Alternative Study Designs

Maurizio Fava, MD Director, Division of Clinical Research, Massachusetts General Hospital (MGH) Research Institute Executive Vice Chair, MGH Department of Psychiatry Executive Director, MGH Clinical Trials Network and Institute (CTNI) Slater Family Professor of Psychiatry Associate Dean for Clinical and Translational Research Harvard Medical School

Disclosures (lifetime): Maurizio Fava, MD

Type Company Advisory Board/ ; Affectis Pharmaceuticals AG; , Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Consultant Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; , Inc.; Cerecor; 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.; ; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; , Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; , Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG;Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, LLC.; Inc.; PharmaStar; Pharmavite® LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PPD; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC ( formerly Clinical Trials Solutions, LLC); 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. Speaking/ 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 Publishing 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.; -Ayerst Laboratories. Research Support Abbot Laboratories; Alkermes, Inc.; American Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; ; ; 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; Lundbeck Inc.; MedAvante; Methylation Sciences Inc; National Alliance for Research on & 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-; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC;PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Wyeth-Ayerst Laboratories Stock/Other Equity Holdings: Compellis; PsyBrain, Inc. Financial Options Royalty/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven.

Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd.

Types of Response to Treatment in Neuropsychiatric Illnesses

Patients’ Response Types:

Placebo – Placebo - Placebo + Drug + Drug - Drug + (P-D+) (P-D-) (P+D+)

Informative Not Informative Not Informative

10% 50% 40%

Borsook, Becerra and Fava, Transl Psychiatry. 2013 Jul 16;3:e282. doi: 10.1038/tp.2013.43.

Effects of Reducing Placebo Response on Types of Response to Treatment Patients’ Response Type:

Placebo – Placebo - Placebo + Drug + Drug - Drug + (P-D+) (P-D-) (P+D+)

Application of Placebo Response Reduction Strategies

Informative Not Informative Not Informative

10% 40% 50% 25% 4 25%

Borsook, Becerra and Fava, Transl Psychiatry. 2013 Jul 16;3:e282. doi: 10.1038/tp.2013.43. Placebo Response vs Placebo Effect • “placebo response” = change that occurs after the administration of a placebo • “placebo effect” = difference between the placebo response and those changes that occur without the administration of a placebo Questions About the Placebo Response • Is the improvement in patients given a placebo: – result of the placebo itself? – due to natural fluctuations in the progression of the disease? – a regression toward the mean? – due to non-specific, treatment effects? Standard Model Design for Testing of Drugs vs. Placebo in Psychiatric Patients

Screening and Randomization

Drug Placebo What are the Basic Assumptions of This Design?

• Minimal effects of regression to the mean phenomenon • Natural course of illness well characterized- uncommon spontaneous remissions • Placebo effect is trivial • Expectations about improvement play minor role • Sample’s responsiveness to drug is greater than to placebo Is the Effect of the Natural Course of Psychiatric Illnesses Trivial?

• From an extrapolation during the first 6 months of illness, MDD on average: – Remits in 2% of subjects per week – Has spontaneous remission rates of 8- 16% over 4–8 weeks

(Posternak and Miller; Journal of Affective Disorders 2001, 66, 139-146) Single-Blind Placebo Wash-Out Followed by Randomized Parallel Comparison Screening and Single-Blind Placebo Wash-out

Exclusion of Randomization of Responders to Non-Responders Placebo

Placebo Drug What are the Specific Assumptions of This Design?

• The clinician’s knowledge of the placebo wash-out does not bias the detection of improvement • The clinician’s reduced expectations of change during wash-out do not get communicated (verbally or not) to the patients • Patient’s overall expectations of improvement are unaffected The Single-Blind, Placebo Wash- Out is Ineffective • Meta-analyses of 101 MDD studies reveal that a placebo run-in does not: – lower the placebo response rate – increase the drug-placebo difference – affect the drug response rate post- randomization in either inpatients or outpatients for any antidepressant drug group

Trivedi MH and Rush AJ. Neuropsychopharmacology. 1994 Aug;11(1):33-43. Randomized Re-Treatment Trial Designs

Dunger-Baldauf C et al; Drug Information J; 2006; 40:209-217 What are the Specific Assumptions of This Design?

• Ideal for fluctuating illnesses where intermittent treatment is reasonable • Minimal or no carry-over effects • Restarting treatment upon relapse is typically required • No significant discontinuation reactions Randomized Re-Treatment Trial in IBS

Tack J et al; Gut 2005;54;1707-1713 Randomized Play-the-Winner Clinical Trials Preliminary Analyses Show Greater Separation With Drug A vs Placebo Randomization Randomization

33.3% 33.3% 33.3% 33.3% 53.3% 13.3% Randomized Randomized Randomized Randomized Randomized Randomized to Placebo to Drug A to Drug B to Placebo to Drug A to Drug B

Rosenberger WF; Controlled Clinical Trials Vol 20, 1999, Pages 328-342 What are the Specific Assumptions of This Design? • The better treatment will actually perform better in the clinical trial (or the treatment works better in one population than in another one) • The treatment with better outcome does not cause some serious toxicity • The degree of placebo response is constant throughout the study Adaptive Design With Progressive Elimination of High Placebo Response Sites

Preliminary Analyses

Randomization Randomization

33.3% 33.3% 33.3% 0% 50% 50% Randomized Randomized Randomized Randomized Randomized Randomized to Sites with to Sites with to Sites with to Sites with to Sites with to Sites with Placebo = Placebo  Placebo  Placebo = Placebo  Placebo Responses Responses Responses Responses Responses Responses

Merlo-Pich E, Gomeni R; Clin Pharmacol Ther. 2008 Sep;84(3):378-84. What are the Specific Assumptions of This Design?

• The degree of placebo response remains constant at each site • The clinician’s reduced expectations of change do not get communicated (verbally or not) to the patients (e.g., clinicians know that their site would get eliminated based on high placebo responses) Adaptive Design With Progressive Elimination of High Drop-Out Sites

Preliminary Analyses

Randomization Randomization

33.3% 33.3% 33.3% 0% 50% 50% Randomized Randomized Randomized Randomized Randomized Randomized to Sites with to Sites with to Sites with to Sites with to Sites with to Sites with  Drop-Out = Drop-Out  Drop-Out  Drop-Out = Drop-Out  Drop-Out Rates Rates Rates Rates Rates Rates

Fava M, manuscript in preparation What are the Specific Assumptions of This Design?

• The degree of attrition remains constant at each site • Decreased attrition is a proxy for quality of patients enrolled and accuracy of measurement Two-Period Crossover Design ABBA

Randomization

A - Drug B - Placebo

B - Placebo A - Drug

Hills M and Armitage P; Brit J Clin Pharmacol 1979; 8:7-20 Three-Period Crossover Design

Randomization

Drug Placebo Placebo Drug

Placebo Drug Placebo Drug

Placebo Drug Drug Placebo

Carrere KC; Statistics in Medicine 1994; 13: 1063-1069 What are the Specific Assumptions of This Design?

• Minimal or no carry-over effects • By using subjects as their own controls, statistical power is maximized • No significant discontinuation reactions Double-Blind, Placebo-Controlled, Crossover Study of Scopolamine in MDD

Furey ML and Drevetz WC; Arch Gen Psychiatry. 2006;63:1121-1129 Sequential Parallel Comparison Design (SPCD) Structure

Active Active Stage 1 Stage 2

Placebo First Placebo responders Stage 2 Randomization

Placebo Stage 1 Active Stage 2 Placebo non- Re- responders randomization Placebo Stage 2 Primary efficacy analysis set

Stage 1 Stage 2

Fava et al, Psychother Psychosom. 2003; 72(3): 115-27 See video at: http://www.ppdi.com/Therapeutics/Neuroscience/Trimentum.aspx Why Two Phases of Treatment? • The first phase is aimed at: – Comparing drug and placebo in a standard parallel comparison design fashion – drug-placebo differences are expected to be smaller – Generating a large cohort of placebo non-responders • The second phase is aimed at: – Comparing drug and placebo in a parallel comparison design fashion in placebo non-responders – drug-placebo differences are expected to be greater – Placebo response is expected to be smaller • The data from the two phases are pooled to estimate the drug-placebo differences averaged (in a weighted fashion) across the two phases • When compared to the conventional two arm clinical trial, SPCD reduces the sample size 20–25% under a wide range of parameters (Tamura RN and Huang X; Clinical Trials 2007; 4: 309–317)

Fava M et al; Psychother Psychosom. 2003 May-Jun;72(3):115-27. Why is Each Phase Shorter than Standard Trials? • To increase the feasibility of the trial • There is a marked congruence between endpoint and half- way drug-placebo differences in standard trials (Yang H et al; Curr Top Med Chem. 2005;5(11):1077-86) • According to the meta-analysis by Posternak and Zimmerman [J Clin Psychiatry 2005, 66, 148-158], on average, more than 80% of the improvement on placebo occurred in the first half of 6-week trials • The best placebo-responder classification score (86.32% true and 13.68% false positive) is associated with the longitudinal model with HAMD-17 measures at week 4 (Gomeni R and Merlo-Pich E; Br J Clin Pharmacol. 2007 May;63(5):595-613) What are the Specific Assumptions of This Design? • Every patient is included in the analysis from phase 1; only placebo non-responders are included in the analysis from Phase 2 • Remission with placebo during the second phase in placebo non-responders is unlikely • The drug-placebo difference is proportionally greater in the second phase • Patients find acceptable to have a 50% chance of being on active treatment at some point during the study Double-Blind, SPCD Study of ALKS 5461 (buprenorphine plus the mu antagonist Alks 33) vs. Placebo*

Marshall et al, ISCTM Annual Meeting, 2013

*Treatment History Assessed with ATRQ by SAFER rater CONCLUSIONS • Placebo responses in antidepressant trials are very robust • There are many possible contributing factors – difficult to control • To enhance signal detection, one may want to: – Enrich trial using adaptive designs – Use subjects as their own control with crossover designs – Lower the placebo response with SPCD