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FDA 2004: Revisiting the 1996

Obesity Drug Guidance
David G. Orloff, M.D.
Division of Metabolic and
Endocrine Drug Products,
CDER

Endocrinologic and metabolic Drugs Advisory Committee
September 8, 2004
1996 Obesity Drug Guidance
• Patient Population
– Body Mass Index (BMI)
• 27 – 29.9 kg/m2 with comorbidities (i.e., HTN, DM2)
• > 30 kg/m2 without comorbidities
• Run-in phase
– Identification of placebo-responders
– Avoidance of treating unnecessarily with drugs
• Duration of Phase 3 Studies
– Historical “bad luck” with anti-obesity drugs
– Absence of outcomes data
• First year placebo-controlled: proof of principle of
efficacy
• Second year open-label: durable efficacy and safety
in long-term use
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1996 Obesity Drug Guidance
- Efficacy criteria at end of year 1: presumed reduction in risk
for sequelae with modest (sustained) weight loss in serious
obesity
- Mean placebo-subtracted weight loss > 5%
- Proportion of subjects who lose > 5% of baseline body
weight is greater in drug- vs. placebo-treated group
- EMEA criteria at end of year 1:
- Mean placebo-subtracted weight loss > 10%
- Proportion of patients who lose > 10% of baseline body
weight is greater in drug- vs. placebo-treated group

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1996 Obesity Drug Guidance

• Patient Exposure
– 1500 patients completing one year of placebo-
controlled exposure
– 200-500 patients completing a second year of
open-label exposure
• ICH E1A
– Drugs for long-term treatment of non-life-
threatening conditions:
– 300 – 600 for 6 months
– 100 for one year

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ICH E1A : Exposure requirements
dictated by demonstrated efficacy
• Larger/longer exposures if benefit of drug is:
– Small (e.g., symptomatic improvement, less serious
disease)
– Experienced by only a fraction of treated patients
(prevention)
– Of uncertain magnitude (reliance on a surrogate)
• Average placebo-subtracted weight loss of drugs evaluated
to date 3-5% of baseline at year 1
• Not all treated patients lose weight; some gain
• Scant data to date from controlled trials of benefits in terms
of irreversible morbidity
– XENDOS (Orlistat)
• No data on cardiovascular morbidity or mortality
– SCOUT (Sibutramine)

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2004: revisiting the guidance

• Charge from Dr. McClellan to OWG/Therapeutics (8-03)
– “…[assess] real or perceived barriers to development of
new or enhanced therapeutics”
– “Make recommendations… on…ways to encourage
development of new or enhanced therapeutics”
• Growing public health problem
• Advancing science
• Multiple new drugs in development; anticipated explosion in
development programs in coming years
• Multiple novel mechanistic approaches
• FDA’s role in assuring that safe and effective drugs are
efficiently and effectively brought forward through
development to marketing for use in the treatment of human
disease

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2004: revisiting the guidance
• Goals
– Guidance appropriate for development of drugs, with
respect to:
– Potential roles of drugs in treatment and prevention
– Target populations at risk for obesity and its sequelae
– Evidentiary standards for proof of meaningful efficacy
– Evidentiary standards for demonstration of acceptable
safety

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2004: revisiting the guidance

• Federal Register Notice
– January 26, 2004
• Request for public comment on the 1996 Obesity
Drug Guidance
• Response
– Approximately 17 submissions to the docket
• Nearly all from industry

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Issues raised in comments
• Broadening of target population
– Adolescents
• Burgeoning problem
• Long-term, population-specific risks (i.e., linear
growth, bone)
• Most appropriate endpoint (i.e., BMI rather than
weight)
• (Specific criteria for selection not proposed)
– Lower BMI limit targeting prevention of weight gain
• “High-risk” treatment and prevention (without
specifics)
• Drugs “effective” in those with lesser degrees of
obesity
– Diabetes, Metabolic syndrome (these are not excluded
based on trials to date)
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Issues-2
• Study design
– Run-in
• Proof of efficacy only in those unable to lose weight
on diet/exercise is an excessive standard
• More generalizable results if no run in required
• Measure of effect is placebo-subtracted weight
change from baseline
• (means of assuring standard of care in context of trial not
addressed)

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Issues-2 (con’t)
• Duration
– One year of controlled efficacy
– Safety at one year
– Questionable utility of additional year if no safety
concerns after 1st year
– (Approach to assessing need for additional time or patients
not addressed)
• Controls/Combination studies
– (Efficacy criteria not addressed)

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Issues-3
• Efficacy criteria
– Total weight loss > 5% from baseline at 12 months
– Placebo-subtracted weight loss > 5% from baseline at
12 months (current criterion)
– Significantly greater proportion (drug vs. plbo) losing >
5% of weight at 12 months (current criterion)
– Define categorical win more specifically (i.e., absolute or
relative difference in percentage of patients achieving
5% or greater weight loss)

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Issues-3 (con’t)
• Efficacy criteria
– Define weight maintenance
– Define prevention of weight regain
– Define drug-induced weight gain
– BMI in pediatric patients

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Issues-4
• Safety exposures
– Arbitrary
– Current obesity guidance
• 1500 patients for one year; 200-500 for second year
– ICH
• 100 patients for one year

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Summary/Points for discussion
• Populations
– Lower entry criterion to a BMI > 25 kg/m2 when
accompanied by comorbidities*
• What evidence supports treatment or prevention in this
population?
• What magnitude of effect would be clinically significant?
• What assurance of safety is required to treat lower-risk
patients?
– Pediatric/adolescents
• What factors should be weighed/addresssed in
assessing risk vs. benefit?
– Obesity-associated metabolic derangements/cv risk
factors as primary targets of drug therapy

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Summary/Discussion-2
• Design
– Run-in prior
• Identification of pbo responders
• Avoidance of unnecessary tx
• Standard of care

– Combination drug regimens
• Standards of efficacy

• Endpoints
– Define obesity prevention, weight maintenance, prevention of weight regain*
• Are these distinct clinical effects?
• Are these distinct pharmacological effects?
• Are studies needed to document efficacy and safety in each?
– Include requirements for approval of treatment or prevention of drug-induced
obesity*
• Data on risks for and associated with drug-induced obesity, by drug
• Issues of interactions impacting safety and efficacy
• Criteria for efficacy
– Include a section on treatment of obesity in pediatric patients*

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Summary/Discussion-3
– Reduce the number of patients in phase 3 study from 1500 examined
over one year to 500 – 1000, or even fewer*
• Rationale based on magnitude/nature of efficacy?
• Rationale based on size of target population?
• Rationale based on expectations regarding safety?
– Eliminate the second year of open-label study*
• Rationale based on nature of drug “toxicities”: acute vs. cumulative?

– Suggested changes
• Require an absolute difference for the categorical weight loss
criterion
• Include metabolic syndrome as a therapeutic endpoint
• Include requirements for approval of drug combinations
– Cosmetic weight loss
• Psychological benefits
• Social/economic benefits
• QOL

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