antidepressant with placebo in the treatment of major depression in adolescents. Paroxetine was significantly more effective than placebo with regard to achievement of both HAM-D total score :::;8, CGI score of 1 (very much improved) or 2 (much improved), and improvements in the depressed mood items of the HAM-D and

the K-SADS- L. Paroxetine did not separate statistically from placebo for K-SADS-L depression subscore, mean CGI score, or HAM-D total score. The demonstration of efficacy for paroxetine in this study is in accordance with findings of open-label studies of SSRis (Ambrosini et al., 1999; Apter et al., 1994; Masi et al., 1997; McConville et al., 1996; Rey-Sanchez and Gutierrez-Casares, 1997; Rodriguez-Ramos et al., 1996; Simeon et al., 1998) and results from placebo-controlled (Emslie et al., 1997) and historical case-control (Strober et al., 1999) studies. These findings of efficacy for paroxetine and other SSRis are notable in that randomized, double-blind, placebo-controlled trials (Geller et al., 1990; Hughes et al., 1990; Kashani et al., 1984; Klein et al., 1998; Kramer and Feiguine, 1981; Kutcher et al., 1994; Kye et al., 1996; Petti and Law, 1982; Preskorn et al., 1987) and one meta-analysis (Hazell et al., 1995) have not shown efficacy for the tricyclic antidepressants in the treatment of adolescent depression. Because efficacy has not been demonstrated for the tricyclic antidepressants and because these agents are associated with an unacceptably high risk of cardiotoxicity, especially in children, further controlled studies are not likely to be conducted. As such, future research involving bupropion or noradrenergic antidepressants not yet clinically available will be required to address more fully the question of preferential efficacy of the SSRis in this age group. Our study used a flexible-dose design in which doses could be adjusted on the basis of clinical response and tolerability. Roughly half of subjects were maintained at the paroxetine starting dose of 20 mg. The mean daily dose of paroxetine in this study, 28 mg, is comparable with that reported in flexible-dose trials in adults (Claghorn, 1992; Cohn and Wilcox, 1992; Dunbar et al., 1991; Fabre, 1992; Feighner and Boyer, 1992; Shrivastava et al., 1992; Smith and Glaudin, 1992). The adverse-effect profile of paroxetine in this adolescent population was concordant with that reported in studies of adult patients with depression (Claghorn, 1992; Cohn and Wilcox, 1992; Dunbar et al., 1991; Fabre, 1992; Feighner and Boyer, 1992; Shrivastava et al., 1992; Smith and Glaudin, 1992). Serious adverse effects were reported during treatment with paroxetine (11 patients), imipramine (5), and placebo (2). Because these serious adverse effects were judged by the investigator to be related to treatment in only 4 patients (paroxetine, 1; imipramine, 2; placebo, 1), causality cannot be determined conclusively. Adverse cardiovascular effects were not

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observed in subjects treated with paroxetine. In contrast, tachycardia, postural hypotension, and prolongation of QT intervals during imipramine therapy resulted in treatment discontinuation in one third of the 31.5% of subjects who stopped treatment prematurely with the tricyclic antidepressant.
Limitations

A high placebo response rate was observed in this study, which is not unusual for clinical trials of major depression in either pediatric or adult populations. In studies of pediatric patients with major depression, placebo response rates range from 20% to 80% (Birmaher et al., 1998; Emslie et al., 1997; Geller et al., 1992; Jensen et al., 1992; Kowatch et al., 1999). Placebo response also is high in adults with major depression as demonstrated by mean placebo response rates of approximately 30% to 40% in short-term studies (Brown, 1994; Schatzberg and Kraemer, 2000; Trivedi and Rush, 1994). Several factors possibly contributed to the observed placebo response rate. A probable contributing factor was the weekly supportive case management sessions, which may have contributed to clinical improvement for patients in the placebo and active-treatment groups. In addition, the lack of a placebo run-in before randomization may have contributed to a higher placebo response. Inclusion of patients with externalizing disorders (e.g., conduct disorder, oppositional defiant disorder) also could be argued to have increased the placebo response rate. A post hoc analysis was conducted to assess this issue. However, the separate analysis of our database revealed that response rates to paroxetine, imipramine, and placebo among patients with attention-deficit/hyperactivity disorder (ADHD) were significantly lower than in patients without ADHD, regardless of treatment group assignment, including placebo (Birmaher et al., 2000). The mean HAM-D total score from our sample at baseline in all three groups was 18 (0.43), possibly accounting for the high placebo response. In fact, there appears to be an inverse relationship between placebo response in adults and clinical severity of depression. Adults with less severe depression exhibit greater placebo response rates than more seriously ill patients. Mild to moderate depression (i.e., HAM-D total score <19 in one study [Stewart et al., 1983], <13 in another [Paykel et al., 1988]) was associated with no drug-placebo difference in tricyclic antidepressant treatment studies of adult outpatients. Moreover, in contrast with our study, the mean

baseline HAM-D total scores in short-term adult SSRI studies range from 23 to 28 (Cohn and Wilcox, 1985; Dunbar et al., 1991; Feighner and Overo, 1999; Reimherr et al., 1990; Stark and Hardison, 1985). It is important to emphasize, however, that comparisons in HAM-D scores between adults and adolescents may not be valid because of possible age-related variability in HAM-D. Another methodological limitation must be acknowledged: the study was not designed to directly compare paroxetine with imipramine. The objective of the study was to determine the efficacy of two antidepressants with different mechanisms of action. To conduct a traditional three-arm comparative trial, this study would require testing at p values of .0167 rather than .05. To power a study at this level, it would have been necessary to enroll a greater number of patients, thus exposing more adolescents to the potential risks of clinical research.
Clinical Implications

Major depression in adolescents is an increasingly recognized clinical problem that is remarkably understudied. The majority of treatment studies involve the tricyclic antidepressants. Because these agents are associated with poor efficacy and cardiovascular adverse effects, their use is not recommended. In contrast, there are few large, wellcontrolled studies of SSRis in adolescents. Our findings are therefore relevant to clinicians who are faced with treatment decisions for depressed adolescents and a relative paucity of data guiding therapeutic choice. Despite some methodological limitations, resulting in a high placebo response rate (outlined above), our study demonstrates that treatment with paroxetine results in clinically relevant improvement in depression scores. The SSRis are the medications of choice for the treatment of major depression in adolescents because they are the only agents that have been shown to be efficacious in this population; they have a safer side-effect profile than other antidepressants, particularly in overdose; and they can be administered once daily. Clinicians should be aware that 8 weeks of treatment may not be sufficient to achieve a full clinical response, that some patients may benefit from higher doses, and that some as-yet unidentified groups of patients (e.g., more severely depressed; non-ADHD) may exhibit more robust responses to SSRI therapy.
Conclusion

The findings of this study provide evidence of the efficacy and safety of the SSRI, paroxetine, in the treat-

770

]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 40:7, JULY 2001

PAROXETINE FOR ADOLESCENT DEPRESSION

ment of adolescent depression. Additional studies are called for to define the optimal length of therapy and dose of SSRis in this population.

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'Nuff~5tCLtl1dLIS
RDSCIENCE v s
D
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Breakthroughs in the Treatment of


Child and Adolescent Depression & Anxiety
Children grow out of shoe~ and clothes. but the odds say it is unlikely they will outr;-ow depression. A d:pressec child is t~ice as likely to be a depressed adult. according to Dr. Karen Wagner, a leadtng child psychta:nst. Dr. Wa!mer soolc:e to Neuroscience consultants at the launch meetine in Los Ane:eles. Dr. Wa!mer is D1rector of the Div;sion ~f Child and Adolescent Psychiatry and the Vice Cha.ir~of the Dcp.;nmc:nt of Psy;h1a1ry and Behavioral Sciences at the University of Texas Med1cal Branch. Her m::ssagc about TnaJOr depression was that ''it is a lclhal disorder and it requires treatment." Threat of suicide Dr. Wagner pointed out that depression in adolescents can lead to suicide for 2.5% of those diagnosed with depression. Left untreated, the percentage rises to 8% as they become adults. Obviously, therapy is needed and Paz.il is one of the few phannaceutical approaches that has safety and efficacy data to suppon its use in this patient population. And more data is on its way. As many of you know. SB is preparing an indication ror adolescent d::?rcssion for Paz.il . n_c:xt year! SB"s clinica,l study dcmonstr.ting the success of Paxil in treatin~ depression among adolescents will be published in a peer revaewed journal during fits~ quaner 2000. Depression results in suicide lor z.s;.
of cases (lrom Puil
Websil)

SB's advantage

Dr. Wagner said the wmdow of opporrunit~ is before SB. Several other competing SSRls and other compounds have srudies ongoing. But Paz.il
and ProUJr: are the only two SSRI5 that have any publlshed data to date and many physscians ha\'c: already iound success m treatmg adolescent patients wnh Paz.il. Episodes of depression typically last nine months. according: to Dr. Wagner. This dmupuon ts equivalent to a whole school year and it may be time that can nev::r be re::o\'ered for the patient. Families with a history of deprcJsion have to~ ::spc::ially vagilant ior these sagos: lnitable mood. complaim:l[t abou! e\'e~thin~. Dirrunished mterest tn aCU\'llleS Loss of we~tht Sleep dtsturbm::::: exhausted wh~n it's ~arne to ~:et up Naps after school Feehn~~ of wonhl::ssn::u or guilt ~Jm stupid. ~obod~Jikcs m~" Dech:un!! grades

Or. Wagner at the Neuroscience Division launch meeting tr~noJO oy


EdWaln\lnOKol

Suicidal tc:ndcnclc:s

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CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

COLPAX_0090516

Adolescent depression and anxiety (continued}


Failure of tricyclics Tr-=ating depression in children illld adolescents is critical. but there are not many options. Dr. Wagner said the tricyclics are almost useless in children.

Does depression run in families?


There is a very strong genetic component to depression. In a study of 9 I famili~ in which one or both parents had depression. the risk for children is: Ei!!ht times hiher to suffer depression Three times higher ofha\'ing an anxiety disorder Five times more likely to ha"e conduct problems Five times the risk of beine a depressed adult -

'1"ricyclic antidepressantS, in all the studies that have been done, have not been shown to work with children or adolescentS. Thev don'r work! Where they fit in is really at the bonom of the list. They jusr don'r work!" To date, only two rigorous studies have been done in children illld adolescents. Dr. Wagner said we can't say that what works in adults will work in children ~cause of the great difference in metabolism. among other things. The only v.-ay to be sure is to compare against placebo, as in the two studies completed: one with fluoxetine and one with paroxetine.

The fluoxetine study was a fixed 20 mg dose for children and adolescents with major depression. The eight week srudy at one site was conducted in 96 patients. in which 48 received medication and 48 received placebo. The results? 56'iC of the fluoxetine ~oup improved. In placebo. 36% irnpro,ed. This was the first published study to show that an SSR! worked in youth.
Large paroxetine study The paroxctine srudy measured treatment of adolescent depression. lt is the largest study to date. invohing 275 adclescet~ts at 12 sites for eight weeks. In the srudy, one of three treatments was possible: imipramine (tricyclic), paroxetinc. or placebo. Results: 66170 of paroxetine group improved 52'70 imiprarrune nnprovcd 4B% of placebo 1mproved.

The paroxctinc: results were statistically significant. The imipramine result was not. showing that uicyclics arc no bener than placebo in treating depression in youth. Since so many rcc:ehed paroxetine. Dr. Wagner said another imporunt finding was with side effects. \V"hile both drugs caused some headaches. dizziness and tremor. in the paroxetinc group. only 1% experienced cardiovascular side effects. as compared with imipramine, in which 43'i of the ~oup had problem~ wilh blood pressure. EKGs or conducuon problems.

Chris Hanson thanks Dr. Wagner in Los Angeles (l)lleto tiV Ed WllnllnskiJ

As a result of this larie study. Dr. Wagner said "We can say th:!t paroxeune has both efficacy and safety daUJ for treating c1epression in adolescents."

Side effects Dr. Wa~mer said she sees the half-life of oaroxetine as 2n ad\anta!!e O\'er fluoxetine. Tne shorter half-life reduces-side effects. During tile Q&A se.ssion. several consuha..'1tS challenged th1s advantage. saymg they hear~
Neuroscience Division News, December B, 1999. Remember to check the Product Pages" for more on Pax/land Requ/p,

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

COLPAX_0090517

Adolescent depression and anxiety (continued)

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the opposite. Some physicians belie\'e the quicker metabohsm of young people ne::ess1ute a longer half-life.

Dr. Wagner pointed out that one of the b1g challenges in tr:.lung depression in children and
adolescents i~ getting them to suy on their therap~. As children. they stop them from taking the drugs.
PhOID by Wamuslti
se~on 35

pa:ents see sid: effects tn the 1:

There are two thing:r. to keep in mind in this re~ard. First of all. b:g:in p2uems on lou. doses o:' 5 to 10m~ and work up to 20 mg over a 12-week course of therapy. In some ~:1ses. 40 mg may be necessary. A graduai butld up reduces noticeable side effects. The other factor to help control
side effects is using paroxetine with its shoner half-life.

Social Anxiety Disorder


Symptoms Children ar: very No sports No music Little interaction.
sh~

Anxiety disorders Dr. Wagner spent a large part of her talL.: on anxiety disorders. as well as de~sion. She said more data is needed. The problem is also vel) serious.
For adults, a 1op fear is spealcing in publk. For children. it is reading aloud in front of the class. Unlike children. though. adults can control a lot their life and avoid painful situations. For children with social anxiety disorder. thir. is a fate and others are too dl"'..aded to be faced. Too painful to be called upon. For a child with soc:ialanxiety disorder. everyday is like the first day of school." according to Dr. Wagner. She said she looks to the futu~e when studies with drugs like Pax.i/. show how SSRl therapy can help children cope with situations in which they have almost no control.

Top Three Fears Reading out loud Athletic: or music performance


Joining mona c:on'-'ersauon

Prevalence About 3% to 4% of children have social a.nx1e1y drsorcler Affects boy and girl!> equaUy Onset is about 60<;(- beiorc: the a~e 16 ..

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Requip dosing
In the previous issues of the newslener. we discussed the ueatrnenl strategy for Parkinson's disease and the imporu.nce of influencing a change m that treaunent srr:uegy. Dr. Ray Waus. Professor of Neuroiogy and Director of r:he Movement Dasorder Proparn at Emol) t:nl\ers1t~ in Atla.nt;l. has been a gTCat source for most of this information. In his lecture at the launch m::ung. he also d1scusscci dosmg.

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Dosing is imponant for two reasons. First. we icnow from market research stud1es that the average dose of Requip is between 3 and 4 mgs per day whi:h is Significantly iower than t~e opurna-ltherapeuric ran5!e as seen m
clinical trials. which is 9- 12 mgs p::r da~. S::conc!. we know that the utrauon schedule for R~qurp can be complicated.

Neuroscience Division News, December II, 199S.. Remember to cheek the "Product Pages" for more on Paxil nd Requip.

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

COLPAX_0090518

Requip dosing (continued)


Efficacy depends on dosing The dosing range is an important issue that you should adciress v.ith physicians because efftcacy is dependent on proper dosing. To ach1eve ~~ effica:y resuits seen in the 5-year triaL it is imperauve to dose Rtquip in the optimal therapeutic nnse. The dose response curve on page 13 in the sales aid shows that over 75~ of p:!tients responded at 9 mgs per day. whereas Jess than 50% of patients responded at the 3 and 4 mg per day doses. By educating your physicians on the optimal ciosin!! for Rtquip. you will incre3.5e their success rates with R~quip.

Titration schedule
Listening to the strategy
for using the Requip.

The tittation schc:<iule for R~quip can


10

be complex. however w~ have tried make it easier by pf9viding a 3 mg detail aid [pnoto t;y Ed staner kit and we will be coming out Warmmski) with a 6 mg staner ki! in 2000. The titration schedule for Rtquip is beneficial in that it allows for a v::ry wide dosing range which gives the physician great flexibility over the long-term. This ties in well with the new .5year data because you can show the physicians that they will be able to maintain their patients over a signiftcant amount of time
onR~quip.

Wide dosing range advantage As the disease progresses, the physician has the: option of incn:.a.sing the Requip dose. Additionally, the wide range allows physicians to stan patients slowly which should help phystcians 10 successfully initiate R~quip therapy.

At the Requlp workshop in Los Angeles


IPI'IO!o by Ed Warm.r>Ski)

Neuroscience Division News, December 8, 1999. Remember to check the Product Pages" for mo~ on

Pa~eil

and Requip.

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

COLPAX 0090519

08/1610! To: All Salts Rrprrsentatives SeUi.ng

cc:

PIUil

RVPs TSM.s
PtUi/DSM~

From:
Zachuy Hawlda$ Puil Product Managcmcal
study rrtle

RMSs

"Effiacy of Paroxetine in the Trntmcnt of Adolescent 1\hjor Dcprcssioa; A Randomized, Controlled Trial"

Mama B. Ktller, M.D.


Journ:1l
D~te

J. AM.ACAD. CHILD ADOLESC. PSYCH/A TRY 2001

Vol Pages

2001, July, Vol. 40:7: 762-772


.~

Significance

of article

Tbis."cvtti.llg-c11gc," Landmark study i1 tbe first to compare -dlic;aq of u SSRI and a TCA with placebo in the trntment of aiaje;,~~I'U3ioa iA adolescents. Ptuil dcmoostntcs RE.~BLE Efficacy and Safety in the trntment of adolc::sce!!..dc.Prcssion.
,~

Key Point$

The treatment ~f depression in adolescents is an aica of burgeoniri& intcrcsL Unfortuna1cly, few well C{)Otrollcd. large scale. tandomW:d"dinical. trials have: been conducted in this

-,

population. (pg![_62, ~ 2, par I) National Comorbidit~ S~'i:l' indicates lifetime prevalence rate .of I S.J~. for a.dol~cnt major dc;pt'l:ssion. comparable: with a l'7t.liferime prevalencelnaiiu.lts. (pg 763 coil par I)
Comorbid anxiety disordc~ lll't::J'CJlreSent 1.0 !9% to 28% of :s~bjects. (pg 765 col I par I )'C{})'lORBIDITY! Paxil wa.s signjfic;:antly more e~tive than placebo with reg:aid to achievement ofbot.h HAM-D 8. CGl scort of I (v~ry mucb improved) or 2 (much improvc:d~1ilid tmprovemc:nts in the depressed mood items of the HAM-D aM_t.l!e K-SADS-L Roughly two-thirds (63.3~'0) of the sUbJects oa Part/, 50% of

tour;o;;e.:

Imipramine subjects, l!lld 46% of placebo subJectS a.crueved remission (a HAM-0 total score: of:: 8! a1 endpon)rbased oo the LOCF D&taset. (Table 2) Among paltents who completd & wetb ofbutmc:nt, 76Yo of Paxil S1JbjC:CIS. t..: J% offmipnunmc: subjects, and 57.6% of placebo subjects Jcl'ut,.,d n:miJSion..(OC Dataset) FIG. I Ne.uly half of the subJects m th~ Paxil ~ruup rc:mained at the initial starting dose of20m~day (48~; 1 lvln.n dose at study
endpoint for Pari/ was 28 0 mg a.nd for lrr.tpramm" "''a.5 205.8 mg. (pg 766 col 2 PM 3 i Pa:.r;i/ was generally well tokrared In um 3cll'inccnl population.

PAROOOB15403

DO NOT PRODUCE WITHOUT ATIORNEY APPROVAL

GSKC0-0003-000426

CONFIDENTIAL: Produced pursuant to subpoena dated February 6, 2004 issued by United States Attorney, District of Colorado.

GC0007 -0429

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JJJO mos.t adverse events were not serious. The most common advCT~ events ou:wnd at rates !bat were sunilar to rates in the placebo group. (pg 768 col I pat~) Ad"erse cardrov~cular effects were not observed in sub]c:ciS treated with Pa:til. Jn contraSt, w:bycardia. postural hypotension,

prolongation of QT intervals during imipramine therapy resulted


in treatment dmantinuation in one third (13. 7%) of the) 1.5~.
subjects who stopped treatment premanuely with the TCA.

In conclusion. the fuulings of this study provide evid=c of the


effic.acy and safety of Paxil in the treatment of a.dolesc:ent depressiOn. Here's another example ofGlaxaSmithKline's

commitmeotto Psyduatry by bringing fonh "eunmg edge" scienufic data. Par1l is truly a REMARKABLE product that continues to demonstrate efficacy, even in r.his understudied population.

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Albert Stunkard, University of Pennsylvania (behavior modification) George Bray, Pennington Biomedical Institute

Robert Atkinson, University of Wisconsin William Dietz, CDC Division of Nutrition and Physical Activity (pediatrics, gastroenteroiogy, nutrition)

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I Bigger than

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03/16/2006 0?:10 PM

Bigger than Viagra?


It sounds too good to be true: a drug to help you stop smoking, stay happy and lose weight. Roger Henderson on the accidental discovery of bupropion
Tuesday July 13, 1999 Guardian

Modern medicine still relies on chance and serendipity far more than it cares to admit. Viagra, the prescription drug phenomenon of the past two years, was originally developed as a treatment for heart disease and it was only when users reported their impotence was a thing of the past that the manufacturers realised they had created a golden goose. If reports from America are to be believed, a new drug that has properties also discovered by accident may take the United Kingdom by storm next year, and could be set to rival the success of Viagra. If approved, it may also go some way in helping health professionals to achieve their goal of reducing the number of premature deaths in this country from heart disease, as set out in the recent department of health white paper on the health of the nation. Originally developed as an antidepressant, the drug - bupropion hydrochloride - was licensed in the US three years ago under the name Wellbutrin. Its main marketing point was that it did not greatly interfere with sexual function, something most antidepressants are notorious for affecting. During trials of the drug, and quite by chance, it was realized that people taking Wellbutrin were finding it far easier to stop smoking than those who were not using it. Early reports suggested that they were not craving for cigarettes as they normally did, and had fewer withdrawal symptoms on stopping their habit. Once the the company involved, Glaxo Wellcome, had picked up on this aspect of the drug, it began further trials specifically looking at the effectiveness of the drug as an anti-smoking aid. The results of this comparative clinical study were published in the New England Journal of Medicine in March this year, and make for impressive reading. Just under 900 smokers were involved, all of whom smoked at least 1 5 cigarettes a day. They were split into four groups- those taking a dummy pill or placebo, those taking bupropion, those using a nicotine patch plus a bupropion tablet, and those using a nicotine patch alone.
http://www.guardlan.eo.uk/prlnt/0,.3882769-103409,00. html Page 1 of 3

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Guardian I Bigger than Viagra?

03/16/2006 07:10PM

After 1 2 months, 1 5% of those on the dummy pill were still not smoking. This was only marginally worse than the 1 6% using only nicotine patches, but nearly 31% of smokers taking bupropion had stopped. The surprising statistic, however, was in the group using both patches and bupropion - a success rate of 3 5%, more than double the usual rate seen in smokers trying to give up. Just as important, side effects appeared to be minor, with few people having to stop the drug because of them. A dry mouth and insomnia were reported by users, but little else. People with a history of seizures or eating disorders should not take bupropion, but otherwise most smokers will be valid candidates for such treatment, which is the first such non-nicotine prescription available. This combination of effective results and low side effects led to the drug being licensed in the US as an aid to stopping smoking, under the name Zyban. This has now been prescribed to some 3m Americans, over 1m of whom have stopped smoking. Some of these ex-smokers who had kicked the habit by taking Zyban appeared on the BBC Watchdog Healthcheck programme in March this year. One of them, Keith Webber, was quoted as saying: "I was thoroughly addicted to cigarettes, which seemed to be a part of me. Zyban does make it easier, does calm that irritability, it keeps you on a far more even keel in dealing with the world.'' Another recovered nicotine addict, Paula Covey, said: "As sure as I'm sitting here I will never have another cigarette_ it's just a better life now." Attempts are now being made to secure a licence across the EU, with the Dutch authorities taking the lead through the regulatory hoops. The drug could be available in this country early next year. Rob Cohen, therapeutic and science communications manager of Glaxo Wellcome, says: "With success rates double that of nicotine replacement therapy, Zyban, upon approval from the appropriate regulatory authorities, will provide an effective weapon for many people in their battle against nicotine addiction. "A combination of Zyban and the nicotine replacement patch has shown a small benefit over Zyban alone, but it should be remembered that it is the addiction to nicotine that drives us to smoke. If you can overcome this addiction without feeding it through another route then the longer-term chances of keeping cigarette-free may be increased." The prospect of a new popular prescription drug arriving on the market will inevitably lead to much debate over funding, and the government will be keen to avoid another debacle like that over prescription of Viagra. Costs are in the region of 2 per day, but as Clive Bates, director of Action on Smoking and Health (Ash) points out: "The big question here is whether the government will allow doctors to prescribe Zyban on the NHS at the normal prescription charge. If not, the market
http: //wv.w.guardian.co.uk/print/0,3882 769-l03409,00.html

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Guardian I Bigger than Viagra?

03/16/2006 07:10PM

could be severely limited. If they do allow it, then the demand could be enormous - of over 13m smokers in the UK, 70% would like to quit. "I believe such treatments are extremely cost-effective because it is much cheaper to help people to quit smoking rather than pour money into the treatment of cancer or heart disease later in life." Nicotine addiction is a medically recognised condition; more than 1bn people smoke worldwide, and 3m died from smoking-related conditions last year. The figure is expected to rise to more than 1Om a year by 2025. Global sales of products to help smokers quit will exceed 500m this year, and a non-nicotine medicine may be welcomed with open arms by smokers who have repeatedly failed to give up using standard nicotine replacement treatments. And while at first glance such a treatment might appear to have a lower success rate than, say, Viagra, the large number of smokers means that there are still far more potential patients - of both sexes - who may benefit. And there is a promising postscript to this story. At the same time as the trials of Zyban, an American psychiatrist- Dr Kishore Gadde from the Duke University in North Carolina- found that obese depressed women who were given the drug in its capacity as an antidepressant began to lose weight quicker than those not taking it, by a factor of about three. Early trials showed this to be a consistent weight loss and the women reported they felt satisfied with smaller portions of food, so ate less. Although it remains unclear exactly why this should be the case, it is probably linked with the neurotransmitters that are responsible for the craving and reward cycle linked to eating. "This is not a flash in the pan," says Dr Gadde. "These patients have continued with their weight loss over a year and there do not appear to be withdrawal symptoms when they stop taking the drug." Bigger trials will take place later this year, and this weight loss aspect of bupropion remains at an early stage of development, but there is already excitement in the pharmaceutical industry about it. A drug that works on depression and helps you stop smoking and may help you lose weight into the bargain? It sounds like a marketing dream. But as the drug regulatory authorities continue their deliberations, it is probably only a matter of time before pleas for the next "wonder drug" are heard by British doctors. One thing can be sure though - decisions over who will get it and who will pay for it will be a headache for doctors, patients, and politicians alike.
Guardian Unlimited Guardian Newspapers Limited 2006

http://www.guardlan.co.uk/prlnt/0,,3882769-l03409,00.html

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GDR177-0366

The Times
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MARCH 2000

HEALTH 19

GDR177-0369

Publication Date: Thursday, May 20, 1999


Popular Glaxo drug effective as weight Joss therapy With just more than a handful of anti-obesity drugs currently on the U.S. pharmaceutical market, Glaxo Wellcome Pic could soon add to that group a drug it already markets for treating two other conditions. In a study of 50 obese women between 24 and 51 years old, researchers found that 67 percent lost more than 5 percent of their body weight after treatment with Glaxo's bupropion and a 1,600-calorie diet; 15 percent of those taking placebo with the diet had the same outcome. Additionally, researchers found that women treated with bupropion lost an average of 13.7 pounds of their original weight as compared with 3.4 pounds for those taking placebo. "The drug group lost four times more weight than the placebo group," said Dr. Kishore Gadde, who presented the study data at the 152nd annual meeting of the American Psychiatric Association. 'The results were much more exciting than we expected initially." Glaxo Wellcome markets bupropion under the name Zyban for assisting in smoking cessation and as Wellbutrin for the treatment of depression. "It's not indicated for weight loss," Gadded said. "Until we have results replicated in a large, placebo-controlled study, I'm not recommending it." Gadde did say, however, that he thinks bupropion might be as effective as the other drugs on the market indicated for weight loss.

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GDR177-0370

JWABQ.

E~e~witness
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News Online: New Procedure to Treat Osteoporosis

2112/99 1:46 PM

t.o a Harvard University study published in the October 6 issue of the Journal of the American Medical Association. The study found that men and women who ate six servings of fruits and vegetables had a 31 percent lower risk of stroke compared to those who ate fewer than three servings a day. Each additional serving eaten per day lowered the risk of stroke by 6 percent, but eating more than six servings didn't have an impact. The reduction in risk may be the result of chemicals found in certain fruits and vegetables that prevent blood from clotting in the brain. The best foods are in the cabbage family: broccoli, cauliflower and bok choy. Broccoli had the greatest impact in lowering risk by 32 percent while vegetables in general only reduced the risk by 4 percent. Also, leafy green vegetables and citris juices were found to be particularly beneficial. In fact, having a daily glass of orange juice was linked to a 25 percent drop in the risk of stroke compared to 11 percent for other fruits. Linda Van Horn, Ph.D., Registered Dietician and Professor of Preventive Medicine at Northwestern University says that, "Many people don't realize bow easy - and fast getting those [six] servings can be. It can be as easy as drinking a glass of orange juice in the morning, snacking on an apple in the afternoon and including a vegetable at dinner." And if you absolutely don't want to eat your brussel sprouts, one to two glasses of alcohol a day can also reduce your risk of stroke, according to Dr. J.P. Mohr of the Columbia Presbyterian Center.

Aired September 20, 1999

Heartburn Treatment
For people who suffer from heartburn, a new, quick procedure provides relief so you can still eat your favorite foods. Heartburn, or acid indigestion, is caused by Gastro-Esophageal Reflux Disease (GERD). GERD occurs when stomach acid flows back up Into the esophagus caused by weak muscles where the stomach and esophagus meet. Currently, diet and antacids are used to control mild heartburn but medications, which are expensive, may be necessary in more severe cases. Another option has been surgery which requires general anesthesia and a one to three day hospital stay. After small openings are made in the abdomen, part of the stomach is wrapped around the lower end of the esophagus. The new treatment involves using surgical stitches during endoscopy, which is used to evaluate reflux symptoms. The stitches are supposed to tighten the area between the stomach and the esophagus to prevent heartburn. No incisions are made and the patient doesn't need anesthesia The procedure lasts about 30 to 60 minutes. The procedure Is appropriate for people who suffer heartburn several times a week. It Is currently being studied at six centers nationwide, none of them are in the tri-state area For more information, contact: Mayo Clinic Cancer Center. 200 First Street SW, Rochester, MN 55905, (507) 284-2511.

Aired August 12, 1999 Anti-Depressant May Help Weight Loss

If you're trying to lose weight, a drug used to battle . depression may also help battle the bulge. Kishore Gadde, M.D., a psychiatrist at Duke University Medical Center, noticed that obese patients taking the anti-depressant Bupropion SR lost weight more successfully. He then studied 30 women who were overweight but not depressed
http:/1204.202.137 .112/local/wabc/oncall/11898_6171998.html Page 4 of 13

GDR177-0371

..
~~

tNABC Eyewitness News Online: New Procedure to Treat Osteoporosis

. ,,

2112/99 1:46 PM

and found similar results. "The people who received buproprion SR did four times better than those who received placebo," said Dr. Gadde. After eight weeks, women taking the drug and eating a 1600-calorie diet lost four times more weight than women on a placebo. Women who completed the study and took the drug lost about 6 percent of their body weight compared to about 1.5 percent for women on a placebo. The drug is marketed under the names Wellbutrin SR and Xyban. The only side effect so far seems to be dry mouth. It does not affect sexual function like other anti-depressant medications. The drug's long-term effectiveness on weight loss has not yet been tested. It could take two years before the drug is cleared for use as a diet aid. Right now, some doctors prescribe it to help smokers kick the habit. For more information, contact Rebecca Levine, Duke University Medical Center, Box 3354, Durham. NC 27710, (919) 684-4148.

Aired August 9, 1999

Exercise to Strengthen Immune System

Exercise builds muscle, fights obesity, and strengthens your immune system. One of the ways exercise stimulates your immune system is to increase the number of infection fighting cells called natural killer cells. But there can be too much of a good thing. Exercise physiologist Robyn Stuhr says exercising everyday or twice a day can lead to over training. She says over-training can be characterized by fatigue and exercise performance suffers. The symptoms of over-training can be subtle. Stuhr says to give yourself recovery time, such as one to two days between each day of intense exercise.

Raising "Good" Cholesterol with Medication

People with cholesterol problems are often treated by their doctors to lower their "bad" cholesterol. But if your "good" cholesterol is not high enough, there's a new treatment to remedy that situation that could help prevent heart problems. According to Dr. Henry Ginsberg, of Columbia Presbyterian Medical Center, normally about 70 percent of our cholesterol is LDL, or bad cholesterol, and about 30 percent is HDL. The HDL, or good cholesterol carries cholesterol away from the blood vessels to the liver where it can leave the body. Good cholesterol should be higher than 35 for men and higher than 40 for women. An article in the August 5 issue of the New England Journal of Medicine confirmed that it is important to increase levels of HDL or good cholesterol if it's low. According to Dr. Hanna Bloomfield Rubins, of the Veterans Affairs Medical Center in Minneapolis, Minnesota, about 20 to 30 percent of people with heart disease have low levels of HDL cholesterol and normal levels of LDL cholesterol. Researchers found that the inexpensive drug lopid was effective in reducing deaths from heart problems. Of the approximately 2,500 men studied, those who took the drug daily for an average of 5 years were 22 percent less likely to die from heart disease or have a nonfatal heart attack and 29 percent less likely to have a stroke. In addition to raising the HDL levels, it also helped reduce levels of the total cholesterol and other blood fats called triglycerides.

htlp://204.202.137 .112/locallwabc/oncall/11898_6171998.hlml

Page 5 of 13

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New Wolghl Lass 0Ng

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lluprnpl!l'l SR, now used tD treat depressl111 and belp paUents quit smcldng, shcrNs promise as a potential wel!lht lass tool. PreUmlnary llndlnts from researchen at Duke University Medical Center have slu~n that women who took the dru; and follaNed a 1t.OQ.calor1e diet last four Urnes more we!Qht than women Who followed the diet and tack a placebo. "Since the withdrawal of fenfluramlne and <le<fenfluramlne, there has been I sreat need for effective medications, noted Kl>hore Gadde, ND, lead lnveUgaiDr of the swdy, which WliS pl'l!SI!IIted last month cturtn11 the American PsyChiatric Association meeting In WashiOIIIDD, DC. Godde's sWdy Included 31 women who did not have depression and wel!lhed an average of 222 pound5. Alter 8 weeks, 11 women Who took buproplon SR lost 6.2ll of their body

wanen who Initially responded to the drug Clllltlnued to lose wetQht as the study passed the 6month mark.
JAJM., June 23/30, 1999-Vol2.81, No. 24 2277

weight, while 13 women who received plac:ebo last 1.6" of their body weight. The data analy>ls Is not Cllll1llete, but Gaddesa1d It oppeared that

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Disclaimer Notice:
Information on this web site Is provided for Informational purposes only.
It b \mpeAtlve that you consun your own physician regarding the appUcabtltty of any optntons or rec:ommenda.t'ons with rnpe=t to your 1ymptDms or medkal cond1t\on, Contact w!th this web site or Dr. Rutledge over the web site d..,. not constitute 1 doctor patient relotlon5hlp and for pd quality medical care you must obtam advfc:e and coraultaUon fonn your own local phys"=ian. Thb site b tntended as 1 rcsouKe for references on the treatment of obesity for health care pft)festonals and educated consumers. The authon and editors hove 1Md sources bell<!ved to be reliable In their efforts to provide Information that 15 complete and generally
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Copyrilht ~ 1998 The Center for Laparoscoplc Obesity Suflery

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GDR177-0373

Fartdly News- LOSE WEIGHT & STOP SMOKING WITH ZVBAN

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Anti-Depressant Diet
BACKGROUND: Ninety-seven million Americans, or 55 percent, are considered overweight according to guidelines from the National Institutes of Health. The new standard Is based upon a person's body mass index (BMI) -- a way of measuring body weight In relation to height and body fat. This puts them at Increased risk for diabetes, heart disease and stroke. WEIGHT LOSS HELP: A drug currently approved to treat depression and help people quit smoking has shown promise as a potential weight-loss tool. Klshore Gadde, M.D., of Duke University Medical Center realized overweight psychiatric patients in the anti-depression drug were able to lose weight easier and more quickly than those not on the medication. Dr. Gadde began a study to see If the drug could help non-depressed overweight patients lose weight. The average weight of women In the study was 222 pounds. In the first eight weeks of the study, women who took the drug combined with a 1600-calorie a day diet lost four times more weight than women on a placebo. The average dally caloric Intake for a woman Is about 2100 calories. At the end of the eight week study, those who completed the study and took the drug lost 6.21 percent of their body weight compared with a 1.56 percent weight loss in the women on a placebo. HOW IT WORKS: Buproplon SR works by Increasing available amounts of norepinephrine and dopamine in the brain. The two chemicals are believed to play a role In the reward and pleasure pathways. The drug marketed under the names Wellbutrin SR and )(yban. Dr. Gadde says Its unique mechanism of action may account for why patients report buproplon SR does not suppress their appetite. Instead they report feeling satisfied more easily. Buproplon SR is not approved by the FDA for weight loss and Is not recommended for use by patients with seizure disorders, anorexia or bulimia. The study will continue for another 18 months. A larger, multi-center trial Is planned for the future. SIDE EFFECTS: The only known side effect from Buproplon SR Is dry mouth. Unlike other medications used for depression, It does not affect sexual function. They have not yet tested the drug's long-term effectiveness on weight loss. OTHER USES: Bupropion Is also currently being studied for its effectiveness In relieving nerve pain called neuropathy which can be caused by a number of factors Including disease or injury. FOR MORE INFORMATION, PLEASE CONTACT: Rebecca Levine Duke University Medical Center Box 3354 Durham, NC 27710 (919) 664-4148
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World Wide Web Edition

Rocky Mountain News (CO)- Print Circ 380,598


Date of Publication: 07/13199 Headline:

Account Number: 25578

NEW DRUG THAT COULD BE BIGGER THAN VIAGRA

By 'ROGER HENDERSON The Guaroian LONDON - Modern medicine still relies on chance and serendipity far more than it cares to admit. Viagra, the prescription drug phenomenon of the past two years, was originally developed as a treatment for heart disease and it was only when users reported their impotence was a thing of the past that the manufacturers realized they had created a golden goose. from America are to be believed, a new drug that has properties also discovered by accident may take the United Kingdom by sto= next year, and could be set to rival the success of Viagra. If approved, it may also go some way in helping health professionals to achieve their goal of reducing the nlll1lber of premature deaths in this country from heart disease, as set out in the recent department of health white paper on the health of the nation. Originally developed as an antidepressant, the drug _ bupropion hydrochloride was licensed in the 0. s. three years ago under the name Welll>ut.rin Its main marketing point was that it did not greatly intErfere with ee>eua1 function, something moat antidepressants are notorious for affecting. During t.rials of the drug, ana quite by chance, it was realiz:ed that people taking Wellbutrin were finding it far easier to stop amoltinc;r than those who were not using it. Early reports suggested that they were not craving for cigarettes as they normally did, and had fewer withdrawal symptoms on stopping their habit. Once the company involved, Glaxo Wellcome, had picked up on this aspect of the drug, it beqan further trials specifically looking at the effectiveness of the drug as an anti-amoking aid. The results of this compaFative clinical study were published in the New England Journal of Medicine in March this year, and make for impressive readinq, Just under 900 8mokers we~:e involved, all of whom smoked at 'least 15 cigarettes a day. They were split into four groups th.ose taking a dummy pill or placebo, those taking bupropion , those using a nicotine patch plus a bu:prop.:Lon tablet, and those using a nicotine patch alone. After 12 months, 15 percent of those on the dwmny pill were still not aaokinq. This was only marginally worse than the 16 percent using only nicotine patches, but nearly 31 percent of smokers taking bupropion had. stopped. The surprising stati5tic, however, was .,in the group using both patches and t>uprop:l.on _ a success rate of 35 percent, more than double the usual rate seen in smokers trying to give up. Just as important,. side effects appeared to be minor, with few people having to stop the drug because o! them. A dry mouth and insomnia were reported by users, but little else. People with a history of seizures or eatinq disorders should not take bupropioa , but otherwise most smokers will be valid candidates for such treatment, which is the first such non-nicotine prescription available. This collbination of effective results and low side effects led to the drug being licensed in the IJ. S, as an aid to stopping 111110king, under the name Z:yi>an , This has now been prescribed to some 3 million Americans, over 1 million of whom have stopped smoking , Attempts are now being made to secure a licen~e across the EU, with the Dutch authorities taking the lead through the regulatory hoops. The druq could be available in this country early next year. Rob Cohen, therapeutic and science communications manager of Glaxo Wellcome, says: "With succes! rates double that of nicotine replacement therapy, Zyban, upon approval from the appropriate requlatory authorities, will provide an effective weapon for many people in their battle against
If reports

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&,:; :;;.Medical Centu, Durham, NC, led a team of rcseaKbcn who cxamiacd me effu ofWclllo11uiP O.upropion SR. Claxo Welleome:), IUJ antidepiti~>ant, l)ll31 overwdght womea. Study participants weighed 222 pounds on average.

After eight weeks of tratmeAl llRd 11 1,600-calarie daily dic1. the 18 w<>mcn on the drug loll more thll.ll
six puccnc of \'ht.ir body weipt, four times more than ) 2 women who ~ a placebo. The treated women rdvcd a JJ1uimu111 of ZOO mg of buptopion daily.

Gadde reported his n:Jlllu in May at chc Americ;ao Psychiatric Auvdation mee~ing in WashiDgwn, PC. The: 'tlldy - . funded by Cluo Wellcome, Gadde <:a11tioDed that bupmpicm, which it also muketed as qban for smoking cessation, is not approved by tbe
FDA

for -=ittht }Q~5. The: main ride effect noted was dry mouth. -DAN V'RGANO C)-

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Drug m.ay help folks be happy~ ~~~~ ~eight and stop sn1oking
SCRlPPs HOWARD

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WASHINGTON _ A drug already approved to combat depression and help people slop smoking has shown promise as a weight-loss tool in a small, preliminary study, researchers say. Speaking during a meeting of the American Psychiatric Association here earlier this week, Dr. Kishore Gadde of Duke University said a small group of women taking buproprion hydroclil5Tiae tosniilii~ Limes 'more. weight "over "ail eight-week period than a

group "'rwomen taking inac"While we have to appru;Kh tive pills. All the women were the results cautiously h~.t:;m~<' also on a relatively modest the long-term results Hr: 11o\ 1,600 calorie-a-day diet. completed, we are veery <.'.Y Gadde said tests with the cited about the polenli:JI thi~. drug - which is sold as Zy- drug has for treating nb~:oily.'' ban as a stop-smoking aid and The psychiatrist first no as Wellbutrin for depression ticed that the drug seemed lo - are continuing, and that have an effect on wci,11h1 the women who responded among a group of wnmen lw during the first eight weeks was treating for mild depre.' appear to be losing additional sion at a Duke diet and f1111o;~> weight as they continue Lak- center. ing the drug more than six Previous studies nlll(:d 'b:n months out, although the re people Laking the dru~ 1;:''""' searchers haven't completed less weight as Lhey qui I ~111";,, analy1:ing their data. ~ng.

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reporbid by IVAHHOI! BROAOCMT NEWI, Die.

ANTI-DEPRESSANT DIET #1460 Television News Service/Medical Breakthroughs Ivanhoe Broadcast News, Inc. August 1999

Imagine taking a pill and POOF! Your hunger goes away. The pounds melt off. Best of all, you feel great, not anxious like with some appetite suppressants. That's what doctors are finding by using an old pill a new way. Jan Lucas has dropped five dress sizes in one year. "I weighed 217, and now I weigh 145," Jan says. She did it by eating 1,600 calories a day, just slightly less than average for most women. However, she also took an anti-depressant pill called hupropion SR. Before long, Jan knew this diet would be different "Other times when I lost weight, I really wanted to eat more food," she says. "I was never satisfied. Now, I feel like it's the answer to my prayers. I just don't have the cravings." Kishore Gadde, M.D., a psychiatrist at Duke University Medical Center in Durham, N.C., came up with the idea after he noticed obese patients taking the anti-depressant lost weight more successfully. He studied about 30 women who were overweight but not depressed.
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Rea!Player

Dr. Gadde reports, "The people who received bupropion SR did four times better than those who received a placebo." After eight weeks, women taking the drug lost an average of 14 pounds. Those on a placebo lost

only ~e-and-a-lialf pounds. The drug triggers the release of dopamine and norepinephrine in the brain. "It's a brain chemical or a brain hormone we normally associate with pleasure feeling," says Dr. Gadde. He hopes more studies will show why the drug is so helpful to dieters. Jan remains in the study counting calories and loving her new look. "I feel like I can do this for the rest of my life," she says. So far, the only side effect of the drug seems to be a dry mouth. It could be two years before the drug is cleared for use as a diet aid. Right now, many doctors prescribe it to help smokers kick the habit (Zyban).
If you would like more information, please contact:

Rebecca Levine Duke University Medical Center Box 3354 Durham, NC 27710 (919) 684-4148
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Or you can share your comments with other readers here. Click here to order additional research and full length news video.

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End obsessive eating with Overeaters Anonymous.

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Feel good, quitleaf&getthin with drug?


By JIM SHAMP
The HeraldSun If you're depressed about the idea of gaining weight when you quit smoking, Glaxo Wellcome Inc. may have just the drug for you. GJ.axo's drug bupropion, sold as Wellbutrin SR for treating mild depression and, in a different form as Zyban to help people quit smoking, lllay have yet another life as a weight-loss agent. Duke University Medical Center psychiatrist . Kishore . Gadde unveiled results of a preliminary study Tuesday in Washington, D.C., showing that women taking the drug while m1:1intaining a 1,600-calorie-a-day diet lost four times more weight than women eating the same amounfwhile taking a placebo - a pill that Looks the same but contains no medi. cine. His presentation to the American Psychiatric Association inarks only}~~ ~tE\8~ ~ ~ ~fi~s .(>(,findings tliat coUld lead to a third new indication for bupropion, an old Burroughs Wellcome drug that has found financial legs since Burroughs was taken over by Glaxo Inc. in 1995. Doctors initially noticed that depressed sm~;~kers trying. to kick the habit had impres;>ivc results when taking Wellbutrin. Research studies ensued, resulting in the introduction of the drug as Zyban. A study published in the New England Journal of Medicine has since shown that 30 percent of smokers who took Zyban were able to quit and stay tobacco-free - double the percentage who quit with a placebo. Similarly, physicians have Qeen noticing weight loss seems easier for people asing some form of the medication. Now, the Duke study is taking it a step further. Gadde said he got the idea for his study while consulting at .the Duke Diet and Fitness Center. He noticed when he gave patients the drug to treat mild depression; they lost more weight than usual. So, he approached Glaxo with a proposal to test Wellbutr.in SR in a group of 50 non-depressed women weighing an average of 222 pounds. He said he chose the .1,600-calorie diet because it's only . 500 calories belciw an average

5ABERING11

With the line of . hopeful ticket purchasers behind them, Jon Tofte (above, lett) and Jesse Stewart duel with lightsabers Tuesday morning in front of the Wynnsong Theatre in Durham. Both spent the night in front of the theater to get tickets for "Episode 1 - The Phantom Menace." TicketS went on sale at noon for the
midnight and 3

a.m. showings Wednesday. Ross Haswell of Durham reads a book while

waiting in line for


tickets to the new Star Wars movie.

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woman's daily intake, so it would Only one of the women in. the be safe and tolerable. study was a smoker, he said. "It wa~ .designel!..tl), quiekly,_get-- . . ;~Nnw ~e are .going:to dfil more an answer," he told The Herald- large-scale studies," said Gadde. Sun. "We wanted to figure out "At this point it looks very promiswhether it was worthwhile doing a ing. We'll be releasing results of large study. The results were ob- our six-month evaluation phase ver;y soon. All we, can say at this viously very positive." Of the SO women who started, point is that th~ 18 women who 25 were assigned .to receive the are continuing the study seem to placebo and 25 to get bupropion. continue losing weight. It's such Only 31 completed the full 'eight an objective measure we can't reweeks of the initial trial, in which ally hide it." participants kept diaries logging Only women who lost S percent their food intake. Women receiv,- of their initial. body weight, or ing the drug were given up to 200 four kilograms, in the first eight milligrams t\yice a day, consid- weeks, qualified for continuation ered the maximum dosage for in the study, said Gadde. Though they're all continuing to lose treating depression. "In weight-loss studies, if people weight, he said he doesn't know aren't losing weight, it's hard to how 'many are receiving the drug keep them in the' study," said and how many are on placebo. "We tried not 'to' take away Gadde. "We asked those who dropped out why they didn't fin- something that benefited them, ish. We found that 32 percentin whether it.was placebo or drug," the placebo group dropped out be- said Gadde. "But if they failed to cause they were dissatiSfied with benefit adequately in the first their results, compar~d with only eight weeks, we offered them the .chance to cross over to the other 4 percent in drug group." Of the women completing the' medication in the double-blind study, those getting the .drug lost trial. If they respond t() the crassan average of 14 pounds, coin- over treatment in the second eight pared with an average loss of only weeks, they'll b1 able to go into 41/z pounds in the group receiving the next phase, for up to two pJacebo. years, as responders. But we're ,:Of those receiving the drug, .12 blinded to the treatment, Only the ()Jil of 19 - 67 percent ..:..,_ com: pharmacy knows what they're get. pieted the study, compared with ting." The researchers used body comonly two out of 13, or 15 percent,. of those receiving placebo. position scans, called DEXA Another significant finding, scans, to measure the women's . Gadde said, was that bupropion percentage of fat and muscle loss. "When you lose weight on a batwas tolerateq "remarkably well, with no significant si,de. effects." anced diet you lose approximately

becimse,Of the 2,000-foot.zoninl .Brough told the Hernld-S April, when the suit was. file the city;'s ordinance violates th three-fourths fat and one-fourth them burn calories . more ef- Amendment for two reasoqs. lean mass, or mud:te," said Gadde. ficiently. First, th~,gov~rnment ~-ol "But;~:lj!'ln you fast,- you lose half - -Un'like fenf:J;U.f.'arrtine and late adult entertainment beeau fat and half lean mass. That's why dexfenfluramine ..::: Fen-Phen, the a for:m hf speech under Co fasting is not a good way to lose diet drug which was withdrawn tiona! protection, he. said. weight, because you lose a lot ,of from the market over safety con Second, the City Council lean mass." cerns, bupropi()n appears to have zone adult businesses !limply b The DEXA scans .at the begin-: no effect on the neurotransmitter. it doesn't like them, he said. Tl ning of the study will-be repeated serotonin, said =Gadde. can only consider the "second< after six months of treatment, at The patent on the original bu- fects" of adult businesses and the end of one year and at the end propion formulation introduced in land-use decisions based on th< of two years, to evaluate the qual- 1989, Wellbutrin immediate re- fects. . But Brough, considered an , ity of weight loss in the partici- lease: expired in 1994, though pants, said Gadde. The scientists sales continued. The sustained re- on land-use law, said city offici; are also looking at bone mass den- lease fortnufation, Wellbutrin SR, not conduct any studies to dete sity, because women who lose introduced in 1996, boosted sales whether adult establishments weight also lose a certain amount of bupropion b~yond $200 million affect the character of the neil of bone mass, increasing their risk in 1997 alone. z;yban, approved in hood when they included an adt 1997' as the. first non-nicotine provision in the 1993 zoning co( of .osteoporosis. Gadde said many .participants pr9duct 'to help smokers quit, gen- r~--...-.P;Iease ~t@ycle .newspllpe reported feeling pleasure after erate(~. another $52.5 million in . eating smaller amounts of food. sales during its f}.rSt six nionths on They didn't say they felt full, just the market. Pharmaceutical analyst EdmUnd sated, said Gadde. The researcher said the .'drug's Debler has projected that sales .of effect is possibly related to brain the. three versions could reach chemicals, the apparent $300 million by the imd of this qopamine-enhancing and norepi- year. nephrine-enhancing effects of the

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"These neurotransmitters modulate pleasure and reward behaviors in the brain," he said. "But the mechanism is not well understood." . . Tnese neurotransmitters are also known to affect energy expenditure, he noted. Energy intake is the food we eat, whil~ _its ex: penditure is how calories are burned. Gadde projected that the drug helps people reduce their de: sire for intake, while also helping

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Raleigh officials object. .to immunity for reporters


Associated Press
RALEIGH: - Raleigh Mayor Tom Fetzer and two members of "You're giving them the sword to attack people with the shield to hide behind."

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UPI News Article: A pill for all that addicts you?

9/19/01 4:49 PM

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A pill for all that addicts you?


Monday, 17 September 2001 20:43 (ET)

A pill for all that addicts you? By PEGGY PECK, l)PI Science News CLEVELAND, Sept. 17 (UPI)- A medication called bupropion, better known as Wellbutrin or Zyban, is generating a lot of buzz because it looks a wonder drug that can help people lose weight or stop smoking. The buzz is especially interesting because the drug initially was approved to treat depression. So does this mean that depression, overeating, smoking and maybe other addictions like drug abuse or alcoholism are all somehow linked? The answer, say addiction experts, is maybe. When smokers light up a. cigarette and down a lung-full of smoke, nicotine triggers the release of a chemical called dopamine in the brain. Dopamine, in turn, acts on the pleasure center of the brain, which sends out those waves of pleasure that longtime smokers describe. Likewise, dopamine is released when eat. "You know you've eaten enough when you feel full or sated," Dr. Kishore Gadde of Duke University told United Press International. But obese people often need to eat large amounts of food -- in fact need to over-eat- to release enough dopamine to feel sated. "They may actually need higher levels of dopamine," he said. People who are depressed, on the other hand, cannot get that dopamine high from smoking or eating or any other know dopamine triggers. Their dopamine levels remain so low they are incapable of feeling pleasure. That is where bupropion comes into the picture. It also regulates the release of dopamine. When depressed patients take it, many of them start to feel better. But smokers and overeaters do not have to be depressed to get a benefit from bupropion. Bupropion is not approved for use in treating other addictions, including alcoholism. But by taking the drug, the smoker may not feel the need for the nicotine rush and the overeater may be able to push away from the table having consumed fewer calories. There are several studies indicating the drug is an effective aide for both weight loss and smoking cessation, but addiction specialists are cautious about looking "for a cure in a bottle," said Dr. Howard Rankin.

Click for complete story

http://www. vny .com/cf/News/upidetail.cfm ?QI 0=221656

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. UPI News Article: A pill for all that addicts you?

9119/01 4:49 PM

.Pt.!nl\in, an adjunct professor of psychology at the University of South Carolina School of Public Health in Columbia, told UPI it does appear there "is probably a general addiction pathway in the brain," but he questions the wisdom of taking that road. He said anyone battling an addiction, whether it is overeating or alcoholism, is "very good at looking outside themselves for both the source of the and a possible cure." He said that "magic bullet :::mr~rn~ar.h"
I

life changes associated with long-term recovery. Those changes include a commitment to a "total life change and to ongoing support," Rankin said, and added it can be a 12-step program or professional counseling. Dr. Tony Tommasello of the University of Maryland at Baltimore, told UPI that drugs like bupropion appear to work best when taken in conjunction with ongoing counseling or support programs. Moreover, a pharmacologic approach to treating addictions is probably most useful in "getting people over the initial difficulties like the physical withdrawal from nicotine." Tommasello said most long-term recovery is linked to the type of lifestyle changes advocated by Rankin. "In the case of a recovering alcoholic, for example, recovery often turns on the ability of the alcoholic not to resist the urge to drink but to act on that urge in a positive manner, for example by going to an AA meeting," Tommasello said. But Dr. James Taylor-Hayes, of the Mayo Clinic in Rochester, Minn., said maybe part of the total lifestyle change Rankin and Tommasello advocate should include lifelong medication to treat the addictive disorder. He has been studying efficacy of long-term bupropion treatment lasting a year or more to prevent relapse among former smokers. Hayes said the bupropion is well tolerated with only a very minimal risk for seizure, and that risk is only seen in people who had a history of head injuries. Many conditions, for example diabetes or high blood pressure, require chronic treatment with medications. But addictions, according to the experts, are not equivalent to illness like diabetes. To illustrate, Rankin pointed to the anti-drinking drug called antabuse, which will cause one to become violently ill if taken in combination with alcohol. "I remember a treatment program where we were implanting antabuse under the skin in the arm and I saw people actually digging it out so they could drink. Chemical police just don't work."

Mcko SS$ With GoTo

Copyright 2001 by United Press International. All rights reserved.

The romantic sounds of classic Cuban music blend with contemporary Spanish guitar in Alicia y Yo, a new CD from Spain. Click here to listen to some tracks and order the CD

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poulble wh&l l ned obwneo ..,.,...,. unmang lfrug 1111118 rnay haYD been a IJDke. 41dfld 1>1 &gpprns,llg lhw But lh.e results or a ,,...._ dlllre ro Nl. Thb tb~tfl oc:ta In month study Involving i8 a -~ ,op~rlsfiea~d wo,. by wom10n wllh an average alr-rng 10M 111 111t hr rdwewelght of 1 !1$1 prO\ed the arigf- ir:g. JOrM d'tle lo wwretJI. nal reporta were ne rnlatllke. Specialisla lreatlJ.'i the ob..., The women lol up te 8 have beon short of drug treatstone - six per cent of their ments. ;Jnc:e the banning of body weight - whOle on a diel popula~ dlel pill~ pbenlormlne of 1,600 "lories a day. an<l fe11fluramlne alter they Dr Gadcle Is convinced ""!'re blamed lor ~using heart Buprol'lon will take off as an discat<e In paJ.nu_ obesitY treatmen~ Dry Ue tbc~e wore overHe UI)"S: to:ews or my Rhody woiP,t women who were able to oc:hleva a ~toot! wclgllt lDSs Ia "'P<'"Ildiag and people are bound to el<perllnent becaue over " sh01't period of lime. "We still need lD carT)' ou\ lheR are not thai many drugs available ror obeaily. further trials wlth a lar&er "Tbt> ifaporlanl thing h thai group of patients bill It look$ then ant no slsnlficant aide as If wa havr dlecVered a effec~ apart from a feeling of new u ... for this drua. . "The resulta &PJ>e!IW . . good a dry mouth." But Ola!W ad"lsft 01'\l NOT as tho.. achieved for Xanlcal to usa !l to treat -patlen"l& sufand It> ROme cues belter. from a h11toJy ~f Bet"SOJWe of the woman 011 the fering anoiexla or bulbnla. trial haV41 been taking ""' '"~,._. Brithlo . o!oetan wiD bJ abl dyug for UJ> to a year arid are lo prasertbe BUproplon . for ~onUnvl"- to lose W91sbt. , obellity once U galna a licence w.......n .., tha tJ;lal re.--ted ror treoUrig unoldng. . that the drug did Jtol sapJi....,. But It eould be ..,...., lime thtlr appetite bl.lt 'belpeo il)em bofor.. it sets o!liclat approval feel more 118llaf!ed, 1'1\DH. elillly. n llm.mln~ pill. . .

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MEMORANDUM
September 20, 1999

TO:
FROM:

Holly Russell Jocelyn Serio Media Update on Weight Data B. Waters, Lisa Weiss, L. Draho

RE:
Cc:

Following is a comprehensive report of media pick up surrounding the Wellbutrin SR weight study. New information since the last report appears in bold and includes television pick up in Detroit, San Diego and Tampa. To date, news of the weight study has been carried by:,

IT IT
IT IT

More than 70 local television stations More than 52 local newspapers and consumer magazines nationwide and in the United Kingdom More than 9 Internet outlets nationwide 12 trade publications in the United States

Media impressions exceed 15 million (not including wire and Internet impressions). I will continue to send new information to you as it comes in.

GTP123-3090

MEDIA INTEREST/COVERAGE ON DUKE STUDY

The Associated Press, 5119, circulation unavailable (millions) Ran story "Glaxo Depression, Smoking Drug Has New Use." Scripps Howard News Service, 5/28, circulation unavailable (millions) Ran weight loss story that was subsequently picked up by smaller daily newspapers across the nation.

Broadcast WSOC-TV(ABC), Charlotte, 5/18, viewer number unavailable Mentioned weight study during 11:00 PM "Eyewitness News Tonight." WTVD-TV(ABC), Raleigh/Durham, 5/18, 102,000 viewers Reported that ''bupropion, a drug that reduces depression and can help quit smoking now shows it can promote significant weight loss as well ... " during 5:00PM broadcast of"News Channell! at 5:00." WKRC-TV(CBS), Cincinnati, 5/18, 122,000 viewers Mentioned bupropion/weight study during 11 :00 PM broadcast of "Channel 12 News Tonight." KHOU-TV (CBS), Houston, 5/19, 250,000 viewers Mentioned weight study on 10:00 PM "11 News at 10." WCNC-TV(NBC), Charlotte, NC, 5/19, 38,000 viewers ''Bupropion SR has been found by Duke University to be able to control weight too, not just depression ... "mentioned on 5:00PM "6 News." WLFL-TV(FOX), Raleigh/Durham, 5/19, 34,000 viewers Mentioned "Glaxo Wellcome's drug" can help people lose weight on 10:00 PM broadcast of "Fox 22 10 O'Clock News" WRAL-TV (CBS), Raleigh/Durham, 5/19, 143,000 viewers Mentioned weight study on 5:30 PM broadcast of "Five Thirty News." WRAL-TV(CBS), Raleigh/Durham, 5/19, 143,000 viewers Mentioned weight study on 11:00 PM broadcast of"Eleven O'Clock News." WRAZ-TV (WB), Raleigh/Durham, 5/19, 23, 000 viewers Weight study mentioned on 10:00 PM broadcast of''News At Ten"

GTP123-3091

WPTF-FM, Durham 5/19, viewer number unavailable Interviewed Dr. Gadde for story that ran same day. WRAL-TV (CBS), Raleigh/Durham, 5/20, 88,000 viewers Mentioned weight study on 5:30AM broadcast of"Morning News." WSOC- TV (ABC), Charlotte, 5/20, viewer number unavailable Mentioned weight study during 5:00AM broadcast of"Eyewitness News Daybreak." WIAT-TV (CBS), Birmingham, 6/6, 26,000 viewers Mentioned Duke weight loss study on 10:00 PM broadcast of"42 Daily News at 10:00."

KFOR-TV (NBC), Oklahoma City, 617, 48,000 viewers "A recent study at Duke University revealed that women who took an anti-depressant drug called Wellbutrin lost four times the amount of weight lost by those who took a placebo" ran on 4:30 PM broadcast of "Newschannel 4 at 4:30."
WISH-TV (CBS), Indianapolis, 6/8, 68,000 viewers Mentioned Duke weight study on 5:00AM broadcast of"News 8 Daybreak." WHBQ-TV (FOX), Memphis, 6/11, 28,000 viewers "Duke University researchers say that Wellbutrin, a drug used to treat depression, may also help you lose weight and stop smoking" aired on 11:00 PM "Fox Midday."

WGAL-TV (NBC), Harrisburg/Lancaster, 6/14, 53,000 viewers "Depression drug is weight loss tool. .. " ran on 5:30AM broadcast of"News 8 Morning Report."
WBEM Radio (CBS), Chicago, 6/24, audience number unavailable Mentioned that Zyban can help people loose-weight by making them feel satisfied. KTNV-TV (ABC), Las Vegas, 6/25, 30,000 viewers "Duke University researchers say Wellbutrin may not only help depression but may also help you lose weight" ran on 11:30 PM broadcast of''News 13 Inside Las Vegas." Piece ran along with images ofWellbutrin box and a woman weighing in. WKMG-TV(CBS), Orlando, 6/27, 118,000 viewers Ran "Depression drug helps lose weight. New study shows patients taking Zyban (Wellbutrin) lose weight" on 11:00 PM broadcast of"6 News." Piece ran along with images of Zyban bottle and pills.

GTP123-3092

WCCO-TV (CBS), Minneapolis, 6/30, 205,000 viewers Ran "Zyban, is an antidepressant but it has also been found to aid in weight loss. Duke researchers say that the drug makes people feel more satisfied with their food intake," on 5:00PM broadcast of"The Five 0' Clock News." Carolina Broadcast News, Raleigh, NC Broadcast News interviewed Dr. Gadde in his office, along with a patient who lost 71 pounds in one year and agreed to be interviewed. Broadcast News sent its raw tape to Ivanhoe Broadcast News (based in Orlando) which shipped tapes to 138 TV stations across the USA. This segment includes three versions of the story - general, women's health and medical news. Stories have begun to air and include some of the following new broadcasts:
WEWS-TV(ABC), Cleveland, 7/26, 243,000 viewers Woman commented on how much weight she lost... been taking a pill called Bupropion SR and ran quote from Dr. Gadde on "Newschannel 5 at 11:00 PM." WSVN-TV (FOX), Miami, 7/26, 116,000 viewers Aired "Miracle weight loss ... old pill used to fight depression is helping overweight people lose weight. It is called Bupropion SR." Also included quote from Dr. Gadde and patient, Jan Lucas, on 6:30PM broadcast of"7 News At 6:30." WSVN-TV(FOX), Miami, 7/27,82,000 viewers Aired "Duke University Medical Center uses Zyban for weight reduction." Included quote from Dr. Gadde and Jan Lucas. Ran on 7:30AM segment of "Today in Florida." KSAT-TV (ABC), San Antonio, 7/26, 55,000 viewers Aired ''New diet drug also fights depression ... dieter had success with the drug bl}propion" on 5:00PM segment of"KSAT 12 NEWS." K.MBC-TV(ABC), Kansas City, 7/27, 182,000 viewers "KMBC 9 News at Ten" ran news ofweight study. KTAR-TV (IND), Phoenix, 7/27, no audience numbers available "Arizona Morning News" ran "Zyban has been shown to help women lose wet'ght. .. , KTBC-TV (FOX), Austin, 7/28, 34,000 viewers "Fox 7 News Morning Report" ran "A drug which is used to fight depression now is being used to fight overweight ..."

GTP123-3093

WHDH-TV (NBC), Boston, 7/28, 144,000 viewers "7 News at 4:00" ran "A Duke University doctor has discovered that the antidepressant Bupropion SR can also suppress appetite ... " WHDH-TV(NBC), Boston, 7/29, 105,000 viewers ''Today in New England" ran "Researchers believe that an antidepressant may help people to lose weight ... " WHDH-TV (NBC), Boston, 7/29, 136,000 viewers "7 News at Noon" ran "A pill that treats depression could help with weight loss ." KOCO-TV(ABC), Oklahoma City, 7/29,88,000 viewers "5 News at 10:00 PM" ran "Depression Pill: doctors say there is a possibility that an old antidepressant medication might be useful in fighting 'ght ... " overwe1 KOCO-TV (ABC), Oklahoma City, 7/30, 230,000 viewers "5 News at 5 AM" aired study news and quote from Dr. Gadde. KOCO-TV (ABC), Oklahoma City, 7/31, 12,000 viewers "5 News Saturday Morning" aired "The antidepressant Bupropion SR could be the latest fat-fighter. A study indicated it can help with weight loss... " WSVN-TV(FOX), Miami, 8/1, 116,000 viewers "7 News at 6:00" aired weight loss news and mentioned "an interesting side effect is that it helps people lose weight ..." KPRC-TV(NBC), Houston, 8/2, 166,000 viewers "News 2 Houston at 4:00" ran "A drug could be used to help people lose weight without anxiety by using an antidepressant. .. the people who received the drug did a lot better than the placebo."
KING- TV (NBC), Seattle, 8/2, 216,000 viewers "KING Five News at Six-Thirty" news ofweight study.

KDFW-TV(FOX), Dallas, 8/3, 103,000 viewers "Fox 4 News At 5" ran "One pill is working without side effects ... Jan Lucas dropped 5 dress sizes. Bupropion SR is an antidepressant that seems to be working .. .it is marketed as Wellbutrin." KDFW-TV(FOX), Dallas, 8/3, 199,000 viewers "News 4 Texas at Nine" ran "One pill is working without side effects .. .Jan Lucas dropped 5 dress sizes. Bupropion SR is an antidepressant that seems to be working ... it is marketed as Wellbutrin."

GTP123-3094

WTVD-TV (ABC), Raleigh/Durham, 8/3, 102,000 viewers "NewsChannelll at 5:30" ran "Troubleshooter weight loss study to shed light on how to shed pounds without dieting ..." WKBW-TV (ABC), Buffalo, 8/3, 104,000 viewers "Eyewitness News at 5:00" ran ''New diet drug ... " information. WPTV-TV(NBC), West Palm Beach, 8/3, 93,000 viewers ''News ChannelS Live on 5" ran "An antidepressant pill can also help people lose weight," along with interview with patient and Dr. Gadde. WKOW-TV(ABC), Madison, 8/3,28,000 viewers "Channel 27 News" ran "Doctors are finding that Bupropion, an antidepressant, is a good diet pill." They showed the patient using the Bupropion SR ("It has worked very well and I feel great") and Dr. Gadde discussing the medication. KDFW-TV (FOX), Dallas, 8/4, 97,000 viewers "Good Day Dallas" ran "Depression drug for weight loss. John Hammarley reports a drug designed for treating depression is helping people lose weight. The drug is Bupropion SR ... Dr. Kishore Gadde, Obesity Specialist, says they did better than those receiving placebos." KDFW-TV(FOX), Dallas, 8/4, 80,000 viewers "Fox 4 News" ran "Depression drug for weight loss ... a drug designed for treating depression is helping people lose weight. The drug is Bupropion SR." KUSI-TV (UPN), San Diego, 8/4, 42,000 viewers "KUSI Morning News" ran news of weight study. KLAS-TV (CBS), Las Vegas, 8/4,41,000 viewers "Eyewitness News at 6" ran "Antidepressant Bupropion SR works as diet pill ... Dr. Kishore Gadde, Psychiatrist, first noticed weight loss in patients on antidepressant." News8 Cable, Washington, 8/4, audience numbers not available "HealthLine" ran weight loss news and comments from Dr. Gadde." KABC-TV(ABC), Los Angeles, 8/6, 361, 000 viewers "Eyewitness News at Four" ran "Wonder pill: Bupropion SR pills ... " Jan Lucas talked about losing weight and Dr. Kishore Gadde talked about the Bupropion SR "Group Effect."

9f-3)
GTP 123-3095

News8 (Cable), Washington, 8/6, audience numbers not available "Daytime Report" ran "Old drug being used in new way..." along with patient and doctor interview and footage of prescription bottle. News8 (Cable), Washington, 8/6, audience numbers not available "Afternoon Report" ran footage news of weight loss study, along with patient and doctor footage. KDFW-TV (FOX), Dallas/Ft. Worth, 8/7, 85,000 viewers "Fox 4 News" ran "A drug normally used to treat depression may help fight obesity; Jan Lucas, diet study volunteer, says she lost 5 dress sizes by taking Bupropion SR. .. Dr. Kishore Gadde, Obesity Specialist, discusses his discovery that the drug helped obese lose weight..." . WHTM-TV (ABC), Harrisburg/Lancaster, 8/6, 32,000 view~rs "ABC 27 News" ran news of the weight study and mentioned the side effect of dry mouth. WHTM-TV(ABC), Harrisburg/Lancaster, 8/9, 17,000 viewers "ABC 27 News" ran weight study news. KOAT-TV (ABC), Albuquerque, 8/9, 33,000 viewers "Action News 7 Live at Noon" interview with Dr. Gadde and footage of bottle of Wellbutrin SR.

ran

KOAT-TV(ABC), Albuquerque, 8/9,77,000 viewers "Action 7 News Live at Five" ran interview with Dr. Gadde. WJRT-TV(ABC), Flint/Saginaw/Clio, 8/9,55,000 viewers "Newschannell2 at 5" ran "Hunger Pills in an old pill: Jan Lucas has dropped 5 dresses in 1 year. She took an antidepressant called Bupropion SR. She says other times when she lost weight, she stil wanted to eat. This took all of that craving away. It is a brain chemical. D. Gadde hopes to learn more about this drug." WICU-TV (NBC), Erie, 8/9, audience numbers not available "News at Eleven" ran news of the weight study.
WLS-TV (ABC), Chicago, 8/11, 719,000 viewers "7 News" ran mention of weight study along with interview with patient and Dr. Gadde.

GTP 123-3096

WLS-TV (ABC), Chicago, 8/15, 185,000 viewers "7 News" ran "The antidepressant drug W ellbutrin can now be used as a diet drug...Dr. Kishore Gadde says that the pill worked four times better then the placebos."

WFTS-TV (ABC), Tampa/St. Pete, 8/23, audience numbers not available "28 Tampa Bay News at 5:30" ran "Use of an antidepressant drug helps lose weight . patient says she bad cravings but does not now." WDIV-TV (NBC), Detroit, 8/23, 221,000 "Newsbeat at 5:00" ran "Jan Lucas, diet study participant, took antidepressant called bupropion SR, lost weight. It may help smokers quite also." WFTS-TV (ABC), Tampa, 8/24, 36,000 viewers "28 Tampa Bay News" ran "There is a pill that makes your hunger go away and the pounds melt off, but it does not make you anxious like some other diet products. Doctors are using this old pill in a new way... " Piece included interview with patient and Dr. Gadde, footage of bupropion SR and details of study. KGTV-TV(ABC), San Diego, 8/31, 119,000 viewers "10 News at Five" picked up the weight study information and ran with an interview with Jan Lucas and Dr. Gadde. KGTV-TV(ABC), San Diego, 9/1,28,000 viewers "10 News Midday Edition" ran weight information, along with a quote from Dr. Gadde. KGTV-TV(ABC), San Diego, 9/1, 119,000 viewers "lQ News at Five" ran.weightinformation, along with aquote from. Dr. Gadde. KOAA-TV (NBC), Colorado Springs, 917, viewer numbers not available "Five Eyewitness News" ran weight study in "Medical Breakthrough" segment, along with quotes from Jan Lucas and Dr. Gadde.

WZZM-TV (ABC), Grand Rapids, 9/15, viewer numbers not available "Eyewitness News 13 First Edition" ran "Old pill a new way .. " weight loss information along with quote from Dr. Gadde and patient.

GTP123-3097

Dateline NBC Producer attended APA and spoke to Gadde at his poster presentation; is interested in the study and wants information about next steps in extending this study to other sites. Dateline contacted GW in July and indicated that they plan to contact Dr. Gadde shortly. Good Morning America (ABC) Producer attended the AP A to research story ideas. She was interested in the weight information, but indicated that she preferred to wait for six-month data. CNN Producer interested in weight study; waiting for six-month data.

Online Media

Medcast, 5/18, audience numbers not available Interviewed Dr. Gadde at AP A; story currently appears on their health and medical site. Also sent out via PRNewswire by PR agency representing Medcast. Doctor's Guide, 5/18, audience numbers not available Picked up weight story and posted it on their health and medical website. OnHealth, 5/18, audience numbers not available Weight story currently appears on their online health site. Site is targeted to consumers with a broad range of health and medical information. BBC.com, 5/18, audience numbers not available BBC picked up the weight story and posted it on their internet site. CNN Interactive, 5/21, audience numbers not available Picked up Patriot Ledger story on weight loss data and posted it on their online news site. HealthScout, 51 25, audience numbers not available Posted "Chase Away the Blues and Fight Fat: Antidepressant May Help You Lose Weight." NewsEdge: Women's Health Weekly, 6115, audience numbers not available Posted "Obesity (Treatment); Anti-Depressant Drug Shows Promise As Weight-Loss Treatment." NewsEdge is a subscription-based, custom news service that reaches thousands of consumers. Ivanhoe's Medical Breakthroughs, 8/3, audience numbers not available Posted "Antidepressant Diet" article and Real Player broadcast of interview with Dr. Gadde and Jan Lucas.

GTP123-3098

AmericasDoctor.com, 8/99, audience numbers not available Posted "Antidepressants and Weight." Picked up information from Internal Medicine World Report and ran information about Wellbutrin SR

Trade Publications

SCRIP World Pharmaceutical News, 5/28, audience numbers not available Ran "Weight Loss with Bupropion" in 5/ 28 edition. Chemical Business NewsBase, 5/26, audience numbers not available Ran "Weight loss results 'Exciting, Promising' In Widely Used Drug For Depression and Smoking Cessation" in 5/ 26 edition. Marketletter, 5/31, audience numbers not available Ran mention of weight study in 5/ 31 edition. Clinical Psychiatry News, 6/99, 31,117 readers Carrying a report of the research presentation at the APA. R&D Focus Drug News, 617, audience numbers not available Ran weight data in 6/7 edition. Archives oflnternalMedicine, 6/14 Mentioned weight study in "Treatment Options for the Weight-Conscious Smoker."

JAMA, 6123, 333,133 readers Ran Duke weight loss information in "Quick Uptakes" column.
Pharmaceutical Representative, 1/99, audience numbers not available Mentioned that trial results were presented at the AP A meeting. OB.GYN News, 7/99, audience numbers not available Ran "Bupropion May Fight Fat." Article included a quote from Dr. Gadde. American Druggist, 7/99, 103,000 readers Ran "Wellbutrin Makes Them Thin and Happy." Article states that Dr. Gadde noticed his depressed patients were losing weight, and he "may have stumbled across a new diet drug ... " Internal Medicine World Report, 7/15, 102,109 readers Ran ''Nondepressed Obese May Slim Down on Bupropion." Article stated that "Weight loss was greater in nondepressed obese patients receiving sustained-release bupropion, compared with patients receiving placebo ... "

GTP123-3099

RX Pad, 7/15, readership unavailable Ran mention of pilot weight study.

Newspapers and Consumer Magazines

The Scotsman (United Kingdom), 5/19, 80,799 readers Ran story, "Anti-Depressant Could Play A Key Role in the Fight Against Obesity." Duke Chronicle, (Durham, NC}, 6/3, audience numbers not available Ran the weight loss story. The Herald-Sun, (Durham, NC), 5/19, 49,883 readers Interviewed Dr. Gadde for a story that ran 5119. Fayetteville Observer Times (Fayetteville, NC), 5/20, 69,650 readers Picked up Associated Press story and ran, "Depression, Smoking Drug Has New Use." Daily News (Jacksonville, NC), 5/20,22,361 readers Picked up Associated Press story and ran "Drug for Depression Could Aid Weight Loss." Mount Airy News (Mt. Airy, NC), 5/20, 9,450 readers Picked up Associated Press story and ran brief mention of weight findings under headline, "Smoking Drug Has New Use." Greensboro News & Record (Greensboro, NC), 5/20, 34,838 readers Picked up weight loss story from AP and ran on 5/20. Press Journal (Vero Beach, FL), 5/21, 34,838 readers Ran "Anti-Depressant, Anti-smokffig Pill May He~ Weight Less, Too" in 5/21 edition. The Atlanta Journal Constitution (Atlanta, GA), 5/21, 332,719 readers Ran brief in 5/21 edition. The Houston Chronicle (Houston, TX), 5/22, 748,036 readers Ran weight loss story and mentioned that results were presented during APA meeting. Los Angeles Times 5/24, 1,385,373 readers Picked up the weight loss news and ran in May 24 edition.

GTP123-3100

The Irish Times (United Kingdom), 5/24, audience numbers not available Mentioned that "a drug currently used to treat depression and to help people give up smoking may help with weight loss. . . it is thought that the anti-depressant bupropion SR may make a person feel satisfied after eating a small amount. .. " Richmond Times-Dispatch, 5127 Ran "Weight Loss Pill?" London's Daily Mail (United Kingdom), 6/15, audience numbers not available Weight study story ran on 6/15. Macoupin County Enquirer, 6/24 Ran news of study in "Ask the Doctor." Province, (Vancouver, BC), 6/25, 220,000 readers Ran "3-For-1 Drug- And It Doesn't Mfect Sex." Edmonton Journal, (Edmonton, CN), 7/26, 152,506 readers Picked up the Daily Telegraph (London) piece and ran with headline, "Pill Fights Depression, Smoking, Overweight." The Guardian, (UK) 7/13, audience numbers not available One ofthe top two newspapers in the UK carried results of the weight study in July. Rocky Mountain News, (CO), 7/13, 380,598 readers Picked up the Guardian (London) piece and ran with headline "New Drug That Could Be Bigger Than Viagra."

Times Record News, (TX), 7/14,38,800 readers Ran mention of weight study in entitled 'iDevelopers Stumble Onto AntiSmoking Aid."
Star Beacon, (OH), 7/14,23,000 readers Picked up information from London's Guardian and ran "New Drug Could Be Bigger in Britain Than Viagra." The article talked about the benefits of bupropion for smoking cessation, as an antidepressant and weight loss.

Allure, 9/99, current audience numbers not available Ran "Wellbutrin and Weight Loss" in Mood News column. Mentioned Duke University and ran quote from Dr. Gadde. FLAIR, 9/99 (Toronto), audience numbers not available Ran information about the study in September issue.

GTP123-3101

Stories Picked Up From Scripps Howard News Service

The Patriot Ledger, (Quincy MA), 5/21, 75,706 readers Picked up the weight study from Scripps and ran on _5/21. GreenVille News, (Greenville, SC), 5/21, 97,399 readers "Drug May Help Folks Be Happy, Lose Weight and Stop Smoking." Daily Press, (Newport News, VA), 5/21, 97,116 readers "Anti-depressant, Anti-smoking pill may help people lose weight, too." Anderson Independent-Mail, (Anderson, SC), 5/21,40,829 readers "New Uses Discovered for Drug", "Pill Fighting Depression, Nicotine Could Help with Weight Loss." Sunday Republication, (Waterbury, CT), 5/23, 77,000 readers Picked up Scripps story and ran with headline, "Antidepressant, Anti-Smoking Drug May Also Fight Fat." Press-Enterprise, (Riverside, CA), 611, 166,708 readers "Study: Stop-Smoking Drug May Help In Obesity Battle." Oxnard Star, (Onxard, CA), 5/2,18,690 readers "Anti-depressant May Help Weight Loss." Camarillo Star, (Ventura, CA), 5/21, 12,136 readers "Anti-depressant May Help Weight Loss." Simi Valley Star, (Simi Valley, CA), 5/21, 12,757 readers "Anti-depressant May Help Weight Loss." Moorepark Star, (Moorepark, CA), 5/21, 6,000 readers "Anti-depressant May Help Weight Loss." Ventura County Star, (Ventura, CA), 5/21, 94,954 readers "Anti-depressant May Help Weight Loss." Sunday Republican, (Waterbury, CT), 5/23, 77,000 readers "Anti-depressant, Anti smoking Drug May Also Fight Fat." Albuquerque Tribune, (Albuquerque, NM), 5/26, 24,294 readers "Study Finds Anti-depression, Stop-smoking Drug Might Help People Lose Weight, Too."

GTP123-3102

Enterprise, (Brockton, MA), 5/21,46,488 readers "Anti-depressant, Anti-smoking Pill May Help Weight Loss, Too." Evansville Courier & Press, (Evansville, IN), 5/21, 107,966 readers "Depression, Smoking Drug May Help With Weight Loss." Times Herald Record, (Middletown, NY), 5/21, 101,725 readers "Depression Drug said to Aid in Weight Loss." Leaf-Chronicle, (Clarksville, TN), 5/21, audience numbers unavailable "Pill That Treats Depression, Smoking May Help Weight Loss." Grand Island Independent, (Grand Island, NE), 5/21,24,419 readers "Smoking and Depression Drug May Also help With Weight Loss." Las Vegas Sun, (Las Vegas, NV), 5/21, 39,483 readers "Drug that Combats Smoking, Depression May Help With Weight." Missoulian, (Missoula, MT), 5/21,30,175 readers "Anti-depressant used by Smokers May Curb Weight." Trentonian, (Trenton, NJ), 5/21, 60,296 readers "New Pill May Help Weight Loss." North Jersey Herald & News, (Passaic, NJ), 5/21, 52,716 readers "Anti-Smoking, Depression Drug May Cut Weight." Thousand Oaks Star, (Thousand Oaks, CA), 5/21 "Anti-Depressant May Help Weight Loss." Record Searchlight, (Redding, CA), 5/21, aurlience numbers unavailable "Researchers Test Zyban!Wellbutrin's Effect on Obesity." Indianapolis News, (Indianapolis, IN), 5/21, 100,000 readers "Weight Loss is Side Effect ofDrug, Anti-Depressant Slimmed Women." Denver Rocky Mountain News, (Denver, CO), 5/21, 380,598 readers "Anti-Smoking Pill May Help Weight Loss, Too." News-Herald, (Willoughby, OH), 5/21, 50,215 readers "Drug May Help With Weight Loss." Union Leader, (Manchester, NH), 5/22, 63,134 readers "Anti-Depressant, Anti-Smoking Drug Could Help People Lose Weight"

GTP123-3103

Sunday Local News, (West Chester, PA), 5/23,34,250 readers "Drug for Depression, Smoking May Help Weight Loss, Too."

Mississippi Press, (Pascagoula, MS), 5/30, audience numbers unavailable "Anti-Depressant, Anti-Smoking Pill May Help Weight Loss."

GTP123-3104

INVOICE PO # 0031908'
Giaxo We1ico'riie, inc.
5 Moore Drive, P.O. Box 13398
. Research Triangle Park, NC 27709 March 31';' T999

Attn:

Holly Russell

Ihvoice No

....i"w

3-120

Services for Wellbutrin for the Month Of March 1999 HONORARIA

Out-of-Pocket Expenses
Honoraria-Or. Drew Pinsky/ I st Installment 100,000.00

Total Out-of-Pocket Expenses

. I OQ,OOO.OO

TotallnvoiceJor the Month of March 1999

$100,900.00

CooneyjWaters Group 141 Fifth Avenue, 9th Floor New York, NY 10010 p.2i2-886-2200 f.212.886.2288 Www.cooneyw~ters:com

Doc: J-120.XLS (5/15/2006) yr

'

INVOICE PO # 0031908
Client:
Glaxo Wellcome, Inc. 5 Moor'e Drive, P.O. Box 13398 Research Triangle Park, NC 27709 April 30, I 999

Attn:

H oily Russell

. Invoice No.

4- I 13

Services for Wellbutrin for the Month of. April 1'999 HONORARIA

Out-of-Pocket Expenses
Dr. Drew Pinsky/ 2nd InstaHment Total Out-of-Pocket Expenses

175,000.00 .
I 75;000.00

Total Invoice for the Month of April1999

$175,000.00

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Cooney/Waters Group 141 Fifth Avenue, 9th Floor New York, NY 10010 p.212-886-2200 f.212.886.2288 www.'cooneywaters.com

MEMORANDUM
June 2, 1999 To: From: Re: Cc: Holly Russell Lisa Draho, Jocelyn $erio

Intimacy & Depression on David Esse!- Alive!


Leslie Miller, Lisa Weiss

Dr. Pinsky recently joined David Essel on his national radio program to talk about intimacy and depression. During the fifteen-minute segment, Dr. Pinsky communicated key campaign messages. Highlights included: Switcl:;ting to or adding .Wellbutrin is recommended for people experiencing a loss of libido Antidepressants such as SSRis can decrease libido, and negatively impact intimate relationships at a time when intimacy and connection with a partner is most important Sexuality is important to maintaining intimacy Depression is an illness that pulls people away from i;ntimacy with their partner Intimacy is essential for healthy relationships, and it's important to talk to your partner and healthcare provider about problems iri your relationship or with antidepressant medication _ . Depression is a very serious illness that affects millions of people: medication can save lives The Seattle Town Hall can be seen on the web site www .IntimacyAndDepression.com Calll-800- 577-8550 for information about campaign
.~

Overall, Dr. Pinsky kept the pro~am focuson the seriousness of depression, its impact .. on intimacy, and the importance'of seeing a healthcare professional for treatment for this illness an interesting and informative manner. We have included a copy of the tape. Please let us know if you would like a transcript to share with you colleagues.

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Transcribed by A STENO SERVICE 60 East 42nd Street, NYC

682-4990

TRANSCRIPTION OF AUDIOTAPE FOR: SUBJECT: DATE: INTERVIEW WITH: TAPE #: SIDE: LENGTH: FILE NAME: DISC NAME: NOTES: DAVID ESSEL - ALIVE May 22, 1999 Dr. Pinsky 1 C-60
A

COONEY/WATERS GROUP

13 Min. C00602 Cooney #2

W:

I'm a 34 year old married woman and have just It's

recently become like super multiple orgasmic.

just, it doesn't seem possible to me to have that many, we're tal king, '']: counted 6 0 one night .

DAVID ESSEL:

60.

Hello Tom.

M:

You all was talking about that la?-y that had the

60 orgasms.

DAVID ESSEL:

Yeah,

non~stop.

M:

I had several women like that.

I had to quit

after about two hours.

DAVID ESSEL:

1 800-743-800.

Whenever I hear that 800 743We have an

line I just ... obviously it cracks me up. 8000. David Essel and the box with you.

expert right now that is going to bring on in just a second and I'm going to ask him some questions about that call because it still amazes me. about Dr. Drew Pinsky. You know him. I'm talking 16 years now

hosting Love Line on the radio, that's with Westwood One. He's also obviously on MTV with Love Lines and

he's chief of service. department medicine and program director of chemical dependency services, Lawson (SENUS ?] hospital in Pasadena. welcome. Dr. Drew,

DR. PINSKY:

David, thank you for having me.

ap.preciate it.

DAVID ESSEL: here.

This is a great opportunity for us

Before we get into one of the events that

you're working with now on intimacy and depression, I wanted to ask you about this question, the liner that you just heard was a woman who called in and said that obviously she was 34 and she started

counting

orga~ms

after she was making lover to her

husband and she laid there in bed and she counted 60 just nonstop. Is that physically possible?

DR. PINSKY:

Oh yeah.

For some women.

What I think

she was amazed about is that it suddenly started and that kind of thi'ng most typically happens from medication, frankly. And she, you know, for women

there's no refractory, for some women anyway, there's no refractory phase and yeah, that's no problem for some women. They just do it until they

exhaust, physically get exhausted, there's no sort of satiation. There's a downside to that too. They

don't get the large release that some people get sometimes with a single orgasm, but interesting, that's one of the things I'm here to talk about, about how medicines effect sexual function. IThere.,'s

no doubt that often times when people have a change ,, in their arousal phase, in their sexual functioning, in their libido, in their orgasmic function, the number one cause for that is medication.

DAVID ESSEL:

What type of a medication would

increase someone's orgasmic potential where they go from three or four to 60?

DR. PINSKY:

Interestingly lots of the

antidepressants, but the one that I have most ... I've seen that from in my clinical practice is or [BUPROPRION ?] . [BUTRIN ?]

It actually is the one we

advocate,. one of the things we suggest people do if they're getting decrease in their libido or decrease in the arousal from an antidepressant which

typically occurs in the seratonin re-uptake inhibitor medication. We think about switching to

or adding [WELBUTRIN ?] or [SERASON ? ] or [RAMRON ? J or other medications that may enhance or at not suppress sexual arousal as much as the seratonin re uptake inhibitors do. So it's a .germane point to

this thing and people, you know, we live in this really screwed up society right now where people are sort of think about sexuality as sort of a recreation and it's been pulled away from the intimacy which is really what it's all about and my show, all I hear about every day is the consequences of empty relationships and the facts, intimacy we hav'e with everybody. the lack of

DAVID ESSEL:

I saw on one of your shows, this had

to be about a month ago where you looked very perplexed and you made a comment about that. said there is no intimacy. You

Whoever you were talking

to, the

ler that had called in you said there's

no connection there.

DR. PINSKY:

There's no connection.

DAVID ESSEL:

You were talking about that they were

trying all this variety and you said that that was a cover up for intimacy.

DR. PINSKY:

Of course.

People are looking for

drugs and fast cars and more money and more partners and weirder sexual acts as a way of filling this amazing emptiness we all have when in fact we know that real health, I know your show is a lot about health, but health and happiness and well be.ing is. all very much tied into the human connectedness, that our intimacy is what sustain us, what allow us to grow, would ultimately happiness. us a sense of

And this other stuff, we could say it's

all our whole lifetime and still have that big empty whole inside of us and not deal with it. In fact,

again, another part of what I'm hear to talk about is how depression{ very often 1 pulls people apart in their intimacy and people who are depressed withdraw from relationships right at the time when they need their the most
1

the partners don t


1

understand this, they get angry, they

guilty,

they feel responsible for the person's feelings. Then we as physicians put people on antidepressants that more often than not, further suppress their libido and.sort of decrease the potential for physical contact and this thing kind of spirals downward. On top of that we live in a time in the

world when managed care is sort of ruling the land. You can't get the kinds of modalities of treatment that are really necessary for complete resolution of things like depression. therapy. Individual therapy, couple

These things are crucial for the ultimate

resolution of these problems.

DAVID ESSEL:

What is your main goal?

You're

involved with this intimacy and depression ...

DR. PINSKY:

My main goal! my personal goal in all

these things, all my endeavors is. to try ways to use the media to create health, to change the culture in a better direction. My clinical practice, all I see

is the negative impact, the last 30 years we've been on a big spiral downward and talk to any physician or anybody that works in mental health, they will tell you, we know what is healthy for people and our culture does in no way confirm this. In terms of

the intimacy and depression campaign, my goal is A, to make p~ople understand that depre~sion is a serious condition. As many as 19 percent of people That is ... that's

with major depression will die.


~ntidepressant

is the cornerstone of treatment but

the individual therapy and couple therapy are crucial. And that communication is an essential

piece of people getting over affective disturbances. Communication with the partners so that they understand what the person is going through and stay connected at. the time they need .them the most and communication with your caretaker, your physician, so you can go back and say hey, this medication is screwing me up. I'm not interested in my husband

any more, what's the deal?

DAVID ESSEL:
sho~,

And a lot of people, I know from our

we get calls, they should'be taking some of

the information to their doctors, they're calling us and saying I've totally lost. my interest ...

DR. PINSKY:

Yup, that's the deal. It's bizarre to me.

They don't go to They don't ...

their doctors.

it' s bizarre to me they go' to the radio to you and me and they don't go where they need to go. all, everything's all messed up right now. It's

DAVID ESSEL:

But part of that reason, I know why

Dr. Drew, and you do to, is because there are .a lot of doctors that do not have people skills, that individuals feel intimidated being in the off they sure as heck feel intimated saying something about their sexuality. and

DR. PINSKY:

That I'm sure contributes but I

to

tell you, since I was in training.there's been a tremendous amount of effort put into helping physicians be skilled in approaching people and being careful to listen and talk about these issues. And I certainly see no weakness in my peers. weakness in the system. people. I see

The system poorly serves They don't

People don't have healthcare.

they're ;:;.fraid it's going to cost them a lot of money. They don't want to wait all day. They're

afraid the doctor won't have time for them or won't listen, that they'll be somehow ungratified by the interaction. It's more a systems issue than it is And it's the same outcome.

the practitioner issue.

People don't go and they don't ...

DAVID ESSEL:

We're speaking with Dr. Drew of course

from MTV and Love Line on the radio, both radio and

television.

Out.of curiosity, how did you get at such

involved in intimacy, relationships, love a big, huge national level?

DR. PINSKY:

Total accident.

DAVID ESSEL:

Was it really?

DR. PINSKY:

Yeah.

If you told me I was going to be

broadcasting I would have been, I would have laughed in your face. I was John Q. Medical Student and involved in my training and

Resident and real

actually for many, many years just practiced 14, 16 hours a day and did sort of radio as a community I did it as a years. for almost ten

I was not paid for it or anything and it

just happened to be In this one vehicle and the vehicle to me was a vehicle whereby I could reach a population that usually didn't listen to the kinds
/'

of things that I needed to tell them about. .like pregnancy and birth control and sexually transmitted diseases. But when I started

Things

broadcasting I was the first to talk about something called GRID, Gay Related Intestinal Disease Syndrome, you now know that to AIDS. And nobody

was talking about it publicly and god forbid anybody


9. cwct

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talked about safe sex with kids because oh jeeze, we can't do that, they might
e~en.have

more sex.

DAVID ESSEL:

You know there's still a lot of people

that believe that today.

DR. PINSKY:

Well I'm encountering that in terms of

talking to people about the morning after pill. There's great resistance to talking about emergency contraception. I see that as a critical sue in

our society and to me a way to completely eradicate abortion. The morning after pill could eliminate But people are ambivalent. No, isn't. Oh, is We know

abortion easily.

it an abortion pill itself?

it suppresses ovulation, that's all it does.


Any~ay,

but I'm here to talk about depression and

communication and the fact that you've got talk to your partner, you've to identify depression. can't be stigmatized by it. You

You got to talk to your

doctor and sometimes you got to take medication because that really, it is a dangerous condition and although the medication too is kind of stigmatized these days, usually fairly short term, and it potentially saves peoples' lives.

10.

Cv)Gt

DAVID ESSEL:

You, I saw in some of the press

materials that y9u <?-re doing some what do you callr like live presentations in Seattle, that you're meeting with this intimacy and depression group, there 1 s a whole panel of you, are you going to do it other than Seattle, is that just the one main city?

DR. PINSKY:

We did it in New York

a~dsan

Francisco

and then the last one was in Seattle.

The Seattle It's

one actually yo~ can see it ori the Web site.

www.intimacyanddepression.com, no spaces, or you can call 1 800-577-8550 for more information on both the town hall meetings and the campaign in general. But

its really cool, look on the. Web, you actually see the event. It was a very neat event. We go into

big halls, three or four thousand people and you sit down with some real.ly exceptional people who themselves are high power professionals in the field of the treatment of depression and one in particular who is actually a therapist who's been seriously depressed and her sort of journey with it and it's very, very touching.

DAVID ESSEL:

What did you learn Dr. Drew?

What did

you learn from being involved in this panel that you

didn't know prior to walking in or was there anything?

DR. PINSKY:

In New York we have the opportunity to

work with a guy named Tom [WISE ?) who is the vice


ch~ir

of the department of psychiatry at Georgetown about some of the numbers

and he taught me a

associated with these and I didn't understand how many, how it was that true bona fide major and how potentially

depression occurs in our

dangerous it is and how much the medication have revolutionized and'in many cases saved l a little maybe ambivalent, I I was

how to \lSe the

medicines but in my practice I ran a department of medic in psychi hospital and I was

having to deal with the medical consequences of medication more often than not so I was a little skeptical but as I 1 ve learned about the disease I've really come to understand.myself the extent of problem.

DAVID ESSEL: of travel

And I know from the experience I have some and speaking that there will be

that are battling serious depression it and work and function ...

can

DR. PINSKY:

Well the same applies to addiction or

any other major ... we, for what ... I mean all ... why we can talk about diseases of the heart but we can't talk about diseases of the brain is bizarre to me. I mean it's it
1

we came out of the dark We

ages andwe know so much about brain function.

even know why that nine.year old can play the piano they way he does.

DAVID ESSEL:

I'm going to ask you to hold that

thought and you're going to come back and give us the answer there. 1-800-743-8000. We're talking to

Dr. Drew, of course, from Love Line and we'll have him back and speak in just a moment or two, 1-800743-8000. Essel. Awesome to have you on board. right there. I'm David

[END OF TAPE]

13.

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Thank: you.
A STENO SERVICE 60 East 42nd Street, NYC

682-4990

Public Relations Activities Supporting WELLBUTRIN SR 1998-2001

Prepared for:
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Need to differentiate within a crowded marketplace Multiple antidepressants - led by Prozac
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SSRI sexual side effects minimized by MDs Wellbutrin SR -- low incidence of related sexual dysfunction

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ACTIONS
Make sexual side effects an issue "Intimacy and Depression" launches multiple high profile mass events with influential organizations Ramp up issue on the agenda of influentials - MDs, family therapists, social workers, patient organizations Additional activities and data publicity extend brand message through several years
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Published Restoring Intimacy with National DMDA - Launched in Fall 1999 at National DMDA annual meeting - Book signing event and satellite TV tour - 10 local market media tours with Drew Pinsky - Contributions from 5 thought leaders, endorsed by Mike Wallace, Kay Redfield Jamison
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Coordinated initiative on communication gaps about depression and treatment side effects in primary care setting, under auspices of National DMDA

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- National survey of PCPs, patients, spouses and social workers in 2000 - Meeting with 11 primary care and mental health organizations to present/discuss results, develop action steps - Issued national "Call to Action" with major media outreach in January 2001, including satellite TV tour with Lydia Lewis, Drew Pinsky
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Publicized 6 studies between 1999-2001 - Sexual Side Effects of Wellbutrin SR vs. Zoloft, Segraves/Groft
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- Obesity in nondepressed patients, Gadde


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- HSDD in nondepressed patients, Segraves


APA, 2000 Journa I of Sex & Marital Therapy, April 2001
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- Prevalence of Sexual Side Effects with Antidepressants, Clayton


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Sexual dysfunction as side effect receiving significant attention by media and key organizations as compliance problem
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Intimacy & Depression Campaign Intimacy & Depression Brochure Women & Depression Brochure "He Loves Me Not" PSA Restoring Intimacy Primary Care Initiative Study Data General Coverage

38, 633,563 7,297,644 9,775,884 145,456,312 22,958,324 28,833,629 110,504,648 24,107,854 387,567,878

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CotJple of r::omments:
Glaxo \\'ellcome Inc - no comma. L 2~ Duke Hedical Center - vs c-r;;}ntre - bottl a:ce used .in thf~ paper- r also Bt.:.hav:iou:r.:, favour.ab1y - the -editor at J.AHA will catch these if yon don~ t
3. J\bstr act - Contt~:x:t Context Ciitecholarnines hnve been implicated in modulatinq hunqer a.nd feedinq behaviors and f.a.c.i.litating energy expenditure. Buprcpicm, a drug which enhances nore.pinephr:ine a.nd dopamir1e in the central nsr~lolls syste.mr may FACILI'l'J\TE \<leigbt loss in obese pa:ti.ents,.

4. lnt.r:odoct ion - suggest t.rceakin9 :i.nto t~t:o paragraphs~ I. c.un faxing over the fol.l.ov-Iin.<; artie let Hl.Hlptlnan et al,. Orli.st:a:t: in t.he J.ong-t:erm t.t'eatrnent of ob!ssity .i.n primary c:ar:e sett:i.ngs. Arch Fam f:.fed 2000; 9~ 160-.1.67 . .Briefly, or.listat, is v.;rell tolerated over 2 years f?:xcept for the GI e:ffectsv This m;.;1y provide some fa ..ir balance to the sentence stat.ing tha:t. sibutr:arni.ne .is cont.raind.icn:ted vrith comorb;i.d conditions ..

IHTRODUC'l'TON
Approximately 97 million aduli:s in the. United St~ites are ewtimcrtt3d to be oveJ."\4e.ight or obeset \-<Jith. an ala.rm.ing increase of t:hi.s epidBmic in t:h.e rc-:.~c:ent yea1:-s (.E'ir::qel Ed..: .a.l, 1.998, Hokdad et. al.,.. 1999). Both condit.ic)ns .;:arry an increase i.n the prevalence of many corncrb:i.d illnesses (Hust et al, 19 9 9) inc.lud.i.ng type 2 diabetes, corona.c-y heart cl.i.sease, hypertensi.on, ga.llbladder: disease, and osteoa:rthrit.i.s r wi:th .an increased .r::Lsk of mortality from all ca.uses (Calle et. al, 1999; Allison et al, 1999). Signi.fica.nt .r:educti.on of obesity-related illnesses and risk factors can occur <'lith a modest (< 10%) vmi.ght .r:eduction (Goldstein, 1992). Although di.et, exercise, behavi.oL1.r t_hera:py and pharmacotherapy can be effect.:i.v<:,, many obese patients faLL to achi.eve significant benefit. from any given treatment modalit.y and long-term outcome w.ith most~ non-su.r:gica.t treatments is often unsa:ti.sfa.c-tory (NI:H tcech assess, 199.3). As is the case with ot.her treatments, di.sc<.:>ntinuation of pharmacotherapy often leads to loss of the aeh.ieved l;'eight loss benefi.ti hence, long-term treatment is necessary in most cases to U'i.<J.intain hea1th benefits ( t.:Jat.ional '"flask Forc-e, 19 96).. Follow.:i.ng wi t_hd.r:awa.l from the market of fenf lu.ramine and dm:.fen luramine in 1.99 7, there has been a growing need for al ter:n.a.t.:i.ve weight 1Ut'1n.a.gemen:t med~ications ~ Of the two C\Jr:cently availa.ble pharrnacologica.'l. inter\rentions :for long-term

DOJ005696

use, orlistat and sibutramine, the latter is contraindicated for use in patients with co-morbid illnesses such as hypertension and cardiovascular disease, which are coamonly associated with obesity. In search of additional strategies for weight management in the clinically obese, we conducted this preliminary investigation examining the efficacy and tolerability of sustained release bupropion (bupropion SR) in obesity. Bupropion SR is commercially available for treatment of depression (Wellbutrin SRE) and as a smoking cessation aid (ZybanE). The clinical benefits associated with bupropion SR treatment of these two conditions are believed to be related to the drug s effects on catecholaminergic system" (Richelson, 1994). The idea for the current investigation originated from a series of clinical observations (by Dr. Gadde) obese patients attending a university diet and fitness center. When these patients were treated for mild depression with bupropion SR, it was observed that they had a greater dGgree of succes$ in losing weight. To our knowledge, the current investigation is the first randomized, placebo-controlled comparison of bupropion SR in obesity.

5.
Diet

Methods

- Suggest changing "habit" to "pattern

Throughout the study, all subjects were instructed to follow a 1,600 kcal/day diet. They were also instructed to record their food intake in a diary, which was provided to them. At the beginning of the study, dietary instructions including the procedures for diary entries were given by a certified dietitian. The diet emphasized a balance of all food groups and daily intake of 8 glasses of water. The diet diaries were reviewed at each visit with the subjects and appropriate guidance was provided. The intent of the relatively loose structure of the diet program was to create a realistic eating PATTERN, which is likely to be sustainable upon discontinuation of the study treatment. Methods - JAMA may want you to describe your scale in a Figure or Table, rather than Appendix. A scale was developed (by Dr. Gadde, copyright, 1999) to assess diet compliance. The best compliance was given a score of 5 and the worst compliance was rated 0 on a scale of 0-5. The description of the diet compliance rating scale provided in Appendix 1. Methods - BDI scores are not discussed in results. I know this is for Paper #2, but do you think the reviewers will ask for it? Similarly, vital signs are provided for 8 week portion of the study, but not the continuation. Similarly, SF-36 and lipids are listed in Methods but no results are given. Initial 8-week Study All 50 subjects were included, with the last observation carried forward, in analyses of the primary outcome measures: 1) percentage weight loss compared with initial weight; 2) actual weight loss in kilograms; 3) percentage of subjects who achieved weight loss of 5% or more; 4) frequency of adverse events. Secondary outcome measures included diet compliance, heart rate, blood pressure, lipids, Ham-D, BDI, CGI and SF-36 quality of life scale. Results - First sentence is a little confusing, suggest clarifying who the 18 subjects were and then going into the description. Continuation phase

DOJ005697

A total of 18 subjects (16 BUPROPION SR; 2 PLACEBO) who had met the responder criteria qualified and entered the double-blind 16-week continuation phase (figure 1). Of the 14 subjects who qualified from the bupropion SR group at the end of the initial 8-week study, 13 entered the continuation phase while one subject was satisfied with the weight loss and chose not to enter the continuation phase. All three responders to bupropion SR in the crossover study entered the continuation phase, thus bringing the total nunber of subjects receiving bupropion SR in the continuation phase to 16. Two subjects qualified from the placebo group at the end of the initial 8-week study and none qualified from the crossover study, thus leaving a total of 2 subjects receiving placebo in the continuation phase. Fourteen of the 16 subjects receiving bupropion SR and both subjects receiving placebo completed a total of 24 weeks treatment. of the two subjects wno prematurely discontinued treatment in the bupropion SR group, one subject withdrew at week 12 citing dissatisfaction with achieved weight logs (3-6%), and another subject withdrew at week 16, after achieving an 11.1% weight loss, citing a family C:t:"i::ds. Results - I agree that improvement in vital signs appears to be correlated with weight loss. I think this should be mentioned in the discussion. But, you may want to "save" this for the follow-up paper. Vital signs At week 24, significant decreases were noted in heart rate (74.68.0 to 70.13.8; p=0.0003) and blood pressure- both systolic (129.018.7 to 115.48.2; p=O.OOOl) and diastolic (83.27.7 to 78.67.8; p=0.003) - in the bupropion SR treoted ~ubjecta. (In the diDcuasian, mention that this correlates with weight loss?) Results - Suggest you move the first sentence to Methods. not add references to the Results. One usually does

Weight loss may result in decrease in bone density in women (Dr. Drezner to provide reference), thus increasing osteoporosis risk. Hence, we examLned bone density at baseline and week 24. The density of lumbar vertebrae was examined using a total body DEKA. There was no significant change in bone density during 24-week treatment with bupropion SR (Paired t-test). Discussion Suggest changing last sentence: The efficacy of bupropion SR in the early phase of treatment was impressive with B-week completers achieving a mean weight loss of 6.2% (SO 3.4%). Because only the subjects who had achieved at least 4 kg or =5\ weight loss in the first 1;1 weeks were eligible to enter the continuation phase, the 12.9% (SD 5.6%) weight loss achieved by the bupropion SR patients completing 24 weeks may be an overe&timate of thQ true effp~~- A comparison between the BUPROPION SR and the placebo in the continuation phase would not be appropriate because only two subjects received placebo in this phase. Both subjects on placebo achieved a WEIGHT LOSS OF APPROXIMATELY 10% at week 24. Suggest changing "active drug" to "bupropion SR" The robust effect of bupropion SR treatment in the first 8 weeks might have been influenced by a greater number of early terminations and poorer compliance with diet in the placebo group. A shortcoming of this study is that the diet prescribed was not individualized. However, the difference between the BUPROPION SR and placebo groups in their diet compliance was

DOJ005698

notable. A possible explanation is that bupropion SR might have exerted beneficial effects in the form of decreasing appetite and food ccaving 1 and perhaps enhancing motivation. This study was designed to capture the weight loss efficacy of bupropion SR in a setting similar to a primary care office. As such, the ancillary interventions such as diet and behaviour therapy were minimal. Failure of 19 of the 50 enrolled subjects to complete the first 8 weeks and the minimal response in the placebo group may be a reflection.of the chosen design. An explanation for the higher discontinuation rate in the placebo group, for all reasons and particularly due to dissatisfaction with treatment is that the BUPROPION SR may have provided a more satisfactory benefit for the subjects. Suggest changing "superiority" to "effectiveness" Results oE the crossover study, although of a very small sample, showed a trend for bupropion SR's EFFECTIVENESS over placebo. When the subjects who failed to respond to placebo were switched to bupropion SR, some of them responded to the drug. Suggest the following changes: clarifying patients at risk, deleting about Web based pharmacies. It may be a real issue, but will the users of Web based pharmacies be reading JAMA? Also, you state earlier that the study was designed to mimic a primary care practice, with respect to diet management. In this paragraph, you imply that the use of bupropion may not be appropriate in primary care practices.
ORIGINAL:

Bupropion SR was generally well-tolerated in this study with dry mouth being the only adverse effect, statistically different from the placebo treatment, in the initial B-week comparison. Two subjects developed a skin rash during the course of treatment. Adverse effects were mild in the 16-week continuation phase. The safety and tolerability data from this study must be interpreted with caution because of the small sample size of this cohort. Clinicians should be aware of the seizure risk associated with bupropion SR The incidence of seizures with in depression and smoking cessation trialM. bupropion SR is approximately 1 in 1,000 which is comparable to the seizure risk associated with other antidepressants {Dunner et al 1 1999). At the maximum dose of 400 rng/day used in the present study, the seizure risk with bupropion SR is estimated at 4 in 1,000 (ref: Product information brochure). People with histories of bulimia, anorexia, and seizures may be at the greatest risk for developing seizures with bupropion SR treatment; hence, its use is contraindicated in those with a history of any of the three conditions. In this study, considerable time and effort were put in to identifying and excluding such high-risk subjects. Because such an extensive assessment may not occur in general clinical settings, the seizure potential discussed above remains the primary concern with use of this drug in weight management. A~ more and more p~tient~ are obtaining prescription medications via the Web-based pharmacies, it is of concern that a person with anorexia or bulinia, for whom use of bupropion SR is not considered safe, might obtain it by providing incorrect information to the Web-pharmacy. Given the high prevalence of binge-eating pattern in obese patients, it is imperative to rule out associated purging behaviour and/or laxative abuse if this medication is considered as a weight management tool. REVISED: Bupropion SR was generally well-tolerated in this study with dry mouth being the only adverse effect, statistically different from the placebo treatment, in the initial 8-week comparison. Two subjects developed a skin rash during

DOJ005699

the course of treatment. Adverse effects were mild in the 16-week continuation phase. The safety and tolerability data from this study must be interpreted with caution because of the small sample size of this cohort. Clinicians should be aware of the seizure risk associated with bupropion SR in depression and smoking cessation trials. The incidence of seizures with bupropion SR is approximately 1 in 1,000 which is comparable to the seizure risk associated with other antidepressants (Dunner et al,_ 19~8). At the maximum dose of 400 mg/day used in the present study, the seizure risk with bupropion SR is estimated at 4 in 1,000 (ref: Product information brochure). BUPROPION SR IS CONTRAINDICATED IN PATIENTS WITH histories of bulimia, anorexia, OR seizures BECAUSE THEY may be at the greatest risk for developing seizures with bupropion SR. Given the high prevalence of binge-eating pattern in obese patients, it is imperative to rule out associated purging behaviour and/or laxative abuse if BUPROPION SR is considered as a weight management tool. Also, is there no data re: body composition with sibutramine or orlistat the other commercially available oral agents? I can appreciate that you want to site previous articles published in JAMA, but given leptin is SC and not commercially available, is it a relevant comparison. Suggest deleting the sentence. The loss in fat tissue accounted for 74% of the weight loss achieved with bupropion SR treatment at week 24. This finding compared favourably with body composition changes associated with loss of weight on a balanced diet (Jim Hill to provide reference?). It is notable that more than 95% of body mass decrease resulted from loss in fat mass during recombinant leptin treatment in a recently reported trial (Heymsfield et al, 1999). There was no change in bone density associated with weight loss achieved at week 24 with bupropion SR treatment. This finding may be of importance in light of the knowledge that wonen lose bone density with weight loss, thus increasing their osteoporosis risk (need reference from Or. Drezner). For years we have been stating that weight gain is not an issue with Wellbutrin or Zyban. The last two sentences imply that before you came along, it never occurred to anyone to consider weight loss studies with bupropion. Original: In S-week pre-marketing trials of bupropion SR in depression, a weight loss of greater than 5 pounds occurred in 14% and 19t of patients treated with 300 mg/day and 400 mg/day, respectively, compared with 6% of patients treated with placebo (Product Information). In a review of pooled data from three controlled triaLs of B weeks duration with bupropion SR, the mean changes in weight for subjects treated for depression were 0.9 kg and 1.3 kg with 300 mg/day and 400 mg/day, respectively (Settle et all999). In short-term trials examining the efficacy of bupropion SR or smoking cessation, the patients in the bupropion SR group gained slightly less weight than the placebo group (Jorenby et al, 1999). The subjects who were treated with a nicotine patch also gained less weight than the placebo group in this trial. Over all, the differences between bupropion SR and placebo on the patients' body weight in depression and smoking cessation trials were relatively small and did not provide stronq signals that the drug might have significant weight reducing effect in obese patients. Rather, i t was a series of clinical ob;ervations that led to the hypothesis that this drug may have a clinically significant beneficial effect on weight in primarily obese patients seeking treatment for this reason.

DOJ005700

REVISED:

In B-week pre-marketing trials of bupropion SR in depression, a weight loss of greater than 5 pounds occurred in 14% and 19% of patients treated with 300 mg/day and 400 mg/day, respectively, compared with 6% of patients treated with placebo (Product Information). In a review of pooled data from three controlled trials of 8 weeks duration with bupropion SR, the mean changes in weight for subjects treated for depression were 0.9 kg and 1.3 kg with 300 mg/day and 400 mg/day, respectively (Settle et all999). In short-term trials exanining the efficacy of bupropion SR for smoking cessation, the patients in the bupropion SR group gained slightly less weight than the placebo group (Jorenby et al, 1999). The subjects who were treated with a nicotine patch also gained less weight tnan the placebo group in this trial. ALTHOUGH the differences between bupropion SR and placebo on the patients' body weight in depression and smoking cessation trials were relatively small, THESE FINDINGS DO SUPPORT THAT BUPROPION SR MAY HAVE A
BENEFICIAL EFFECT ON WEIGHT IN
PRIMARIL~

OBESE

P~TIENTS.

CONCLUSION:

Same comnent as above re: primary care clinics.

Original: In summary, the findings of this study provide the preliminary evidence that bupropion SR may help some obese patients. Further studies with larger sample sizes with inclusion of both genders are needed to confirm these preliminary observations. Also warranted are studies to examine the possible mechanisms by which bupropion SR might affect weight, e.g., effects on energy expenditure, thermogenesis, and direct and/or indirect effects on adipose tissue. The amall sample size of the study does not permit us to make any definite conclusions regarding the safety of bupropion SR in obese subjects. Moreover, the special and time-consuming attention, paid in this study to screen for risky subjects, may not be feasible in the busy offices of primary care due to practical difficulties such as time constraints. As such, these data should not be extrapolated to general clinical settings until further safety and efficacy data are gathered in large-sample studies. Revised: In summary, the findings of this study provide the preliminary evidence that bupropion SR may FACILITATE WEIGHT LOSS IN some obese patients. Further studies with larger sample sizes with inclusion of both genders are needed to confirm these preliminary observations. The small sample size of the study does not permit us to make any definite conclusions regarding the safety of bupropion SR in obese PATIENTS. IT IS IMPERATIVE TO SCREEN PATIENTS WITH PURGING OR LAXATIVE-ABUSE BEHAVIORS. Also warranted are studies to examine the possible mechanisms by which bupropion SR might affect weight, e.g., effects on energy expenditure, thermogenesis, and direct and/or indirect effects on adipose tissue.

Table 2 - what is intercurrent"

Let me know if you have any questions about my suggestions. Tim

> -----Original Message-----

> From:

Melissa Kennedy [SMTP:melissakennedy@prodigy.net]

DOJ005701

charts with one and two year data. This data needs to be summarized for the 2000 NAASO meeting. Also, the follow-up manuscript needs to be prepared and target journal needs to be discussed. Regarding target journal, I was surprised to learn of the change to Lancet. I support the decision (given their rapid turnaround time and given submission of t,his.manuscript has been delayed), although l think JAMA would have been very interested, given that they highlighted the APA data in their June issue. Regardless, GW should have input into decisions like this. Given your grant is approx 140K, of which approx 130K has been paid, emphasizes that we partner in publishing decisions that consider both patient and brand issues. It is unlikely that additional support for other investigator-initiated projects will be embraced enthusiastically if there is no input from GW or i input from GW is not considered. Thanks and I look forward to talking with you next week,
Tim

> -----Original Message-----

> From:

Leadbetter, Robert A

>Sent:
> To:

Friday, March 17, 2000 2:20PM


'gaddeOOl@mc.duke.edu'

> cc: Metz, 1\.lan; Kuhn, Timothy A > Subject: Manuscript > > Kishore,

>
> I have tried to reach you today but without luck. We have had a chance to > review your manuscript and are pleased with the latest version. However > please contact me or Tiln at your earliest convince and before you submit > it. There are still some concerns that we think could compromise the

> success of getting it published.

I look forward to talking to you.

> > Bob > Robert A. Leadbetter, M.D. > Principal Clinical Research Physician, Psychiatry > us Medical Affairs

> Glaxo Wellcome Inc


>ph: (919) 483-7152

> fax:
>

(919) 483-0053 email: ral73653@glaxowellcome.com 18 Mar 00

To: cc:

"Leadbetter, Robert A" <rai73653@GlaxoWellcome.com>, gadde001 "Metz, Alan" <am31422@GlaxoWellcome.com>

Subjec
t:

RE: Manuscript

Kishore, One other point.

DOJ005703

In the version of the manuscript that was faxed to Alan, the figure was changed. In your original, it listed "bupropion SR" and now the figure lists "bupropion"
Why was the "SR" removed?

l'ha!fks Tim

23 Mar 00
To: cc:
Subject
gadde001 "Metz, Alan'' <am31422@GiaxoWellcome.com>, "Kuhn, Timothy A" <tak8925@GiaxoWellcome.com>

FW: Kishore response

>

Kishore,

>
regret it has been so difficult to reach you, however it is important we an opportunity to be sure your manuscript is ready for publication > prior to submission. I will attempt to respond via email, however please > feel free to call me if our input is not clear.
> I

> have

>

>

* On page 4, 2nd paragraph you note "The idea for the current >investigation originated from a ser:-ies of clinical observations . that > obese patients., when Rxd with bupropion SR for mild depression, had a > greater degree of weight loss." However, on page 17-18 you note the

> hypothesis re: weight loss was observed in "primarily obese patients > seeking treatment for this reason." These two statements seem > inconsistent. > * GW did recognize the potential of bupropion SR to have weight > reducing effects from the depression and smoking clinical trials which > supported the idea of pursuing your study. > * On page 15 you have a sentence about blood pressure effects. I > think it is awkward, as it stands alone, and would suggest a brief > elaboration noting the observed decrease and that this may be addressed in >a future paper (?correct). > * Page 15-16 paragraph. Your revision here was excellent. However I > still think you should drop the reference to web-pharmacies as this is not > something observed in your study and may be viewed a~ ~peculative. It >risks compromising the manuscript's review. > * Also I would advise dropping the 7th sentence in the page 15-16 > p~r~gr~ph (In this study, considerable,,,,) as it is dealt with in the > Method:> section, <lud your safety points are otherwi::se well presented in > this paragraph. Yo~ are particularly correct to point out the high > prevalence of bingc-coting in obc~o patients and thus the imperative to > R/0 purging or laKative use.
>
> > > > > > > > We look forward to your response and an opportunity to review further versions of the man~script, as well as an expedient submission. I hope

the obesity protocols you are currently participating in are qoing well. llob Robert A, Leadbetter, M.D. Principal Clinical Research Physician, Psychiatry US Medical Affairs

DOJ005704

> > > >

Glaxo Wellcome Inc ph: { 919) 48 3-7152 fax: (919) 483-0053 email: ral73653@glaxowellcome.com

> >
> >

>
>

-----Original Message----From: gaddeOOl@mc.duke.edu [SMTP:gaddeOOl@mc.duke.edu) Sent: Wednesday, March 22, 2000 2:43PM

>
> > > > >

To:

Leadbetter, Robert A

Subject:

I have been extremely busy in the past week and hence not been able Can you send a detailed e-message?

> to return
~ your phone calls. 27 Mar DO

To: cc;

gadde001 "Metz, Alan" <am31422@GiaxoWellcome.com>, "Kuhn, Timothy A"


<tak8925@GiaxoWellcome.com>

Subjec t:
Kishore,

Manuscript

I am assuming you Leceived our comments on the manuscript and want to knew if you have had an opportunity to incorporate them. Wben do you plan to submit the manuscript?

Bob

Robert A. Leadbetter, M.D.


> Principal Clinical Research Physician, Psychiatry > US Medical Affairs Glaxo Wellcome Inc ph: ( 919) 483-7152 fax; (919} 483-0053

email:

ral73653@glax:owellcome.com

29 Mar 00

To:

gadde001

cc:
Subjec RE: your visit

t:
Kishore,
28 April, first thing 1n the morning.

1.
2. 3.

How many subjects have completed 1 year follow-up (all assessments) How many subjects have completed 2 year follow-up (all assessments) 2000 NAASO abstract deadline is 1 July; will we be submitting lyr vs

2yr vs both

DOJ005705

4. What is the status of the manuscript? Have you spoken with Bob? I need to see the final version before it is submitted. I leave at noon on Friday and will not be back in the office until 13 April so I would like to see the final version before close of business tomorrow 30 March. Thanks,
'l'im

> -----Original Message----> From:

gaddeOOl@mc.duke.edu [SMTP:gaddeOOl@mc.duke.edu]

> Sent: Tuesday, March 28, 2000 5:51 PM > To: Kuhn, Timothy A

> Subject:
>

your visit

>
>
> Can you pick of the one the following dates for your visit? >

> April 2l > April 2B > May 1 > May 3 > May 5
25 Apr 00
To gadde001

cc:
Subjec lack of contact

t:
Kishor-e, Would you please call me at your earliest convenience so we may arrange a time to get together. There are a number of issues I would like to discuss with you. How about lunch?
Bob Robert A. Leadbetter, M.D. > Principal Clinical Research Physician, Psychiatry > US Medical Affairs Glaxo wellcome Inc
ph: (919) 483-7152

fax: (919) 483-0053 email: ral73653@glaxowellcome.com

DOJ005706

One Liberty Place 1650 Market Street, Suite 3550 Philadelphia, PA 19103 (215) 2825226- Phone I (215) 851-8656- FAX

To:
Fax:
Phone: Re:

Chris Singer

From:

Bill

P~sek 1/.rff

Pages:
Date:

March 22, 2000

Customer Program

CC:

The attached brochure is for the Tall Ships, which will take place in Boston this summer. I wanted to Inform you that we have a number of physician programs planned around this event We're in the early stages of planning but have some programs already confirmed. We intend to maximize this opportunity with the Tall Ships. On July 12th we will have an IBS evening program from 6:30 p.m.-9:30 p.m. We will have some of the bigg.est Gastroenterologists from New England in attendance. Ori July 141h we have two Wellbutrin SR Pride programs. Dr. James HudZiak, a big supporter from Burlington, VT, is confirmed to speak. Lafman Morgan from Wellbutrin SR marketing will also be attending.

My MOM, Tom Nichols, also extended Bob Ingram an invitation while in Las Vegas. I hope his schedule allows him to make the trip. Chris, I hope your travel plans and work schedule allow you to attend. We are trying to create innovative and creative programs to maximize turnout. I will keep you informed as details become available.

..:trjr RECEIVED

:~

i> "'

~.~~R-' ;:u!;

9~ ... o

CHRISTOPHER?SINGER

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0071-001376
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Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0071-001377
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Confidential: Produced pursuant to 02/06/04 subpoena

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Blevin1i,
From: Sent:

B~rbara
Pasek, Bill Tuesday, July 11, 2000 12:28 PM Singer, Chris FW: Tall Ships

To;
Subject:

Chris,
I am forwarding to you information on the customers who will be attending the PRIDE program on Friday. Attached is specific prescribing habits along with personal information. I have had numerous communications with Don regarding your travel. Hopefully you have been kept in the loop.
--Original MessageFrom: Bean, Gary {US Sales) Sent: Tuesday, July 11,200012:18 AM

To: Subject:

Pasek, Bill; Nichols, Thomas A; US CNS Marketing Group Mailbox FW: Tall Ships

Hi Everyone.

Cathy Hanwell has an excellent track record of conducting well-planned, highly effective customer focus programs and this Friday is no exception! Cathy has once again gone above and beyond to ensure the success of these programs. Trust this information is helpful to prepare for an awesome event day!
From: sent:

Hanwell, tathleen
Thursdav, JUlY 06, 2000 2:52 PM 'Bean, Gary' Tall Ships

To: subject:

Dear Gary,

Please find the list of clinicians that will be attending both Tall Ship programs. I have compiled data that I felt Bill, Tom, and Lafman would appreciate. If you wouldn't mind reviewing it and making any changes, I would greatly appreciate it. It Is amazing when you run the numbers how influential some of these physicians are to our business!
I am n~the process o~ering the names of each guest attending for name badges ... wish me luck ....

Tall Ship~ 4pm

crulse.doc

12 PM Tall snip Attendees.doc

Sincerely, Cathy

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0071-001365
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GlaxoWellcome
William L Pasek
Central N<rvou> Svsl<m El MctllK>IIc 8usinm 011~011

Regional Sales l)ircctor. New E11gland Rcgi001

July 21, 2000

Gary Bean

t 70 Plain Street Hanover, MA 02339

Dear Gary: I want to thank you once again for the wonderful PRIDE Program on July 13th. You and your staff did a great job coordinating this meeting. Dr. Hudziak gave a solid presentation on the effectiveness of SR. The weather was perfect, along with the boat cruise and viewing of the Tall Ships.
However, I believe one of the most important factors in the success of this program was you. Your leadership and vision for your district is evident in everything you do, and it was especially clear that evening. Your attention to detail and our customers is what made the night special. It's no secret why we lead the nation on WellbutrinSR. It's because of the hard work by you and your team. Thanks again for a great weekend. Please accept the enclosed gift cheque as a small token of my appreciation. I look forward to our continued success. I'll see you in Montreal.

~/4/
William L. Pasek Regional Sales Director New E11gland Region Enclosure

Sincerely.

'' '

Glaxo

Wellcom~ One Liberty Place

Inc.
Telephone
800 452 !1658

Suite 3550
Phil1delphla P"nnsylvnra 1910l

Fu
215 851 8626

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0071-003425
GC0840~3425

FL

Nichols, Thomas A From: Morgan, Lafmin c Sent: Monday, July 24, 2000 6:26AM To: Nichols, Thomas A

Subject:

RE: WSR

Tom, It was my pleasure. I always learn a lot about how we can do more to support our team in the field. My thanks to you and Gary for the invitation and for putting on an excellent WSR program.
---Original Message---Nichols, Thomas A From: Sent: Saturday, July 15, 2000 7:26PM To: Morgan, Lafmln C Subject: FW; WSR Importance: High

Lafmln, FYI. Thanks for attending the Hudziak program and spending quality time with some of our heavy hitters. This is a powerful statement to customers when the director of the brand visits them in their geographic area. Thanks for the continued support. Regards, Tom Tom Nichols TAN19232@glaxowellcome.com
-----Original Message--- From: Nichols, Thomas A Friday, July 14, 2000 8:29AM Sent: StLouis, Julia H To: Nichols, Thomas A; Mastrianni, Serene (US Sales) Cc: Subject: WSR Importance: High

Julia For your review, please respond. First of all, congrats on the numbersl!!HFantastlcjob and the POA is working. The greatness of this product (and diversity) is starting to be recognized and only going to get better. 2nd.: ThankS for the 5 additional Pride programs. Re$t a$$ured, you and your team will get a $lgnificant ROl. (do I hear 10, ha-ha). 3rd.: I have communicated via octel to the management team regarding Dr. Gadde. I rec'd quick response last night from Serene Mastrianni that she has him booked for several events in August anq was wondering what to do. I do not know the specifics surrounding this individual however I shared your comments and to what level of the company he has created attention and Involvement Therefore, I have asked her to call you live-line asap because you are the one who should direct her on this issue. The last thing any of us want to do Is to have an "uncontrolled loose canon" representing GWI that damages WSR sales and customer relationships I credibility. 4th.: I would like to ask for your help in providing "goodies" that you have available to be given away by Ventiv at a RAB meeting. As an FYI we are building a great program with Jim Hudziak and Elizabeth Goodale. I'm sure you'll agree this is going to be infonmative and entertaining, If you have tote bags, WSR sunglasses, fancy pens etc that would be provided upon registration, this would be helpful. (you know, that brand recognition thing at arms length, ie via Ventiv). Please let me know so we can make the appropriate arrangements regarding mailing and receiving at the hoteL

Confidential: Produced pursuant to 02/06/04 subpoena

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Again, thanks for everything. It is a pleasure working with you and your team. I believe I will be seeing Lafmin tonight at the Hudziak I Boston Aquarium I TaU Ships program. Regards,

Tom

Tom Nichols TAN19232@glaxowellcome.com

Gonfidentia!: Produced pursuant to 02/06/04 subpoena

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Nichols, Thomas From: Sent: Cc: Subject:

A Nichols, Thomas A Thursday, July 13, 2000 9:50AM Nichols, Thomas A FW: FW: Bermuda WSR RAB

Importance: High Bill. FYI a response to Jim on behalf of D1 and relationship building with a valuable partner to our business. Regards, Tom Tom Nichols TAN19232@glaxowellcome.com
---Original Message--From: Nichols, Thomas A Sent: Tuesday, July 11, 2000 10:06 PM To: James J. Hudziak Cc: Nichols, Thomas A Subject: RE: FW: Bermuda WSR RAB Importance: High

Jim, it is my pleasure to help a friend and a partner with our Depression franchise. As I mentioned I can truly empathize and appreciate what the getaway win mean to the two of you. Thanks to Bill Pasek's support, I am confident you will be pleased with all the arrangements including your honorarium. I know you and Elizabeth will provide a very dynamic, interactive and productive advisory board. Elizabeth is on vacation and upon her return, perhaps the 3 of us can piece together what we believe to be the best approach and content for the Bem1uda meeting via a conference call. I hope to be seeing you Friday evening at the program. Best regards to you and your family, Tom. Tom Nichols TAN19232@glaxowellcome.com
-----Original Message--From: James J. Hudzlak [SMTP:jhudziak@zoo.uvm.edu] Sent: Tuesday. July 11, 2000 7:49AM To: Nichols, Thomas A Subject: Re: FW: Bermuda WSR RAB

Tom, thanks for everything! I am sure that you are a bit sick of me. I know my honorarium requirements alone probably gave you fits and then I turn out to be a high maintainance ahole as well. Anyway, I wanted to make sure that you knew how grateful J am to you for aJJ of your help in a~suring that T has a wonderful first (13 years) vacation away from our babies. On the business side, as I am sure you know, Elizabeth and I are pals, so you can expect a great time, jim On Man, 10 Jul2000, Nichols, Thomas A wrote: >Jim, FYI > > Tom Nichols > TAN1 9232@glaxowellcome.com
>

> > > ---Original Message---> > From: Nichols, Thomas A

Confidential: Produced pursuant to 02/06/04 subpoena

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SPEAKER CONFIRMATJON LETTER

James Hudziak, MD University of Vermont

Department of Psychiatry Given Room B229


Burlington, VT 05405

Dear Dr. Hudziak: Thank you for agreeing to speak at the next meeting of the Wellbutrin Advisory Board which will be held on August 11-13, 2000 at the Fairmont Hamilton Princess Hotel. Attached are the meeting agenda and a list of the Advisory Board members. The subject under discussion at the next Advisory Board meeting is Depression and your presentation on the Treatment of Depression will provide the Advisory Board members with important information relevant to their discussion. In consideration for your services as a speaker, Glaxo Wellcome will pay you $5,000, and will provide you with transportation to and from the meeting and accommodations at the meeting location. Enclosed is a copy of an Advisory Board Speaker Agreement for your signature. Thank you again for your willingness to speak at our Advisory Board meeting. Please do not hesitate to contact me if you have any questions. I can be reached at 603-595-1388. Sincerely, Tom A. Nichols, Rl'h Market Development Manager

Signedby:

(Spe(Iker -please Sl

~~
ere)

00 On this date of: :.,...____.:_r_1 ~'~..., ,_ _ _ _~--SSorTax.Id: :sz...r- !'2- -i"'Z--Db

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Nichols, Thomas A From: Nichols, Thomas A Sent: Thursday, August 03, 2000 10:36 AM To: Goodale, Elizabeth; Hudziak, Jim MD Cc: Forland, Judith; Reardon, Kim; Nichols, Thomas A Subject: Depression RAB Agenda Importance: Gang, High

I hope everyone is doing well. Enclosed is a "rough agenda" for the upcoming Depression RAB
in Bermuda, 8/11/8/13. Elizabeth, Jim and I can talk to expand some of these areas and "talking points" which need to be conveyed as part of the program. I will gladly accept any additional thoughts, comments or content changes that you feel necessary to benefit t~gram. Looking forward to seeing everyone in Bermuda. "Warm regards,"

Depression RAB

Tom

Agonda.doc

Tom Nichols TAN19232@glaxowellcome.com

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Depression Regional Advisory Board Agenda Fairmont Hamilton Princess Hotel Hamilton, Bermuda August 11-13, 2000
Fridav August II
2:00pm-9:00pm

Registration
R<oeptiun/Dinn<r

Pre-Function Area

7:00pm I 0:00pm
Sntnrday, August 1l
6:00aml:00pllt

TBD

Information Desk Breakfast


C'..encral Session
We-lcome, lntJoductiOus m~d Meeting Objective~

Pre-Function Area

7:00am-8:00ano
8:00am
&:Oflam-ll:I5am

TBD
TBD
Tom Nichols, RPh Glaxo Wellcome, Inc
Eliza beth Goodale, Phnrm D Glnxo W cllcomc, Inc,

8:15am-9:00am

Depression In Your Practice-Your"Wisn" List

Diagnosis, Mannge.meut., and Treatment Augmcnlaiion Thc:::lrtpy


Safety of SSRI' s and WSR

ADHD Sexual Dysfunction


Weight Gain

9:00am- I 0:15am
I 0: 15am-l 0:30am
IO:JOam-Jl :30am

Pathophyslrt!ogy and l'osltlve Diagnosis l)f Depression

.lames Hud1.lak, MD
Pre~Function

Break
Stoengths/\Voaknesses/Op(Sorlunltlesfl'hr..,ats Worksltop

Area

Jan>es H udzlak, M I> EUznbNh Goodale, Phorm D

11 :30am-12:15pm l2:15pm-l:l5pm

Strategies for Regional Suece'"

Eli1.abcth Goodale, Pharm D

Lunch
AJl~noon

TBD
Adivilit:s

I :15pm-7:OOpm

7:00pm! O:OOpm
Sunday, August J3
7:00am9 :DO am

Cocktail Reception and Sunset Dinner Cruise


Aboard USS Wdlblllrin SR

TBD

Breakfast and D<:pat1U!'es

THD

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0027 -064183
GC0348-4805 FL

Nichols, Thomas A Mastrianni, Serene (US Sales) From: Sent: Friday, July 21, 2000 3:08 PM
To: Nichols, Thomas A

Subject:

RE: Attendee Status

Tom, In case there are any last minute WSR openings. Here is the information on the prescriber who wishes to attend the meeting and is available for the dates.

Richard Tomb, MD 9 Cedar Street Worcester, MA 01609 Phone: 508 757~5526

Pager: 508 753~7140


Email: rctomb@aol.com No fax available, please email any information
Let me know if Dr. Tomb will make it into the WSR RAB Program. Thanks, Serene
From: Nichols, Thomas A Friday, July 21, :2000 7:17AM Bean, Gary (US Sales); Davey, Todd; Davies, Thomas (US Sales); Doherty, Eric (US Sales}; Fenstermaker, Bill (US Sales); Gallagher, Paul (US Sales); Guyer, David (US Sales); Huston, Pete W (US Sales); Mastrianni, Serene (US Sales); McNeill, Jack (US Sales); Pasek, Bill; Tisdell, John (US Sales) Essa, Mark (US Sales); Ciarlo, Nicholas (US Sales); Dudek, Joann (US Sales); Hanwell, Cathleen (US Sales); Kamieneski, Brian (US Sales); Amati, Michelle (US Sales); Mimnaugh, Michael (US Sales); Baranowski, Patti (US Sales): Yelsils, James (US Sales); Johnson, R~y (US Sal!'ls); Nichols, Thomas A; O'Connor, David (US Sales); Mrazik, Ernest (US Sales); Feeley, Robyn (US Sales); Palazzo, Jim (US Sales); O'Neil, James W FW: Attendee Status High

Sent: To:

Cc:

Subject:
Importance:

01 Team
FYI RAB Roster Update

ACTION ITEM due by Next Friday: 7/28 coordinated by DSM's,

TAS and

On each of Your key customer(s) send a single page via e-mail with the following info. rnkt share of eg lmitrex Tabs. lnj, NS, Amerge 2. chief competitor, mkt share 3. your wish to achieve with this customer attending the RAB. eg safetv of triptans, constipation mgt., qd vs bid dosing of lotronex, formulary issues, weight gain with SSRI's vs WSR, etc. 1.

the more the specifics, the better prepared the GWI

team

will be to implement into the RAB's in an effort to~


ROI for you and 01.

obtain the greatest

Whatever format that works better for you, an excel spreadsheet, or a word document is fine. If you have any questions, please call me at home: ofc 603-595~1388, octel: 88085. This is for your/our benefit and I expect full compliance with this request

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0027-064237
GC0348-4859 F

Regional Advisory Board Meeting


August
11th-

13 111, 2000

Bermuda

Attendees:
1. Dr. Philip Reimherr

Antidepressant $

WeUSR%

$542,498 Total Rx-35% 30 Boston Street Lynn, Mass. 01970 Phone: (781) 593-5110 ext. 215 Fax: (781) 593Guest: Kathy Reimherr (Wife) Competition: Prozac@ 20.3%; Effexor@ 13.3% Objective: Dr. Reimherr is very pleased with the use ofWellbutrin SR especially with its effectiveness in ADHD. Please utilize his positive experience and enthusiasm ofWellbutrin SR to influence other clinicians. $433,031

2. Dr. Richard Netsky


21 o Whiting Place, Suite 4 Hingham, Mass. 02043 Phone: (617) 876-4099

Total Rx-8.3%

Fax: (617) 497-7776 Guest: Unknown Competition: Prozac@ 35.6%;Zoloft@ 17.9%; Ejfexor@ 17.6% Objective: Dr. Netsky is comfortable with using Wellbutrin SR, however it is not considered first line in his treatment algorithm. Dr. Netsky is a Child Psychiatrist and I would like the safety and efficacy of a first line antidepressant and treatment option tor ADHD to be relayed to him.
3. Dr. Alexander Accardi
1261 Furnace Brook Parkway Quincy, Mass. 02169 Phone: (617) 479-4545

$496,985

Total Rx-7%

Fax: (617) 479-4555 Guest: Husband, Dr. Kenney Competition: Prozac@ 44.8%; Zoloft@ 12.3%; Paxil@ 12.1% Objective: Dr. Accardi is an incredibly busy Psychiatrist in both private practice as well as her role in Nursing Homes. She does not think ofWellbutrin SR as a first line agent but more of an adjunctive option. The features and benefits ofWellbutrin SR for the treatment of depression first line in both adult and geriatric populations would be my wish to be relayed to her. This information will be hopefully relayed to her husband as well for he is a Primary Care Physician.

Glaxo Wellcome Representative: Cathy Hanwell/DlCJOl Glaxo Wellcome Manager: Gary Bean

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0027-064241
GC0348-4863 FL

...

Nichols, Thomas A From: Kamieneski, Brian (US Sales) Sent: Thursday, July 27, 2000 8:44PM To: Nichols, Thomas A Cc: Huston, Pete W (US Sales) Subject: Market Share info on RAB Attendees Tom, Here is the information you requested on the physicians attending the RAB Programs in Bermuda. Wellbutrin RAB. 1. Stephen C. Ellen, MD Welfbulrin market share 5.5% Chief competitor Prosac 30.5% and Effexor 25.3% Uses Wellbutrin SR mainly in bipolar disease since it does not cause mania. Does not feel Wellbutrin SR is an effective first line agent as an antidepres-

sant.
2. Maria C. Gaticales, MD Wellbutrin SR market share 6.9% Chief competitors Prosac 19.8% and Zoloft 17.1% Number 1 PI physiCian in my assigned territor)~. Wrote $157,387 worth of antidepressants in the past four months. Still concerned about seizures with Wellbutrin. lmitrex RAB 1. Richard L. Levy, MD lmitrex Injection 13.2%. lmitrex nasal spray 9.9%. lmitrex Tablets 29.2%. Amerge 8. 7%. Maxalt 19.4%. Zomig 16.5%. Number 4 PI physician in territor)~. Need to emphasize lmitrex advantages over Maxalt and Zomig. He feels they work taster than lmitrex. 2. M. CeCilia Pinto-Lord, MD lmitrex injection 0%. lmitrex nasal spray 22.4% lmitrex Tablets 22. 7%. Amerge 7. 7%. Maxalt 14.6%. Zomlg 31.2% Dr. Pinto-Lord has been prescribing more and more Maxalt and Zomig lately. Need to empasize differences between triptans. Lotronex RAB 1. Stuart Brogadir, MD Lotronex market share 13.7% Chief competitor Dicyclomine 41.4% Still concerned about about safety profile on Lotronex. Very conservative. Needs more info on appropriate patient candidates and usage in males. 2. Dennis Shea, MD Lotronex market share 0% Chief competitor Hycscyamine 66.5% Cost is a concern. Writes 98% generic. Needs more data on efficacy and and safety. Attended program in Cape Cod.

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0084-486824
GCY055-5335 FL

..

Nichols, Thomas A From: Mastrianni, Serene (US Sales) Sent: Friday, July 21, 2000 11:35 AM To: Nichols, Thomas A Subject: WSR RAB Attendee Tom, Here are the details you requested. The spreadsheet contains the WSR Market Share and competitive shares. (All final attendees are indicated by the yellow highlight). In addition, I have red flagged the competitive trends for each attendee. Attendee Needs: None of the attendees are using WSR as first-line. My goal is to have them all leave the RAB thinking of WSR as a first-line antidepressant alone or in combination with SSRI's. In addition, I would like them to switch/add WSR to existing SSRI patients.

WSR Targets.~s

Thanks,

Serene

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0027 -064245
GC0348-4867 Fl

WSR

Original list from Ray Johnson, John Tisdell's TAS rep sent in an e-mail dated 7/11 at 11:23 AM to Gary Bean with cc to John Tisdell, Eric Doherty, Carlo Bontempo and Tom Nichols. All 3 were not confinned, ie Drs. Weiss, Patnaude, and Clark. The list did not include a fax munber for Weiss or Patnaud. Ray followed up the next day with Dr. Weiss' fax number. I called and got Dr. Patnaud's. 7/13/00 lrec'dan octet from Ray Johnson at 11:15 AM that "Dr. Gordy Clark is a no go". Approx. 7115 Dr. George Nowak declined
7/17 Dr. Marc Sadowsky cancelled.

7/l9 I rec'd an e-mail from Kim Reardon at 10:02 AM that they had rec'd a call from Dr. Patnaud. He said

he would like someone to give him a call regarding what the expectations will be from him at the meeting 110d as an advisory board member. Ventiv felt it best a GWl person handle this. I spoke live line wi1h Dr. Patnaud on 7/20 early AM. I asked if he were recruited by Ray Johnson and he said no. Said a brand new rep had asked him to go and her understanding was to sit for 4 hours, share your thoughts around WSR. get paid at a nice place in Bettnuda. Dr. Pamaud also conveyed this was a new rep that shared be was being asked because he was the number one potential doc in the entire state of Maine prescribing antidepressants. He expanded that he was surprised because ofhis work schedule. I conveyed this to the RSD because I thought this was inappropriate and places D1 at risk. 7/19/00 Rec'dan e-mail from Kim Reardon sent at 2:47PM that'' Dr. Parnentier would not be able to attend the WSR meeting due to an office move." 7/19/00 Dr. Mark Waynik cancelled. 7/20/00 Rec'd a phone call live line from Serene Mastrianni regarding Dr. Pramila Naphan as a replacement for Dr. Waynik. Confinned with Ventiv 7/20/00. 7/21/00 asked Serene to send an extra person in case of cancellation because she said she had someone in mind. R.ec'd fax 3:08 on 7/21 for Dr. Richard Tomb. 7127/00 I called Dr. Tomb and left a message at 11:45 AM. He called me back at 2: 15 PM and said he was interested, willing and able. I obtained his fu:x nwnber and called Ventiv at 3:30 PM. I called Dr. Tomb back at 4 PM and left a message to confirm that he was good to go and provided both home and office phone numbers. 7/27/00 left messages to the managers regarding physicians that did not send back their TRF's for tickets. Dr. John Worthington. Thorn Davies Included are Dr. Michael Patnaude, Eric Doherty Dr. Pramila Nathan, Serene Mastrianni Dr. Da-shih Hu, Paul Gallagher Dr. Stephen Ellen, Eric Doherty

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0086-057297
GCY225-2863 L

Page 2 of2

Fairmont Hamilton Princess


Bermuda

Saturday, August 12

8:00-8:15 PM 8:15-9:00 N..t.

Vlielcome10bjeclilles

Tom NiChOls, RPh


Tom NWooJS, RP11

Wel1buliill S:W.Q.T, AJ'\alySi$


~:s.tr~"'d!M, Weakrl~;,

Oppiul'itie!, Thr~~}

Clinical Oata around the Issues


9:~ -10:00 AM

Elitwt'h Gooda.lel PharmD

Break Mo!et:ularTargeting, The PharrnacologyJm Hudliak, MD of Ncrepinephrinel Dopamine Medications


Q&A

10:00-11:15 AU
11:15-11:30AM

Jim Ht1(1Ziak~ MD

~liV.Wellr Gooda~, ~D

Tom Nfchots, RP!J

12:00 -1:0() PM
1:00-6:00 PM
7:00-10:00 PM

Bo::a:ed LU!lcMS

Monanfn& Lwei

Eventng Dinner Cruise

Lady Tamara Yacht


((,o::.iJtrxl by fhll' i:rt$/l JII'Jll'lr M\llmilig pa(i.!)

Sunday, August 13
8~00 -10:00 AM Bre~ast

https://c-port.aspensys.com/iconect!iconect.exe?uid=sbloom_ 52DA4044&img_doc= I &im... 1/22/2007

Cross, Bennett & Hessel, L.L. C.


Attorneys at Law
Keith F. Cross Joseph F. Bennett Chad J. Hessel
108 East St. Vrain, Suite 20 Colorado Springs, CO 80903
Phone: (719) 633-1359 Fax: (719) 633-5788

E-maJJ:Kc:ross@cbhlaw.com

October 16, 2001 Carrie Rubright Regional Director of Human Resources GlaxSmithKiine pic 5 Moore Drive -:- Research Triangle Park North Caronna, 2n09 Re: Greg Thorpe Dear Ms. Rubright Greg Thorpe has retained me for assistance in connection with his employment situation. As you know, Greg has been a dedicated sales representative for Glaxo for almost 23 years. He was one of the first 100 sales employees hired for Glaxo Inc. and has made outstanding contributions to the company throughout the years. Greg has been a top performer in sales, and, as of today, is ranked ninth out of 31 in his Cerenex Division for the Rocky Mountain Region. Greg could easily obtain testimonialS from as many as 50 prominent local physicians with whom he has built a network of trust and confidence over that past two decades. In addition, Greg is the devoted father of four children, two in college, one in 6111 grade and one in 1st grade. He would like to be able to stay with the company to which.he has devoted the last 23 years of his working life at least until his retirement age of 62%. Having received nothing but commendations for the work he has been doing for GlaxoSmithKiine, Greg was shocked to receive a formal "VERBAL WARNING" from District Sales Manager Pat Keith on October 1, 2001. He is concerned that this disciplinary action may simply be the pro forma prelude to an unwarranted and possibly illegal termination. Having reviewed both the VERBAL WARNING and Greg's Field Coaching Reports over the past year, I have to admit that the disciplinary action does not appear to have any factual support and may simply be pretextual in nature. More specifically, the VERBAL WARNING has foul;' bullet points that purport to. represent grounds for disciplinary action:
You have reacted inappropriately to constructive feedback from management This has . been done through e-mell. and voice mall. An example of this ls your recent voice malls

WN0002345

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056334

GOV0269-014

Human Resources Director GlaxoSmlthKiine October 16, 2001 Pa e2


rebutting your rating- for teamwork that appeared on the Sept. 18 coaching report.

Taking this statement at face value, if the rec~nt v?ice mail: reb_utting ~is ratings for teamwork are merely an "example" of what is bemg discussed 1n this wammg, ~en there must necessarily be other examples that preceded the September 17"' coaching report, which, overall, rated Greg Thorpe as ''fully effective." . However, the September 17" coaching report also contains the following:
Note:

Are 1here any areas of skil, knowledge, behavior, or results that have been marked on
page 1 (or onprevtous reports) as "needs development", that are of such a serious nature due to: 1) the degree of the deficit, and/or 2) the seriousness of the action, ancllor3) the . lack of suitable progress toward Improvements, that without Immediate corrective action

wiU necessitate the manager to begin the formal disclplins process? YES NO

There do not appear, then, to be any areas of skill, knowledge, behavior. or results that could have formed the basis for discipline at that point.in time. In fact the four ~aching reports up to September 17, 2001, for the periods ending 02106/01, 04119/01,06/20/01 and 09/17/01, are excellent, and, again, in the "Note" box contain a negative indication that Greg had done anything in the areas of skill, knowledge, behavior or results that could merit some kind of discipline. Nevertheless, Greg was disciplined based primarily on his negative reaction to "constructive feedback~ and his lack of "teamwork." If anything, the acci.Jsation that Greg has exhibited a lack of teamwork is even more discOncerting, because this criticism would appear to be solidly based upon Greg's disapproval of peer behavior and activities that were inappropriate and probably illegal. The concern about teamwork is evidenced by the second bullet In the disciplinary warning:
You. have had a negative attitude that has affected {.sic) your team members in the territory. Your team membem have shared that your overall attituds regarding tne company hall Inhibited lhelr ablnty to work with you. You have made numerous negative comments pe<1alnlng lo yourTSR counterpart (Ron Crews), In lhe presence of management

Since no additional d~tan Is given, it is difficult to tell who among Greg's team members have communicated a problem with Greg's attitude. The only individual actually mentioned is Ron Crews. However, the fact that only Crews is named is a cause for concem. In a meeting attended by Pat Keith, Mike Benn~tt and my client, Greg expressed quite valid criticisms of Ron Crews for specific violations of company guidelines and. F .D A. regulations. Crews, for example, insisted on a "wine tasting" event at a

WN 0002346

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056335

GOV0269-015

Human Resourtes Director GlaxoSmlthKiine October 16, 2001 Pa e 3 physicians' program, which is clearly in violation of the company guidelines. Greg also pointed out that Crews was violating F.D.A. policy r?lati~g to promo~on of drug products "off-label." Greg also pointed out that Crews was VIOlating FDA policy relati~ to promotion of drug products "off-label." On May 23, 2001. a nationally recogmzed . speaker on ADHD. Dr. Paul Wender, spoke to a group of physicians ~bout the use of WellbutrinSR and its potential use In ADHD/ADD cases. The meeting was set up by Ron Crews and approved by Pat Keith. Apparently, GSK has employed this well-known physician to speak on this subject nationwide, advocating the benefits of WellbutrinSR in the treatment of ADD and ADHD in children. Greg Thorpe's objections to these presentations were made for the purpOl:le of protecting the company from being involved in Illegal activity and, as such, his protests are protected by law. Upon being approached by Greg Thorpe concerning the potential illegality of these presentations, Greg's supervisor, Pat Keith, should immediately have called Crews in for reprimand or discipline. Instead, it was Greg Thorpe who received the disciplinary action. In response to the allegation that Greg exhibited a negative attitude in his comments about" the performance evaluation and other company policies, Greg assumed that the program instituted by then GlaxoWellcome C.E.O. Robert Ingram called "Straight Talk" encouraging discussion and differences of opinion among employees and their supervisors was still in place, at lea~t in spirit. He has now found out, to his dismay and perhaps to his detriment, that the new corporation has no intention of honoring that policy and desires whel)ever possible to stifle any criticism of company policies, regardless of how constructive or helpful that criticism might be to the company or the morale of the employees. Greg feels strongly that certain current employee policies have a defil')able negative impact on older employees such as himself. Again, his criticisms have been intended to reflect his thoughtful analysis on the negative impact changes in policy are having on the older employees of GlaxoSmighKiine, with a view to having ultimately a positive impact by voicing his concerns. However, his willingness to criticize, however constructively, these policies has instead been met with this disciplinary action. Greg also expressed valid criticisms about his TSR counterpart Crews in connection with the failure of Crews to perform even the minimum required followup with assigned psychiatrists. Crews had been responsible for calling on 25 top psychiabist for the last four months at least every two weeks. GSK records will confirm that Crews had not called upon or even sampled 12 of these psychiatrists, and 7 had been contacted no more than twice. A minimum 25 calls every two weeks would have meant 200 calls to these Important clients. Instead, Greg's review of the records for a 4 month period indicated that Crews had made a total of only approximately 40 calls. It is really the failure of Crews to do his job that has resulted in the diminution of teamwork, not Greg Thorpe's legitimately pointing that failure out to his supervisors.

WN0002347

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056336

GOV0269-016

Human Resources Director GlaxoSmithKiine October 16, 2001 Page4 Greg was totally blind-sided by Pat Keith's criticism of ~reg's 'teamwork' as it relates to Jim Butler. In Mr. Keith's field contact report of Apnl 20, 2001 there was no mention of any teamwork problems involving Greg and Jim Butler. Subsequently Pat Keith spent an entire day riding with Greg Thorpe on Greg's calls yet never made mention of some alleged problem with Jim Butler. Pat Keith has also been critical of Greg's comments to a co-employee, Annie Cutter, concerning the "Power of Performance" commission plan. Greg had been asked by Pat Keith to explain the plan to Cutter. At the time Greg attempted to detail the commission plan to Cutter, the volume increase factor had essentially been taken out of the equation and only market share and malket share change were a part of the calculus. As Greg explained it to Annie Cutter, this was why she had seen her rank and pay-out so drastically reduced in just one month. It is no wonder she reacted negatively. However, her reaction is attributable to the change in the commission plan, not.to anything Greg might have said to her. Although not specifically spelled out in the VERBAL WARNING, Pat Keith informed Greg that he was also disappointed in Greg's lack of "teamwork" with Annie Cutter. However, similar to the criticism of Greg's lack of "teamwork" with Crews, Pat Keith's negative assessment of Greg in this regard stems In part from Greg's open criticism of an incident in which Cutter engaged in illegal activity. Cutter arranged to have Pikes Peak Community Health Center Chief Psychiatrist Fred Michel address a group of 60 physicians qn the benefits ofWellbutrinSR in the treatment of ADD and ADHD children, which, as indicated earlier in this correspondence. is not a use that has been approved by the FDA. Greg informed Cutter that the lecture was inappropriate and illegal, yet Pat Keith approved the lecture in spite of this, and Cutter submitted the lecture as one which would be about "depression". Notwithstanding that designation, Cutter's own notes on the lecture clearly indicate that the subject of the talk was the treatment of ADD and .ADHD. As far as the current commission plan, Greg feels that the plan, as well the changes in benefits plans and his own current salary1 have an obviously negative impact on older workers such as he. Greg is aware of at least one fellow sales representative with only four years of experience and without any significant difference in results who is paid a salary roughly equivalent to Greg's, and many other similarly situated employees are paid more. Greg's prevlousconfidential inquiry to HR in July of 2001 requesting information about how Greg's salary was set- and whether tenure or

as

1 Greg Is paid $81,000 as a top performer with manyyeMI of experience under his belt, when compared to the published Minimum - $60k, Midpoint- $90k, and Maximum- $12Dk of the. CUITIInt salary plan.

WN0002348

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056337

GOV0269-017

Human Resources Director GlaxoSmithKJine October 16, 2001 Page 5 performance were taken into account- has been completely ignored. Last but not least, the teamwork issue has been colored by understandable problems that Greg has encountered with District Sales Manager Pat Keith. To the extent possible, Greg would like to have you keep confidential his comme.nts concerning Pat Keith, since Greg wiD continue to be in the position of havmg to work with him. Pat Keith has taken confidential communications - statements that Greg specifically requested be confidential- to other people within the company with the 111 expected result of causing dissension and divisiveness. On June 18 of this year, by agreement with Pat Keith, Greg waited at a designated spot to meet with Pat Keith for a tide-along. Pat Keith failed to appear. After a period of time, Greg telephoned Keith to find 0 ut the reason for the delay. Pat Keith Informed him that he had been 'partying' the evening before and was too 'hung over' to attend the ride-along. Besides his legitimate criticism of the compensation plan, Greg has expressed a legitimate concern over the drastic diminution of his benefits under the new retirement plan as well as the negatiVe impact the changes to the plan have for older employees. The former plain 1.1% X final average earnings plus .6% of earnings that are in excess of Yz of the Social Security wage base in effect on the first day of the first year in which full time employment comes to an end times years of service yielded approximately twice the amount Greg will now receive at age sa under the current Cash Balance Plan . . Wrlh 23 years of devoted service to the company, how could he help but be justifiably upset about the impact of the new plan - an impact which will be felt by all of GSK's . older workers similarly situated to Greg. For that reason, I am requesting that GSK provide us with its own calculations under both plans as they apply to Greg Thoq)e, particularly the calculation of the ''transition credit as is applies to an employee like Mr. Thorpe who plans to work until at least age 62 and a %.. Even more troubling are the changes in medical benefits upon retirement. In years past, the company provided full medical coverage upon retirement for tt'le . employee and his dependents. It was then changed to provide full medical coverage after 25 years with reduced percentages calculated after 20 years of employment Most recently the benefit was reduced to a maximum of 90% of medical expenses to retired employees and only 70% for their dependents. This goes into effect after 20 years of employment with no additional credit for employees with additional years. Additionally, a cap of $10,000 has been placed on medical benefits, further limiting medical benefits upon retirement. Similarly, the GSK 401 K plan has been reduced from a 6% match to a 4% match

with 2% share in company stock. This would also appear to be a reduction for older
workers such as Greg Thorpe who have been with the company for an extended period-

WN 0002349

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056338

GOV0269-018

Human Resources Director GlaxoSmithKIIne October 11~. 2001 Pa e6 of time. While I understand that an international company such as GSK, with some 39,000 employees world-wide, may find an exemplary employee such as Greg Thorpe expendable, my intent is to by to persuade you to continue to give Greg the opportunity he deserves after so many years as a dedicated and proficient employee. If Greg were to be forced into the general workplace at this point in his career, there is little doubt that he would be able to find replacement employment that would even approach his current financial position with GSK. I believe it is in the best interest of both GSK and my client to give Greg Thorpe the opportunity to finish his career. However, Greg will be eligible for early retirement in May of 2002 because fo the newly implemented "Rule of 75." In light of the significant discord between District Manager Pat Keith and Greg Thorpe, my client might be persuaded to accept a reasonable severance package from GSK, one that takes lnto'.account his current medical benefits (96% paid benefits with no 'caps') and Greg's 23 years of dedicated service to the company. Because of the considerable physical and emotional strain caused by the recent developments in his employment with GSK and particularly the difficulties Greg has encountered with.District Manager Pat Keith, Greg has been compelled to seek treatment from a medical professional, Dr. Elliott Cohen, who has placed Greg on medical leave from his job until at least October 29, 2001, at which time he will reevaluate Greg's condition and make a further recommendation about his ability to return to work. Therefore, I am requesting that you contact either Greg or me before that date to discuss any suggestions you have in response to this letter.

Thank-you for your -ntion 10 ~~

Keith Cross KC/cw

c.c. Greg Thorpe

WN0002350

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056339

GOV0269-019

.,

Thorpe, Greg
To: Subject: ar401 04@gsk.com RE: Your High Road Partner/WHO?

I have had some serious complaints, regarding my DM taking disciplinary action against me for refusing to participate In obvious VIolations of company policy regarding mainly, but not limited to speaker events/promotion etc.. These events 21l11!DJl wlth no response whatsoever back to me from Human Resources, who has been given most 'of the material evidence (not all). HR has most recently refused to respond to my latest grievance and request to view my file within the required 10 days(response time). They have violated every published policy in regards to the matter at hand. Initially Carrie Rubright was handling this-most recently I wrote to Cynthia Kelly with no response. Is HR responsible to anyone fror their own violations of published policy, if so to whom??. Please check this out, TAP Pharm. recently had to pay almost 1 billion dollars for similar conduct, yet this company will not even acknowledge my existence. My DM, Pat Keith has had full knowledge of the conduct, yet I was the one reprimanded by him for reporting it to him and refusing to participate. I suggest that someone Inform me of the status of the matter. Cynthia Kelly now has the materials I sent In, and will get more if they wish to contact me per published policy.Thanlcs. After over two months with no response, and my reputation and employ at stake, I hope this can be referred to someone who has the ability to oversee HR. I have tried all I can to no avail.
Sincerely,
Greg Thorpe 1280 Painted Rocks Rd Woodland Park Co. 80863 Sr. Exec. Sales Rep. (CNS) 719-687-7675

From:
Sent:

US Internal Communications

Subject:

Tuesday, December 11, 2001 8:20AM


Yot.r High Road Partner

Dear Sales Colleagues:

The enclosed fact sheet, Pharma Compliance: Your Partner on the High Road, will introduce you to the newly created Pbanna Compliance department. Pharma Compliance, which reports to me, was established in response to David Stoufs "Taking the High Road initiative, to make OJaxoSmithKline the leader for ethics and compliance in sales and marketing practices. Phanna Compliance is a resource to US Pbanna to address potential policy compliance violations, and meet new requirements for independent audits of sample accountability under the Prescription Drug Marketing Act (PDMA). Because of the heavy scrutiny the pharmaceutical industry faces, your management is determined to make GSK the leader for ethical promotional practices. That is the reason our Commercial Practices Policies regulate the use of promotional materials. activities with physicians such as advisory boards and speaker events, and prescription drug samples. These rules are your safe harbor - they protect you and GSK. More important, it's the right thing to do.
Page1

WN 0002353

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056342

GOV0269-022

The Phanna Compliance team will work within US Phanna to provide an independent resource to conduct investigations of potential non-compliance with company policy, and random and for-cause audits of compliance with the PDMA. Your management will always be consulted ~ investigations are conducted. In addition, the team will send the sales representatives to be audited and their District Sales Manager a detailed information packet in advance ofPDMA random audits. Global Internal Audit (GIA} will conduct regular audits in other policy areas.
In my role as Phanna Compliance Officer, I will also be working with other groups on processes and resources to support this effort. Please feel free to contact me with your questions, concerns or feedback. My phone number is (919) 483-9938. You can also send me e-mail through the internal email system or the Web at ar401 04@gsk.com.

As employees of the one of the world's largest pharmaceutical companies, it is more important than ever that we set the standard the industry strives to achieve. Our success in achieving this standard depends on you.

Page2

WN0002354

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056343

GOV0269-023

To Whom: Re: Pharma Compliance Report 1107/02


It is obvious to me prior to giving the information I am about to give that "retaliation" for informing certain individuals of severe violations of company policies has already begun. I have been given a "verbal warning" which is totally untrue, and docs not follow company guidelines for disciplinary action. I have been ignored by Human Resources since July o2001, regarding.various requests for information. Most importantly they have even ignored letters from my attorney, and two other letters from me requesting appropriate action according to published guidelines and policies. I bad to go all the way to the bead of Ph anna Compliance for any action. This matter has been ignored/covered up it seems by my District Manager, Pat Keith, Carrie Rubright and Cynthia Kelly in Human Resources, and Mike Bennett, Regional Vice President.

Regardless of what company policy may be, my letters to Human Resources and my previous complaints ofmisconduct have been quashed. My 23+ year career with this company has been trashed, and it is obvious that I can no longer work with my District Manager, or friends/counterparts just because I have come forward with the truth, which could save the reputation of GSK, and millions of doUars in fines. After investigating the TAP Pharm. issues and what we have here, possibly nationwide, I personally am extremely upset and angered at the indifference and pompous attitude of all of the above individuals, for ignoring my claims for over three months. The False Claims Act is no joking matter, nor a matter to be taken lightly, especially under the current attitudes regarding pbanuceutical companies in ge!leraL

This is not some minor violation ofpolicy,the conduct I have attempted to report could result in severe legal and monetary penalties if left unche<:ked. I think that should be very evident and need no further explanation. I do not want to be the one responsible for a child's injury or worse because we PAID a physician, who wrote a book on ADHD, to tell others that Wellbutrin SR was a great drug for ADHD. Nor do lwant to be responsible for paying a Nurse Practitioner to te11200 others that Amerge Is a great drug for Pediatric migraine. Further I will not take part in paying for an expensive lunch, and day at the SPA ($350) for 25 physicians and physicians . assistants, just for listening to what they already know about Wellbutrin SR for 112 bour. I also believe expensive programs now approved and pending by Pat Keith, DM- re: Ski bus trips to Breckenridge, Dinner and tickets to Avalanche games with a "guest" for physicians is no more than "buying the business through bribery." Is this the "high road"? We have been told that "public perception" is everything now. Well just imagine the calli received ten minutes ago from a physicians assistant, not a physician, ordering

WN0002357

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056346

GOV0269-026

a I) 65 minute deep tissue massage a 2) a 60 minute Colorado cleansing facial3) a 30 minute foot reflexology and 4) a pedicure and French manicure. This would be after her "lunch at the Broad moor" and 30 minute lecture by Brendan Montano, MD who Oew in from Connecticut for several thousand dollan to talk about weight loss and the benefits ofWellbutrin SR!!!! I want to promote the benefits of my products, but this sickens even me. Can you imagine if the Wall Street Journal got a copy of this invitation, it would make the "dine and dash" look like a walk in the park. All of the above has been approved by my District Manager Pat Keith, who disciplined ME for refusing to participate in a ledure by Paul Wender MD, who came here as be seemingly has all over the US to promote Wellbutrin SR for ADHD, as well as his own book. I am not the one to determine what disciplinary action should be taken for these repeated violations of dear company policies and FDA law, among othen. It is clear to me what needs to be done, however. Further retaliation by Pat Keith or the othen mentioned is, it seems to me Inevitable. How could one work for a DM such as this after reporting his repeated proven misconduct? The question for me is, what now? I have not taken the advice of my attorney, to become a whistleblower and go to Federal Court. I do not want a $77 million whistleblower payment, like former TAP salesperson Douglas Durand received. I do want, however my reputation restored and those responsible for KNOWINGLY violating company policy or failing to report it held responsible. I would consider a severance/retirement plan approprillte for the losses I have suffered to date and wUI suffer ifl am forced to work.for Pat Keith or fmd other employ at my age. The inconsideration and violation of published policy by those in Human Resources have also contributed to the seemingly rapid demise of my career with this company for reporting wrongdoing. My wife and 4 children are my first and only concern after reporting these violations, and I would hope for a fair and logical treatment without resorting to any court actions. My previous complaints, gone unheeded are very clear in my attorneys letters to 11R followed by my own letten. In a letter dated 7/1/01 from David Stout, "'CompUance with these policies is mandatory--managers will be held accountable for ensuring all employees are trained on and comply with these policies. He further states in a letter dated 10/26/01, "'all of you have completed your training on the new polic:ies but to demonstrate our leadership, policies are not enough. We must ensure we are following the policies as well through compliance. It shows we "walk the talk" by having policies and checking to see that they are being followed .positive documentation of our commitment to the high road. JP, Bob iznd I are fuUy behind a

strong compliance program-it's good for patients, it's good for each of us, and it's good/or our profiiability and reputation.
The most recent message from Arjun Rajaratnum among other things specifically states .. These policies reflect how GSK sales representatives must conduct their

WN 0002358

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-05634 7

GOV0269-027

business, and underscore the fact that GSK sales representatives are professionals, not ENTERTAINERS or CATERERS. That's why lavish meals, extravagant events and "Dine and Dash" are not acceptable. Your strict compliance with these policies shows that GSK is really on the HIGH ROAD. Finally, I assume JP Gamier~ what be says when he states, "Conducting our business with honesty and integrity is paramount. It is every employee's responsibility." No one is above the Jaws established by the PDMA and FDA, or very clear company policy. This includes DM's who knowingly violate company poHcy, and RSD's, and HR personnel who ignore it when it is reported to them. I have not reported anything that I cannot document, nor anything trivial. I have put everything on the line, hoping for fair results. We shall see I suppose what the "high road" is and what "walk the talk" really means. Thanks for your time and efforts.

Siticerely,

~~
Greg Thorpe Sr. Executive Sales Rep.

WN0002359

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056348

GOV0269-028

Ra]aratn~m. Arjun
From:

Sent: To: Cc:


SubJect:

Singer, Chris A Friday, February 22,2002 6:15PM Rajaratnam, Arjun Werner, Mark M RE: Pride Program

Arjun- Thanks for the update on the Greg Thorpe situation. On the first issue, although I'm sure we have communicated that the CPP parameters apply to these types of programs, I'm not sure that reps are as aware as they should be. This is principally because PRIDE and FIRST programs are marketing funded programs that are administered through a vendor (SCS). Thus, the degree of involvement in the logistics of the programs at the rep level is generally marginal at best. My advice would be that we communicate to all parties involved (e.g. the field, marketing and the vendor) that all GSK programs, whether they are field or marketing generated are subject to the CPP limits and guidelines. We need to do this universally across all divisions. On the second issue, I'm assuming that these physicians have gone through speaker training on WSR. If so, they should be aware of what the guidelines are around discussing off-label indications since that is normally covered in the training process. Can we confirm that these individuals have been trained? In any case, I cannot condone allowing physicians to use GSK speaker programs as venues to market their books, irrespective of whether they involve off label indications or not. If you can get me more details around this, I will be more than glad to discuss with the local management team and RVP. Thanks

cs

----Original Message----From: Rajaratnam, Arjun Sent: Friday, February 22. 2002 2:31 PM To: Singer, Chris A Cc: Werner, Mark M SubJect: Pride Program

PRIVILEGED AND CONFIDENTIAL Chris: In investigating allegations by Greg Thorpe, a Rep. in Jim Lamb's region (I think you know about this guy), two observations have come up.

1. PRIDE program. Two perceptions about this program arise from the interviews with several Reps. On~ is that
CPP limits do not apply to PRIDE as it is not noted in the PRIDE manual. The second is that the vendor for PRIDE monitors and manages the CPP limits so the Rep. has no responsibility for meeting CPP limits. Let me add that I don't know anything about this program except that it is used for speaker events. Should we should do something to correct this with the Reps and/or the vendor, or in the manual? Also, does this vendor work through Professional Programs under Bill Judd?

2. Off-Label Speaker Events: We also found use of two doctors who seem to be experts on ADHD used for many events sponsored by Wellbutrin, although generally the topic noted was general- e.g. Depression. One of these guys has written a book it seems on using wellbutrin for ADHD and was even selling his book at one event. We have noted observations here that off-label discussions by these two doctors at. these events was normal.
Any thoughts on how to respond to this from a GSK perspective? Given that these doctors have been used by several districts on several occasions, this would not appear to be localized or indiVidualized. In summary, can you help me find a way to show GSK's due diligence in response to these observations. Thanks

Arjun Rajaratnam Compliance Officer Global Pharmaceuticals GlaxoSmithKline

WN 0002416

CONFIDENTIAL: Produced pursuant to 02/06/04 subpoena

GSKC0-0252-056405

GOV0269-085

6/axoWe/Jcome Memo

To

. RSDs

From

Robert

fadg~tt,

l\$$ociate Manager Sale> Training

DSMs
Elion Sala Force

0J1r

3/23/00

subjert James Pradko, MD Slide Presentation

Commercial Operations Training and Devdopment is re5JXlnding to your eothusiastic re~ponsc: to D~

James Pradl';o'l presentation. Neuroreceptor Basis of Initial Antidepressant Choice. As vou will remember,
Dr. Pradko provided an essential pllrt of ycur Wellbuttin SR
trai~i~g

experienc:e by sharing his view~

~sa

primary care physician treating d~pressed patients. attgehed a copy of his presentatio~ 'I ides.

As~

follow up to his presentation, please find

Bc:t:ause all anti-depressants hav~ been shown to be compara~le In efficacy for the treatment of depression, Or. Pradko's presentation focuses on the importlnce of selecting :~n antidepressant b~sed on it's n!lurotransmitter effects and related sicl~ effect profile. BaS(d on the differences between the neurotransmitter effects of different antidepr6sants, Dr. Pradl:o encourages prim~ry care physici;111s to ask themselves when selecting :an antidepressant: "Where do I want my patients to be dter four months of treatment?"

Remember, Wellbutrln SR offers patients. efficacy comparable to an SSRI, Zoloft, with up to a 72'fo lower lnw inridt>nrr of ~dation and w~ight gain has b~en d:mun~lr~ltd uy Wtllbutrin SR, m~king it an c::xcdl~nt first line choice: for many dc:prc~d patients.

inddence of orgasm dysfunction. Additionally. ::o

lh~se

materials

ar~

h~althcm profession~ Is.

lor your information only and shoulrt not tJe used for promotion or in discus.sioos with Please cantac:t me at (91914837633 if you have any questions and continued

success to you stlllng Wellbutrin SR.

Slncer~ly,

Robert Padgett

Glaxo Wellcome Inc.


Five Moor Drive
PO Sox 13396
Rtstarch Trianglf Prlc.

Fa>< (Vl V) 4l1Hlll81

N:

27709-JJ98

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0066-015309
GC0783-7519 FL

GOV0096-001

GOV0096-001

James Pradko MSc.

~1.0.

3/S/00

Neur.oreceptor Basis..of Initial


~tidepressanthoice-

James P.radko, M:"Sc.,.. M.D.


-Copyrigill N99

Copyrigllt@. 1999 Jmries Pmdko M.Sc. M.D.


All rightsre$Crved No pm.ofthis.preselllaiioA.{.in.the form of slides, bancbut, audiotape, video,.c:om.IQlef CIJ.O&:--, book or other form) may be reproduced or tmDsnli.tted iB auy fonn or by any means, electronic or mechanical, iDcluding photocopy, recoJding or any iDfonnation storage or retrieval system, without written perllliision f'rom 1he copyrigln holder.

Neuroreceptor Basis of Antidepressant


Choice

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0~0066-01531 0

GCD783-7520

GOV0096~002

GOV0096-002

. - - - - - - - - - - - - - - - -----------------

James Pradko MSc. 11(1.0.

3/5/00

This talk iJ dcsi,Sned to pTCSCDt-a-!!imple ~ elemeDt approach to UDderstauding the


ueurophysiologie ~ti01).8 of eci1D1liiOlr an11depressants.

Introduction

7,;~-prcvllco~

i uf1hvitb:recu..,.,t depreooion tUiamittuicide

This talk will ~t a mdhoo.....t:.~.ti&Re of these elements tc ltelp in the- sel.ectien oftho best :tim choioe utidepressant-f&r-avariety of patient types.

70"/o of auictac victims - aoctor witllill 7 wocOC.s Suicide ii..7t'b lc:adille ~use of clcatb ov<ta!!

Wbat is your favorite antidepressant ?

1-.rl

Side effects
Side efrc<:uo may nol happca Side fiact. tl.at afi'a;ta patient in a negative wa~ ralu<:<: compl!anco: Side effects tl.at effect a patient in ll J>O"itive way
increase ouu1plianc.c

"LEAP""
Libido . -En "'B)'

Auentionl Addirooo
Poiats 'to
pcnd~r

A likely li<lo .,ffc.;t is NOT 811 iodiwion for u110

Neuroreceptor Basis of Antidepressant Choice

Confidential: Produced pursuant to 02/06104 subpoena

GSKC0-0066-015311
GC:J783-7521

GOV0096-003

GOV0096-003

J e.mes Pradko M. Sc. M.D.

3/5/00

Common AntidepreS3ants
SSRI't

Veola!axlJ.e

N<>fil;z.od""'~

(Eff~Jalf XR)

(&n;...,,.)
(Reme~t~~)

Mirtazapmc

Buproptoa Hycirwblorllic (W cllbutrin SR)

Differences B etw:e.enSSRJ' s._

-How to SSRI's differ from one another


. l
u.

llh f:llili

Bifference Between Serotooin and


Dopamine Reuptak.e
a..Md~1

Ull.ltO.fL~"

:PC'ti!XttiDt

1-1'1:-

l.l3t00
17~600

).OS
U5
20!;1

2$3.00
22.22200 0.0!

i"'"-

,.,..,......

Ci:llc!nm
v~

4\1
I~~

U6<1

119

C-&C.W... ... I-IolooMN... _,V.. II,N<4,1.....

Neuroreceptor Basis of Antidepressant Choice

Confidential: Produced pursuant to 02106/04 subpoena

GSKC0-0066-0 15312
GC0783-7 522

GOV0096-004

GOV0096-004

James Pradko M.Sc. M.D.

3/5/00

Dift'eterleea Betweec S$1U'I

EFFEXOR:-n
L:-

!UMEMBJ:R;
"(;"lJY"'III'IG(l.-cr-~r~~~~ ......a-! by

r:...."'~
me<li~

l!!mlGlLING CCJW>IIIIor Jolbqy)

_,..,.._.
""'JbmJ

urn..

AZJ SSJtro -

bo octnlio8 (l'loDc) b.< oo :!SR.li>

L:-

REMER ON
L:E:~

1!:~

A. IIGUA1

A: i:Ja-caoed

Patient Profiles
"What ilhc bos1 fillil cbui<xl or
antuleprc~unt therapy

1".0.14< .......

l'r"' dasl
~HT3 ...... I

"

Neuroreceptor Basis of Antidepressant


Choice

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0066-015313
GC0783-7523

GOV0096-005

GOV0096-005

James Pradko M.Sc. M.D

3/S/00

Trred Tony
Patient Proti1es
"What is lAo bo.l fitat choico of

. Miid lO ~ impact-oo c:to~m.til)lmip Tire<!, poort111ngy_

antJdqlrnqrJt 1hc111py ?~

Trouble cooconnlins now O..C.aot ....ut to sain--'abt-

Active Alex
Acting out sexually to incJ1l!IUO SCI If fStOO:III
Fair zuc~y

~lnlioo ok

Active Alex
_...--..,
fsSRI'o\l!ll't><or San= Rrn...,. WellbuliD \ ...W0., I rc:<iua: n<UiraJ liC.-n.J ~ \ u..,tllll { . , _ nduoo re<faloo* U.oce&~o ~ bolpa\00 Winl n-.1 holpf\>1

CryingCa~

Acting out oe~ally 10 iMRIIIIII....U: estec~m Titod, JIO<lr cnorgy

Cau:eutnlion ok:
~_,-..,.

s.:A...-1

Neuroreceptor Basis of Antidepressant Choice

Confidential: Produced pursuant to 02106/04 subpoena

GSKC0~0066~015314

GC0783-7524

GOV0096-006

GOV0096-006

----

- - - - - - - - - - - ..

---

.. -- ...

- .....
3/~/00

James Pradko MSc. M.D.

Crying Casey
Mila' 10 110\'WC im~t 04 " " ' - pWitfonliip

. .0.,-ati-""

ll110~r to ~pmllion

---kl'!lw-R

---

Pacing Pat

]~+~--

Timo+!J.....daq~

"Ralphing" Robin
Mild to ~~<VCre impiC( oo. ;loaest relatiooship FoodcormdciCCIMpoisoa", loW'\\Ieight Good energy Coo""'!tntioo ot

'"Ralphing""Robin
..... SSRl'1 EJrcxor 'knm/Jteou:roo \ WeDln11rin
rc:docc reduoe mcunl } aeolnl J>CIIlral ;.,,_. ~~ ~ ; - . n...nl bclpf\>1 0 n.-.1 \.!:.~ he~

eutral\

-"

Neuroreceptor Basis of Antidepressant


Choice

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0066-015315
GC0783-7525

GOV0096-007

GOV0096-007

ralnesPradko M.Sc. M-D

3/5/00

Premature ~ta;ticm v.. SliP" .


Li>illo
I'.IOIJ}I ~

Depression With Other Conditions

SSRV.. FJI'cxor-

s..-.

~ -~

.-.!- ....-!

IIAUIIII. lll.-.~.-

-~.

~-

Blllml bclpful! nmlraL. nt:Uial

Chronic Fatigue Syndrome..


""'-"""'s--pbiioo
UlidoLOllY

"'='

S3IU' Ell'""or s..n.- - - w.m....u. JUice rodDao ~~~ - . 1 """- .....__ root-!. " ' zuodlal bolpful** ..-nJ_ ....mL ~-

Attention Deficit Disorder


~DA

SSRI' E1l'cl<or Scrmltc 1\.amaul,

Wcllliu~Jin

Libido Eomgy

"""'- J..duoc u...tn>l ~ "rutral inoreooe t<dlJt.e_ ~

-IAIiDereuo.

A&lilill'

-~l&--.1. - ~

1\f'.tlroreceptor Basis of Antidepressant


Choice

Confidential: Produced pursuant to 02106/04 subpoena

GSKC0-0066-015316
GC0783- 7526

GOV0096-008

GOV0096-008

James Pradko MSc. M.D.

3/S/00

Antidopre..,ta .,
cff.,.t-~ fua~.

in-~:

Mechilllism3 of Antidepre~iWt Induced Se1cua1 Dys.flmotioo


2.
~.-..-..o.,-;-.....,..-~M~c~o.

3. -~~ mnAinhibil> tll'glll'lll

Dire h.hibition of NittoliS Olcidc Syothetas.e Caoses Less ffiood Flow to Erectile T'"~S&Ue

Indilwtly Suppromng Dopamii:K; wiich Reduces l:ibilhl


Salllmio

w~_!)~~
R.JIIlm

'' ' -'- ~ .,.,..!Do

Summary of Sexual Dysfunction


MocS.ic.atii:Ul Etec;tia.. L&billt> OJA.u.m CmTCtivG Aetioa
Y ...... 'tla..~t

$-llrs

....

--.
-I+

W~

Add

w .........
1.eft7Cilll

-1+
0
0

1fl:.._u+v;-.n.
~

...~.

"f+

l.~cra.

w.m...,;,"

Neuroreceptor Basis ()(.Antidepressant


Choice

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0066-015317
GC0783 7527

GOV0096-009

GOV0096-009

Jaines Pradk<l M.Sc. M.D.

315/00

Drug Interactions

- - .mf
~~

JC

.l.M

tDfi

IUld

~IDOl - IDI

Antidepressants

The lmpor1allt Substrates


WCi
M

0
II

....
)'I

. '""

c
A
1'

-cllldopclal
~

The important 'Sobs a ates

:v;~

...
c

QuinidSlo gm....H~
Alpoazolaa "' Alni>inb

tx:rtmy .t...m..i.J.Ja 1'CA.'1

" E
I)

~ T....,.

ZCHJI,!O f'

...

-l'oytiiOo

~
E~Y=

~- oj

J"n>p<1n0lol
~

w..;..;.

Interactions: P450
~ Wc:bA~

"~ ~

WCllA'N

MCDNN
N;c:;:a.At){

IJIIP'Of'OD

V.....,.,._ MCBN!l ... HIILOI'!:II.IXX. ......,._ MCBAtw" mi PA.W ml q,)Acntl ~-- P'AY .S (JJ.ACKED -.1 CAT'

Neuroreceptor Basis of Antidepressant


Choice

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0066-015318
GC0783-7528

GOV0096-01 0

GOV0096-01 0

lames Pradko M.Sc. -D.

3/5/00

Summary Chatt..
S51U'o
SffOT.Ott'<l

Scrz>oooc- -

w.t~Wiritt~.
~I.e..

11

Libido
htw'S)I

""'neutnl:

a=tnoJ.. -aal
~

ir.cn..e tedaoe..
bolftal.. ..........

Attt.l'

ll..nnl

IUOIInl.- bclp1l>L.

-------"LEAP"
Lil:ido

..

NE ........

~-.

What is yow favorite

antidepressant 7

Enargy
AUmtiOIII Addiction Poir:lta to ponder

--.. -. .... _c;o....-..


All~-

NopotoftJu-(lOa..r-.t

GhrbJa)'*'lflia~w-.'MII'--,"-bJ
_,-..a.=-c-.~_....,__,.,

r~GC"'V~~~ot ........... .,.-.~

....,..,.,..,a.~

.. -tlo~bll<ilr.

Neuroreceptor Basis of Antidepressant


Choice

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0066-015319
GC0783-7529 L

GOV0096-011

GOV0096-011

Status Update- Respiratory


ADVAIR
Regulatory A successful teleconference was held yesterday with FDA following an exchange of correspondence over the last ten days. The indication has been broadened to "Advair Diskus is indicated for the long-term, twice daily maintenance treatment of asthma in patients 12 years of age and older." This is clearly a very successful outcome. Despite the implication that Advair Diskus is indicated for all asthma, FDA is not comfortable that Advair be used or promoted for mild disease. They propose to describe the appropriate patient populations in the "Dosage and Administration" section of the label. This section now contains language that allows Advair to be used in patients currently taking noncorticosteroid maintenance therapy (salmeterol, LTMs, etc.), as well as inhaled corticosteroids. In addition, FDA appear comfortable in allowing Advair to be used in patients currently taking albuterol if we qualify they have moderate or severe disease. We are submitting proposed wording to include this patient population. In summary, it now looks like we will have a broad indication with specific dosage recommendations for patients on any maintenance therapy, as well as a subset of patients taking albuterol only.

The issues around warnings (oral steroid sparing and paradoxical bronchospasm) have been resolved to our satisfaction. Other less significant issues have been raised by FDA (e.g. logo), which are being addressed . The high level of interaction indicates FDA are actively working to an approval on August 25.

Manufacturing Glaxo Wellcome cannot successfully validate against the NDA specification. In order to preserve the launch we plan to seek approval from the Compliance Division of the FDA to validate against the ROW specification, but then only release product to the US that meets the NDA specification (failed batches will be redirected). In order to make this even possibly acceptable to the Compliance Division, we also need to submit an SNDA with the new specification soon after approval. The Compliance Division may not accept this proposal, in which case we would face a significant delay in launch. There is a reasonable chance they will, but it is not a "given". FDA is still insisting we conduct release testing on overwrapped product. This would add 2-4 weeks to the launch timeline. We have requested this be waived for the launch stock and be instituted subsequently. There are indications they may acquiesce to this, but it is not yet confirmed.

Ill:.-----....,..

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0295-001382

In summary, it looks likely we wi1l gain approval on 8/25 with a good label. The risk is now in the acceptability of our proposed manufacturing strategy.

OTHER
The PDI agreements for Ceftin and Relenza are progressing well, and we expect to have assigned contracts before October 1, 2000. Month-to-date (August 16) factory sales for the Respiratory Division are 87% of Outlook, . reflecting de-stocking in Flovent, Serevent, and Ceftin as a result ofthe June price increases. July prescriptions are in line with Outlook. The FDA has accepted the Relenza prevention flling with a Priority Review status. Approvability remains questionable without additional data in high-risk populations. Without such data, the resulting label is likely to be uncompetitive vs. Tamiflu. Accordingly, we will not commit to major upfront investments to launch the prevention indication in the 00/01 season. The New England Journal of Medicine study demonstrating reduced death rate associated with ICS utilization has been approved for Level 1 promotion and is being utilized by the sales force to blunt the uptake of Singulair as a first line treatment for asthma.

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0295-00 1383

Airee, Hans N
From:

Sent:
To:

Cc:
Subject:

Wilson, Lorna C Thursday, February 28, 2002 10:01 AM Palmer, James BD; Yamada, Tachi (Notes); Gustafson, Andy N; Rickard, Kathy; Baker, Darrell; Jose, Simon A; Elder, Dave R (US Marketing); Abdalla, Joseph; Jones, c. Elaine; Bohinski, Robert J; Watson, Dawn; House, Karen W; Dorinsky, Paul M; Gerding, Tom A; Sykes, Andy P; Kunka, Bob L; Hackett, Charles P; Airee, Hans N; Edin, Heather M; Soriano, Joan B; House, Karen W; Knobil, Kate; Davis, Kourtney J; Gill, Louise K; Frith, Lucy; James, Mark H; Riebe, Michael T; Clay, Michelle M; Sharma, Raj K; Ho, Shu-Yen Y; Taylor, Stephen W; Yancey, Steve; Davis, Suzanne L; Crim, Courtney; Shrewsbury, Steve B; Ferrell, Joy E; Brannick, Lesley Y (Notes); Wheadon, David E (Notes); Hull, Stan; Skalsky, Steve D; Boyko, David A; Traber, Peter G (Notes); Rockhold, Frank W (Notes); Gibbs, Trevor G; Cree, Fiona (Notes); Pyke, Stephen D; Shah, Tushar P; Hardy, Michele M; Goodwin, Annette G; Rogenes, Paula R; Salyer, Mark W; Reisner, Colin; Devoy, Mike Cass, Malcolm; Fitzgerald, Kevin C; Baitinger, Leslie A; Schaaf, Lynne ADVAIR DISKUS SUPPLEMENT FOR INITIAL MAINTENANCE THERAPYNOT APPROVABLE

This supplement to Advair Diskus was submitted on April27, 2001 and a Not Approvable letter was received late yesterday (letter attached below). This supplement requested a revision to the Dosage and Administration section of the package insert (see wording below) to provide guidance on the recommendations for the starting dose of Advair Diskus for patients with uncontrolled asthma on SABA only and sought to delete the statement whose disease severity warrants treatment with 2 maintenance therapies. Current wording: For patients who are not currently on an inhaled corticosteroid, whose disease severity warrants treatment with 2 maintenance therapies, including patients on non-corticosteroid maintenance therapy, the recommended starting dose is ADVAIR DISKUS 100/50 twice daily. Proposed wording: For patients who are currently taking short-acting beta2-agonists alone or for patients currently taking non-corticosteroid maintenance therapy, the recommended starting dosage is 1 inhalation of ADV AIR DISKUS 100/50 twice daily. Clinical Studies: To support the proposed labeling change, data were provided from five clinical studies which included patients on short-acting beta2-agonists alone. One 12-week pivotal clinical study (SAS30017) was conducted in adult and adolescent subjects with persistent asthma that was uncontrolled on short-acting beta2-agonists alone. Four supporting studies were also included, including two replicate DISKUS studies (SAS40020 and SAS40021) conducted in subjects 2_15 years with asthma uncontrolled on short-acting beta2-agonists alone. Two additional supporting studies (SAS30001 and SAS30003) were

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0280-001 048

conducted which evaluated the combination product delivered by hydrofluoroalkane propellant metered dose inhaler (HF A :MDI). The SAS3000 1 study enrolled patients on short-acting beta2-agonists alone, while SAS30003 included a subset of patients on short-acting beta2-agonists alone. In the pivotal clinical study (SAS30017) Advair Diskus won on two prespeci:fied primary efficacy endpoints: Mean change from baseline in morning pre-dose FEV1 at endpoint for the DISKUS combination product compared to salmeterol DISKUS. Area under the serial FEV1 curve at Treatment Week 12 relative to Treatment Day 1 baseline for the DISKUS combination product compared to fluticasone propionate DISKUS. However, for pre-dose FEV1 fluticasone did not achieve significance.

Asthma exacerbations and withdrawals due to worsening asthma were numerically higher, but not statistically significant, across all studies. FDA Review Comments (in total) We do not believe that you have provided sufficient evidence of efficacy to support this broadened indication for Advair Diskus. Notably, clinical trial SAS30017 failed to demonstrate the stperiority of the combination product Advair Diskus to the single component fluticasone propionate using the protocol-specified analysis. In addition, this supplement did not provide adequate assurance of the relative safety of the combination product compared to the single component fluticasone for the proposed population. Withdrawals due to asthma exacerbation and withdrawals due to worsening asthma (clinical and stability-specified) were higher among subjects treated with the combination product compared to the single componentfluticasone. In order for this application to be approved, you must provide substantive efficacy and safety data supporting that this specific population uniquely benefits from the combination product in comparison to the individual moieties and that this benefit is not outweighed by any additioned risks. Regulatory Assessment While this is disappointing, it is not unexpected. While we won on the prespecified endpoints, it was always a concern that the FDA would require statistical significance for both primary endpoints for both chemical entities. In addition, the FDA raised safety concerns of the combination product versus fluticasone alone for the proposed population. The implication that can be read from this is that the FDA believes that certain patients can be controlled on fluticasone alone. Next Steps There appears to be no additional substantive efficacy and safety data to respond to FDA's comments, however, a recommendation to either amend or withdraw the application will be discussed with key stakeholders in the next few days.

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0280-001 049

FAX. PDF

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0280-001 050

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Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0236-016732

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_)

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0236-016737

From: To:

Robert J Jagt!PharmUS/GSK[robert.j.jagt@gsk.com] AmyL Scott!PharmUS/GSK@GSK[amy.l.scott@gsk.com]; Lois A Nelson!PharmUS/GSK@GSK[lois.a.nelson@gsk.com] ; Lafmin C Morgan!PharmUS/GSK@GSK[lafmin.c.morgan@gsk.com] ; Ted T Geiger/PharmUS/GSK@GSK[ted.t.geiger@gsk.com]

CC: BCC: Date Sent: Subject:

6/28/2004 7:31:18 AM Re: Chris V. Presentation

I think this is final- unless anyone else has made changes over weekend ...

Rob

Amy L Scott!PharmUS/GSK 25-Jun-2004 15:08 Respiratory Marketing

COC- F3150

919-483-2952

To Lafmin C Morgan!PharmUS/GSK@GSK cc Ted T Geiger/PharmUS/GSK@GSK, Robert J Jagt/PharmUS/GSK@GSK Subject Chris V. Presentation

Lafmin, I have made to change to slide 7 as discussed. Updated version attached.

Amy Scott Respiratory Marketing Location: F3150 Telephone: (919) 483-2952 Fax: (919) 315-3153

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0271-339143

Advair Update
June 28, 2004

1
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0271-339144

Fueling Growth of Advair

Advair as foundational therapy in COPD


3.3M*
* Number of Patients not yet on Advair

2
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0271-339145

Advair TRx Growth


120%~--------------------------~------------~

100% 80% 60% 40% 20% 0%

--- Aavalr- Growtfi


Actual: +20.3 Forecast: +23.3
Market Growth ---Actual:--- "'"."7.3Forecast: +9.0

q ...
~

M 0

111

M 10 10 10 10 10 10 M M 0 q q q """" q """" q """" q """" q q q 0 q q q q """" """" ... c ... >. a. c >. a. >. :::1 a. > > > :::1 :::1 111 111 111 .., 111 ..., 111 ..., Gl 0 ..., 0 .., 111 111 Gl Gl 0 ~ ~ ~ ~ en z en z en z ~

3
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0271-339146

Why aren't all asthma patients on Advair?


Strong Advair Penetration

Insight
Patients complain about symptoms Physicians prevent events Physicians fear of disease is greater Patients have low expectations of therapy and treat symptoms with albuterol - they modify behavior to cope Physicians expect patients to have symptoms and treat them Physician fear of drug is greaterminimize medicine

4
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0271-339147

How did we address the insight?


2003
Asthma is Variable; - mild now is severe later Barriers to success Professional Efforts focused on disease 'Those aren't my patients' - mild patient is different for each doctor Risk benefit ratio: Advair is too much medicine for my 'mild' patients

Asthma is unpredictable - Mild patients are at risk of exacerbations Use Advair to effectively treat both components of asthma in .11 patients

5
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0271-339148

How will we address the insight more effectively?


Barriers in 2003 Professional Efforts focused on disease; not Advair 'Those aren't my patients' - mild patient is different for each doctor Advair is too much medicine for my 'mild' patients 2004 Efforts focused on benefits of Advair, not disease Specific 'mild' patient target; not ALL patients

-symptoms on SABA
Same objection should still arise - Address the objection with variability, burden, and unpredictability of asthma

6
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0271-339149

Why do we think this approach will work?


Share of Treated Asthma Patients by Rx Therapy (Jan '04)
60%

'MILD'
60%

'SEVERE'

40% 30%

lliAdvair Ill Controller &SABA

20%

10%

0%

Rescue Only

1 Controller

2 Controllers

3+ Controllers

+2.2%

+1.0%

-1.1%

Source: SOl 'SLEDs', Jan'04, filtered for asthma total, includes all ages and all specialties

7
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0271-339150

Asthma Strategy: Make Advair the First Controller


Core Message: Advair should be the First Controller in patients symptomatic on albuterol. Supporting Data - Advair Gains Control as Early as Day One (Murray and Calhoun) - Advair Provides Sustained Control (Murray and Calhoun) - Advair Diskus is an Easy-to-Use Device

As I mentioned earlier, our promotional focus for semester 2 is to drive earlier use of Advair. Our core message is to "Make Advair the First controller and help prevent symptoms" Our support data will help you effectively communicate the messages that Advair allows patients to gain control as early as day I and provides sustained control overtime. These messages will supported by two key studies: Murray (SAS 30017) et al and Calhoun et al.

In the Study by Dr. Murray eta!, Advair was superior to Flovent in every efficacy measure. Patients in this study were symptomatic on albuterol alone prior to randomization. This study has been submitted for publication. In the study by Dr. Calhoun et al, Advair was superior to Singulair 1Omg on every efficacy measure. Patients in this study were also symptomahc on albuterol prior to randomization. We feel confident that the results from these studies and our core message for semester 2 will be helpful in achieving our objective of driving earlier use of Advair.

8
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0271-339151

Asthma Strategy: Make Advair the First Controller


LEVER Adult Field Promotion Childhood Asthma Asthma DTC Asthma PR 2 selling teams 1 selling team PATIENT TYPE Uncontrolled on SABA Uncontrolled on ICS Make Advair the first controller Advair safe & effective for 4 and older Advair increases symptom-free days Missed School Missed Work Activity limitations Raise Expectations of Asthma Control

Avg. 125 GRP/mo (Aug-Dec) Childhood Asthma in America Asthma Care Net ACT

Fewer Symptoms Coping w/asthma Parent and their Children with asthma Uncontrolled asthma patients

Market Development

9
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0271-339152

From: To:

CC:

Dave R Elder/PhannUS/GSK[ dave.r.elder@gsk.com] BrianD Phillips/RTP/PSF/GSK@GSK[BrianD.Phlllips@gsk.com] ; David A Swift/RTP/PSF/GSK@GSK[David.A.Swift@gsk.com] ; David J Mosher/RTP/PSF/GSK@GSK[David.J.Mosher@gsk.com] ; Elizabeth C Sylvia!RTP/PSF/GSK@GSK[Elizabeth.C.Sylvia@gsk.com]; Glenn W Kirclmer/RTP/PSF/GSK@GSK[Glenn.W.Kirchner@gsk.com]; James C Rollins/RTP/PSF/GSK@GSK[James.C.Rollins@gsk.com] ; James J Altrichter/RTP/PSF/GSK@GSK[James.J.Altrichter@gsk.com] ; Jolm J Dimaggio/RTP/PSF/GSK@GSK[Jolm.J.Dimaggio@gsk.com] ; Jolm J Mayer/RTP/PSF/GSK@GSK[Jolm.J.Mayer@gsk.com] ; Jolm K Foy/RTP/PSF/GSK@GSK[John.K.Foy@gsk.com] ; John K Richardson/RTP/PSF/GSK@GSK[John.K.Richardson@gsk.com]; Jose M Montanez/RTP/PSF/GSK@GSK[Jose.M.Montanez@gsk.com] ; Ken B King/RTP/PSF/GSK@GSK[Ken.B.King@gsk.com] ; Lisa A Machado/RTP/PSF/GSK@GSK[Lisa.A.Machado@gsk.com] ; Mary M O'Neill/RTP/PSF/GSK@GSK[Mary.M.O'Neill@gsk.com]; Rick R Gatlin/RTP/PSF/GSK@GSK[Rick.R.Gatlin@gsk.com]; Robert P Hastings!RTP/PSF/GSK@GSK[Robert.P.Hastings@gsk.com] ; Ross J Metzler/RTP/PSF/GSK@GSK[Ross.J.Metzler@gsk.com] ; Shannon M Heath/RTP/PSF/GSK@GSK[Shannon.M.Heath@gsk.com] ; Stephen C Gaddy/RTP/PSF/GSK@GSK[Stephen.C.Gaddy@gsk.com] ; Tom J Tyma!RTP/PSF/GSK@GSK[Tom.J.Tyma@gsk.com] ; Troy B Fowler/RTP/PSF/GSK@GSK[Troy.B.Fowler@gsk.com] ; Vivian L Ryan/RTP/PSF/GSK@GSK[Vivian.L.Ryan@gsk.com] ; Luis E OrtizOrtiz/RTP/PSF/GSK@GSK[Luis.E.Ortiz-Ortiz@gsk.com]; Arturo R Sanabria/GNB/Phanns/SB_PLC@SB; Michael D Hossenlopp/RTP/PSF/GSK@GSK[Michael.D.Hossenlopp@gsk.com] ; William E McNey/RTP/PSF/GSK@GSK[William.E.McNey@gsk.com] Ted T Geiger/PharmUS/GSK@GSK[ted.t.geiger@gsk.com] ; David M Foye/PharmUS/GSK@GSK[david.mfoye@gsk.com]; LisaM Spiess/PharmUS/GSK@GSK[lisa.m.spiess@gsk.com] ; Charles K Gayer/PharmUS/GSK@GSK[charles.k.gayer@gsk.com]; Anne J Grimm!PharmUS/GSK@GSK[anne.j.grimm@gsk.com] ; Robert A Y anez/PharmUS/GSK@GSK[robert.a.yanez@gsk.com] 8/22/2004 3:14:37 PM Asthma Presenation at PCMM

BCC: Date Sent:


Subject:

Ol_Asthma_PCMM_Presentation_-_081804.ppt

574976

Microsoft Powerpoint slide deck

Attached below is the Asthma Presentation that was given at the PCMM. Please let me know if you have any questions.

Dave Elder Senior Product Manager, Asthma Marketing

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0259-028579

ADVAIR
Dave Elder Asthma Marketing

Opening:
Vision (What is your vision for Advair?)

There are two parts to a vision:


Having a vision Having confidence in your ability to make the vision a reality

Having confidence in your ability to make the vision a reality is the hardest part:
Maintaining your confidence when you have already achieved great success

We want to help you maintain, if not increase, your level of confidence in Advair.
Reshape your vision Share with you the plan to make the vision a reality

1
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028580

The Opportunity for ADVAIR


Performance Metrics
-ADVAIR
Sales: $3.018 Billion
- 27% Sales Growth (Yr-Yr)

Rx Volume: 16.9 Million


-23% Overall Growth (Yr-Yr)

-Childhood Asthma
Sales: $105 Million Increase from Pediatricians
- $30 Million Stretch Goal

46% Increase in Pediatrician TRx (Yr-Yr)

Performance metrics:
We are all familiar with these numbers Advair is now the engine that drives GSK.

2
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028581

The Opportunity for ADVAIR


Total Advair
Sales ($)
1,761,139M

Budget

o/o to
Budget
97%

($)
1 ,814, 154M

o/o Growth vs. VAG


28%

How confident are your?


Maintaining your confidence when you have aheady achieved great success Customers telling you that they aheady prescribe a lot of Advair

3
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028582

The Opportunity for ADVAIR


Year2 Lipitor Celeb rex Vioxx ADVAIR 193% 39% 125% 97% Year3 50% 6% 4% 33% Year4 30% -70/o -20% 23%

4
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028583

The Opportunity of ADVAIR in Asthma


500,000 , - - - - - - - - - - - - - - - - - - - - - - - - - - -

Fall is Asthma Season

Source: Verispan SPA

Why is Fall the season?


Increase in prescription volume Increase in symptoms coincides with increase in prescription volume

A great Fall will set-up a great Spring

5
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028584

The Asthma Opportunity


Realize
- What are we trying to achieve

Identify
- Who are we trying to move

Attain
- How are we going to move them

Maximize
- Focusing on the plan

Reshaping the vision:


Realizing the opportunity. This is about agreeing on what it is that we are trying to achieve. Identifying the opportunity. This is about agreeing on who it is that we are going to have to affect in order to realize our vision.

Making the vision a reality:


Attaining the opportunity. This is about agreeing on how we are going to move these people. Maximizing the opportunity. This is about focusing on, and staying true to, the plan we have put together.

6
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028585

Realize the Opportunity of ADVAIR in Asthma


Newly Treated Patients, Entry Into the Market Asthma Only, All Ages
70%
80%

50%
40%

..--------...
!

....-

-----------

~
~

30% 20% 10% 0%

,., ..,
~

,.,
'l
oC
~

. .,.,. ...
'l
Only

,.,
~ 0

,.,
'l > 0 z

,.,
'l
u

. . . ..,."
<;'
Controllers

'l

.'l .. .t .. .. 'l ...


...
:E

...

:E

<;'
~

" ..,

--+-Rncu
-1f-LTM
~

---Advalr Alone orin Combo


~Other

.........-lcs Alono or In Combo

Aone or In Combo

Source: SDI, June 2004

Source of business:
Existing patients New to asthma therapy Very little product switching

New to asthma therapy:


40%-60% of patients new to asthma therapy will be put on Rescue-only Remainder is equally split among the other products

What are we trying to achieve:


Realize that one opportunity is in patients new to asthma therapy Understand that getting your product on first is the most important thing to do

7
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028586

Realize the Opportunity of ADVAIR in Asthma


Majority of Rescue-Only Patients are Uncontrolled
Rescue Rx's Filled per RescueOnly Patient per Year

3 or Less

4 to 10+

0%

10%

20%

30%

40%

50%

60%

70%

Source: SDI, Jtme 2004

Control of Rescue-only patients:


Only 1/3 are using 3 or less canisters per year 2/3 are having to use 4 or more canisters per year 27% are using 10 or more canisters per year

Why Rescue-only? Patients have 'mild' symptoms (more seasonal - annoyance)


Physician are generally unaware of impact of symptoms Goal is to treat symptoms (patients 'get' asthma vs. 'have' asthma)

What are we trying to achieve:


Realize that another opportunity is in Rescue-only patients Understand that 2/3 of Rescue-only patients are uncontrolled Agree that Advair is an appropriate first choice for these patients

8
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028587

Realize the Opportunity of ADVAIR in Asthma


2/3 of Patients are Getting Something Other Than ADVAIR
Asthrna Patients New ta Controller Therapy,. All Ages

Advair ~Alone or in Combo

ICSwAiona or in Combo

LTM- Alone orin Combo

Other

0%

5%

10%

15%

20%

25%

30%

35%

Source: SDI, Jrme 2004

Patients on Controllers:
1/3 of patients are getting Advair (why physicians say they prescribe a lot of Advair) 2/3 getting something other than Advair (tremendous opportunity)
Why Advair?

Patients complain about symptoms Physician are acutely aware of impact of symptoms on patients Goal is to prevent events
Why not Advair?

Patients have 'mild' symptoms (mix of seasonal/year round- hindrance) Physician are generally aware of impact of symptoms on patients Can always add/switch to Advair if necessary

9 Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028588

Realize the Opportunity of ADVAIR in Asthma


Majority of Patients Continue on Initial Therapy
Changes in Therapy of ICS Patients Changes in Therapy of LTM Patients

70%__,--------------,

Ad vail'

ICS

L TM

Other

SABA Only

Advail"

ICS

LTM

Other

SABA

Only

Source: SDI, June 2004

Do physicians change patients initial therapy?


About 60% of patients stay on the product they started on

What are we trying to achieve:


Realize 2/3 of patients on Controllers are getting something other than Advair Realize that there is little switching of patients from their initial therapy Understand that getting your product on first is the most important thing to do

10
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028589

Realize the Opportunity of ADVAIR in Asthma


Fall is the Season!!! It is about Getting AD VAl R on First!!!
- 50% of Newly Treated Patients Start with Rescue-Only - Majority of Patients Continue on Initial Therapy

The Upside for ADVAIR is BIG!!!


- Majority of Rescue-Only Patients are Uncontrolled - 2/3 or Patients are Getting Something Other than ADVAIR

What are we trying to achieve?


It is all about getting Advair on frrst

Why Advair first?


Majority of Rescue-only patients are uncontrolled (Myth of Mild Asthma) Advair is superior to Flovent and Singulair

What does this mean to you? Large number of symptomatic patients who would greatly benefit from Advair
New source of Advair prescriptions (increase in prescription volume) More incentive compensation

Who are we trying to affect to make this happen?


PCPs see the majority of these patients

11
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028590

Identifying the Opportunity for ADVAIR in Asthma


Research Learnings
Symptom Impact on Patients

Patients complain about symptoms Physician goal is to prevent events by treating disease Product efficacy is most important

Patients complain less about symptoms Patients modify behavior to cope with symptoms Physicians treat symptoms Product convenience and safety is most importa

What have we learned about PCPs?


Symptoms is what drives PCPs (not Rescue use -look at Rescue-only patients) Choice of medication is primarily driven by impact of symptoms on patients

12
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028591

Attaining the Opportunity of ADVAIR in Asthma


Strategic Objectives
Establish Earlier Use of ADVAIR in Adults Establish Efficacy and Convenience of ADVAIR in Kids

Focus on moving the PCPs:


Increase use of Advair as Single Controller

Two ways to move PCPs:


Move Advair to the patient Move the patient to Advair

13
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028592

Attaining the Opportunity of ADVAIR in Asthma


"Move ADVAIR" Efficacy & Convenience

Asthma Control "Move Patient"

Confirmation of promotional strategy:


Research with physicians has confirmed that our approach the past two years has been correct Research with the Sales Force has confirmed that our mix was wrong

14
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028593

Attaining the Opportunity of ADVAIR in Asthma


"Move ADVAIR" Efficacy & Convenience

When: When your goal is quick control and prevention of asthma symptoms Why: Advair provides early improvement that is sustained over time
ADVAIR 'simplifies' asthma management

How: Make Advair 100/50 your first choice for patients symptomatic on rescue medication.

Lead with Advair:


Create the setting (talk about the specific patient type) Describe the problem (even these patients experience symptoms and need relief) Offer the solution (share how Advair is the appropriate first choice for these patients)

Handling the common objection:


Understand why the physician is giving the objection (Advair superiority data) Separate the two patient types (new to controller therapy- switch patients) Stay focused on the new to astluna therapy and/or Rescue-only patients

15
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028594

Attaining the Opportunity of ADVAIR in Asthma


Message Testing Research Study
- "Quick and Sustained Control" was the most compelling message
Caused physicians to think about prescribing ADVAIR for a broader range of patients Many physicians mentioned they did not realize ADVAIR worked as rapidly as stated Physicians inferred that the addition of salmeterol allowed ADVAIR to gain control of symptoms quickly Increase in symptom-free days was the goal physicians wanted to achieve for their patients

- Affirmed at PCP National Advisory Board

Why will this approach work?


Extensive research with physicians Goals of research (ability to reach patients not on Advair) Involvement of large number of people across multiple disciplines

What have we learned?


"Quick and compelling" was the best way to move the PCPs Affirmed at PCP National Advisory Board

16
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028595

Attaining the Opportunity of ADVAIR in Asthma

Asthma Control "Move Patient" Objection Handler Sell Sheets for Adult Asthma
- Variability & Unpredictability (Calhoun & Dorinsky) - Asthma Control (Fuhlbrigge & Stempel) - Safety Profile (Prescribing Information) - Refill Persistence (Stoloff)

Move patient to Advair:


Stay focused on new to therapy or Rescue-only patients (little switching) Understand what the physician is saying (Advair adds nothing) Use Objection Handler Sell Sheets (pick one) Gives them another reason to start on Advair (not switch patients)

17
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028596

Attaining the Opportunity of ADVAIR in Childhood Asthma


When: When your goal is control and prevention of asthma symptoms. Why: Advair provides improvement that is sustained over time.
o

Advair provides 90% increase in symptom-free days vs. FP (Kavuru) Advair provides 60% reduction in Rescue use vs. FP (Kavuru) Advair provides improvement in lung function vs. Baseline (30031 and Van den Berg)

Children 4 years of age and older have the inspiratory flow necessary to use the Diskus device

How: Make Advair 100/50 your choice for patients symptomatic on an ICS.

Childhood Asthma Campaign: Keep doing what you are doing - it is working

18
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028597

Attaining the Opportunity of ADVAIR in Childhood Asthma


Childhood Asthma Message Tracking Study
- 95% remembered being detailed on ADVAIR
Goal was 90%

- Unaided message recall is good


71% remembered efficacy message 53% remembered the indication

- 56% said they would increase their prescribing of ADVAIR


49% of Pediatricians 82% of PED-Like PCPs

What have we learned?


95% oftargets remembered being detailed (above goal- outstanding) Unaided message recall is really good Indications are that prescribing of Advair will increase

Next steps:
Fall is even bigger in Pediatricians Stay the course (general direction) Improve detailing efforts to targets

19
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028598

Maximizing the Opportunity of ADVAIR in Asthma


Promotional Materials
- Adult Asthma
Core Sales Aid, Objection Handlers, Sell Sheet, File Card Reprints: Calhoun and Fuhlbrigge on the Go Program Brochures

- Childhood Asthma
Core Sales Aid, Sell Sheet, Leave Behind Promise Program Patient Brochures Reprints: Kavuru, Van den Berg and Allen

Promotional Programs
- Asthma & Allergic Rhinitis Case-Based CD-ROM
Faculty-Led Video Conference (Main Presentation) Faculty-Led Video "Quick Hits" (Objection Handlers) Three (3) Case-Based Slide Presentations

New Asthma Sales Aid:


Will review in workshop

Case-Based CD-ROM:
Review components

20
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-028599

Maximizing the Opportunity of ADVAIR in Asthma


Program Delivery Expectations
-Asthma & Allergic Rhinitis Case-Based CD-ROM
35 physicians per TBU
-Adult & Childhood Asthma - Rep Delivered In-Office Program Faculty-Led Video Conference (Main Presentation) Rep Led Case-Based Presentation - Physician-to-Physician Program Live Physician Led Case-Based Presentation

Deliverables in Semester ll: 35 "touches" per TBU (agreed upon with the MDMs)

21
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028600

Maximizing the Opportunity of ADVAIR


Lead with strong detail that positions Advair as the "First Choice".
- Started Working as Early as Day One - Helped Maintain Symptom Control Over Time

Use available tools to handle objections


- Objection Handler Sell Sheets - Faculty-Led "Quick Hit" Videos

Deliver on Program Expectations


- 35 Physicians per TBU

Reshaping the vision: New to therapy and Rescue-only patients (these patients have symptoms)
It is all about getting Advair on ftrst (even the patients with more seasonal symptoms)

Making the vision a reality:


It will take everyone in order to maximize our opportunity (cannot do it alone)

22
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-028601

Advair Asthma POA Semester 2, 2004

SLIDE 1 Hello I'm Ted Geiger Director of asthma marketing and I'd like to welcome you to the introduction of our new and exciting Advair campaign for Semester 2. But first let me thank you on behalf of the entire asthma marketing team for your superb efforts and contributions to the success of Advair to-date. The launch of our new childhood indication has been a tremendous success and we'd like to thank you for everything you continue to do to make our 411 indication a great success. In the next few minutes I'd like to update you on Advair's current performance, review our goals for 2004, and outline our promotional campaign for semester 2.

1
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-008622

Weekly TRx Volume vs Key Competition


(unfactored)

--+---o--

Flovent Pulmicort

_,_ Singulair Atrovent/ lp

--serevent -e- Combivent

""*""Advair - Spiriva

~~JGiaxo5milhKI1ne
- - - - ~-

--- -

~------

-----

----~------

As you can see from this slide Advair's weekly TRx volume continues to grow. An important milestone is that we're generating over 300 OOO_scripts per week. This is a phenomenal performance and we'd like to thank you for your contributions to this success. We are confident that with your efforts and the addition of our 4-11 indication we'll continue to grow Advair's script volume.
2
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-008623

2004 Advair Performance Goals


Sales: $3.018 Billion - 27%> Growth Rx Volume: 16.9 Million

-23% Growth
- 46% increase in Pediatrician TRx Market Share: 27.9%

- 3.2% Share Point Increase

,.,.-;-'

-,

(:5JGI3XnSmltrKIIne
---------~-------

With your efforts and commitment we can achieve our 2004 performance goals to~ Generate over $3.018 billion dollars in Advair sales. This goal represents a 27% sales growth over last year. Increase Advair script volume to 16.9 million. This will require the volume of Advair scripts to grow 23% vs. last year. Including 46/o increase in Pediatrician TRx. And, for Advair to have a Total market share of 27.9%. This represents a 3.2% share point increase over last year.

3
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-008624

How Will We Deliver the Advair Goals for 2004?

@~YGIxoSmrthKIIIlP
~

------

----~-~

Let's now take a look at our promotional plan to accomplish these goals.

4
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-008625

Source of Advair Business


Share of Treated Asthma Patients by Rx Therapy (Jan '04)

lilliAdvair
Ill! SABA
20%

10%

0%

Rescue Only

1 Controller

2 Controllers

3+ Controllers

~~)GiaxoSmltrKIIn
- - - - - - - - - - - -

First, let me take a moment to share with you the source of Advair's current business based on treated asthma patients. As you can see from this slide, the majority of Advair's prescriptions come from the 2 and 3-plus controller market, respectively. Only 31.5/o of Advair's scripts are currently generated in the 1 controller market. These segments represent a great opportunity for Advair.
5
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-008626

Adult Asthma Strategy: Drive Use of Advair as First Controller

~~JGia<o,mltoKIIne
- - - - - - - ---------

In order for us to capitalize on the great opportunity we have within the 1 controller and rescue-only segments, we must focus on driving earlier use of Advair. As you know physicians have a tendency to adhere to stepwise treatment. Singulair and Flovent are currently being chosen frequently as first-line controllers when patients are symptomatic on albuterol. Our opportunity in the marketplace is to make Advair the first controller by encouraging earlier use.

6
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-008627

Advair: The First Controller


Core Message: Make Advair the First Controller and help prevent asthma symptoms. Supporting Data - Advair Gains Control as Early as Day One (Murray and Calhoun) - Advair Provides Sustained Control (Murray and Calhoun) - Advair Diskus is an Easy-to-Use Device

~-

~5)GiaxoSmltcKIIno
- --------------------

. ,.,.,.,.,

As I mentioned earlier, our promotional focus for semester 2 is to drive earlier use of Advair. Our core message is to "Make Advair the First controller and help prevent symptoms" Our support data will help you effectively communicate the messages that Advair allows patients to gain control as early as day 1 and provides sustained control overtime. These messages will supported by two key studies: Murray (SAS 30017) et al and Calhoun et al. In the Study by Dr. Murray et al, Advair was superior to Flovent in every efficacy measure. Patients in this study were symptomatic on albuterol alone prior to randomization. This study has been submitted for publication. In the study by Dr. Calhoun et al, Advair was superior to Singulair 1 Omg on every efficacy measure. Patients in this study were also symptomatic on albuterol prior to randomization. We feel confident that the results from these studies and our core message for semester 2 will be helpful in achieving our objective of driving earlier use of Advair.

7
Confidential: Produced pursuant to 02/06/04 subpoena. GSKC0-0259-008628

Establish Efficacy & Convenience in KIDS


Core Message Make Advair the first controller for children with asthma who are symptomatic on an ICS-alone. Supporting Data - Advair provides 90% increase in symptom-free days vs. FP (Kavuru) - Advair provides 60% reduction in albuterol use vs. FP (Kavuru) - Advair provides improvement in lung function (Van den Berg) - Children 4 years of age and older have the inspiratory flow necessary to use the Diskus device

~~)GI'Xo~mothKIInA
-

- - - - - - - - - - - -

With regards to our childhood indication, thanks to you, we're having a tremendous success with pediatricians. Our continued success will require our focus on delivering the core message: "To make Advair the first controller for children with asthma who are symptomatic on an ICS-alone''. Our supporting data will continue to be the Kavuru and Van den Berg studies. Please continue to communicate the key messages from these studies: Advair provides 90o/o increase in symptom-free days and 60/o reduction in albuterol use vs. FP from the Kavuru study. And .. Advair provides improvement in lung function from the Van den Berg study We are very proud of your performance to-date with the childhood indication so please keep up the great work!

8
Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0259-008629

What are we asking of you?


Focus on the specific patients who will benefit from Advair and help us deliver our objectives -Adults: Uncontrolled on Albuterol -Kids: Uncontrolled on an ICS Use peer-to-peer programs to compliment your selling efforts Deliver "Make Advair the First Controller" on Each and Every Sales Call

rP:~rt" ~)GiaxoSm1tt'KI1ne
- - - - - - - - - - - - - - - - - - - - - - -

In closing, we'd like to ask you to please continue to focus on the specific patients who would benefit from Advair. In the adults market on patients who are uncontrolled on albuterol alone And, in the pediatrics market on patients who are uncontrolled on ICS Continue utilizing peer-to-peer programs to compliment your selling efforts. And finally, please remember to deliver the message "Make Advair the First Controller" on each and every sales call.

9
Confidential: Produced pursuant to 02/06/04 subpoena. GS KC0-0259-008630

From: To:

CC:

Tom Curry!FPL/Corp/SB _PLC[Tom.Curry@gsk.com] Stan X Hull/PharmUS/GSK@GSK[stan.x.hull@gsk.com] ; Lafmin C Morgan/PharmUS/GSK@GSK[lafmin.c.morgan@gsk.com] Ted T Geiger/PharmUS/GSK@GSK[ted.t.geiger@gsk.com]; Duncan Learmouth/CORP/GSK@GSK[duncan.learmouth@gsk.com]; Philip C Thomson/CORP/GSK@GSK[philip.c.thomson@gsk.com] ; Frank J Murdolo/FPL!Corp/SB_PLC@GSK[Frank.J.Murdolo@gsk.com] ; Anita E Kidgell/CORP/GSK@GSK[anita.e.kidgell@gsk.com] 7/14/2004 3:25:05 PM JP request on Advair growth

BCC: Date Sent: Subject:

01 7 11 2004_Deutsche_B_GlaxoSmithKline_- Breathi_wpk21522.d0 l.pdf 02_ 6_ 24_2004_Smith_Barn_ GlaxoSmithKline_Downgrad_szd26969.dOl.pdf

661408 489874

Adobe PDF Adobe PDF

Stan and Lafmin,

JP called regarding the recent Deutsche Bank report that focused on Advair's growth in the US. JP believes a lot of investors on the Earnings' call will have read this report. So, for JP and David to be prepared, JP requested a summary of the major points in the DB report regarding Advair's growth opportunities and our rebuttal to those points.
I called and spoke with Ted so he will be starting on this, which is somewhat similar to answering some of the Q's Frank forwarded for our call on Friday.

Also, for your convenience, here is the Citigroup report that also recently commented on Advair and dropped their forecasted sales for Advair.

Please call if you want to discuss this. Tome

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056037

Europe UK Pharmaceuticals

Deutsche Bank
Primer Hold
Price at 8 July 2004 (GBPI Price target-12mth (GBPI 52-week range (GBPI

9 July 2004

IZ1

GlaxoSmithKiine
Reuters: GSK.L Bloomberg: GSK LN Exchange: L Ticker: GSK.L

Breathing easy over Advair?


Mark Clark
(+44) 20 7545 0470 mark.clark@db.com

1,091.0 1200 1,390.0- 1,060.0

Price/pri!le relative
120 1600 1400 1200 -""' .t!"M 1000 800 600 400 200 0 1/04

Mark Purcell
(+44) 20 7547 6522 mark.purcell@db.com

Lucas Herrmann
(+44) 20 7547 3636 lucas.herrmann@db.com

100 80 60 40 20

~"~

Slowdown in Advair places even more emphasis on pipeline delivery An abrupt slowdown in US sales of Advair, GSK's leading drug, reflects a peaking in its asthma market share and suggests that consensus sales forecasts are significantly too high. This places yet further pressure on GSK to deliver on its pipeline if it is to shake off its discount rating. While we do see cashflow and yield attractions, we retain our neutral stance. Advair's US prescription growth has slowed markedly The asthma drug Seretide/Advair is GSK's No.1 drug and its key growth driver, accounting for >50% of consensus group revenue growth 200308E. US sales of Advair have slowed markedly during 2004- IMS data suggests volume growth of 15% in 02, after 22% in 01 and >30% in H2 2003- despite recent approvals for use in COPD and in paediatrics. Consensus forecasts too high, although growth opportunities remain Our analysis suggests that Advair's slowdown reflects an abrupt peaking of its asthma market share (now close to 40% of all patients treated). With growth comparisons over the rest of 2004 also strained by prior-year wholesaler stocking trends we see downside pressure on near-term sales forecasts. Looking longer term, we do see fresh growth opportunities over 2005 and 2006 from two major outcomes studies, GOAL (asthma) and TORCH (COPD). We would then expect growth to be curtailed again by the likely 2007 launch of AZN's Symbicort. Taken together, we forecast global Seretide/Advair sales of 3.5bn in 2008, c.20% below consensus expectations of >4bn. A further risk to sentiment on Advair is a likely US patent challenge, although generics could not be launched before 2008. Retain neutral stance; shares need pipeline newsflow Given GSK's pedestrian near-term prospects we continue to argue for a discount rating. Our price target applies a c.1 0% 2005E P/E discount to the sector. Cashflow-based metrics (eg, CROCI) suggest a higher value but near-term newsflow (difficult 02/03 comparisons, litigation/patent concerns, limited pipeline news) seems unlikely to unlock this value.
Foreeasts and ratios
Year End Dec 31 EPS (p) DPS (net) Div./Yield % P/E x EV/EBITDA x Revenue PBT stated (m)
SaUtee' Deurscfle&arrksstlrnems endCO!n!J81JYdere

0 7/02 1/03 7/03 - - FTSE (L.H. SCALE)

- - GlaxoSmithKiine (R.H. SCALE) Performance (o/ol 1m Absolute 6'.,;>!!; FTSE .2:1'% 3m 12m 70.9!!;

-7.6'!!; .2sl%

1'5:%

Stonk data

--

.
62,361 5,716.0 100.0o/o 6.0% 4381.1 FTSE, STOXX 22o/o

Market Cap (GBPI Shares outstanding (ml Free float Est. 5 year EPS growth FTSE Index membership Major shareholders: US shareholdina

Advait's contribution to Pharma growth

Advair US prescription growth trends

-- -

2003 82.10 41.00

:
2004E 76.70 42.00 3.9% 14.20 9.Dx 20 572 6,195

::
2005E 80.50 43.00 4.0% 13.60 8.8x 21 283 6,331 2006E 86.90 44.00 4.1% 12.60 8.2x 22 357 6,652

~~~.-:~~~:-:;::~:~.~:;~~;..;~~~ot~~~~~:/.~~~~:~t:.;:~"~-:::~~~
-Newpronaipions
-rctalpre~crl:>tloos

..

~--.-.-.-~~~~~.--.-+-~~----+~~

source: llvJS am f:mlrsche Bank estirnares

3.2%
13.30 8.2x 21 441 6,719

Deutsche Bank AG Deutsche Bank does and seeks to do business with companies covered in its research reports. Thus, investors should be aware that the firm may have a conflict of interest that could affect the objectivity of this report. Investors should consider this report as only a single factor in making their investment decision. DISCLOSURES AND ANALYST CERTIFICATIONS ARE LOCATED IN APPENDIX 1

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056038

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

Model updated: 08 July 2004

Year Ending 31 December


SUMMARY
Headline EPS (GBp) P/E ratio Headline (x) Headline EPS growth(%) EPS FD (GBpl P/E ratio FD (x) Operating CFPS IGBpl Free CFPS IGBpl P/CFPS lxl DPS (GBp) Dividend yield (%) BV/Share (GBp) Price/BV (xi Weighted average shares (m) Average market cap (GBP m} Enterprise Value (GBP m) EV/Sales EV/EBITDA EV/EBIT EV/Operating Capital INCOME STATEMENT IGBP m) Sales revenue Operating EBITOA Depreciation Amortisation EBIT Net interest income (expense) Associates/affiliates Investment and other inc./exp. Exceptionals/extraordinaries I nco me tax expense Minorltiee/preference dividends Net income CASH FLOW (GBP m) Cash flow from operations Movement in net working capital Capax Free cash flow Other investing activities Equity raised/!bought back) Dividends paid Net inc/(dec) in borrowings Other financing cash flows Total cash flows from financing Net cash flow

2000

2001

2002

2003

2004E

2005E

2006E

Equity Research Europe


UK

Pharmaceuticals

GlaxoSmithKiine
Reuters: GSK.L Bloomberg: GSK LN

Hold
as of 08 July Target price
Price

GBp 1091.00 GBp 1200.00

Company website

http:/{www.gsk.com
Company description
research~based GlaxoSmithKii ne is that develops, group pharmaceutical manufactures and markets v8ccines, prescription and over-the-counter medicines, as well as healthrelated consumer products. GSK has leadership in

60.96 30.6 15.7 68.49 27.3 64.90 49.05 28.8 38.00 2.0 127.14 14.87 6,065 113,253 112,564 6.23 19.0 21.2 13.0 18,079 5,926 626 0 5,300 -182 65 144 467 1,464 176 4,154 3,936 297 -961 2,976 -42,374 43,269 -2,028 4,032 -56 45,207 5,808 -1,776 3,421 6,642 170 966 2,544 7,847 21,590 4,032 8,603 12,635 7,711 1,244 8,955 873 611 9,566

72.30 25.8 18.6 50.33


37.0

76.39 59.08 24.4 39.00 2.1 121.85 14.14 6,065 113,020 112,755 5.50 16.6 18.5 11.9 20,489 6,803 713 0 6,090 -88 71 96 -1,332 1,663 131 3,053 4,633 67 -1,060 3,683 -847 -1,731 -2,325 200 34 -3,890 -1,154 1,354 2,131 6,845 174 1,673 3,228 8,292 22,343 4,232 9,859 14.091 7,390 862 8,252 801 2,101 10,353 13.3 33.2 29.7 54 40.4 31.3 49.1 6.1 1.6 26.6 69.2

78.26 18.3 8.3 66.22 21.6 91.46 74.80 15.6 40.00 2.8 111.32 10.71 5,912 84,499 84,520 3.98 11.3 12.8 9.0 21,212 7.492 909 6,583 -141 75 0 -712 1,760 130 3,915 6,407 98 -986 4,422 -209 -2,106 -2,327 411 -20 4,042 171 240 2,308 6,649 171 1,637 3,121 8,441 22,327 4,643 10,296 14,939 6,581 807 7,388 1,023 2,335 9,723 3.5 35.3 31.0 51 56.0 40.0 50.8 4.6 1.1 31.6 46.7

82.08 15.0 4.9 77.24 15.9 83.88 69.71 14.6 41.00 3.3 132.97 9.63 5,806 71,256 70,580 3.29 9.0 10.4 7.0 21,441 7,808 1.021 0 6,787 -161 93 0 -281 1,848 106 4,484 4,870 697 -823 4,047 -143 -964 2,333 460 -12 -2,839 1,065 -605 3,466 6,441 143 1,697 3,069 9,170 23,975 5,103 10,407 15,510 7,720 745 8,466 1,861 1,648 10,113 1.1 36.4 31.7 50 62.7 46.4 50.4 3.8 0.8 19.6 42.2

76.70 14.2 -6.5 76.68


14.2

89.16 74.29 12.2 42.00 3.8 143.52 7.60 5,716 62,362 61,441 2.99 8.6 9.9 6.0 20,572 7,123 888 6,233 -140 101 0 0 1,704 107 4,383 6,096 300 -860 4,246 -160 -1,500 2,393 0 -8 3,901 195 195 3,211 6,403 143 1,847 3,168 9,470 24,241 5,103 10,580 15,683 8,204 355 8,568 2,188 1.892 10,451 4.1 34.6 30.3 55 55.1 43.6 44.3 4.1 1.0 22.1 44.6

80.46 13.6 4.9 80.46 13.6 94.99 78.82 11.5 43.00 3.9 148.91 7.33 5,566 62,362 61,613 2.89 8.5 9.7 6.8 21,283 7.291 925 0 6,366 -140 106 0 0 1,741 112 4,478 6,287 310 -900 4,387 -160 -2,000 -2,453 0 -8 -4,461 -224 224 2,987 6,378 143 1,997 3,271 9,780 24,556 5,103 10,758 15,861 8,289 407 8,695 2,520 2,116 10,811 3.5 34.3 29.9 53 54.3 43.1 44.2 4.2 1.0 24.3 46.6

86.88 12.6 8.0 86.88 12.6 84.65 66.19 12.9 44.00 4.0 159.00 6.86 5,416 62,362 62,645 2.80 8.2 9.3 6.3 22,357 7,674 963 0 6,711 -170 111 0 0 1,829 117 4,706 4,686 326 -1,000 3,686 -160 -2,000 2,512 0 -7 -4,519 -1,065 1,085 1,901 6,416 143 2,147 3,380 10,106 24,092 5,103 9,917 15,020 8,611 461 9,072 3,888 3.202 12,274 5.0 34.3 30.0 51 55.7 41.8 43.3 4.6 1.0 36.3 39.6

four

major therapautic areas anti-infectives,

central nervous system, respiratory and gastrointestinal/metabolic and also has a growing portfolio of oncology products. GSK was formed in 2000 through the merger of Glaxo Wellcome end SmithKiine Beecham and currently ranks

second in market capitalisation within the global


pharmaceutical industry.

Research Team
Mark Clark +44 20 754 50470
mark.clark@db.com

Lucas Herrmann
+44 20 754 73636 Mark Purcell +4420 754 76522
lucas.herrmann@db.com

mark.purcell@db.com

Movement in net debt/(cash)


BALANCE SHEET IGBP m) Cash and other liquid assets
Tangible fixed assets Goodwill Other intangible assets Associates/investments Other assets Total assets Interest bearing debt Other liabilities Total liabilities Shareholders' equity Minorities Total shareholders' equity Net work in(} capital Net debt(cash)

Absolutll' Pries Return{%)


~10%

-5%

C;;opital
-2%?

-0%
1m

3m 12m

10%

------~~

Market Cap (m)

GBp1060.00 1390.00 GBP 62,362 USD 115,849

-;:::==============:;Price and Price Relative


21500 2000 1600 1000 500

Company identifiers Cusip SEDOL

NA

0925288

RATIO ANALYSIS Sales growth !%) Op. EBITOA/sales 1%1 EBIT/sales (%) Payout ratio (%) ROE(%) Return on Capital(%) Operating Return on Capital(%) Capax/sales (%) Capax/depreciation (x) Not debt/equity(%) Net interest cover (x)

nm
32.8 29.3 62 53.9 44.8 44.4 6.3 1.5 6.8 29.1

Margin Trends(%)
40 70

Return Ratios (o/,)

Not Debt (Cash) I Equity (%)


3600
3000 2600 2000 1600 1000

35
30 26 20 16 10 6 0 6 -10

eo
50

......

40
35

;o

. -02 03

30

~
00 01 02 03

!j\

"'
25 20 16

.. -.'

20 10 0 500 0

-
O<E OeE. 06E

07/99 07/00 07/01

07102 07/03 07/04


~

00

01

04E 0!5E 06E

--GiaxoSmithKiine {LJ-l.S.)

.. - .. - Sa lee growth(%)

" .. " ROE(%)


- - - R e t u r n on Capital(%) ---Operating Return on Capital(%)

- N a t debt /(cash) (GBP m) --Natdabtjoquhy(%)

- - R e i . to F.T. INDEX 100 fR.H.S.J

- - - O p . EBITDA/sales (%)

Source; Company data, Deutsche Bank estimates

'
00

10

'
02
03 04E 05E 06E

01

Page 2

Deutsche Bank AG

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0279-056039

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

Investment thesis
Outlook
GlaxoSmithKiine is the world's No. 2 drug company with a near-7% market share. In the first year after its merger, its performance was encouraging, with 2001 sales and EPS growth of 12% and 14%, respectively, in constant currency terms. By 2003, Pharma sales growth had slipped to just 5%, although the last tranche of merger savings allowed EPS to rise by 10%. The marked sales slowdown reflected the early onset of generic competition to GSK's lead antibiotic Augmentin, in 2002, and to its lead anti-depressant Paxil, in 2003. Each followed successful patent challenges by generic companies. Given the timing of the arrival of Paxil generics (in September 2003) and the 01 2004 launch of generics to GSK's No. 2 antidepressant Wellbutrin (yet again, following a patent challenge), 2004 will be a tough year for GSK. Company guidance for this 'transition year' is for EPS to be at least in line- in constant exchange rate terms - with the business performance in 2003 (ie, 82.1 p). The latter included a raft of non-recurring charges in 04 (totaling 401 m or 5p per share) which should ensure that this target is achieved without undue difficulty. Meanwhile, GSK continues to work hard to (as its respected CEO, J-P Garnier, puts it) "butld the best fJ/fJelthe th the thdustry". The first opportunity to present this pipeline in detail was at last December's R&D Day. In the event, this turned out to be a somewhat mixed affair, with news of a further sizeable uplift in the number of pipeline candidates more than counter-balanced by delays for certain projects and generally distant submission timelines for the majority of compounds. Later this year, however, Phase II data should emerge on several important pipeline candidates (respectively for depression, pain and rhinitis) and in early 2005 we expect Phase Ill results for the potentially exciting breast cancer drug 572016.

Valuation
We have consistently argued that GSK's shares deserve no more than P/E parity with the drugs sector on our longer-term EPS forecasts, given its unspectacular medium-term growth prospects (2003-07E EPS CAGR 3%) and the still-unproven nature of its large but early-stage R&D pipeline. Putting the shares at a 10-15% P/E discount to the sector on 2005E EPS would imply fair value in the range of 11401210p and our established target price is at the top end of this range, at 1200p. The shares (at 1091 p) are currently around 9% below our target price. Using DB's CROCI (Cash return on Capital Invested) methodology - which can be used to determine absolute rather than relative value- suggests a value of 1350p. Taking the two methodologies together suggests that the shares are somewhat undervalued but we do not feel confident that near-term newsflow (difficult 02 and U:::l comparisons, litigation and patent concerns, limited pipeline news) will unlock this value quickly and thus retain our 'Hold'.

Risks
We judge the key downside risks to our neutral stance to be those that apply to the majority of other large-cap pharma companies, namely patent losses and challenges and R&D setbacks. In addition, continuing US dollar volatility represents a continuing risk to EPS forecasts (although this is also true tor most of GSK's European peers). The principal upside risk in our view could come from positive developments in R&D and from legal victories on key drug patents.

Deutsche Bank AG

Page 3

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0279-056040

9 July 2004

Pharmaceuticals GlaxoSmith Kline

Deutsche Bank

IZJ

Table of contents

Advair's importance to GSK ............................................................. 5


Seretide/Advair accounts for 14% of GSK's Pharma sales ........................................ 5 ... and has driven half of GSK's growth in recent years ............................................... 5 Sales growth has slowed markedly in 2004 ................................................................ 6 The US accounts for >50% of Seretide/Advair's sales ............................................... 7

Asthma penetration peaking ............................................................ 8


Background .................................................................................................................. 8 Advair's penetration in asthma .................................................................................... 9 Advair's growth has slowed abruptly in asthma ........................................................ 11 GOAL could provide the next impetus to growth ...................................................... 12 AstraZeneca's Symbicort is a longer-term threat ...................................................... 14 Paediatric opportunity? .............................................................................................. 15 Modelling Advair in asthma ....................................................................................... 16

TORCH is the key in COPD ............................................................... 17


Background ................................................................................................................ 17 Step-wise drug therapy in COPD ............................................................................... 18 Advair's position in COPD is strong and growing ...................................................... 19 Biggest opportunity arises from the TORCH mortality trial ....................................... 21 Does Spiriva threaten Advair? .................................................................................... 22 How will Daxas (roflumilast) be positioned in COPD? ............................................... 22 Modelling Advair in COPD ......................................................................................... 23

A US patent challenge? ................................................................... 25


Advair enjoys several layers of US patent protection ................................................ 25 The UK combination patent was recently ruled invalid .............................................. 25 US challenge looks likely but generics impossible before 2008 ................................ 26

Advair forecasts & conclusions .......................................................... 28


Aggregating our US asthma and COPD forecasts ..................................................... 28 Consensus global sales forecasts are too high in our view ....................................... 28 Concluding remarks ................................................................................................... 29

Valuation .......................................................................................... 30
P/E and EV/EBITDA comparisons .............................................................................. 30 CROCI ........................................................................................................................ 31 Yield and cashflow considerations ............................................................................ 31

Forecasts to 2007 ............................................................................. 33

Page 4

Deutsche Bank AG

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0279-056041

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

[Z]

Advair's importance to GSK


Seretide/Advair accounts for 14% of GSK's Phar.ma sales ...
GSK's respiratory drug Advair, marketed as Seretide in Europe, combines the longacting bronchodilator salmeterol (Serevent) with the inhaled steroid fluticasone (Fiixtode/Fiovent). Launched in 2000 in Europe and in April 2001 in the US, Seretide/Advair is now the company's top-selling product, accounting for 14% of 01 2004 Pharma sales. With 2004 sales forecast at 2.45bn ($4.4bn), we estimate that it will rise two places to become the industry's No.5 selling product (Figure 1).
Figure 1: Top ten global pharmaceuticals by sales, 2004E ($m)
Rank
2

,
2004E sales ($m)
10.400 5,000 4,850 4,700 4.410 4,375 4.231
3,884

Product
Lipitor Zocor Plavix Norvasc Seretide/Advair Zyprexa Nexium Procrit/Eprex Zoloft Effexor

Company
Pfizer Merck Sa noli/Bristol-Myers Squibb Pfizer
GSK

3
4 5

6
7
8

Lilly AstraZeneca Johnson & Johnson Pfizer Wyeth

3,210 3,165

10

Source: Wutsohe Bark

... and has driven half of GSK's growth in recent years


We calculate that Seretide/Advair has been responsible for half of GSK's Pharma growth over the past three years (Figure 2).
Figure 2: Contribution of Seretide/ Advair to Pharma CER sales growth
15%

.c

10%

"' "' " :l


~

..
5%

.c Q_ a: w
U I

c .2

O%r-~------~

:;
0

1999 2000 2001 2002 2003

.0

;;:

01 02 03 04 01 02 03 04 01 02 03 2001 2001 2001 2001 2002 2002 2002 2002 2003 2003 2003

2004

c
-5%

-10%

Saratida/Advair Other

Deutsche Bank AG

Page 5

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056042

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

Furthermore, consensus market forecasts (as supplied to us by GSK) suggest that Seretide/Advair will continue to be responsible for around half of GSK's group sales growth over the next five years (Figure 3).
Figure 3: Consensus sales forecasts for Seretide/ Advair and GSK (bnl
bn
Seretide/Advair GSK group sales Seretide/Advair as %growth
s00r00 GfsX:oSrnithkflne

2003
2.21 21.44 255%

2004E
2.63 20.88 n/a

2005E
3.14 21.92 49%

2006E
3.60 23.05 41%

2007E
3.90 24.23 25%

2008E
4.40 25.68 34%

Change 2003-0SE
2.19 4.24 52%

Sales growth has slowed markedly in 2004


Seretide/Advair's growth has, however, slowed noticeably recently, slipping to 22% in 01 2004 as compared with the 39% CER growth reported in 2003 (Figure 4).
Figure 4: CER sales growth of Seretide/Advair by region since 04 2002
80%

71% 70% 67 60%

71%

~
0

50%

0,
~

Q)

40%

-----50%

57% 52% 51% 41'

4~~

"Til

:ii
(..)

~~'~'

40%

30% 23%
20%

'"
15%

'
%

,,.
24%

H:f?.
18%

17% 10%

0% 04 2002 012003 022003 03 2003 04 2003 012004

-USA -Europe -International -Global total

The principal area of slowdown has been the US, where growth slowed from 54% in 2003 to 24% in 01 2004, despite the long-awaited approval of the drug in November 2003 for use in COPD (chronic obstructive pulmonary disease). We suspect US wholesaler stocking trends distorted the apparent 03 and 04 2003 growth rates, as reported growth numbers of 57% and 51% respectively were substantially in excess of the 37% and 30% growth figures indicated by IMS prescription data (Figure 5). Nevertheless IMS data also shows a sustained downtrend in Advair's prescription growth over the past few quarters, with 01 2004 growth slipping to 22% and 02 showing a further deceleration to around 15% (with monthly MAT growth falling to 12% by end-June). Of note, the continued slowdown in 02 has been evident despite GSK's receipt in April of approval for the use of Advair in paediatric asthma (ie, ages 4-11). Thus the two key indication extensions for Advair received over the past eight months appear to have done little or nothing to halt the slide in the drug's growth.

Page 6

Deutsche BankAG

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056043

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

Figure 5: Advair US prescription growth is faltering (monthly MAT)


50% . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Q3 2003

Q4 2003

Q1 2004

Q2 2004

-New prescriptions -Total prescriptions


Soutr::fi f:xautsche Bank

The US accounts for >50% of Seretide/Advair's sales


Given that the US accounts for over half of Seretide/Advair sales (Figure 6) this marked slippage in growth is of considerable concern and prirnq fqcie suggests that the consensus forecasts shown in Figure 3 -which imply a CAGR in global sales of 18% over three years and 15% over five - could well prove overly optimistic. The purpose of this report is therefore to examine Advair's prospects in the crucial US market and to assess whether consensus expectations are indeed too rosy.
Figure 6: Geographic split of Seretide/Advair sales, 2003

International 9%

Europe
35%

USA 56%

Deutsche BankAG

Page 7

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056044

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

Asthma penetration peaking


Background
Around 20 million Americans, or 7% of the population, suffer from asthma (source: NHIS Study 2001 ). Of these, close to two-thirds are aged under 40 (Figure 7) and just over a quarter are children and adolescents (ie, aged under 18). The incidence of asthma is growing at an estimated 4% pa in the US.

Figure 7: Distribution of asthma patients (n= 20 million) in US by age group


yet~rs

0-3

5%

12-17 years
10%

40..55 years 24%

19-39 years
34%

Asthma is classified by short-term symptom observation into mild intermittent, mild persistent, moderate persistent and severe persistent. Approximately two-thirds of patients fall into the two mild categories (Figure 8).

Figure 8: Distribution of US asthma patients by disease severity

Severe Persistent
9%

Mild Intermittent 19%

Moderate Persistent
26%

source: survelilfJnoo DJra Inc. as citoo by Glaxosrnithlr;line

Page 8

Deutsche BankAG

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0279-056045

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

Treatment of asthma tends to follow a step-wise approach, based on recognised disease management guidelines (Figure 9). Patients with mild intermittent asthma primarily use short-acting beta2-agonist bronchodilators (mainly salbutamol/albuterol) on as 'as needed' basis. Increasing symptom frequency that results in daily use of such drugs indicates that the patient has mild persistent asthma at which point a low-dose inhaled steroid or an alternative anti-inflammatory agent tends to be added in. Moderate and severe disease require the stepping up of steroid dosage and the addition of a long-acting beta2-agonist, such as GSK's Serevent or of course via Advair. Note that strict adherence to the US guidelines would imply that Advair usage should be confined to patients with moderate and severe persistent disease.

Figure 9: US asthma management guidelines (NHLBII


Asthma management guidelines Asthma classification
Mild Intermittent

Clinical features (before treatment)


Symptoms :>2 days per week, asymptomatic and normal PEF between exacerbations, brief exacerbations with varying intensity, nighttime symptoms ,;;2 nights per month

Lung function
FEV1/PEF :;,80% predicted PEF variability <20%

Long-term control (daily medications)


No daily medication needed

Quick relief (intermittent)


Inhaled short-acting 82-agonist as needed Intensity of treatment depends on severity of exacerbations Daily use of short-acting 82 agonist, or increasing usage, indicates need to start or increase long-term control therapy

Mild Persistent

Symptoms >2 times per week but <1 time per day, exacerbations may affect activity, nighttime symptoms >2 nights per month Daily symptoms, daily use of inhaled short-acting 82-agonist, exacerbations :;,2 times per week that affect activity and may lsst days, nighttime symptoms >1 night per week

FEV1/PEF :280% predicted PEF variability 20-30%

Low dose inhaled corticosteroid Alternatives: cromolyn, leukotriene modifier, nedocromil, OR sust-rel theophylline Inhaled corticosteroid (low-tomedium dose) AND long-acting inhaled 82-agonist Alternatives: increase inhaled corticosteroid within mediumdose range OR inhaled corticosteroid (low-to-medium dose) and either leukotriene modifier or theophylline If needed (esp in patients with recurring severe exacerbations): Increase inhaled corticosteroid within medium dose range, AND add long-acting inhaled 82-agonist Alternatives: increase inhaled corticosteroid in medium-dose range, AND add eitiher leukotriene modifier or theophylline

As for Mild Intermittent

Moderate Persistent

FEV1/PEF 60-80% predicted PEF variability >30%

As for Mild Intermittent

Severe Persistent

Continual daytime symptoms, limited physical activity, frequent exacerbations and frequent nighttime symptoms

FEV1/PEF :560% predicted PEF variability >30%

Inhaled corticoteroid (high dose) AND long-acting inhaled 82agonist AND if needed: corticosteroid tabs or syrup long-term; repeatedly attempt to reduce systemic dose and maintain control with high-dose inhaled corticosteroid

As for Mild Intermittent

Advair's penetration in asthma


Advair has been very successful in penetrating the US asthma market. Although IMS sales data does not clearly separate out asthrna from COPD prescriptions (due to the overlap in treatment), Figure 10 shows that Advair is the dominant product in the US respiratory market. accounting for close to 30% of overall sales. Only Merck's leukotriene antagonist Singulair also breaches the $1 bn sales mark.
Deutsche Bank AG

Page 9

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0279-056046

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

Figure 10: US asthma and COPD market, 2003 ($m)


Year to December 200:3 Inhaled steroids lplaln/combol Advair Flovent Pulmicort Azmacort Aerobid Others Retail :3,:309.5 2,073.2 529.7 519.0 114.8 50.0 22.8 Non-retail 455.2 241.1 113.5 54.3 27.0 9,1 10.2 Total 3,764.7 2,314.3 643.2 573.3 141.8 59.1 33.0

o/o total
46.6% 28.6% 8.0% 7.1% 1.8% 0.7% 0.4%

Beta2-agonists Serevent Foradil Brethine Branded and salbutamol/albuterol

1,042.0 154.8 51.0 5.6 830.6

281.9 61.4 5.6 41.7 173.2

1,:323.9 216.2 56.6 47.3 1,003.8

16.4% 2.7% 0.7% 0.6% 12.4%

Leukotriene antagonists

1,724.9 1,632.8

123.0 116.0 7.0

1,847.9 1.748.8 99.1

22.9% 21.6% 1.2%

Accolate

92.1

Anti-cholinergics Combivent Atrovent Duoneb Generic

765.3 430.2 176.4 104.4 54.3

230.0 106.4 49.3 44.5 29,8

995.3 536.6 225.7 148.9 84.1

12.3% 6.6% 2.8% 1.8% 1.0%

Xanthines Uniphyl Theo-24 Generic theophylline

83.2 30.0 16.1 37.1

26.6 1.7 3.5 21.4

109,8 31.7 19.6 58.5

1.4% 0.4% 0.2% 0.7%

Other ant-inflammatory Intel Generic cromolyn, Tilade, others Xolair Total


SOifCS'

40.2 22.9 12.0 5.3 6,966.1

4.5 2.7 1.1 0.7 1,121.2

44.7 25.6 13.1 6.0 8,08&.3

0.6% 0.3% 0.2% 0.1% 100.0%

1/vfS !mkh /)q'*

Allowing for patients receiving multiple therapies, we estimate that Advair is used in just under 40% of asthma patients in the US. Its penetration of the various disease categories ranges from a low of around 5% in mild intermittent asthma to a high of 55% in moderate and severe persistent asthma (Figure 11 ). In the category that represents by far the largest proportion of diagnosed patients, namely mild persistent asthma, Advair's market share is around 40%. This is despite the drug not being recommended in the guidelines for this level of disease severity.
Figure 11: Asthma severity and Advair market shares
Asthma classification Mild Intermittent Mild Persistent Moderate Persistent Severe Persistent Total

o/o of total patients treated


19% 47% 25% 9% 100%

Estimated Advalr share 5% 40% 55% 55% 38%

Page 10

Deutsche BankAG

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-05604 7

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

There is a growing debate, however, about the appropriateness of disease categorisation when measured purely by short-term symptoms. A landmark 2002 study by Fuhlbrigge et al ('The burden of Asthma in the United States', A'h J Aespir Crit Cere f'v?ed Vol. 166 pp 1044-1 049) strongly suggests that a large number of patients diagnosed as 'mild' should in fact be classified as 'moderate-to-severe' based on a more rigorous assessment of the functional impact of their asthma on their lives. Specifically, in this 1,800 patient study, 67% of patients were classified as mild based on reported daily and nocturnal symptoms over the previous four weeks. However the proportion fell to 30% when the clinical assessment also took into account the functional impact (physical, social. and nocturnal) on patients' lives and just 22% if long-term symptoms (eg, frequency of exacerbations over a 12month period) were also considered (Figure 12). This clearly suggests that patients diagnosed as mild should be more broadly assessed for their disease severity and that more aggressive (steroid-containing) therapy may often be warranted.

Figure 12: Underestimation of asthma severity in the US


90%

80% 70%

77%

~
;;
M

60%

" ;;
"0

.s
0
0
0

'0

50%

40%

e
0.

0 0.

30% 20%

10%
0% Short-term symptoms

long-tenn symptoms

Functional impact

Global symptom burden

Mild intermittent Ill Mild persistent Moderate/severe persistent


Sooroo Gl<t<oSrrithk;lin9 prasenta ~!011 of data from 4.tnsrlc<M Joor!)fJ! of Respiratory Critic;:;! C-e/Vfadicins :xxQ: 7e::r 104.4--4.9

Advair's growth has slowed abruptly in asthma


Verispan data cited by GSK suggests that the percentage of Advair's US sales accounted for by COPD jumped from 16-17% in mid-2003 to just over 20% in 01 2004. Given the slowdown in Advair's overall sales growth, we calculate that this implies that sales in the asthma setting have slowed dramatically in 2004, from around 50% growth in 2003 to 19% in 01 2004. Furthermore, the continued slowdown in Advair's prescription growth in 02 implies that sales growth in asthma may have slowed to just 10% year-on-year (Figure 13). Repeating the same calculations using IMS data. which suggests that the proportion of sales from COPD has in fact leaped from 20% in 04 2004 to 28% in 01 2004 would imply even slower growth in the asthma setting, of around 14% in 01 2004 and 6% in 02.

Figure 13: Advair has slowed markedly in asthma in 2004


2002 2003 Q1 2004 Q2 2004E

Advair sales growth (GSK) %sales in COPD (Verispan)

nm 16% 84% nm nm

54% 17% 83% 52% 64%

24% 21% 80% 19% 50%

17% 22% 78% 10% 51%

% sales in asthma (Veri span)


Implied growth in asthma sales Implied growth in COPD sales

Deutsche BankAG

Page 11

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0279-056048

9 July 2004

Pharmaceuticals GlaxaSmithKiine

Deutsche Bank

IZJ

In assessing this marked slowdown in the asthma setting, we understand that GSK believes it may have devoted too high a proportion of its marketing resources behind the new (and smaller) COPD indication. This could well lead to a redeployment of resources back to the asthma indication in the relatively near term. Certainly, from our discussions with the company, we believe that GSK foresees the biggest single opportunity for Advair to be expanding sales in the mild asthma setting rather than COPD. Here GSK hopes to exploit two factors: first, a growing body of clinical data in mild asthma (for example, it has trial results that show that continued treatment with Advair in mild patients provides better asthma control compared to abbreviated control on Advair followed by a switch to Flovent, Serevent or Singulair); and second, the aforementioned debate over mis-diagnosis of patients as 'mild' which could lead to more aggressive therapy. We are less optimistic, however, that a shift in marketing resources will lead to a major rebound in growth in asthma, at least over the remainder of 2004. We find it difficult to believe that the steroid-based asthma market is in fact very promotionally-sensitive given the limited competition that GSK faces in this category (Figure 10 showed that Advair and Flovent constitute c.80% of steroid sales in the US respiratory market). Furthermore, we believe an equally - if not more - valid explanation for Advair's abrupt slowdown in the asthma setting is simply that the drug has been so successful in such a short space of time: In the severe persistent setting, Advair's penetration has in our view neared its peak. From our discussions with GSK, we believe the company feels it will be difficult to move share beyond 60%, as compared with c. 55% currently. In the moderate persistent setting, Advair's penetration is also high, at around 55%, although we see scope for further share expansion with new clinical data (see discussion of GOAL study below). We believe share could ultimately reach around 60% (based on steroid penetration of 80% and Advair increasing its share within the steroid category to around 75%). In the mild persistent setting, Advair's penetration of around 40% must also be considered fairly high, given that usage of the drug in this patient group would not follow from strict adherence to the treatment guidelines. Indeed, GSK acknowledged in our discussions that it will take time to build further share here. We also note that the low-dose formulation of Advair (1 00/50). typically used in milder patients, is the slowest growing according to IMS data. We see little or no opportunity to expand use in the mild intermittent setting in which treatment with Advair is largely inappropriate and not recommended.

A further challenge to the US growth of Advair over the remainder of 2004 follows from the tough wholesaler-inflated comparisons in H2 2003. As noted earlier, GSK reported US sales growth of over 50% in each of 03 and 04 2003 whereas IMS indicated volume growth respectively of around 37% in 03 and 30% in 04. Unless similar wholesaler stocking trends are seen in H2 2004, this will clearly impact on Advair's quarterly reported growth rates. We are, however, much more optimistic that GSK can at least stabilise the prescription growth trend for Advair in 2005, based on the opportunity afforded by the GOAL study.

GOAL could provide the next impetus to growth


In our view, GSK has a major marketing opportunity in 2005 when it expects to unveil the results of a major 3,500-patient outcome study, known as GOAL (Gaining Qptimal Asthma ControL). This trial assesses the use of Advair across differing
Page 12 Deutsche Bank AG

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056049

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

severities of asthma and asks the question "is total control or clinical remission of asthma achievable". GSK has used a very exacting definition for total control that includes all the following criteria (which must be maintained for at least seven out of eight consecutive weeks when assessed over an 8-week closing period): Normal lung function (morning PEF 280% predicted) No daily symptoms No exacerbations No night-time awakenings due to asthma No rescue medication (salbutamol) No emergency hospital visits No treatment-related adverse events forcing a change in therapy.

The complex study design includes three groups of just over 1,000 patients of which one was initially steroid treatment-naive, one had previously been treated with a low dose of inhaled steroid, and one had previously been treated with a moderate dose of inhaled steroid. In effect these groups reflect differing levels of asthma severity as indicated by the level of baseline steroid therapy. Patients in each were then randomised to receive either Advair or Flovent and treatment was stepped up every 12 weeks until patients reached total control. Patients then remained on this dose for the rest of the one-year double-blind period. An analysis was conducted in the final eight weeks of the study on all patients who had previously achieved total control to identify if total control had been maintained. While the full results from GOAL are expected early next year, some preliminary findings have already been presented at medical meetings (EAACI, MAAI) in 2004 (Figure 14). These showed that: (1) in all groups Advair allowed the majority of patients to be symptom-free and not in need of rescue medication for more than half the time (note that these end-points are not as exacting as for the full trial); (2) Advair numerically outperformed Flovent on each of these two efficacy parameters (although p significance values were not divulged); (3) the more intense the level of prior steroid-based therapy (ie, the more severe the disease). the worse the level of disease control; and (4) adverse event rates between the two drugs were similar.
Figure 14: Early data from GOAL study
Advair Steroid-naive No symptoms for > half of the time No need for rescue medication for > half of the time Overall rate of adverse events Rate of serious adverse events Lowdose prior steroid therapy No symptoms for > half of the time No need for rescue medication for > half of the time 66% 81% 60% 3% 51% 66% 57% 2% 15% 15% 3% 1% 72% 86% 56% 2% 66% 77% 55% 4% 6% 9% 1% 2% Flo vent %difference

Over aII rate of adverse events


Rate of serious adverse events Moderate dose prior steroid therapy No symptoms for > half of the time No need for rescue medication for > half of the time Overall rate of adverse events Rate of serious adverse events
Sooroo

54% 71% 69% 6%

40% 57% 67% 4%

14% 14% 2% 2%

o-'14 Cl .<I:X>t. 44.<14/ :;>wt


Page 13

Deutsche Bank AG

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056050

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

The trial has been completed and the results submitted for publication. Assuming the full results are positive - which seems likely given the recent remarks of the international coordinator, Dr Eric Bateman, that cqn Sc/Y for sure tn<Jt there t-vtl! he <1 significqnt proportion of patients 'vi)Jo can enjoy an astn~na free status" (source: Medical Post, 17 February 2004) - then we would expect this to result in increased share for Advair in the moderate intermittent category. Depending on the precise details of the data, this could also spur growth in share in the larger mild intermittent setting (although this might require a guideline change). Growth in the asthma setting overall would then be likely to continue until at least 2007 when we expect AstraZeneca's competitor combination drug Symbicort to be launched in the US (we do not believe Aventis/Aitana's steroid Alvesco - which was filed in December 2003 and could be launched in late-2005 or 2006 - poses any significant threat as it is a plain steroid).

"vve

AstraZeneca's Symbicort is a longer-term threat


Symbicort is essentially a look-alike of Seretide/Advair, combining the long-acting bronchodilator Oxis (formoterol) with the steroid Pulmicort (budesonide) in the breath-actuated Turbuhaler device. The drug has been launched in over 60 countries, including all the major European territories (where its first launches began in 2001 ), but it is not yet available in the US (see below). The principal therapeutic difference between Advair and Symbicort is that the bronchodilator component of Symbicort has a fast onset of action (<15 minutes versus 30-48 minutes with the Serevent component of Advair). This has allowed AstraZeneca to devise a more tailor-made approach to therapy which it terms 'adjustable maintenance dosing'. Essentially, this does away with the need for a separate fast-acting bronchodilator and allows the patient to vary his/her medication with the severity of symptoms (ie, it allows the patient to switch between once- and twice-daily inhalation of Symbicort, depending on whether the need is for base-line therapy or for treating exacerbations). AstraZeneca has branded this new approach 'Symbicort Single Inhaler Therapy' (SiT) and submitted this for approval in the EU in November 2003. If approved -which is far from guaranteed as the regulators may feel it places too much emphasis on the patient to monitor their own disease - we would expect this patient-friendly (and cost-effective) concept to help Symbicort to expand its current c.25% share of the European combination therapy market. In support of the SiT concept, AstraZeneca has cited, amongst others, the SUND study in 658 moderate-to-severe asthmatic patients (Aalbers; Curr !\;Jed Res Opin 2004; 20(2)). This showed that adjustable maintenance dosing with Symbicort resulted in a 40% lower rate of exacerbations and 27% less use of rescue medication compared with fixed dosing with Seretide/Advair. GSK has unsurprisingly taken issue with this study as it believes that the trial design was flawed (notably it did not allow patients with worsening control to adjust their Seretide/Advair dosage upwards, which clearly does not reflect a 'real world' situation). Development of Symbicort in the US has been very protracted and the filing date has slipped several times. We believe this reflects issues surrounding the inhaler device. While the Turbuhaler is approved in the US for delivering Pulmicort, problems with its dose-repeatability held up the FDA review for several years during the 1990s. AstraZeneca has switched to developing Symbicort in the US in a pressurised metered-dose inhaler (pMDI) and it currently targets an FDA submission for use in asthma in 2005 (and in COPD beyond 2006). We understand that the pMDI device chosen by AstraZeneca is patented and novel and consequently based on the FDA's relatively tardy track record in this area - we conservatively

Page 14

Deutsche BankAG

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056051

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

assume that the regulatory review of Symbicort will take around two years. Our best estimate is that AstraZeneca will launch Symbicort in the US during 2007. Clearly Advair's likely six-year marketing head-start and its more extensive clinical database will mean that Symbicort is unlikely to capture a very large market share quickly. Nonetheless the newer drug's faster onset of action and the associated adjustable dosing concept are likely to prove genuinely attractive attributes to many patients and physicians and hence - in our modelling - we assume that Symbicort will capture close to a 10% market share of combination therapy in 2008.

Paediatric opportunity?
Children and adolescents represent around a quarter of diagnosed asthma sufferers (Figure 15). In absolute terms this equates to around a 6 million patient opportunity. Advair was already commercially available - as part of its original FDA approval in 2001 -for use in the 12 and over age group prior to its April 2004 approval for use in 4-11 year olds. The latter group accounts for around 13% of asthma sufferers. The fact that this latest approval appears to have had little or no impact to date on Advair's sales trajectory is likely to be explained, in our view, by a permutation of one or more of the following factors: a pre-existing significant level of 'off-label' use; the particular dynamics in this young patient group, in which steroid-related safety fears loom larger (see below); and/or the fact that GSK has been slow to market this indication, having only introduced detailing aids in June, two months after approval.
Figure 15: The US asthma market- breaking out the paediatric population

4-11 years

Adult

Paediatric

13%

1217 years 10%

72%

28%

source GfQ);oStnitfJK!me

In terms of the dynamics within this segment of the market, Verispan estimates Advair's market share among paediatricians to be around 15%, a figure that has barely changed since mid-2002. Strikingly, this represents approximately half of its share (of c.30%) among all other key prescribing audiences (eg, primary care physicians and pulmonary and allergy specialists). The major difference in Advair's penetration is explained by the dominance in the paediatric segment of Merck's leukotriene antagonist Singulair, which enjoys a c.40% market share. As a simple once-daily tablet, Singulair offers a major convenience and compliance advantage for younger patients compared with inhaler-based therapy as well as an absence of steroid 'taint' (ie, fears over growth retardation etc). The fact that Singulair is only moderately efficacious and that it has been shown in clinical studies in adults to be
Deutsche BankAG Page 15

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0279-056052

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

[Z]

inferior to Advair (for example, 'First-line maintenance therapy in asthma: fluticasone propionate/salmeterol combination vs montelukast'. 1\tn J Respir Crit Cf!re f'vJed 2001; 164(5):759-763) appears to have made little difference to the success of this drug. Merck reported US sales of Singulair of $1.4bn in 2003 (vs. Advair's $2.0bn) and 01 2004 sales grew by 32% in prescription terms (aided by approval in 2003 for use in allergic rhinitis). Without head-to-head clinical data showing Advair's superiority in the children (we are not aware of any such studies being planned), we find it difficult to see what could dislodge Singulair's entrenched position and thus view the paediatric opportunity for Advair as relatively limited. Indeed, we see this as a smaller growth opportunity than both mild adult asthma and COPD.

Modelling Advair in asthma


In modelling Advair's sales in asthma (Figure 16) we make the following key assumptions: Growth in US asthma patient numbers is a steady 4% pa and the proportion treated with an inhaled steroid rises from 67% in 2003 to 75% by 2008, driven mainly by increasing treatment of mild adult patients. Advair's apparent share of inhaled steroid therapy dips slightly in 2004, given that wholesaler stocking trends appear to have over-stated 2003 sales, but rises to 62% in 2006 from 59% in 2004. Key here is the unveiling of the GOAL data in 2005. This equates to Advair's share of total treated patients in asthma rising from 37% in 2004 to 40% in 2006. GOAL could possibly also increase the average duration of therapy although we have not reflected this in our model. This suggests that Advair sales in asthma will grow by 10% in 2004, picking up to 15% in 2005 and 12% in 2006. We assume the launch of Symbicort in 2007 sees some market share loss for Advair, leading to a flattening of sales in 2007 and 2008. Over this period we see Advair's sales in asthma holding level at around $2.5bn pa.

Figure 16: Modelling Advair in the US asthma market ($m)- excludes COPD use
Sales Sm Total asthma patients (m) %treated Treated asthma patients (m) %taking steroid Steroid-treated patients (m) % Advair share of steroid-treated Advair overall patient penetration % o/o Symbicort share of steroid-treated Adva ir treated patients Average length of therapy (months) Total Advair scrips (m) Monthly AWP pre-discount($) Average realised price($) Advair revenues in asthma Yay change Note: Symbicort revenues in asthma
Apte "' Mdesele st<:J.Xing trends inf/fite<:f f-/2 X1J3 seles Md tw hCJtre chose11 to reflect thi:s

2003 20.00 67% 13.48 63% 8.49 60%* 38%*

2004E 20.80 69% 14.33 63% 9.03 59% 37%

2005E 21.63 70% 15.23 64% 9.75 61% 39%

2006E 22.50 72% 16.18 65% 10.51 62% 40%

2007E 23.40 73% 17.17 65% 11.16 60% 39% 2%

200BE 24.33 75% 18.23 65% 11.85 55% 36% 7% 6.52 3.0 19.85 146 124 2,470 0% 319

CAGR
4%

6%

7%

5.10 3.0 15.52 128 108 1,683 n/a

5.33 3.0 16.23 134 114 1,847 10%

5.95 3.0 18.11 138 117 2,123 15%


tre(Jted

6.52 3.0 19.86 141 120 2,375 12%

6.64 3.0 20.23 144 122 2,468 4% 103

5% 0% 5% 3% 3% 8%

in Cl.Jt np:iel thrrx.gh 4d\-elr-s s/tEiJOO of p;Jtients

SOIJ(Cf! Dootscf"!> &Jnk

We discuss Advair's prospects in the US COPD market next.


Page 16 Deutsche Bank AG

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056053

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

[Z]

Advair forecasts & conclusions


Aggregating our US asthma and COPD forecasts
Figure 25 aggregates our updated models for Advair in asthma and COPD. In summary we expect Advair's US sales to grow in the teens (in US$ terms) until 2006. Thereafter we assume that the arrival of AstraZeneca's Symbicort causes growth to flatten off. Our rev1sed forecasts are very close (within $70m in all years) to those we have previously assumed in our GSK model. Importantly, we have not assumed a successful patent challenge and generic launch in this time-scale. Figure 25: Summary Advair (and Symbicort) US forecasts ($m)
Sales $m Advair sales in asthma Advair sales in COPD Total Advair sales yoy US$: rate Total Advair sales in m Yoy

2003
1.683 342

2004E
1.847 516

2005E
2.123 579

2006E
2.375 685

2007E
2,468 846

2008E
2,470 900

CAGR 8% 21%

2,026
54% 1.64

2,363
17% 1.80

2,703
14% 1.80

3,060
13% 1.80

3,314
8% 1.80

3,370
2% 1.80

11%

1,236
83% 17%

1,313
6% 78% 22%

1,602
14% 79% 21%

1,700
13% 78% 22%

1,841
8% 74% 26% 120 3%

1,872
2% 73% 27% 372 10%

9%

% of sales in asthma
% of sales in COPD Note: Symbicort total revenues Symbicort share of combination revenues
Soures D&utsche &ink estitn<J ms tJfld CO/!JP"IIY oo ta

Figure 26 shows our forecasts for the US combination bronchodilator/steroid category and indicates that we expect a CAGR sales of 13% to 2008, a rate of growth that would be deemed very healthy in many other therapy areas. Figure 26: The US combination bronchodilator/steroid market
4,000

3,500

3,000

2,500

Jl

:n

2,000

;:l
1,500

1,000

500

2003

20041:

2005E

2006E

2007E

2008E

Advair sales in asthma IIAdvair salas in COPD Symbicor

Consensus global sales forecasts are too high in our view


Adding in our non-US forecasts (Figure 27). we project an 11% rise in global Seretide/Advair sales in 2004 in sterling terms, with sales ultimately reaching 3.5bn by 2008. This leaves our forecasts significantly below consensus in all future years
Page 28 Deutsche Bank AG

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GS KC0-0279-056065

9 July 2004

Pharmaceuticals GlaxoSmithKiine

Deutsche Bank

IZJ

and > 10% below consensus from 2005 on. In short, to answer our original question, we do believe market expectations for Seretide/Advair are too rosy and almost certainly based on overly optimistic US sales growth assumptions. Figure 27: Seretide/ Advair global forecasts: DB vs. consensus (bn)
Year to December lbn)
US sales Non-US sales

2003
1.24 0.98

2004E
1.31 1.14

2005E
1.50 1.28

2006E
1.70 1.41

2007E
1.84 1.52

2008E
1.87 1.62

DB Advair sales Consensus Advair !source: GSK) Difference%


Source: Doot:sche 8otKesti!T'iJissi1f?dco!TJPfJn}'dQte

2.21 2.21
n/a

2.45 2.63
-7%

2.78 3.14
-11%

3.11 3.60
-14%

3.37 3.90
-14%

3.49 4.40
-20%

Concluding remarks
In conclusion, we would summarise our findings as follows: While we believe it would wrong to be overly bearish about recent US prescription trends for Advair- given the fresh growth opportunities afforded by the GOAL and TORCH studies in 2005 and 2006 respectively- we nevertheless believe that consensus forecasts for Seretide/Advair are significantly too high. In H2 2004, reported US growth could be pressurised by a short-term peaking of Advair's market share in asthma and by prior-year wholesaler stocking trends. Beyond 2004, we do expect Advair to sustain growth in double digits until such time as Symbicort is launched in the US, which we currently project in 2007. In the mean time, a challenge to Advair's US combination patent by a US partner of Cipla seems likely in our view, which could adversely impact GSK's share price. However. we cannot call the likely outcome of such a challenge and we note that generics could not be launched before February 2008. The impact of a successful challenge would hence be distant and difficult to quantify. All of the above will serve to increase investor focus on GSK's follow-on, oncedaily 'Beyond Advair' combination, which is expected to be filed in H2 2008. More generally, our below-consensus forecasts for the drug imply that GSK cannot rely so heavily upon Advair to drive significant growth in future years (Figure 28), thereby placing further pressure on the R&D pipeline to deliver.

Figure 28: Advair's contribution to GSK's CER Pharma sales growth


15.0%

...
~

:'

~
10.0"(o

&
u B
.Q

!
'

s.mr.

]
o.oo;.
2001

2002

2003

2D04E

2005E

2006E

2007E

2008E

Seretide/Advair 11 'Base business' ex Seretide/Advair New products (2004+ ) Sooroo t:'Eutscha &<mk:asti~tes sndOOOJP'JflY d$ta

Deutsche Bank AG

Page 29

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GS KC0-0279-056066

c1t1groupJ
Smith Barney

See page 26 for Analyst Certification and Important Disclosures

~:r!l~l'tl~::'i~i~l;r~9-lfijliiiJJ1tlnJr~r1fl.
Low Risk (L)
EQUITY

Price:

11.61 12.35 68,638.3m

RESEARCH:
UNITED KINGDOM

I Target: I Mkt Cap:


24 June 2004

Pharmaceuticals

Kevin Wilson +44-20-7986-4498


kevin.c.wilson(l)citigrrup.com

Landon

Alistair Campbell +44-20-7986-4164


alistair. cam pbell@citigroup .com

.. w
0
::::s

G>

a.

London

Peter Verdult, CFA* +44-20-7986-4499


peter.verdu lt@citigroup .com

London Joanna Jarman* +44-20-7986-4207


joanns.jsrman@citigroop.com

London Priyan Ratnasingham* +44-20-7986-4464


priyan.ratnasingham@Citigroup.com

Landon

*US investors should contact Kevin Wilson

Smith Barney is a division of Citigroup Global Markets Inc. (the "Rrm"), which does and seeks to do business with companies covered in its research reports. As a result, investors should be aware that the Firm may have a conflict of interest that could affect the objectivity of this report. Investors should consider this report as only a single factor in making their investment decision.

Citigroup Global Markets

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056078

GlaxoSm~hKiine-

24 June 2004

Table of Contents
Investment Summary
~1/Wtil" (Asthma,

3 4 4
5 5

COPD) Reassessed

Advair : we scale back our aggressive growth assumptions, and are now below consensus................. Advair in COPD: GSK unable to promote benefits due to narrow wording of approval.......................

Scepticism about ICS a handicap to use ......... ..... ....... ......... .... .. ................. ... ...... ...... .......... .. ................
Advair in asthma ..... .. ... ............. .... .. ... .. ..... .. ... .... .. ..... .. .... .. ... ... ....... .. .... .... .. ... .. .... ............. .... .. .... .... ..... ...

7
9 10 10 11 11 11 11 11 12 12

Forecast Changes R&D Pipeline Newsflow Oral anti -cancer dual kinase inhibitor 572016 ............ ............. ......... .......... ... ... ... ...... ...................... ...... The novel pain compound, dual COX inhibitor (406381) in arthritis and neuropathic pain.................. The 'son of Wellbutrin' for depression (353162)................................................................................... The 'son offluticasone' (685698) for allergies, then asthma.................................................................
Entereg (alvimopan) in post-operative bowel dysfunction....................................................................

Given the pipeline depth, some disappointments likely.........................................................................


R&D seminar to be held later in the year, probably 4Q04, with therapeutic bias..................................

Pipeline no longer for free . .. .. .... .. ............ ... ..... .. .. ............. .... ... ..... .. .. .... .. ... .. . .. .. .. . .. .... ... .......... ........ .......
~/-New

Litigation Risk Casts a Shadow

13
13
17

New York State files suit 2 June 2004................................................................................................... Proposed clinical trial database presages tectonic shift in how industry controls data, with attendant increased risks.... .... ... .. . .. .. .. . ..... .. .. .. . .. . .. ... .... .. . ... .... ... .. . .. .. .. ... .. . .. .. .. . ... ..... .. .. ... .. .. ... .. . .. .... .. . ... ... ... ... .. ... .. .. . Investment Thesis and Valuation Investment thesis.................................................................................................................................... Cash flow yield underpins value............................................................................................................ Valuation................................................................................................................................................ Risks......................................................................................................................................................

18

18 18 19 19

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056079

GlaxoSmithKI'Ine- 24 June 2004

Following our significant teductions in Advair sales forecasts and, consequently, EPS fotecasts, we downgrade our recotntnendation to HolcJ/Low Risk (<L) frotn Suy!Low Risk (1 L). We expect further litigation o~rer Paxil use in children and lillhile R&D pipeline news will etnerge during <H04, it should not catalyse a terating of the shates. Forecast 2005 EPS growth is 8% ~rersus 11% for the sector and 8% for the tnarket.
-4~11' (asthma

and COPD) & EPS forecasts cut from above to below consensus

We cut our Advair (for asthma and COPD -chronic obstructive pulmonary disease) forecasts by 15% for 2004E and by between 21% and 33% for 2005E08E. We cut our EPS forecasts by 1% for 2004E, 4% for 2005E and 7% for 2006E.
~I (depression)

~ en t!
c
CD
,A 1

litigation likely to expand

We expect the New York State lawsuit for fraud over alleged suppression of . . . . Paxil clinical trial data showing increased suicidal tendencies in children and adolescents to result in a fme of US$500m. However, a flood of plaintiff cases V may be expected, which will be bad for sentiment, if ultimately hard to prove.
More pipeline news In 2H04

Following modestly encouraging early data on the novel oral anti-cancer drug 572016 at ASCO (American Society of Clinical Oncology), we expect further phase II data on 4063 81 for arthritis, 3 53162 for depression and 685698 for allergies. Additionally, an R&D seminar will be held later in the year with further information on certain areas ofthe pipeline. We do not believe phase II data will drive a major rerating of the shares. Stripping out the underlying business implies a value of 7 billion for the pipeline, or 125p per share, which seems about right given its early stage of development.
2005E P/E discount to sector of 20%, premium of 20% to UK market

...
ftS

On our 2005 forecasts the shares are trading at a 20% discount to the European pharmaceutical sector and a 20% premium to the UK market. However, 2005E EPS growth is 8% versus 11% for the sector and 8% for the market.
We downgrade to Hold/Low Risk (2L) from Buy/Low Risk (1 L) with a revised target price of 1,235p from 1,400p, based on a 15% discount to the sector on 2005E EPS forecasts, or a multiple of 15.4x.

C1t1groupJ
Smith Barney

........
3

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056080

GlaxoSmithKiine - 24 June 2004

~C/WIIr(Asthma,

COPD) Reassessed

~~ctil': we scale back our aggressive growth assumptions, and are now below consensus

Figure 1. Seretide/Advairforecast Changes, 2003-07E (Pounds in Millions)


2003 2004E 2005E 2006E 2007E 2008E

Serettte/Advair Seretlde/Advalr %change

12/02/2004 24/0612004

2,214 2,214 0%

2,928 2,489
-15%

3,876 3,059
-21%

4,972 3,559
-28%

5,891 3,975
-33%

6,182 4,131
33%

Consensus
Sources:
Glaxosmlth~ine

2,636
(Consensus) and Smith Barney estimates.

3,146

3,603

3,990

4,429

Following a review of the recent volume growth in the US and after the American Thoracic Society (ATS) conference in Orlando, we have reduced our forecasts for Advair by between 15% and 33%. We have moved from above to below consensus. We have reduced out forecasts for the following reasons:

>>>-

W ~: ha v~: lowered our assumed rates of Advair market share growth in moderate and severe COPD in the US. We have marginally reduced our assumed penetration rates in mild to moderate asthma. We have adjusted 2004 forecast~ for a weaker US dollar/sterling exchange rate.

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0279-056081

GlaxoSmithKiine - 24 June 2004

~C/tli!til'

in COPD: GSK unable to promote benefits due to narrow wording of approval


GSK presented data at ATS that clearly showed significant improvement in lung function and dyspnoea (breathlessness) compared with Combivent (ipratropium and salbutamol combination) in a broad population ofCOPD patients.

Good data vers1.1s Combivent, b1.1t I=DA will not allow promotional use

Advair is only approved for treatment of COPD associated with chronic bronchitis (and not associated with emphysema). The above trial was conducted in an allcomers population with COPD, including patients with both bronchitis and emphysema. Consequently, the FDA will not allow GSK to publicise the result (no press releases) nor allow it to use the trial result in promotional material.
Physicians we spoke to at ATS suggested that there must have been asthmatics included in this trial, given the dramatic difference between the two drugs. Bearing in mind that it took two attempts with the FDA to getAdvair approved (two approvable letters before fmal agreement on the label), this is perhaps not surprising, as the trial would have been started in the expectation that the label wording would have been broader than it has turned out to be.
It is not clear whether it will be possible to broaden the Advair label, or whether the promotional restriction will be lifted. We believe both will be difficult to overcome.

This gagging of apparent superiority of Advair will restrict GSK' s ability to supplant Combivent given together with inhaled corticosteroid, which is GSK's principal competitive target and pricing reference in COPD.
SpMva launch ongoing

Furthermore, the competitive landscape will toughen with Pfizer/Boehringer Ingelheim's Spiriva currently being launched in the US. Spiriva benefits from a wider label including use for all COPD patients.

I Scepticism about ICS a handicap to use

TORCH may be critical to 4c~W~Iis fortunes in COPD >- There is a clear lack of consensus among clinicians over the role of inhaled corticosteroids (ICS) in COPD despite the fact that guidelines recommend them in more severe disease.

>-

We believe that the TORCH (Towards a Revolution in COPD Health) study, GSK's three-year trial investigating the impact of Advair on survival, will be critical to reinforcing the marketing message. However, results are not expected before 2006.

4fll,.:til'is competing against 8/Jiiwt and physician reluctance to prescribe steroids Two relatively new treatments have become available in the US for COPD during 2003 and 2004 (both have previously been available in Europe).

>-

GSK's Advair was approved in the US in November 2003 for the treatment of COPD in patients with associated chronic bronchitis.

This section is an extract from our report, Smith Burney ui ATS, published in May 2004.

"""" ctttgroupJ
Smith Barney

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056082

GlaxoSmithKiine- 24 June 2004

>-

Pfizer/Boehringer rngelheim's Spiriva was approved in the US in February 2004 and although aheady available, the official 'launch' will take place in the next couple of weeks.

Spiriva has a wider label and is indicated for all COPD patients.
Osteoporosis risk & steroids in COPD Steroid risk -benefit in doobt ...

In general, there appears to be a lot of concern within the COPD community over whether the benefits of using res outweigh the risks. Although it has not been defmitivelyproved as a side effect of res treatment in COPD, one of the main areas of concern appears to be over the potentially increased risk of osteoporosis.

... despite goide line changes

Despite this, however, the ATS and European Respiratory Society (ERS) updated their guidelines on the treatment of COPD during the recent ATS conference to confirm that res should be used in patients with an FEVl <50% who have suffered at least one exacerbation (moderate or severe) in the last year.
4avalr data remain strong

GSK presented some relatively strong data at ATS reinforcing the role ofiCS, andAdvair in particular, in managing COPD. Highlights included:
COSMIC sopports Advalr

>-

role

Results from the COSMIC study: a one-year withdrawal of fluticasone after three months' treatment with combined salmeterol/fluticasone (Advair) in patients with moderate to severe COPD. This study showed that withdrawal of fluticasone resulted in deterioration oflung function (FEVl and FEVl/FVC) and an increase in exacerbations. Analysis of the results of two trials comparing Advair and Combivent (ipratropium/albuterol). These demonstrated that Advair produced a significant improvement in both lung function and dyspnoea (breathlessness) when compared with Combivent over an eight-week period.

>-

Clinicians remain sceptical

In general, we believe clinicians still feel that there is not enough convincing data supporting Advair use in moderate disease. In addition, many would apparently prefer to add a standalone steroid (eg Flovent) to existing bronchodilators (eg Spiriva) rather than switch tack completely by switching toAdvair.
TORCH may change thinking TORCH may illotninate Advair's troe potential

All the physicians we spoke with felt that GSK' s TORCH study had the potential to radically change prescribing practice within COPD. This is a large, three-year study assessing the effect of Advair versus its individual components alone on mortality in COPD. It will also study any negative effects on bone mineral density. Only long-term oxygen therapy has been shown in prospective studies to have a significant effect on survival in COPD patients so a positive result for Advair in this trial would provide a significant boost to the drug. However, we arc not expecting results of this trial before 2006. Until the TORCH data are available (a~suming a successful study), we anticipate that GSK will have to work hard to win over clinicians and encourage them to prescribe Advair for COPD.

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056083

GlaxoSmithKiine- 24 June 2004

l4cN~II' in asthma 2
Jldlr.,.ll'scores with GOAL- raising control in mild disease
Design of the Advair
QOAL trial

At ATS GSK presented further results from the Gaining Optimal Asthma ControL (GOAL) study (some preliminary results had been released at the AAAAI meeting in March 2004). The trial design was as follows:

>>>>>>-

N=3,421, double-blind, parallel group. Patients received either Advair or fluticasone alone. Patients stratified by previous corticosteroid use: Sl = ICS-free, S2 =low-dose ICS, S3 =moderate-dose ICS. Phase I - doses stepped up every 12 weeks until total control achieved (or maximum dose reached). Phase II patients remained on this dose for remainder of the year.

Asthma control was measured using a composite measure of seven goals of GINA (Global Initiative for Asthma)/NIH (National Institute of Health) over an eight-week assessment period. The primary endpoint was the proportion of patients achieving well-controlled asthma in Phase I with a number of additional secondary endpoints.

This section is an extract from our repor~ Smith Burney IJt ATS, published in May 2004.

c1t1group1'
Smith Barney

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0279-056084

GlaxoSmithKiine - 24 June 2004

Results of GOAL- will it promote earlier use of combination treatments?

Overall the study proved very successful. The key highlights included:
Advalr: Afore people to goat. ..

>>-

Significantly more patients achieved total disease control with Advair tlmn fluticasone alone across all strata and both phases of the study at a lower steroid dose. The risk of exacerbation (annualised rates) was significantly reduced with Advair. Patients achieved total control significantly faster with Advair than fluticasone -for example, with patients who were previously on res, 50% taking Advair had achieved total control by 21 weeks whereas it took 45 weeks for 50% of patients taking fluticasone to achieve the same result.

. . and taster

>-

From a physician's point of view, and particularly those who were involved in the study or drafting up guidelines for asthma treatment, this was a very important study.
ftl/lkllmoderate asthma still poorly treated

Some physicians feel that asthma is still chronically under-treated, particularly in the mild to moderate disease stages, where patients fluctuate with their disease severity and are often at the risk of exacerbations. Although the GINA guidelines indicate the use of res as early as mild persistent disease, the drug is often not prescribed and when it is, it is often only prescribed for a short period of time (up to four weeks). It was felt by the investigators that the results from the GOAL study can be used to:

>-

Demonstrate to physicians that it is possible to achieve aggressive asthma goals and that they should aim higher in their treatment strategy at all stages of the disease (it was felt that many physicians and patients accept slightly uncontrolled asthma, particularly when it is classified as mild); Reinforce the GINA guidelines of res use in mild persistent asthma; and Encourage doctors to prescribe steroids for longer periods of time to allow the patients to get their asthma fully under control.

>>Advair best for milcf/rnoderate asthma

Advair is already accepted as an excellent treatment for asthma and is popular in the moderate/severe stages of the disease. Expanding into the milder stages of asthma is one of the key ways for GSK to expand market share and the GOAL study should support this aim.

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0279-056085

From: To:

CC: BCC: Date Sent: Subject:

Tom Curry/FPL!Corp/SB _ PLC[Tom. Curry@gsk.com] Ted T Geiger/PharmUS/GSK@GSK[ted.t.geiger@gsk.com] ; Lafmin C Morgan!PhannUS/GSK@GSK[lafmin.c.morgan@gsk.com] ; Robert J Jagt/PhannUS/GSK@GSK[robert.j .jagt@gsk.com] Stan X Hull!PhannUS/GSK@GSK[ stan.x.hull@gsk.com] 7/20/2004 5:34:00 PM Fw: As requested - Deutsche Bank Report Overview

fyi -----Forwarded by Tom Curry/FPL/Corp/SB _PLC on 20-Jul-2004 05:33PM----Tom Curry/FPL/Corp/SB_PLC 20-Jul-2004 17:30 To gamier cc David M Stout/FPL/Phanns/SB_PLC@GSK, Jolm D Coombe/CORP/GSK@GSK, Duncan LeannouUJ.!CORP/GSK@GSK, Frank J Murdolo/FPL/Corp/SB_PLC@GSK, Anita E Kidgell/CORP/GSK@GSK, Philip C Thomson!CORP/GSK@GSK Subject As requested - Deutsche Bank Report Overview

As requested, the document below was prepared by the US advair marketing team to address issues that may be raised as a result of the recent Deutsche Report that referenced "an abmt slowdown in US sales of Advair". Tome

-----Forwarded by Tom Curry!FPL!Corp/SB_PLC on 20-Jul-2004 05:26PM----Ted T Geiger/PharmUS/GSK 20-Jul-2004 17:23 To Lafmin C Morgan/PhannUS/GSK@GSK cc Tom Curry/FPL/Corp/SB_PLC@GSK, Robert J Jagt/PharmUS/GSK@GSK Subject Deutsche Bank Report Overview

Lafmin- final copy of the assessment of the DB report.

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0262-080735

TG Ted Geiger Director, Asthma Marketing 919-483-8838 919-483-0201 (fax) ted.t geiger@gsk. com

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0262-080736

Deutsche Bank Report Commentary


The following comments from the Advair Marketing Team on the Advair Report from Deutsche Bank provide clarification and context for specific comments made regarding Advair and the asthma and COPD markets.
Advair Performance

Advair growth rates for 2004 are in line (slightly behind) corporate expectations (23% vs. 20% ). Net sales growth at the end of 2003 % was somewhat higher than underlying TRx growth during the same time period; 302003 (57% vs. 37%) and 402003 (51% and 30%). These differences can be explained somewhat by a price increase earlier in 2003, and a worse than expected along with an earlier than expected influenza season that resulted in artificial inflation of the new prescription volume during that time period. Many of the patients treated during this period received a single Advair prescription since they were not asthma or COPD sufferers. Any inventory build at the wholesaler level has burned off, as inventory levels are at an all time low of Advair (Approx. 11 days in 2004) Comparing Advair to other blockbuster products suggests that our growth rate is in line with other products exhibiting blockbuster performance (see below). Year2 Lipitor Celeb rex Vioxx ADVAIR 193% 39% 125% 97% Year3 50% 6%
4%

Year4 30% -7% -20% 23%

33%

The Deutsche Bank report projects monthly MAT growth to be 12% by end-June. Early Alert Rx reports have projected a 16.2% June TRx growth rate for Advair, with MAT growth of 26.2%. Deutsche Bank is pessimistic about the opportunity to impact the Advair growth rate in 2004, despite changes in resource allocation and promotional focus. Advair currently has 27% share of asthma/COPD controller prescriptions, which implies that nearly% of these prescriptions are in competitive products. We are confident that the changes that we have made to the selling POA and the promotional message will drive growth in 03 and 04. The changes include:

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0262-080737

Refocusing selling efforts towards asthma, both childhood and adult With the childhood asthma indication, we are poised to take advantage of the highly seasonal pediatric asthma market Focus on earlier use of Advair, specifically in patients who are have uncontrolled asthma but are typically thought of as 'mild' by primary care physicians

Asthma Market penetration peaking

The Deutsche Bank report presents Advair penetration of the asthma market using the NIH Guideline severity classification. "Strict adherence to the US guidelines would imply that Advair usage should be confined to patients with moderate and severe persistent asthma". The report also points out that asthma is managed via a step care approach, which limits Advair use to a more severe population. Finally, Deutsche Bank concludes that Advair already has 40% of use in the overall asthma population. To our knowledge, there is no reliable quantitative source of data that provides Advair share by severity classification, and we do not support the analysis. Additionally, the most recent patient level data suggests that Advair has approximately 32% share of asthma patients (SOl, May '04). Considering that each percentage point in patient share represents $75MM to Advair, significant opportunity remains if we only achieve the estimate of 40% currently asserted by Deutsche Bank. The report also suggests that step-care in asthma is appropriate given the guidelines. The asthma guidelines do not support step-care; the guidelines recommend therapy based upon physician assessment of patient symptom severity. Primary care physicians typically do not take the time to objectively assess patient symptoms; hence, they adopt a step-care approach to treatment, relying on the patient to return with complaints if therapy is not sufficient to relieve symptoms. If PCPs assessed their patients, they would prescribe Advair to more of their population. GSK strategy is to provide a simple, quick and accurate assessment tool (Asthma Control Test: ACT) to drive proper patient assessment, which will result in more patients on Advair. We agree with Deutsche Bank that there is significant opportunity in the 'mild population' if that patient population is defined as those using short acting beta agonists (SABA) alone to manage their asthma. 75% of SABA users fill3 or more units of albuterol per year, while 25% fill 10 units, clearly indicating they should be prescribed maintenance mediations. (Source: SOl, May 2004) Given the step-care approach to treatment, many of these patients treated with SABA would benefit from earlier treatment with Advair. Deutsche Bank points out that GSK will use the results of the step-down study and the misdiagnosis of asthma data to drive Advair growth. Additionally, we will

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0262-080738

use two studies which enrolled patients symptomatic on albuterol, a population typically viewed as 'mild' to fuel growth. One study compared Advair to Singulair, and the second compared Advair to Flovent. In all studies Advair helped patients achieve more symptom free days and dramatically reduced SABA use. Both of these studies have been replicated and published in peer reviewed journals. GOAL could provide the next impetus to growth We agree that the GOAL study results represent an excellent opportunity for Advair, and have been used in promotional activities by the EU since early 2004. The US plans are to incorporate the study results into speaker training meetings to make certain that they are briefed and able to handle questions from other physicians regarding the data. Using the data in direct promotional activities by the sales force has been problematic due to FDA comments on the study regarding the limited population in the US (10%) and the lack of validation of the total-control endpoint. Pediatric Opportunity Deutsche bank suggests that the 4-11 population represents about 13% of the pediatric opportunity, with Advair market share within the pediatrician prescribers is only 15%, half of the share in other specialties. They also suggest that GSK has been slow to take advantage of this new indication. The report highlights Singulair's position in childhood asthma, and the lack of Advair data in the 4-11 population as preventing strong penetration for the brand. For clarity, the pediatric indication was received on April 23rd, with final preparation of materials in May and a launch meeting the first week of June. Additionally, pediatricians account for only about ~ of the prescriptions written for childhood asthma; the balance coming from other prescribers, primarily PCPs and allergists, who also treat adults. We believe the 4-11 indication provides an opportunity for us to expand Advair business within these adult treating physicians. COPD Commentary Use of Advair in COPD is high, and is growing faster than use of anticholinergics: SOl data indicates that Advair is used in 34% of all treated COPD patients, and this share has increased by over 5 points in last year. In the same time period, anti-cholinergics grew only 1 share point in % of treated patients. Verispan uses for Advair in COPD have accelerated in first four months of '04 with strong gains among both pulmonologists and PCPs

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0262-080739

IMS data also show a strong 1Q for Advair in COPD, with share increases for Advair in treatment consultations and market revenue. Also, IMS showed that COPD is growing as a % of the overall use of Advair.

Opportunity to continue growing in COPD market is significant: Patients with COPD suffer from poor lung function, frequent symptoms and are high utilizers of healthcare Use of multiple products is high (45% of treated patients are on 2+ maintenance products). In fact, nearly half of all treated patients are on an ICS, often with bronchodilator therapy (beta-agonist and/or anticholinergic). The majority of patients in the clinical development program for Spiriva were on ICS. 66% of 5M treated COPD patients are not yet on Advair 65% of patients using anti-cholinergics are not yet on Advair There are 15M untreated and mis/un-diagnosed patients with COPD Spiriva launch into the COPD market is significant: Spiriva uptake from launch is much less than that for Advair Initial uptake of Spiriva has not appeared to effect Advair Diskus TRx volume Although patients may eventually be treated with both Spiriva and Advair, Advair will compete successfully with Spiriva for early use in COPD: Only Advair Diskus 250/50 offers both an anti-inflammatory and a long-acting bronchodilator that work together to help patients breathe easier Only Advair Diskus 250/50 is superior to a long-acting bronchodilator (salmeterol) in improving lung function and helping patients with moderate or severe COPD breathe easier, due to the contribution of FP Advair Diskus is indicated for maintenance treatment of asthma, as well as COPD associated with chronic bronchitis. ATS guidelines state that it can sometimes be difficult to distinguish between the two conditions. About half of patients who are treated for COPD also have an asthma diagnosis. Advair Diskus is convenient and ready to use Advair vs. Combivent studies: Donahue et al now published in Treatments in Respiratory Medicine Make et al (second study) presented at ATS Representatives are unable to promote these data affirmatively. A Medical Information letter is sent in response to unsolicited questions. Advair will succeed by effectively managing these opportunities and challenges in the COPD market, while also pursuing growth opportunities in the larger asthma market.

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0262-0807 40

Other Corrections Page 6: Figure 3 Advair growth as a percentage of GSK growth is artificially inflated by including the 255% growth rate in Advair for 2003. Using the 2004- 2008 time period suggests that Advair is important, but continues to decline as a percentage of GSK growth to 34% in '08, with an average of 37% (vs. 52% as reported by DB) for the 5-year period.

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0262-0807 41

02/27/02

17:33

PULMONARY DIV FDA~ 919 315 0033

FOOD AND DRUG ADMINISTRATION OFFICE OF DRUG EVALUATlON II

TO:
r

Ms. Lorna Wilson

Phone Number:
Fax Number:

FROM:

Ladan Jafari, Project Manager

DIVISION OF PULMONARY AND ALLERGY DRUG


PRODUCTS
CDER Pulmonary Group (H.FD-570), S600 Fishers Lane
Roekvme, Maryland 20857

PHONE: (301) 827.. JOSO FAX: (301) 817..12'11


Total number of pages, including cover beet:4 Date: February li) 2002
THIS DOCUMENT IS INTENDED ONLY FOR. TH.E USB OF 1'HE PAltTY TO WHOM IT 1S ADDRESSED Ali<D MAY CONTAIN INfORMA1'ION THAT IS ?RNILEOEO, CONFIDBNT!AL, AND :PROTECTED FROM DISCLOSURE UNDER APPLICABLE LAW. !f you are not the addressee, Gr a persou aufuor'.:ted to deliver the document to the addressee, you are hereby notified thit any teview, discloaute, dtsserninatiort, eopying, or other action based on the content of this communication ill not authorized. If you have received this document in error. pl elllil! immediately notify us by telephone and reU.!l'Jl it to us at th!i above address by mail. Th.ank JIOI.l.

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0280-001 051

02/27/02

17:33

PULMONARY DIV FDA

919 3:5 0033

N0.251

P002/004 _

Food tllru::! Orug Administration R~-:ltli!Ha Mu 20857

NDA 21077/S002

GlaxoSmithKiine P.O. Box 13398 Five Moore Drive


Research Triangle Park, NC 27709
Attention: Joy E. Ferrell

Direct()r, Regulatory Affairs Dear Ms. Ferrell:


,. Please refer to your sttpplemental new drug application dated April27. 2001, received April30, 2001,
submitted under section 505(b} ofthe Federal Food, Drug, and Cosmetic Act for Advair Diskus (tluricasone propionate and salmeterol xinafoate inhalation powder).

We acknowledge receipt of your submissions dated June 6 and 29, and August 31. 2001.
This supplemental new drug application provides for the revision in the DOSAGE AND ADMINISTRATION section to provide specific guidance on the recommendations for the starting dose of Advair for patients 'vith l..U:lCOntrolled asthma who are currently on ~hcrNtcting betaagonist
therapy alone.

We have completed our review and fmd the information presented is inadequate. and the supplemental application is not appravable under section 50S(d) of the Act and 21 CFR 314.125(b). The deficiencies may be summarized as follows:

We do not believe that you have provided sufficient evidence of efficacy to support this
broade11ed indication for Advair Diskus. Notably$ clinical. Uill SAS30017 f!iled to demonstrate the superiority of the combination product Advair Diskus to the single component fluticasone using the protocol-specified analysis. In addition. this suppl~ment did not provide adequate assurance of the relative safety of the combination product compw-ed to the single component fluticasone for the proposed population. Withdrawals due to asthma exacerbation and withdrawals due to worsening asthma (clinical and stabilityNspecified) were higher among subjects treated with the combination product compared to the single component fluticasone. In order for this application to be approved, you must provide substantve efficacy and safety data supporting that this specific population uniquely benefits from the combination product in comparison to its individual mojeties and that this benefit is not outweighed by any additional
risl~s.

,.

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0280-001 052

02/27/02

17:33

PULMONARY DIU FDA

919 315 0033

N0.251

P003/0~-----

NDA 21077/S-002 Page2

Within 10 days after the date of this letter, you are required to amend the supplemental application, notify us of your intent to file an amendment, or follow one o!your other options unde:r 21 CFR 314.120. In the absence of any such action FDA may proceed to withdraw the application. Any amendment should respond to all the deficiencies listed. We will not process a partial reply as a major amendment nor will the review clock be reactivated until aU deficiencies have been addressed.
This product may be considered to be misbranded under the Federal Food, Drug, and Cosmetic Act if it is marketed with these changes prior to approval of this supplemental application.
It' you have any questions. ?all Ms. Ladan Jafati, Regulatory Project Manager, at (301) 827-5584.

Sincerely,

Robert J. Meyer, M.D. Director


Division of Pulmonary and Allergy D:rng Products Office of Drug Evaluation II Center for Drug E~aluation and Research

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0280-001 053

02/27/02

17:33

PULMONARY DIU FDA

919 315 0033

N0.251

P004/004

This Is a representation of an electronic record that was signed electronically and this page Is the manifestation of the electronic signature.

/e/ Robert Meyer


2/27/02 01:20:01 FM

Confidential: Produced pursuant to 02/06/04 subpoena.

GS KC0-0280-001 054

FOOD AND DRUG ADMINISTRA~riON OFFICE OF DRUG EVALUATION II

TO:
Phone Number: Fax Number: FROM:

Ms. Lorna Wilson

Ladan Jafari, Project Manager

DIVISION OF PUL~IONARY AND ALLERGY DRUG


PRODUCTS
CDER Pulmonary Group (HFD5'10), 5600 Fishers Lane
RoekviUe, Maryland 20857

PHONE: {3tH) 827..1050 FAX: {301) 817..1271 Total number of pages, intRuding cover heet:4 Date: February 2i~ 2002
THIS DOCUMENT IS INTENDED ONLY FOR TI:IE USE OF 1."fre PAR.'IY TO WHOM IT IS ADDRESSED A~D MAY CON'TA!N INFORlVIATION THAT IS ~RNILEGEO, CONFIDBNT!AL, AND PROTECTED F~OM DISCLOSURE UNDER APPLICABLE LAW. lfyou art not the addre$iee! o.r a ~rsou authorized to deliver the document to the addressee, you are hereby notified that any review, discloslil'e, dissemination, copying, or other action based on the content of this col!l.munication is not authorized. If you have received i:hi& dotument in error. ple11se immediately notify us by telephone and reu.rrn it to us at th~ above ad\lress by mail. Thank J'Ol.l.

DEPARTMENT OF HEALTH & litJMAN SERVICES

Public

H~aith

Servlce

------------------------------~--------------------~---------------------f"t)t.!tl !ilnr:1 Drug Administration N~ckt.t!Ha ;-,1!i 20857

NDA 21077/S002 GlaxoSmithKline P.O. Box 13398 Five Moore Drive Research Triangle Park, NC 27709
Attention: Joy E. Ferren Director, Regulatory Affairs

Dear Ms. Ferrell: Please refer to your sttpplemental new drug appH\:ation dated April27, 2001, received April30, 2001 1 submitted under section 505(b) oftbe Federal Food, Drug, and Cosmetic Act for Advair Diskus (t1uticasone propionate and salmeterol xinafoate inhalation powder). We acknowledge receipt of your submissions dated June 6 and 29, and August 31, 200 l.
This supplemental new drug application provides for the revision in the DOSAGE AND ADMINISTRATION section to provide specific guidance on the recommendations for the starting dose of Advair for patients with m:acontrolled asthma who are curre.m:ly on sh,:rHtcdng beta:~agonist therapy alone.

We have completed our review and fmd the information presented is ir..adequate. and the supplemental application is not approvable under section 50S{d) of the Act and 21 CFR 314.125(b). The deficiencies may be summarized as foliows: We do not believe that you have provided sufficient evidence of efficacy to support this broadened indication for Advair Dislrus. Notably~ clinical trial SAS30017 fsiled to demonstrate the superiority of the combination product Advair Diskus to the single component fluticasone using the protocol-specified analysis. In addition, this supplement did not provide adequate assurance of the relative safety of the combination product compElled to the sin.gle component fl.uticasone for the proposed population. Withdrawals due to asthma ~ace.rbation and withdrawals due to worsening asthma (clinical and stability-specified) w~e higher among subjects treated with the combination product compared to the single component fluticasone. In order for this application to be approved, you must provide substantive efficacy and safety data supporting that this specific population UDiquely benefits :from the combination product in comparison to its individual mojeties and that this benefit is not outweighed by any additional
risl<S.

NDA 21077/S-002
Page2

Within 10 days after the date of this letter. you are required to amend the supplemental application, notify us of your intent to file an amendment, or follow one of your other options under 21 CFR 314.120. In the absence of any such action FDA may proceed to withdraw the application. Any amendment should respond to all the deficiencies listed. We will not process a partial :reply as a major amendment nor will the review clock be reactivated until all deficiencies have been addressed.
This product may be considered to be misbranded Wlder the Federal Food, Drug, and Cosmetic Act if it is marketed with these changes prior to approval of this supplemental applicat!on.
If you have any questions,
~all

Ms. Ladan Jafaris Regulatory Project Manager, at (301) 827-5584.

Sincerely,

Robert J. Meyer, M.D.

Director
Division ofPulme>nary and Allergy Dmg Products Office of Drug Evaluation II Center for Drug E-valuatiotl and Research

,.

This is a representation of an electronic record that was signed electronicaUy and this page Is the manifestation of the electronic signature.

/e/ Robert Meyer


2/27/02
01:20~01

PM

From: To:

John F Del Giorno/PharmUS/GSK[john. f. delgiorno@gsk. com] Stan X Hull/PharmUS/GSK@GSK

CC:
BCC: Date Sent: Subject:

10/27/2008 3:17:51 PM Advair

Stan, This is the step edit we discussed. This concept would be used in AR and TN. If approved, a 10% supplemental rebate would be paid.

Advair would be filled POS (point of sale) with no restrictions if following a 90 days claims look back (point of sale), the following conditions were met: Claim for ICS and /or SABA and I or Advair was located in the claims history. In addition, COPD and Pediatrics would be exempt from step edit criteria. All patients currently on Advair would be grandfathered. To address the Advair naive moderate I severe patient: ICD 9 code for asthma on script would suffice for claim to be processed at POS with no restriction. This step edit would of course be negotiated with Medicaid agencies before final approvals at the State level. Let me know what you think. Thanks for your time today and "God save political donations".

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0276-012770

From: To: CC: BCC: Date Sent: Subject:

Lafmin C Morgan!PharmUS/GSK[lafmin.c.morgan@gsk.com] Stan X Hull/PharmUS/GSK@GSK[stan.x.hull@gsk.com] Sharon L Sharo/RTP/PSF/GSK@GSK[Sharon.L. Sharo@gsk.com] 6/11/2007 7:51:16 AM Re: Fw: P&T committee testimony

Sharon, If you have not already done so, please put forward Spirit Awards for all of the folks that worked to make this possible.

Stan X Hull/PharmUS 08-Jun-2007 17:33 To Sharon L Sharo/RTP/PSF/GSK@GSK, Lafmin C Morgan/PharmUS/GSK@GSK cc Subject Fw: P&T committee testimony

FYI, This is why these spirit awards were put forward. Stan Stan Hull Tel: 919-483-7427 Fax: 919-315-3183 Cell: 919-302-3408

-----Forwarded by Stan X Hull/PharmUS/GSK on 06/08/2007 05:32PM----John F DelGiorno/PharmUS Sent by: Karen A Pottebaum 11-May-2007 10:42 State Government Affairs

A-3442

3-8883

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0276-029132

To Stan X Hull/PharmUS/GSK@GSK, Steve F Stefano/PharmUS/GSK@GSK cc Subject Re: Fw: P&T committee testimony

Steve & Stan, The following GSK folks were instrumental in causing OH Medicaid to table for at least three months the idea of a step edit on Advair. Would you like me to request the Spirit Awards? How much do you have in mind? May I split these between your cost centers? Thanks for your support! Joe Marchant- SGA John Dumford- Medical Center Representative Todd Edwards- Regional Medical Scientist Tracy Fischer - Regional Medical Scientist Bob Lewis - Market Development Manager Charley Williams - SGA

John F DelGiorno/PharmUS Sent by: Karen A Pottebaum 07-May-2007 10:35 State Government Affairs To Dan M Keeney/RTP/PSF/GSK@GSK cc Subject Re: Fw: P&T committee testimony

A-3442

3-8883

Dan,

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0276-029133

Please provide me with a list of those who made significant contributions to this project. Thanks.

Stan X Hull/PharmUS 05-May-2007 09:30 To John F DelGiorno/PharmUS/GSK@GSK cc Dan M Keeney/RTP/PSF/GSK@GSK, Karen A Pottebaum/PharmUS/GSK@GSK, Steve F Stefano/PharmUS/GSK@GSK Subject Re: Fw: P&T committee testimony

John, I think this is a result of great teamwork. I would support Spirit Awards for the main team members. Let me know how you would like to progress. Thanks, Stan Stan Hull Tel: 919-483-7427 Fax: 919-315-3183 Cell: 919-302-3408

John F DelGiorno/PharmUS Sent by: Karen A Pottebaum 26-Apr-2007 11:20 State Government Affairs

A-3442

3-8883

To Stan X Hull/PharmUS/GSK@GSK, Steve F Stefano/PharmUS/GSK@GSK cc Dan M Keeney/RTP/PSF/GSK@GSK

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0276-029134

Subject Re: Fw: P&T committee testimony

Stan and Steve, A truly great win in Ohio. Several GSK people did outstanding work to get this result. I suggest Spirit Awards for those that led the fight, starting with Joe Marchant. The battle is not over but this is a significantly positive start. John F. DelGiorno Vice President State Government Affairs

Dan M Keeney/RTP/PSF 25-Apr-2007 13:16 To John F DelGiorno/PharmUS/GSK@GSK cc Subject Fw: P&T committee testimony

John, The second of two messages rec'd so far re: OH Medicaid. Dan Keeney Area Vice President State Government Affairs GlaxoSmithKline Tel 608-935-3902 Fax 414-386-7922 Cell 608-574-6068 Success is a team sport. -----Forwarded by Dan M Keeney/RTP/PSF/GSK on 25-Apr-2007 01:16PM-----

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0276-029135

"Dan Jones" <djones@capitol-consulting.net> 25-Apr-2007 11:30 Please respond to djones@capitol-consulting.net

To "Daniel M. Keeney" <dan.m.keeney@gsk.com>, "Charles. G. Williams" <charles. g. williams@gsk. com> cc Subject Fw: P&T committee testimony

Tracy's recap below Dan Jones Capitol Consulting Group, Inc. 37 West Broad Street Suite 820 Columbus, OH 43215 614-224-3855 office 614-224-3872 djones@capitol-cohsulting.net -----Original Message----From: "Tracy Intihar" <tracy@intiharcommunications.com> Date: Wed, 25 Apr 2007 15:13:55 To:"Alderson, Mitch" <Mitch.Alderson@ohr.state.oh.us> Cc: "Dan Jones" <djones@capitol-consulting.net> Subject: Re: P&T committee testimony Dr john parsons did testify. He kicked it off by saying that despite a lot of work, he could not secure a 10 minute slot so asked GSK for their time. Said he is not being paid a dime. He was a great witness and did a great job explaining why this step edit goes agst guidelines, creates an unnecessary burden to docs and is dangerous for patients. He really did a great job. The P and T committee tabled the proposal until July to get more data and have more discussion. So this is not over. Thanks again for your work on Dr Parsons behalf. I know he appreciates it.

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0276-029136

Tracy -----Original Message----From: "Alderson, Mitch" <Mitch.Alderson@ohr.state.oh.us> Date: Tue, 24 Apr 2007 16:49:16 To:" Alderson, Mitch" <Mitch. Alderson@ohr. state.oh. us>, <djones@capitol-consulting.net>, "Tracy Intihar" <tracy@intiharcommunications. com> Cc:"Barger, Brad" <Brad.Barger@ohr.state.oh.us> Subject: RE: P&T committee testimony Okay, I just spoke with Margaret and she said that "yes" ... this would go to JCARR in September. Mitchell L. Alderson Legislative Aide State Rep. Jon Peterson Ohio House ofRepresentatives 614.644.6711

-----Original Message----From: Alderson, Mitch Sent: Tuesday, April24, 2007 4:41PM To: 'djones@capitol-consulting.net'; Tracy Intihar Subject: RE: P&T committee testimony Dan & Tracy, Not certain, but a little more specific info from Margaret's response might help shed some further light for us: She said according to OAC, there will be a filing in July, followed by public testimony in August. Does this help? I just left a voicemail on Margaret's line to call me as soon as she gets my message- either tonight or first thing in the morning. Mitch Mitchell L. Alderson Legislative Aide State Rep. Jon Peterson Ohio House ofRepresentatives 614.644.6711

-----Original Message----From: Dan Jones [mailto:djones@capitol-consulting.net] Sent: Tuesday, April24, 2007 4:30PM To: Tracy Intihar; Alderson, Mitch

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0276-029137

Subject: Re: P&T committee testimony Sounds like this will go to JCARR? Is that what she is saying? Dan Jones Capitol Consulting Group, Inc. 37 West Broad Street Suite 820 Columbus, OH 43215 614-224-3855 office 614-224-3872 djones@capitol-consulting.net -----Original Message----From: "Tracy Intihar" <tracy@intiharcommunications.com> Date: Tue, 24 Apr 2007 16:26:46 To:<Dan.M.Keeney@gsk.com>, <Joseph.X.Marchant@gsk.com>, <charles. g. williams@gsk. com>, <John. S.Dumford@gsk. com> Cc: '"Dan Jones"' <djones@capitol-consulting.net> Subject: RE: P&T committee testimony Below is a detailed from a follow-up conversation Peterson's aide had with Margaret.

Tracy

From: Alderson, Mitch [mailto:Mitch.Alderson@ohr.state.oh.us] Sent: Tuesday, April24, 2007 4:20PM To: Tracy Intihar; Barger, Brad Cc: Jon Peterson Subject: RE: P&T committee testimony Importance: High

Hi Tracy, I just spoke with Margaret Scott concerning the Medicaid P&T Committee tomorrow. She provided me with the following info:

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0276-029138

*While tomorrow's proceedings are open to the public for attendance, the folks providing testimony are by invitation only *The folks tomorrow include mainly, if not only, drug manufacturers *According the Ohio Administrative Code, public hearings will be held in mid to late August. *Dr. Parsons is more than welcome to testify at the public hearings in August on this matter *Dr. Parson is more than welcome to contact Margaret directly (614.752.4613) anytime to discuss the matter *Margaret encourages Dr. Parson to attend the meeting tomorrow to see the plan unveiling *There is a lot of mis-information floating around- they are not taking away drugs but rather encouraging appropriate use

I hope this info helps. Please let us know if there is anything we can do for you. Also, let us know how it goes tomorrow.

Thanks, Mitch

Mitchell L. Alderson Legislative Aide State Rep. Jon Peterson Ohio House ofRepresentatives 614.644.6711

Confidential: Produced pursuant to 02/06/04 subpoena.

GSKC0-0276-029139

Memo
GlaxoSmithKiine G.B. Elion Pharmaceuticals Pharmaceuticals
Dl DSMs
From

Burroughs Wellcome

Cerenex

To

Gary L. Bean 9/28/00 Fleet Center Tickets for 2001/2002 season

Date
subJeot

The Fleet Center tickets for the Bruins and Celtics went out today. Only the 2001 tickets were available the 2002 tickets should be in soon as I will forward ASAP. Enclosed in your Airborne mailing you will find the following:

+ 14 PRE-PAlD Premium Seating Tickets


Standing Room Only Order form (you have the options to purchase an additional 7) Directions to the fleet Center Important Fleet Center numbers Boston Celtics Directory Advance Order form for food and beverages
NEWSecurity procedures

Copy of Fleet Tracking form to be emailed Master list of all games Oct- Dec in the event you would like to swtich with someone.

Please note: you can gain entrance to the Premium Seating 2 (two) hours before game time. If you want to conduct a speaker program prior to the game, there are rooms available for a small fee and you must call in advance for reservation. Take care of these tickets, as they are non-refundable if lost or stolen.

Cc: Bill Pasek, Cynthia Johnson

Glaxo Smith Kline


170 Plain Street Hanover, Ma 02339 Telephone 781-878-2321

Fax 781-681-7038

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0019-003580

JOM76396@3489 11/1 0/2000 03:09 PM

To: Bontempo, Carlo, Long, Ann-Marie, McCrea, Ker()', Mintz, Harry, Nye, Tonya, Palazzo, Jim, Parks, John, Register, Mark:, Shepherd, Linda cc: Subject: FW: glb. Fleet Center Schedule for 2000-2001

Pleas; read and keep in your files if you haven't see11 this. Note that we have a Celtics game in ApriL 20tH.
From: Sent:
Tu:

Bean, Gary
Tuesday, September 12, 2000 !0:02 AM 'Davey, T ..1dd'; 'Davi~s, 11lumaN'; Tit'Jhe:rty, F.ric'; 'Essa, Mark\ 'Fenstennab:r, Rill'; 'Gallaglu:r, Pete'; 'Mastrianni, Serene'; 'Mc~eill, J.flck'; 'Nichols, Thomas'~ 'Tisdell, John'
Paul~

'Cnyer. David'; 'Hush)ll,

Cc:
Subject:

'Pasek, Bill' glb. Fleet Center Schedule for 2000-200 I

Hi Everyone, Well here's what you all have been wailing for. .. the Fleet Center Schedule for 2000-2001. This year Bill P. has purchased 60 games, (30 for CNS and 30 for RESP) investing $250,000 of customer focus money. Each district will get 3 games. The cost of the Premium Seating Suite per game is $4200 or $300/seat. When you add food/drink figure about $350/seat. For ROI it's impemtive only KEY Customers attend these valuable venues. Games have been allocated and are on the attached spreadsheet. In an effort to please 20 managers you will definitely have a date that wouldn't be your first choice. So if you do have major conflict with a date you may do your wheeling-dealing on a district lcvcl.(Wc arc still in sales) Because the respiratory managers are conducting Advair programs tlus fall and looking for fall dates, l've tried to accommodate them. Since we purchased the tickets from the Celtics there are more Celtic games than Bruins. I've tried to give everyone at least one Bruins game and separated the games by at least 4 weeks. Attached Tracking form must be completed no later than 3 days post game. Some Fleet Center infonnation: You have 14 tickets (paid), however if you wish to purchase an additional 7 standing room only (SRO) you may at your expense. You will receive 2 parking passes. As soon as they're available you will receive tickets/parking passes to all 3 games. Put them in a safe place as lost tickets are non-refundable Included wiU1 your tickets you will receive directions, food/drink menus, floor plan of box, SRO forms, etc. If you want to conduct a progmm the day of a game: you may enter the Fleet Center 2 hours before the game, meeting rooms are available at an additional charge.

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0027 -000458
GC0339-0458 F

EPD15084@3489

12/20/2000 11 :20 AM

To: Baldomir, Jason, Benjamin, Martha, Finn, Michael, Lambert, Roger, Bowler, Sean, Deremeer, Susanbeth, Reardon, Sean, Yelsits, James cc: Subject: FW: glb. Fleet Center Event follow up form

Attached please find the form for registering attendees to the Fleet Center box. Please choose a point person for each event. That person will then fill Ollt this information, send it to GaryBeru1 a11d cc me. Please do this within 72 hours of the event. The last event on Dec 16th at the fleet center should be registered. Sean--Please fill this sheet out and submit it before 12/22. Eric
Bean, Gary Tuesday, December 19,2000 7:55PM 'Davey, Todd'; 'Davies, Thomas'; 'Doherty, Eric'; 'Fenstermaker, Bill'; 'Gallagher, Paul'; 'Guyer, David'; 'Huston, Pete';
'Mastrianni, Serene'; 'McNeill, Jack';
'Tisdell~

From: Sent: To: Subject: Importance:

John'

glb. Fleet Center Event follow up form High

Season's Greetings Everyone, I've had a request for the follow-up form for all Fleet Center events. This form is to be completed a11d sent to me to ensure ROI and continued funding by Mr. Pasek. If you have any questions please call me. thanks

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0019-050424
GC0288-0920 F

PSR

To ensure we get contmued fundmg by Bill Pasek we are obligated to track who 1s attending these games and she No later than 3 days after a game please forward to Gary Bean this tracking sheet At the end of the season we will have some valuable information This also acts as management tool to account for all tickets and ensure reps are getting quality customers to thes Any questions please call me

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0019-050425
GC0288-0921

Fleet Center Tracking Sheet


2000-2001 Season

Day Date Key Customer

Specialty

#of Product Guests Target

Target List Rank

'JWROI

;e games

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0019-050426
GC0288-0922

Post Current 4-mon Market Market Sh Mise Share

Confidential: Produced pursuant to 02/06/04 subpoena

GSKC0-0019-050427
GC0288-0923 L

SAMPLE OF MEDICAID CLAIMS FOR PAXIL FOR PATIENTS UNDER 18

Page 1
.

Year
:: ..

Drug Type

NDC

Prescription Fill Date

2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002

Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil

00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613

25SEP2002 020CT2002 300CT2002 26NOV2002 100EC2002 20NOV2002 20NOV2002 260EC2002 20NOV2002 19AUG2002 17SEP2002 17NOV2002 10SEP2002 18JUN2002 29JUL2002 19AUG2002 29SEP2002 15NOV2002 16JUL2002 18AUG2002 14SEP2002 100EC2002 29JUN2002 29JUL2002 08AUG2002 040CT2002 04SEP2002 020CT2002 260CT2002 300CT2002 18NOV2002 190EC2002 070EC2002 13JUN2002 12JUL2002 200EC2002 210EC2002 170EC2002 22JUL2002 07AUG2002 10SEP2002 300EC2002 05NOV2002 050EC2002

Medicaid Am()Unt Paid 40 $ 87 $ 87 $ 49 $ 30 $ $ 76 79 $ 80 $ 76 $ $ 76 76 $ 76 $ $ 76 76 $ 41 $ 79 $ $ 79 82 $ 76 $ 76 $ $ 76 79 $ $ 76 76 $ 79 $ 79 $ 76 $ 76 $ $ 79 76 $ $ 79 79 $ 80 $ 76 $ 76 $ $ 76 76 $ 76 $ 29 $ $ 68 92 $ $ 80 86 $ 86 $

Prescribing ProviderlD
c

.. .Billing . . Provider lD
M01824 M01824 M01824 M07066 M07066 21355 21355 9215 22335 20646 20646 20646 24390 19943 19943 19943 19943 19943 13158 13158 13158 9980 13158 13158 3728 3728 13404 13404 13404 13404 13404 13404 M01590 00546 00546 FL82771 12534 00126 M04226 M04226 M04226 M00108 M00016 M00016

PH0466 PH0466 PH0466 PH0466 PH0466 100003218 100003218 100010014 100001695 100002354 100002354 100002354 100001190 100002420 100002420 100002420 100002420 100003338 100002023 100002023 100002023 100002023 100000805 100000805 100000805 100000805 100003080 100003080 100003080 100003080 100003080 100003080 PH0094 100001687 100001687 100200014 100003103 100000046 PH0466 PH0466 PH0466 PH0004 PH0092 PH0092

SAMPLE OF MEDICAID CLAIMS FOR PAXIL FOR PATIENTS UNDER 18

Page 2
' '

,,

Year.

Drug <Type

NP.C
00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613

Prescription Fill Date

2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002

Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil

21AUG2002 25SEP2002 01NOV2002 04NOV2002 12JUL2002 12AUG2002 21AUG2002 16SEP2002 230CT2002 230CT2002 25NOV2002 180EC2002 310EC2002 22NOV2002 010EC2002 060EC2002 130EC2002 190EC2002 260EC2002 010CT2002 20NOV2002 170EC2002 250CT2002 21NOV2002 240CT2002 060EC2002 15NOV2002 29NOV2002 260EC2002 31DEC2002 03MAY2002 250CT2002 19NOV2002 23JUL2002 21AUG2002 19SEP2002 070CT2002 160EC2002 160CT2002 02AUG2002 12AUG2002 10SEP2002 100CT2002 08NOV2002

Medicaid Amount Paid 80 $ $ 80 13 $ 26 $ 85 $ 85 $ 89 $ $ 89 $ 46 89 $ $ 89 89 $ 80 $ 45 $ 29 $ $ 29 29 $ 29 $ 29 $ 81 $ 81 $ 76 $ 53 $ 76 $ $ 76 $ 76 75 $ 78 $ $ 78 80 $ $ 38 76 $ 76 $ $ 76 76 $ 76 $ 79 $ $ 76 76 $ 76 $ 79 $ 79 $ $ 79 $ 79

. Prescribing Provider ID

Billing . ProvidedD

PH0157 PH0061 PH0266 PH0266 PH0155 PH0155 PH0155 PH0155 PH0155 PH0155 PH0155 PH0155 PH2051 PH0256 PH0256 PH0256 PH0256 PH0256 PH0256 PH0712 PH0712 100003201 100001127 100001127 100002192 100003197 100010014 100010014 100010014 100010014 100002583 100002346 100002346 100001245 100003160 100002569 100002565 100003319 100002276 100002708 100002708 100002708 100002708 100002708

M084482 M04226 M002512 M002512 5392647 6723484 6723484 7521963 8354278 8354278 4172862 4172862 M00016 MH0159 MH0159 MH0159 MH0159 MH0159 MH0159 M00229 M00229 11590 15921 15313 19045 21066 9215 9215 9215 9215 19943 440 440 GA37886 GA37886 GA37886 GA37886 10617 21958 21066 00349 00349 00349 00349

SAMPLE OF MEDICAID CLAIMS FOR PAXIL FOR PATIENTS UNDER 18 Page 3


'

' :.

Yea,r
,,.
.

Drug Type .,

I
'/.

NDC

Prescription Fi11 Date

2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003

Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil

00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613

100EC2002 190EC2002 24SEP2002 21NOV2002 05JUN2002 01JUL2002 22JUL2002 23AUG2002 170EC2002 170EC2002 120EC2002 240CT2002 10SEP2002 100CT2002 12NOV2002 130EC2002 17JUN2002 26JUN2002 100EC2002 180CT2002 22NOV2002 200EC2002 110EC2002 17AUG2002 06JAN2003 11 FEB2003 08APR2003 08AUG2003 18AUG2003 15SEP2003 130CT2003 24APR2003 18MAY2003 05MAY2003 08MAY2003 15MAY2003 22MAY2003 12JUN2003 19JUN2003 19JUN2003 26JUN2003 01JUL2003 01JUL2003 03JUL2003

Medi.caid ,Amount Paid 79 $ 76 $ 76 $ 76 $ 76 $ 76 $ 79 $ 79 $ 24 $ 79 $ 76 $ 76 $ $ 76 $ 76 76 $ 76 $ 38 $ 57 $ 79 $ 76 $ 76 $ 76 $ 76 $ 76 $ 80 $ 83 $ 91 $ 51 $ $ 83 83 $ 72 $ $ 86 86 $ 16 $ 26 $ 26 $ 26 $ 26 $ 26 $ 27 $ 19 $ 13 $ 15 $ 33 $

Pr~,scribing,
<

Pr~vider 10

. , . Billing ProvideriD
....

100002708 100003393 100000412 100003316 100002792 100002792 100002792 100002792 100001169 100001169 100002886 100001751 100001216 100001216 100001802 100001216 100002818 100002818 100000391 100000835 100000835 100000835 100003191 100002883 PH0095 PH0252 PH0302 PH0013 PH0013 PH0013 PH0013 PH0154 PH0154 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026

00349 00283 15920 15920 20646 20646 20646 20646 19896 19896 14295 5626 6974 6974 18150 6974 22917 22917 13653 21066 21066 21066 20646 3811 MH3725 M017091 M01905 M028574 M028574 M028574 M028574 MH4264 6451379 M011861 M011861 M019051 M019051 M019051 M019051 M019051 M019051 M019051 M019051 M019051

Sample of Medicaid Claims for Wellbutrin With No Depression Diagnosis (One Year) Page 1

Year

Drug Type ..

NDC
..

Prescription Fill Date


010CT2001 01NOV2001 01 DEC2001 01JAN2002 13MAY1999 06JAN1999 31MAR1999 05MAY1999 23JAN2002 15FEB2002 01MAR2002 05JAN1999 14JAN1999 19JAN1999 02FEB1999 16FEB1999 23FEB1999 03MAR1999 09MAR1999 17MAR1999 23MAR1999 30MAR1999 06APR1999 13APR1999 18MAY1999 25MAY1999 01JUN1999 08JUN1999 15JUN1999 22JUN1999 29JUN1999 06JUL1999 13JUL1999 20JUL 1999 03AUG1999 07SEP1999 21SEP1999 190CT1999 02NOV1999 07DEC1999 14DEC1999 21DEC1999

Prescribi Medicaid Billing ng Amount Provider Provider Paid ID. ID


$ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $
61 PH0013 56 PH0013 55 PH0013 13 PH0013 49 PH0156 82 PH2070 85 PH2070 85 PH2070 32 PH0288 18 PH0288 109 PH0288 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 28 PH0156 28 PH0156 28 PH0156 MD0523 MD0523 MD0523 MD0523 CL0260 MD5950 MD5950 MD5950 MD0723 MD0723 MD0723 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260 CL0260

2001 2001 2001 2002 1999 1999 1999 1999 2002 2002 2002 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999 1999

Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR

00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555

Sample of Medicaid Claims for Wellbutrin With No Depression Diagnosis (One Year) Page 2

Prescribi Medicaid ng Amount .Provider Paid . , 10:


1999 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 2001 Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 28DEC1999 23JAN2001 30JAN2001 07FEB2001 13FEB2001 20FEB2001 27FEB2001 06MAR2001 13MAR2001 20MAR2001 27MAR2001 03APR2001 10APR2001 17APR2001 24APR2001 01MAY2001 09MAY2001 15MAY2001 21MAY2001 29MAY2001 05JUN2001 11JUN2001 18JUN2001 26JUN2001 09JUL2001 16JUL2001 23JUL2001 30JUL2001 06AUG2001 14AUG2001 21AUG2001 27AUG2001 04SEP2001 11SEP2001 18SEP2001 24SEP2001 020CT2001 080CT2001 150CT2001 240CT2001 290CT2001 05NOV2001

$ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $
$

28 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 18 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 29 PH0156 30 PH0156 30 PH0156 30 PH0156 52 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156 30 PH0156

CL0260 MDG215 MDG215 MD2183 MD2183 MD2183 MD2183 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MDG215 MD2199 MD2199 MD2199 MD2199 MD2199 MD2199 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MDG215

$ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $

Sample of Medicaid Claims for Wellbutrin With No Depression Diagnosis (One Year) Page 3

Presc.ribi ng Provider

lD
2001 2001 2001 2001 2001 2001 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR Wellbutrin_SR 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 00173013555 12NOV2001 19NOV2001 04DEC2001 11 DEC2001 17DEC2001 27DEC2001 08JAN2002 14JAN2002 21JAN2002 28JAN2002 04FEB2002 13FEB200? 19FEB2002 26FEB2002 06MAR2002 12MAR2002 18MAR2002 25MAR2002 31MAR2002 01APR2002 09APR2002 15APR2002 22APR2002 29APR2002 07MAY2002 14MAY2002 21MAY2002 28MAY2002 03JUN2002 10JUN2002 19JUN2002 24JUN2002 03JUL2002 16JUL2002 29JUL2002 05AUG2002 13AUG2002 19AUG2002 27AUG2002 03SEP2002 09SEP2002 16SEP2002

$ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $

30 30 30 30 52 30 30 30 32 32 32 32 32 32 32 32 32 32 12 32 32 32 32 32 32 32 32 32 32 32 33 33 58 58 33 33 33 33 33 33 33 33

PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0659 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156 PH0156

MDG215 MDG215 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 HS030P MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2199 MD2199 MD2199 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2183 MD2199

SAMPLE OF MEDICAID CLAIMS FOR PAXIL FOR PATIENTS UNDER 18

Page 1
'

Year

Drug Type

'

NDC
,.

Prescription Fill Date


'

Medicaid Amount Paid

..

Prescribing. ProvideriD

. Billi~g .

ProvlderiD

2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002

Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil

00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613

25SEP2002 020CT2002 300CT2002 26NOV2002 100EC2002 20NOV2002 20NOV2002 260EC2002 20NOV2002 19AUG2002 17SEP2002 17NOV2002 10SEP2002 18JUN2002 29JUL2002 19AUG2002 29SEP2002 15NOV2002 16JUL2002 18AUG2002 14SEP2002 100EC2002 29JUN2002 29JUL2002 08AUG2002 040CT2002 04SEP2002 020CT2002 260CT2002 300CT2002 18NOV2002 190EC2002 070EC2002 13JUN2002 12JUL2002 200EC2002 210EC2002 170EC2002 22JUL2002 07AUG2002 10SEP2002 300EC2002 05NOV2002 050EC2002

$ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $ $

40 87 87 49 30 76 79 80 76 76 76 76 76 76 41 79 79 82 76 76 76 79 76 76 79 79 76 76 79 76 79 79 80 76 76 76 76 76 29 68 92 80 86 86

PH0466 PH0466 PH0466 PH0466 PH0466 100003218 100003218 100010014 100001695 100002354 100002354 100002354 100001190 100002420 100002420 100002420 100002420 100003338 100002023 100002023 100002023 100002023 100000805 100000805 100000805 100000805 100003080 100003080 100003080 100003080 100003080 100003080 PH0094 100001687 100001687 100200014 100003103 100000046 PH0466 PH0466 PH0466 PH0004 PH0092 PH0092

M01824 M01824 M01824 M07066 M07066 21355 21355 9215 22335 20646 20646 20646 24390 19943 19943 19943 19943 19943 13158 13158 13158 9980 13158 13158 3728 3728 13404 13404 13404 13404 13404 13404 M01590 00546 00546 FL82771 12534 00126 M04226 M04226 M04226 M00108 M00016 M00016

SAMPLE OF MEDICAID CLAIMS FOR PAXIL FOR PATIENTS UNDER 18

Page 2
.

Year

Drug Type

'

...

NDC

Prescription Fill Date

2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002

Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil

00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613

21AUG2002 25SEP2002 01NOV2002 04NOV2002 12JUL2002 12AUG2002 21AUG2002 16SEP2002 230CT2002 230CT2002 25NOV2002 180EC2002 31 OEC2002 22NOV2002 010EC2002 060EC2002 130EC2002 190EC2002 260EC2002 010CT2002 20NOV2002 170EC2002 250CT2002 21NOV2002 240CT2002 060EC2002 15NOV2002 29NOV2002 260EC2002 310EC2002 03MAY2002 250CT2002 19NOV2002 23JUL2002 21AUG2002 19SEP2002 070CT2002 160EC2002 160CT2002 02AUG2002 12AUG2002 10SEP2002 100CT2002 08NOV2002

Medicaid Amou.ht Paid 80 $ 80 $ 13 $ 26 $ $ 85 85 $ $ 89 89 $ 46 $ $ 89 89 $ $ 89 80 $ 45 $ $ 29 29 $ $ 29 29 $ $ 29 81 $ 81 $ 76 $ $ 53 76 $ 76 $ 76 $ 75 $ $ 78 78 $ 80 $ 38 $ 76 $ $ 76 76 $ 76 $ 76 $ 79 $ $ 76 76 $ $ 76 79 $ 79 $ 79 $ 79 $

Prescribing . Provider lD ...

. ... . ..Billing Pr~videriP

PH0157 PH0061 PH0266 PH0266 PH0155 PH0155 PH0155 PH0155 PH0155 PH0155 PH0155 PH0155 PH2051 PH0256 PH0256 PH0256 PH0256 PH0256 PH0256 PH0712 PH0712 100003201 100001127 100001127 100002192 100003197 100010014 100010014 100010014 100010014 100002583 100002346 100002346 100001245 100003160 100002569 100002565 100003319 100002276 100002708 100002708 100002708 100002708 100002708

M084482 M04226 M002512 M002512 5392647 6723484 6723484 7521963 8354278 8354278 4172862 4172862 M00016 MH0159 MH0159 MH0159 MH0159 MH0159 MH0159 M00229 M00229 11590 15921 15313 19045 21066 9215 9215 9215 9215 19943 440 440 GA37886 GA37886 GA37886 GA37886 10617 21958 21066 00349 00349 00349 00349

SAMPLE OF MEDICAID CLAIMS FOR PAXIL FOR PATIENTS UNDER 18 Page 3

::

Year
. 1

Drug Type .

NDC
.. /
.

::

Prescription Fill Date


..

2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2002 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003 2003

Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil Paxil

00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613 00029320613

100EC2002 190EC2002 24SEP2002 21NOV2002 05JUN2002 01JUL2002 22JUL2002 23AUG2002 170EC2002 170EC2002 120EC2002 240CT2002 10SEP2002 100CT2002 12NOV2002 130EC2002 17JUN2002 26JUN2002 100EC2002 180CT2002 22NOV2002 200EC2002 11 OEC2002 17AUG2002 06JAN2003 11FEB2003 08APR2003 08AUG2003 18AUG2003 15SEP2003 130CT2003 24APR2003 18MAY2003 05MAY2003 08MAY2003 15MAY2003 22MAY2003 12JUN2003 19JUN2003 19JUN2003 26JUN2003 01JUL2003 01JUL2003 03JUL2003

.Medicaid Amount Paid $ 79 76 $ 76 $ $ 76 76 $ 76 $ $ 79 79 $ 24 $ $ 79 76 $ $ 76 76 $ 76 $ 76 $ $ 76 $ 38 57 $ 79 $ $ 76 76 $ $ 76 76 $ 76 $ 80 $ $ 83 91 $ 51 $ 83 $ $ 83 $ 72 $ 86 86 $ 16 $ $ 26 26 $ $ 26 26 $ 26 $ $ 27 19 $ $ 13 15 $ $ 33

PrJ$cribing / 'Pr~vider ID

' Billing Provide riD .. . :.

100002708 100003393 100000412 100003316 100002792 100002792 100002792 100002792 100001169 100001169 100002886 100001751 100001216 100001216 100001802 100001216 100002818 100002818 100000391 100000835 100000835 100000835 100003191 100002883 PH0095 PH0252 PH0302 PH0013 PH0013 PH0013 PH0013 PH0154 PH0154 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026 PH0026

00349 00283 15920 15920 20646 20646 20646 20646 19896 19896 14295 5626 6974 6974 18150 6974 22917 22917 13653 21066 21066 21066 20646 3811 MH3725 M017091 M01905 M028574 M028574 M028574 M028574 MH4264 6451379 M011861 M011861 M019051 M019051 M019051 M019051 M019051 M019051 M019051 M019051 M019051

Sample Claims for Advair for Asthma Patients With No Asthma Drug Claim in Prior Year

IP~u:r'Am'~unt
700 1831207224 1720016074 02-Jul-08 15-Jan-08' 12 60 60 60 60. 60 11-Feb-10;
O:~pr-08,

'";senefi~ia ry'

30i 30' 30! 30'

252' 182 182 182' 182' 198:


"'"
~

2 2

254.331 184.28

89.02; 30

2 2 1.5' 0.75 2 1.75 2 1.75 1.5 2 2 2 2 2: 1.5 1.5 2


-

184.28 184.28, 199.02' 210.05 186.45i


---~-""""

30 30 39 20 9.31 3.1 3.1 3.2 85.82 85.82. 0

39~
30' 30 30 30i 30[ 30: 30 30 30 60 60 30: 30: 30 3Q,

60 60 60 60 60 60 60 60 60 1 60 60 60 60 60

209'
"V"""'-

184!
m""

0078643 0089202

600 600

1265536189 1508804196

1245343672 'AN7897359

08-0ct-07; 25-Mar-08 11-Jun-OT 04-Dec-09 23-Jan-09 23-Jan-09


04-Sep=O~

184' 189: 175 199' 193 193' 191: 191: 174' 209: 209 155

o:
190.79\ 176.68 200.21' 194.64' 194.64 .-.--., . 0' 0' 175.9 210.15! 210.15 157.05

0141880 0150355 0151739

600 600 600

1689665820 3371779 1417051335

AN8453108 BW0999031 1063431682

04-Sep-09 21-Feb-07' 01-Feb-10

o.
43.98 6.3' 6.3, 157.05

0178063 0178063

600 600

1598869554 1598869554

BF4594378

16-Jul-08 16-Jul-08,

60 60 30

>- -

1.5 1.5 ..
.,
_.

183.78' 183.78'

3.1: 3.1

182i

Sample Claims for Advair for Asthma Patients With No Asthma Drug Claim in Prior Year Paee 2

170.28i 12-Apr-07 !AA2019241 12-Apr-07 60 60: 60 30' 30' 30: 30' 120 120! 60 60' 1134146525 1134146525 1003808544 1003808544 07-Aug-10 07-Aug-10' 60 60 60 0252525 '0260569 0267231 0267231 600 600 500 .500 1811902810 23-Jan-07 24-0ct-08, 24-0ct-08 12-Nov-09' 1124125612 1336218650 1396717971 12-Nov-09, 06-Nov-09 60 60 60 60 60 60 180 60 AW2329111 1629172580 IAW2329111 13-Jul-07. 19-Aug-08 180' 180 180 60 30 30! 30 30! 30 301 30 30 30 30 30 30; 30' 90' 30. 173 173! 173' 173 219' 219! 2061
< "' , ... _ . " ' " '

6.3 30 30 30: 30: 3.1 3.1. 3.3 3.31 42 42 184.03

2. 2 2 2 1.5 1.5 1.25 1.25


1S

174.87' 174.87i 174.87 174.87' 220.05 220.05 207 .4'


~~

206i 20T 207' 182' 195 175' 153 153 160 160 460: 141; 422\
422~

207.4: 208.9 208.9' 184.03' 196.41 176.68 154.72' 154.72; 161.181 161.18' 462.27 142.8!

1.5 1.75 1.5 1.75 1.5 1.5 0.75 0.75 2

28 3.1 3.1 39 39 3.2 34.

go,
90 90 30

2.1 2.1 2.1


"w. '

424.51 424.51 194.64 60 3.1

422i 193[

Sample Claims for Advair for Asthma Patients With No Asthma Drug Claim in Prior Year
Pa~e

'Ben~ficiary<
,"J> .. >. '\"'

P<Hdf\n:munt
140.64 BP5545667 1003815788 16-Jul-08 29-Mar-10 60 60 60 'AB8831186 05-Jan-07 60 60 60 BT2032693 0557807 520 1720093826 4434611 '1023055761 BE0853879 BE0853879 14-0ct-09' 27-Apr-09 11-Apr-OT 11-Apr-07 11-Apr-07 60 12 60 60 60 180 0611044 0611044 0611044 0615093 0615093 0615093 0625169 '0633540 0633540 0633540 500 500 500 500 500 500 500 600 600
'""V""

20 20; 108.95' 3.1: 3.1 30, 30: 33 3.2 39 391 39i 6 5.35 5.35; 5.35 25 25 25 155.22' 155.22;

30 1 184 30 30 30[ 30 30 30. 30 301 30 30' 90 30' 30 30 30 30 30 30. 30 30, 30. .. .. 167, 142. 142 155; 155' 1611 162 173\ 173: 173i 480 149 149 149 148 148 148< 153( 153!

1.5 1.25. 4 4' 1.5


l.S

185.95 168.18 145.63 145.63 156.55 156.55. 162.29, 164.33 174.37 174.37) 174.37. 481.31' 156.08 156.08 156.08; 149.96, 149.96 149.96. 155.22'

1.4' 2 1.5' 1.5 1.5' 1.5 6.75: 6.75' 6.75 1.5 1.5 1.5; 2'

1127302

AP1764124 ;AP1764124

26-Sep-07 26-Sep-07

60 60 60 60 60 60

1558395368 1137000 1137000 1137000 'BC6385238 BC6385238 BC6385238

19-Jan-09' 10-Aug-07
10-A~~-0!

12

60 60 60'

178! 178
m
~

.,.

600

10-Aug-07

,, , ,."'"""'" , ,,

178 .. ...

4:

182.02

45.51

_ -~

Sample Claims for Advair for Asthma Patients with No ICS and No More than 2 SABA in Prior Year, No Asthma Related Hospital or Emergency Visit in Prior Month, Page 1

cc

Quantity,
;

':,;\

Disp~nsed

18-0ct-08! 18-0ct-08'

60' 60 60 60 60; 60 60: 60 60 60: 60 60 180: 60 60i 180 180 180 60[ 60' 60

30 30 30 30 30 30 30' 30: 30i 30 30 90 30 30 90 90 90 30 30

188.79 153.22i 153.22. 153.22( 146.71! 146.71' 146.71' 146.7L ...... 158.7 146.71 190.38' 408.7, 184.45: 184.45 516.73 516.73 516.73 186.62: 203.71:

2 2 2 2 4.5 4.5 4.5 2 0.75 1.75 0 2 2 0 0 0 1.5 1.75

190.79 155.22: 155.22 148.71 151.21 151.21; 151.21 160.7

5.6 30 30 148.71 0 0 0 3.2 5.6 3.2 48.03 102.18 3.1 3.1 129.18 129.18 129.18 47.03 0, 3.1 3.1 3.1 0 28

0190111 0207467

A$8317011 A$8317011 1629177894 1770585093 1699792002 1104945773

14-Aug-08 14-Aug-08 19-Jul-08 18-Dec-09 . 23-Apr-08 pr-08 23-Apr-08

192.13: 408.7 186.451 186.45 516.73 516.73: 516.73 188.12' 205.46' 188.12

0282787

00173069600

AB6449703 i 1467 466581 1922108372 AA1111119 1922108372 AA1111119


""

.. '"'"''" ""..... ,,."'"'""

"""

23-0ct-07 13-Nov-10 13-Feb-09 13-Feb-09

""'''"0"W~"'"Wh"0"0W

60: 60: 60. 60: 60: 60

30 30 30 30 30 30

'"T"''"

190.96 182.28 182.28 168.T 189.24: 189.24'


'"'""' '"'''V'"'

5 2 2 1.5 1.5 1.5

195.96: 184.28' 184.28 0 103.83 103.83

109.83 109.83:

Sample Claims for Advair for Asthma Patients with No ICS and No More than 2 SABA in Prior Year, No Asthma Related Hospital or Emergency Visit in Prior Month, Page 2

.'~~~1Ettrw'J ~~~;! i~[~~, ~~~;ez~.


1649297920 2115093 0803115 60 60' 60: 60' 60' 60 60 60 60 60 60' 60: 60; 60 60 60, 60l 60 60 60: 60 60 60 60 60: 60 60 60 60 60 30 30 30 30 30 30: 30' 30 30 30 275.7 267.94 195.14' 182.28( 182.28: 202.68: 172.87: 142.46, 172.87; 207.11: 208.02! - 208.02' 208.02; 198.71' 192.64' 236.5: 150.21' 146.71; 168.56: 151.95i 151.95 151.95. 237.91 197.44 197.44 203.71! 199.1, 246.39! 246.39 182.28
-~'

1.5

a:
1.5 1.5 0 1.75. 4 1.75 1 1.75 ---- 1.75 1.75 1.5 183.78 183.78. 202.68. 174.62 146.46 174.62 208.11 209.77' 209.77 209.77 200.21 194.39: 238.5[ 151.71 174.06' 156.45. 156.45' 156.45 239.91' 199.04 199.04; 209.82 200.1' 253.43 253.43; 190.52 3.1' 5.6 38 5.35 5.35 3.1 31.22 3.3 1 3.3 3.3 50.05 5.6 3.1 3.1 35 0
27 27

3iJ'
30 30 30 30i 30 30 30 30: 30: 30 30 30 30 30 30 30 30 30 30

16-Jan-08 16-Jan-08; 16-Jan-08

4.5 4.5 4.5


2

1.6 1.6
2

0837925

00173069700 00173069700 '00173069600

1629144563

01-Jul-08' 01-Jul-08' 13-Jun-08

1 1.5 1.5 4.5

27 28. 38; 38: 3.2 3.3 3.1 3.1: 0

Sample Claims for Advair for Asthma Patients with No ICS and No More than 2 SABA in Prior Year, No Asthma Related Hospital or Emergency Visit in Prior Month, Page 3
.:.:(:>_,:>)

P(escr'iber 1q..
code, ...
1508838848
"""M""'"'"

.s]~~l" '.\ ... '!'' .',Cost . .\ .,~ . , . ,..


~()st ,.. ,. lngiFeg , ,,
191.51
60:

pai~. P<3iCi ... 'Ri~pen~i~gf~yf>~ldA~()unt


2 1.75 1.75 1.1 1.1 1.5 1.5. 2 1.25 2 1.5 1.5 1.5 1.5 1.85 1.8 1.8 1.8 4 4 4 1.25 1.25 2 1.5 1.5 1.5 1.15 195.43 208.1 205.46' 205.46' 153.41 153.41 208.9 191.88 174.87; 208.65 142.8: 153.81 153.81 153.81 153.81 186.3 208.1 208.1. 208.1 143.97 180.99' 180.99 207.4; 207.4 214.11 191.88 191.88 191.88 181.26
~-"

and . . ,sen,efleiary<
45 113.2 3.2: 3.2 5.6 5.6. 42 191.88 5.35 6.3 3.1 153.81 153.81 153.81 153.81. 25 30 30 30 3.1 3.1 3.1 3.3 42 42 6.3 191.88 191.88 191.88 30

0887715 0887715 0929662 '0929662 :0934896 0953464

:xK4659706 1922002799 '1922002799

1012927 1012927 1012927 1104174 1118889 1118889 1119667 1154955


,.

09-Jan-09 09-Jan-09 09-Jan-09 00173069600 '00173069600 00173069600 00173069500

60 60 60 60! 60. 60' 60 60 60 60! 60 60 12 60 60 ... 60' 60 60 60


....

----~-

.....

13-Mar-10

1329977 .1346141

':AN8475419

60: 60 60 60i 60; 60 60

~~

--;c.-

30 30 30 30 30 30 30, 30 30' 30 30 30 30 30 30 30 30 30 30 30 30 30; 30 30: 30 30 30 30

->.-w

203.71 203.71' 152.31. 152.31' 207.4 190.38' 172.87' 207.4' 140.8' 152.31! 152.31 152.31' 152.31 184.45' 206.3' 206.3' 206.3 139.97 176.99 176.99: 136.39 206.151 206.15 212.1. 190.38 190.38 190.38 180.11'

c c

Sample of Claims for Advair for Patients with no Asthma or COPD


ft)ispens,. .Tot~lof()rug l!ing F~e ' .. \Cost and a~d~tidiarv Dispensing Fee f'a~Amount: bispef1~9'l supply oPciiri . .. '.. 194.64 3.1 60 30 193 174.37 60 3 173 1.5 0 -- 176.93 28 30 175. 60. 2' ___ .. 60' 30 175' 2 176.93 28 ..... 183.78; 60 30 182.: 1.5 3.1 214.4 60 30 210; 3.3 4.5. 195.5 30 194 1.5 3.2: 60 3.1 30 191 2 192.96' 60 2 155.22 25 60 30 153.--,O! 0 60' 30 187 1.5 200.21. 3.2 60 30 199 1.5 2 205.9 205.9 60 30 204: 154.72 30 ....... 60 153 1.5 154.72 30 153 60. 12 30 147 12' 30 147. 12 30 161 0.06 30 205' 30 266 60 60 30 266 0 0 184.03 3.1 60 30 182i 1.75 60; 30 173 1.75 174.62 28 169.43 -- 60, 30 168 1.5 3.3 60. 30 168 169.43' 3.3 1.5 448.65 99, 180 90 448 0.45 164.81' 60 30 163 2 3.2 3.1 16-Apr-07. 60 . 60' 3.1 ... 60: 30: 16-Apr-07 174.37 ---- - 3.1 1S 142.8 60 30 05-May-07. 2 3.1 18-Dec-08' 60, 152.9 30 152.9 1.5'

{}~~s: d~~~~
-~.-

l
-

'

--

,--

w~---

,,

0077555 0088612

----

_ , __-_,

~-----

---

0204344 0205999 0221207 0231001 0231001

--N

-w--

3319527 BC3839505 109389833 121595277

Sample of Claims for Advair for Patients with no Asthma or COPD Diagnosis in Prior Year, Page 2
Benefidacy Drug td Code .... code 0017306 '117466337 0343957 0344246 0017306 0017306 0349370 0349370 0349370 0370876 05-Nov-07 Nation(;! I orug Qi$pens~" TotatqfDrug ingf:ee . cost:<mQ . B~n~fifiatY Paid. [)ispen$il1g Fee Paid Amount 1.5 210.15 3.3 1.5 0 0 161.44] 1.5 30 30 160, 1.5 161.44 161.44: 30 160i 1S 2 148.71 30. 147' 148.71 30 147 2 15 147 15 148.71 30 2' 167.58 45 1.75 192.13 3.1 30! 190 30 175 1.75 176.68 29 30 210 210.61 3.3 1. 30 210 1 3.3 210.61. 20 181' 5.95 187.05 0 5.95~ 181] 20 0. 187.05 _, . ._. 5.95: 187.05 20. 181: 0 1.75 146.72 30 145 25 186.1' 181 30 0 30 261 30 139 1' 30 207: 208.11 39.54 1.5 30 198 0 9.95 148 30 2 150.46 5.35. 5.35. 30 148; 150.46 1.5 174.37 30 173 28 20' 1.5 170.26 30 169 30 173 2 174.87 28 2 174.87 30 173 28 2 174.87 30 173 3.1 656.88! 650' 0 80 90. 656.88 90 650. 0 80
m

J. .

60 60 60 60

'"'''

"""'Y""

0551162 0551162

0017306 149770109.138662760 0017306 149770109 138662760

03-Apr-07 03-Aor-07 16-Jun-08 08-Mar-07. 29-Aug-09 11-Jul-07 10-Mar-10 23-Nov-09 06-Dec-07 06-Dec-07'

0579451 0590306 0615759 0626197 0630442 0630442

0017306 167958886 199279455] 0017306 .0017306 .0017306 0017306 115433627 BG8001149 '0017306 115433627 BG8001149

60 60 60 60' 60' 60 60 60: 60. 60' 60. 60. 60 60 60: 60 180 180

___ __

oov

'"'"'V"'"

'0714060 0714060

0017306 1466285 0017306 1466285

AG3713458 AG3713458

13-Apr-07 13-Apr-07

Sample of Claims for Advair for Patients with no Asthma or COPD Diagnosis in Prior Year, Page 3 Drug ()is pensoate . J'otal afOrus.: ..
'

--- .

. ',

;.

Presc~iption

Filled 0714060 .0758540 0765859 '0785006 0785006 0785006 0811323

Dispensed 180 60.

0017306 0017306 0017306

118466177

16-Dec-10 26-Feb-07 15-Jan-07

..

0915310 :0915310 0915679 0947137 0949691 0949691

30-Mav-08

60 120: 60 60 60 60 60 60 60. 60 60 60 60' 60i 60 60. 60 12: 60


60!

,..,<,v~ v '

1073183 1099287 1099287

0017306 0017306 0017306 1919616

FH0655730 MT087936 iMT087936

10-Feb-10 24-Sep-07 24-Seo-07'

1117039 1118355 1129190

0017306 136651846 AS9007091 0017306 115436975 165930385 .0017306 3720491 BM306899

06-0ct-08. 18-Nov-09 20-May-07'

60' 60' 60 60!

iog Fee . . ,costand :~aict , Paid < 0' 90 650 30 153 2 o 90 508. 0 30 175 176.68 30 175 1.75 30 175c 1.75 176.68 a 4.25' 30 217 60. 350' 1.75 351.61 30 139 142.06 1S 30 180' 1 181.11 30 180 1 30 188; 30 182 30 182 1.5' 185.62 30 157: 5 161.87: 194.39' 1.75 30 193r 148.71 2 30. 147 30 147 4' 30 220. 4. 30 220. 223.59' 30 220 4 223.59 4' 191.71': 30. 188 30 188 4 191.71 30' 188l 191.71 4' 1.35' 28 188 189.46 213.13, 30 209! 4 30 158 0 158.29' ... 0 158.29 30 158 30 196' 4 142.38 30 160 4.75 164.73 60 144 2 146.11 Cost '":' ..
':'
~
-~--~-

'

25.39 30

Q;

3.1 35.52 45.28

40.471 3.1 25 25 O 0 0 191.71 191.71i 191.71: 40'

o
158.29 .. 158.29 3.1' 164.73 36.03