1. Early Clinical Development Planning via Biomarkers, Clinical Endpoints, and Simulation: A Case Study to Optimize for Phase 3 Dose Selection (Musser et at, TIRS, 2015, vol 49(3), 405, 414) A Discussion Aloka Chakravarty, Ph.D. Office of Biostatistics, CDER,FDA Center for Drug Evaluation and Research/FDA | May 25, 2016 1

2. Innovative Idea Use of biomarkers and clinical endpoint in Ph1/Ph2b in the outlined manner quite innovative –Cut the losses early Use of Bayesian framework in this context - innovative More on both later Start with the definitions ………. Center for Drug Evaluation and Research/FDA | May 25, 2016 2

3. Biomarkers – Same name for different things ? 3 Biomarker Diagnostic Risk Safety Candidate surrogate Clinical validation Biomarker Monitoring Pharmacodynamic Fit-for-purpose Reasonably likely surrogate Diagnostic Surrogate Analytical validation Surrogate Context of use Predictive Prognostic Intended use Accelerated approval Biomarker Qualification Monitoring Prognostic Predictive Pharmacodynamic Reasonably likely surrogate Candidate surrogate Endpoint Analytical validation Clinical validation Context of use Intended use Fit-for-purpose Qualification Accelerated approval

4. BEST Resource A standard glossary of terminology and uses of biomarkers and endpoints in basic biomedical research, medical product development, and clinical care Publicly available at NLM: http://www.ncbi.nlm.nih.gov/books/NBK3267 91/ Opportunity for feedback: biomarkers@ncbi.nlm.nih.gov An FDA-NIH Joint Leadership Council Initiative (Acknowledgement: Mellissa Robb, CDER) 4

5. Example - Biomarker Initial Definition A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (this definition was used in the paper). BEST - Final Definition A defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers. A biomarker is not an assessment of how a patient feels, functions, or survives. 5

6. Example Term: Biomarker Identify Existing Definitions and Related Terms A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a[n]... intervention. Example: cholesterol level (11) pathologic processes, or biological responses to a therapeutic intervention (7) pathogenic processes, or biological responses to a therapeutic intervention. A biomarker can be a physiologic, pathologic, or anatomic characteristic or measurement that is thought to relate to some aspect of normal or abnormal biological function or process (5) pathogenic processes, or pharmacologic responses to a therapeutic intervention (6 and 2) pathogenic processes, or responses to a therapeutic intervention. A biomarker can be a physiologic, pathologic, or anatomic characteristic or measurement that relates to an aspect of normal or abnormal biologic function or process. Examples of BT include: an instrument or method for measuring blood pressure (e.g., sphygmomanometry); an instrument or method for measuring certain concentrations of serum proteins (8) pathogenic processes, or pharmacologic responses to a therapeutic intervention (12) 6

7. References for Existing Definitions 1.Amur, S, et al. "Biomarker Qualification: Toward a Multi-stakeholder Framework for Biomarker Development, Regulatory Acceptance, and Utilization." Clinical Pharmacology and Therapeutics (2015). 2.Biomarkers Definitions Working Group. "Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework." Clinical Pharmacology and Therapeutics (2001): 89-95. 3.FDA/CBER & CDER. "Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics." 2014. 4.FDA/CBER, CDER, CDRH. "Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims." 2009. 5.FDA/CDER. "CDER MAPP: Drug Development Tool Qualification Programs." 2014. 6.FDA/CDER. Clinical Outcome Assessment (COA): Glossary of Terms Webpage. 30 April 2015. 9 June 2015. 7.FDA/CDER. "Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools." 2014. 8.FDA/CDRH. "Draft Guidance for Industry, Tool Developers, and Food and Drug Administration Staff: CDRH Medical Device Development Tools." 2013. 9.FDA/CDRH, CBER. "Guidance for Industry and Food and Durg Administration Staff: Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions." 2014. 10.FDA/CDRH. "Guidance for Industry and Food and Drug Administration Staff: In Vitro Companion Diagnostic Devices." 2014. 11.IOM. Evaluation of Biomarkers and Surrogate Endpoints in Chronic. Washington DC: National Academies Press, 2010. 12.Khleif, SN, JH Doroshow and WN for the AACR-FDA-NCI Cancer Biomarkers Collaborative Hait. "AACR-FDA-NCI Cancer Biomarkers Collaborative Consensus Report: Advancing the Use of Biomarkers in Cancer Drug Development." Clinical Cancer Research (2010): 3299-3318. 13.National Cancer Institute. NCI:Tumor Markers. 7 December 2011. 9 June 2015. 14.Parkinson, DR, et al. "Evidence of Clinical Utility: An Unmet Need in Molecular Diagnostics for Patients with Cancer." Clinical Cancer Research (2014): 1428-1444.

8. Common Biomarker Categories Diagnostic biomarker Monitoring biomarker – biomarkers BM1 and BM2 discussed? Pharmacodynamic/response biomarker – BM1? BM2? Prognostic biomarker –– first set of biomarkers referred in the introduction of the paper Predictive biomarker – second set of biomarkers referred in the introduction of the paper – of main interest in this paper Safety biomarker Susceptibility/risk biomarker -Is BM3 a biomarker or an intermediate endpoint? -Same endpoint measured longitudinally - Use of consistent terminologies minimizes confusion 8

9. A few comments (1) Simulation cases (pages 408-409) –Treatment effect assumed to be 0.4 and 0.6 –It is lot more modest in many therapeutic areas – how will the method perform in those situations? Results (page 409-411) –“Simulation errors” - quite high for 500 simulation case –Scenarios 1 to 5 - The performances are quite modest 14% for direct to Ph2b cases, 21-25% for seq PoC-DF cases –N=100 /dose is not feasible in Ph2b for many therapeutic areas –Scenarios 1b-1d – sample sizes of n=(100,250,850,2500) estimated at or near the target dose in (50%, 67%, 87%,96%) –The sample size requirement will limit usability –What do authors mean by “near-perfect biomarkers”? Center for Drug Evaluation and Research/FDA | May 25, 2016 9

10. A few comments (2) Bayesian framework –What is the added advantage of going this route? –Sample size or trial duration considerations? –Diminishing biomarker variances and computing effective sample size – quite a strong assumption to be of practical use –Bayesian joint tri-variate normal distribution for biomarkers and clinical endpoint - driven by analytical ease? Trough concentration often have plateau effect –Prior selection – justification? –Gibbs sampling was a clever choice – direct sampling THANKS for giving an opportunity to comment and discuss!! Center for Drug Evaluation and Research/FDA |May 25, 2016 10