Informative Studies of New Therapeutic Agents in Major Depression, GAD

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Informative Studies of New Therapeutic Agents in
Major Depression, GAD Panic

• W Z Potter, M.D., PhD.
• Merck Research Laboratories

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Overview

• For depression, current approaches deliver data
  necessary to drug use in broad population
• Greatest need is to find novel antidepressants
  that may provide broader efficacy, faster action
  and/or better risk benefit ratio for acute active
  phase of illness
• Recent research into achieving optimal yields
  with current designs should be applied to the
  above need
• Whether alternate studies supporting registration
  would yield benefit is a matter for research
• GAD and Panic might benefit from formal consensus
  discussion among experts as to best studies to
  support registration

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Goals of Treatment Studies

• Safety over period of likely treatment
• Establish meaningful drug efficacy
• Clinically significant relief
• Cure
• Maintenance of Response
• Prevention of Recurrence if episodic
• Cost effectiveness from societal point of view

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How well do the Current Requirements for
Submission and Approval Meet these Goals?

• Major Depression Remarkably well despite many
  failed studies and reasonable standard for novel
  agents given that we are beginning to understand
  sources of variability
• GAD Not well studied as primary indication but
  no published evidence on clinically detrimental
  gap in knowledge
• PANIC Even less studied as primary indication
  open question as to best study designs for
  providing most clinically relevant information

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Selected Potential Antidepressants in 1997 Wrong
Targets for Better Responses or Poor Signal
Detection?

• Compound Mechanism Company
• R-Fluoxetine SSRI Sepracor/Lilly
• MK-742694 NK-1/Sub P Merck
• EMD 68843 5HT1a agon MerckKGaA
• /SSRI
• Flibanserin 5HT1a agon Boehringer
• /2a antag Ingleheim
• YKP-10A NMDA antag? SK Corp
• NS 2389 SNDRI Neurosearch
• Sunepitron 5HT1a agon Pfizer /alpha 2
  antag
• Robalzotan 5HT1a antag Zeneca
• CGP 49823 NK-1/ sub P Novartis

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Signal Detection A Major Problem Using Standard
Designs with Proven ADs

• Proportion of Failed Antidepressant Trials in FDA
  SBA Data Sets
• Khan A, et al. J Clin Psychopharmacology
  200222(1)40-45.

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Drug
Patient
CNS entry?
Source
Pharmacologic effect?
Severity
Dosing?
Diagnosis
Comorbidity
Expectations Behaviour
Design
Complexity
Instrumentation
Investigator
Lead-in
Affiliation
Duration
Training
Blinding
Specialty
Flexible/fixed
Interaction
Data analysis
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Similar Problems in GAD starting with Drug
Placebo Differences














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Venlafaxine FDA SBA Variation Across Doses
Studies in Effect Size
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Researched Factors Contributing to Variance in
Signal Detection with Current Designs

• Marked US vs OUS differences in terms of efficacy
  and safety Different Patients Practices
• Ski Slope phenomenon from Single Blind Lead-In
  Tests of Double-Blind Alternative
• Evidence of systematic bias -- Constriction of
  severity assessment around entry criteria
• Rating Scales Relevant items and mode of
  administration evolving

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Enhanced Signal Detection with Current Designs vs
Other Issues for AD Development

• Impact of wide availability of SSRIs Why enter
  a study?
• Partial or non-responder to SSRI?
• Lack of novel agents -- Can drive over
  investment in single mechanism vs assessing many
• Expectation around and wish for novel treatments
  can drive premature studies in large numbers of
  patients prior to acute efficacy being
  established (Substance P Antagonist Experience)

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Depression Value of Current Study Design Acute
Maintenance

• Heterogenous disease and population of patients
  available for studies affect trial designs
  supporting registration
• Establishing subacute efficacy for a novel
  mechanism would itself constitute a breakthrough
• Large drug effect size (twice that in acute
  designs) in discontinuation studies after 2-3
  months on drug (only 50-60 of treated reach this
  point) has consistently predicted long-term
  efficacy -- 6 months on drug would mean more drop
  outs, have restrictive effects on patient
  selection and be less informative at this stage
  of development
• 2-3 month design captures both those who truly
  require drug and those who are out of episode by
  6 months

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NIMH Funded Classic Study of Relevant
Drug-Placebo Difference within 12 weeks of
Discontinuation after 12 weeks on Drug
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GAD Panic Efficacy

• Chronic conditions which when treated with
  benzodiazepines risk attendant dependence and
  rebound after acute discontinuation
• Recent data in GAD with SSRIs conform remarkably
  to pattern seen in depression
• Little informative data in panic -- last primary
  indication studies with alprazolam

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Double Blind Discontinuation Results for an SSRI
in GAD
Stocchi, F et al, J Clin Psych, 2003
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Conclusions

• For depression, current approaches deliver data
  necessary to drug use in broad population
• Greatest need is to find novel antidepressants
  that may provide broader efficacy, faster action
  and/or better risk benefit ratio for acute active
  phase of illness
• Recent research into achieving optimal yields
  with current designs should be applied to the
  above need
• Whether alternate studies supporting registration
  would yield benefit is a matter for research
• GAD and Panic might benefit from formal consensus
  discussion among experts as to best studies to
  support registration