Reduction of placebo response in depression trials via
independent remote (SAFER) patient interviews
Martina J. Flynn, Marlene Freeman, Maurizio Fava, David Mischoulon, James Pooley, Daniel Burch, Heather Bryson
Massachusetts General Hospital Clinical Trials Network and Institute (CTNI), Boston, MA, and PPD
Abstract
Objective: Systematic approaches are required to increase the quality and
precision of clinical trials for major depressive disorder (MDD). The development
of new treatments for MDD and treatment resistant depression (TRD) is hindered
by high placebo response rates that impair ability to identify signals of efficacy
from potentially promising new therapies. Background: In order to increase the
precision in making the correct diagnosis of MDD and of treatment resistance, our
group has created and implemented two clinical trial tools. The SAFER Interview
and the Antidepressant Treatment Response Questionnaire (ATRQ) are designed
to provide clinical researchers with user friendly tools to enrich the qualitative
assessment of MDD and treatment resistance. This reliable assessment of the
patient’s diagnosis and severity is made in a way that reflects the illness in a real-
world setting. Methodology: A retrospective review of SAFER and ATRQ
interviews conducted in five clinical drug trials in TRD was performed. In each
trial, all subjects had passed screening procedures at the site and were
considered to be eligible for the trial. A structured severity interview was
performed in addition to the SAFER and ATRQ. The SAFER interview was
performed remotely by clinicians from Massachusetts General Hospital, who
called the patient directly. The interview typically took 45 minutes. Results: Across
five independent trials of TRD,1,935 remote SAFER interviews were performed
Of the 1,935 interviews, 1,562 patients were deemed eligible for continued
screening. Of the remaining patients, 97 (4%) did not meet severity criteria, 39
(2%) did not meet only SAFER criteria, 151 (7%) did not meet ATRQ criteria for
treatment resistance, and 86 (4%) did not meet criteria on more than one
component of the SAFER Interview. A total of 373 (16%) of the patients were
deemed ineligible upon completion of the interview. In all of the studies, placebo
response rates were within a range of 18-28%, below the 30-37% average in
studies of treatments approved for TRD (olanzapine-fluoxetine combination,
quetiapine and aripiprazole). Conclusion: A substantial proportion of potential
participants in drug trials of TRD are excluded based on the rigorous application
of these tools. If SAFER interviews were not applied, many inappropriate patients
would likely have been included impairing assay sensitivity and potentially
resulting in a failed trial. These methods enhance the quality of clinical trials and
increase the likelihood of positive trials for efficacious compounds, based on low
placebo response rates when the appropriate patients are enrolled.
Objective
Systematic approaches are required to increase the quality
and precision of clinical trials for major depressive disorder
(MDD). The development of new treatments for MDD and
treatment resistant depression (TRD) is hindered by high
placebo response rates that impair ability to identify signals
of efficacy from potentially promising new therapies. The
investigators sought to develop a tool which, applied after
patient screening at the site, would further refine the patient
population in order to only include patients with the protocol
specified history and presentation.
Background
Conducting studies to assess the efficacy of a new
investigational product in patients with MDD or TRD is fraught
with difficulties such as the complexities associated with
obtaining an accurate diagnosis and determination of true
disease severity. The SAFER Interview and the Antidepressant
Treatment Response Questionnaire (ATRQ) represent two
clinical trial tools developed by our group which serve to
increase the precision associated with the diagnosis of MMD
and of TRD. The SAFER and ATRQ provide researchers with
tools that are particularly suited for use in a clinical setting and
which enrich the qualitative assessment of MDD and TRD. A
retrospective review of SAFER and ATRQ interviews
conducted in clinical trials confirms these tools provide a
reliable assessment of disease diagnosis and severity in a way
that reflects the illness in a real-world setting.
Methods
SAFER Criteria
State versus Trait:
The identified symptoms must reflect the current
state of illness and not longstanding traits
Traits do not generally change in 4–12 weeks
Assessability:
The patient’s symptoms are measurable with
standard, reliable rating instruments
The symptoms of valid patients can be reliably
assessed with standardized measurement tools
Face validity:
The patient’s presentation is consistent with our
knowledge of the illness (symptoms map to the
nosological entity; clear change from previous level
of function; similar to previous episodes if recurrent)
Ecological validity:
The patient’s symptoms reflect the characteristics of
the illness in a real-world setting (frequency,
intensity, duration, course, impact over at least 4
weeks)
Rule of the Three Ps:
Identified symptoms must be pervasive, persistent,
and pathological
The three Ps must interfere with function and quality
of life
The SAFER is an 11-question clinician performed
structured interview:
Paired with severity instrument for MDD
(MADRS or HAM-D) and the MGH ATRQ
Patients deemed eligible by the sites were
called at home by the SAFER rater at a time that
was convenient for the patient
SAFER raters were all psychiatrists and
psychologists on staff at MGH
If additional information was needed to
assess whether the patient met SAFER criteria,
the site clinical staff was contacted for more
information and/or pharmacy or primary
psychiatrist records
Decisions represented collaboration of the
SAFER team at MGH, with an internal process for
verification of decision making
Communication with sites was encouraged in
cases of SAFER failure, in the event that more
information was needed and to provide feedback
about the SAFER outcome
MGH Antidepressant Treatment Response Conclusions
Questionnaire (MGH ATRQ) (Fava and Davidson, 1996;
Fava, 2003): This is a self-rated questionnaire that
examines the antidepressant treatment history, using Quality control of subjects entering into a clinical trial
specific anchor points to define the adequacy of both dose continues to be a concern for CNS trials. Various methods
and duration of each antidepressant trial, as well as the have attempted to ensure that the intended patients are
degree of symptomatic improvement obtained with each being enrolled in trials to reduce placebo response and
trial. This questionnaire, which has been validated
increase the likelihood that a trial will provide data which is a
(Chandler et al, 2010), allows for the determination of true reflection of the efficacy of the drug or device being
treatment resistance in depression. studied.
The SAFER interview is a tool which allows for greater
control over the patients being entered into trials, and in
Results combination with the MGH ATRQ, provides a means for
“second opinions” rendered by experienced clinicians for
patients sites deem eligible. Of the five trials described
Study Design
*
SAFER SAFER Fail Result here, an average of 19% of the patients were determined
Sponsor Phase Interviews Rate not to meet enrollment criteria for TRD, illness severity
and/or Major Depressive Disorder.
Double Blind,
GSK 2 510 18.4% separated
Parallel In the absence of strategies such as SAFER and the MGH
ATRQ, a greater proportion of trial data will be generated
active
Euthymics 2 17.2% comparator from inappropriate patients hindering the assay sensitivity
SPCD* 483 and hence the ability to discern a true treatment effect
separated
where one exists.
Alkermes 2 SPCD* 211 23.6% separated Increasing the proportion of patients contributing informative
data serves to increase the likelihood that an efficacious
drug will separate from placebo.
Double Blind, study
Undisclosed 3 Parallel with 449 24.2% stopped, did
Lead-In not separate
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Disclosures
Fava, Maurizio – Research Support: Abbot Laboratories, Alkermes, Inc., American Cyanamid,Aspect Medical Systems, AstraZeneca,
BioResearch, BrainCells Inc., Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clintara, LLC, Covance, Covidien, Eli Lilly and
Company,EnVivo Pharmaceuticals, Inc., Euthymics Bioscience, Inc., Forest Pharmaceuticals, Inc., Ganeden Biotech, Inc.,
GlaxoSmithKline, Harvard Clinical Research Institute, Hoffman-LaRoche, Icon Clinical Research, i3 Innovus/Ingenix, Janssen R&D, LLC,
Jed Foundation, Johnson & Johnson Pharmaceutical Research & Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals,
MedAvante, National Alliance for Research on Schizophrenia & Depression (NARSAD), National Center for Complementary and Alternative
Medicine (NCCAM), National Institute of Drug Abuse (NIDA), National Institute of Mental Health (NIMH), Neuralstem, Inc., Novartis AG,
Organon Pharmaceuticals, PamLab, LLC., Pfizer Inc., Pharmacia-Upjohn, Pharmaceutical Research Associates., Inc., Pharmavite®
LLC,PharmoRx Therapeutics, Photothera, Roche Pharmaceuticals, RCT Logic, LLC (formerly Clinical Trials Solutions, LLC), Sanofi-Aventis
US LLC, Shire, Solvay Pharmaceuticals, Inc., Synthelabo, Wyeth-Ayerst Laboratories. Advisory/Consulting: Abbott Laboratories, Affectis
Pharmaceuticals AG, Alkermes, Inc., Amarin Pharma Inc., Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer AG,
Best Practice Project Management, Inc., BioMarin Pharmaceuticals, Inc., Biovail Corporation, BrainCells Inc, Bristol-Myers Squibb,
CeNeRx BioPharma, Cephalon, Inc., Cerecor,Clinical Trials Solutions, CNS Response, Inc., Compellis Pharmaceuticals, Cypress
Pharmaceutical, Inc., DiagnoSearch Life Sciences (P) Ltd., Dinippon Sumitomo Pharma Co. Inc., Dov Pharmaceuticals, Inc., Edgemont
Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, EnVivo Pharmaceuticals, Inc., ePharmaSolutions, EPIX Pharmaceuticals, Inc.,
Euthymics Bioscience, Inc., Fabre-Kramer Pharmaceuticals, Inc., Forest Pharmaceuticals, Inc., GenOmind, LLC, GlaxoSmithKline,
Grunenthal GmbH, i3 Innovus/Ingenis, Janssen Pharmaceutica, Jazz Pharmaceuticals, Inc., Johnson & Johnson Pharmaceutical Research
& Development, LLC, Knoll Pharmaceuticals Corp., Labopharm Inc., Lorex Pharmaceuticals, Lundbeck Inc., MedAvante, Inc., Merck & Co.,
Inc., MSI Methylation Sciences, Inc., Naurex, Inc., Neuralstem, Inc., Neuronetics, Inc., NextWave Pharmaceuticals, Novartis AG,Nutrition
21, Orexigen Therapeutics, Inc., Organon Pharmaceuticals, Otsuka Pharmaceuticals, Pamlab, LLC., Pfizer Inc., PharmaStar, Pharmavite®
LLC., PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals, Inc., Puretech Ventures, PsychoGenics, Psylin
Neurosciences, Inc., Rexahn Pharmaceuticals, Inc., Ridge Diagnostics, Inc., Roche, Sanofi-Aventis US LLC., Sepracor Inc., Servier
Laboratories, Schering-Plough Corporation, Solvay Pharmaceuticals, Inc., Somaxon Pharmaceuticals, Inc., Somerset Pharmaceuticals,
Inc., Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Inc., Synthelabo, Takeda Pharmaceutical Company Limited, Tal Medical, Inc.,
Tetragenex Pharmaceuticals, Inc., TransForm Pharmaceuticals, Inc., Transcept Pharmaceuticals, Inc., Vanda Pharmaceuticals, Inc. Patent
for Sequential Parallel Comparison Design (SPCD), which are licensed by MGH to RCT Logic, LLC; and patent application for a
combination of Scopolamine and Ketamine in Major Depressive Disorder (MDD). Copyright for the MGH Cognitive & Physical Functioning
Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-
Emergent Signs & Symptoms (DESS), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd.
Equity Holdings: Compellis; PsyBrain, Inc. Speaking/Publishing: Adamed, Co, Advanced Meeting Partners, American Psychiatric
Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim GmbH, Bristol-
Myers Squibb, Cephalon, Inc.,CME Institute/Physicians Postgraduate Press, Inc., Eli Lilly and Company, Forest Pharmaceuticals, Inc.,
GlaxoSmithKline, Imedex, LLC, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, Novartis AG, Organon
Pharmaceuticals, Pfizer Inc., PharmaStar, United BioSource, Corp., Wyeth-Ayerst Laboratories.
Mischoulon, David – Back Bay Scientific, Lippincott Williams & Wilkins, Bowman Family Foundation, BMS, Cederroth, FisherWallace,
Ganeden, Lichter Pharma, Nordic Naturals, Laxdale (Amarin), Methylation Sciences, Inc. (MSI), PharmoRx Therapeutics, SwissMedica,
Pamlab, BMS, Nordic naturals, Virbac, Pfizer, Reed Medical Education, MGH Psychiatry Academy
Freeman, Marlene – DSM Nutritionals, GSK, Otsuka, Takeda, Lundbeck, J&J, Genentech, Relizen/JDS Therapeutics
Bryson, Heather – PPD
Burch, Daniel - PPD