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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/LillyMK-742694 NK-1/Sub P MerckEMD 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 Novartisantag

ORG 12962 5HT2c agonist Organon

Befloxatone MAO- A inh Synthelabo

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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 2002;22(1):40-45.

RCTs (#) Drug = PBO (%)

New AD 44 23 (52%)

Standard AD 22 8 (36%)

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DrugCNS entry?Pharmacologic effect?Dosing?

DesignComplexityInstrumentationLead-inDurationBlindingFlexible/fixedData analysis

PatientSourceSeverityDiagnosisComorbidityExpectationsBehaviour

InvestigatorAffiliationTrainingSpecialtyInteraction

Studying SignalDetection

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Similar Problems in GAD starting with Drug Placebo Differences

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N: 326 344 54 45 22 20 19 10 54 67 63 81 99 104 109 58 101

Year: ‘81 ‘81 ‘83 ‘83 ‘85 ‘86 ‘89 ‘91 ‘91 ‘97 ‘97 ‘98 ‘98 ‘98 ‘98 ‘98 ‘00

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Venlafaxine –FDA SBA: Variation Across Doses & Studies in Effect Size

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N: 92 91 91 102 101 87 87 86 81 86Year: |---------- Venlafaxine NDA---------| ‘99 ‘99 ‘00 ‘00 ‘00

Dose: 75 150 225 75 150 75XR

150XR

75XR

150XR

225XR

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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