Use of Biomarkers in Drug Development. Janet Woodcock M.D. Director, CDER, FDA

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1 Use of Biomarkers in Drug Development Janet Woodcock M.D. Director, CDER, FDA

2 Biomarkers: Extremely Critical to Drug Development Availability of a pharmacodynamic response marker (e.g., viral load) truly stimulates drug development As of Sept 2014 over 150 new (i.e., nontraditional) biomarker-drug pairs described in drug labels 47% metabolism/transport 30% target/pathway 23% immunologic/safety

3 Disease-Related Biomarkers Susceptibility: critical for certain prevention indications Diagnostic: most noticeable when missing Alzheimer s, depression, ME/CFS, chronic pain, bipolar disorder, fibromyalgia, rapid diagnostics for infections, etc. Lack of diagnostic creates huge challenges for drug development Prognostic Enrichment designs enroll people more likely to have an event Stratification benefit/risk assessment may be different on various parts of the disease spectrum

4 Drug Response Biomarkers Drug target: patient selection markers a very hot area 8 approvals since 2014 plus multiple supplemental approvals Primarily cancer therapy, antivirals, and treatments for genetic diseases About 20% of protocols/meeting packages submitted over past 6 months contain molecular testing elements (primarily targeting) as part of development strategy Drug monitoring Drug safety: rare SAEs; biomarkers for drug-induced renal toxicity Drug metabolism: pharmacogenomics

5 Biomarkers as Surrogate Endpoints Up to 45% of drug approvals use surrogate endpoints Biomarker used instead of a clinical endpoint when the former takes so long development is infeasible, or there are so few events that the trials could not be done, and/or the biomarker is well established (blood pressure) Critical to drug development in diseases with these characteristics and also for many preventive interventions Traditional or full approval with well established surrogate EP Accelerated approval (really conditional approval ) with surrogate EP reasonably likely to predict clinical benefit Scientific community has struggled with defining the criteria/process by which new surrogate EP are established; even well-established ones may be controversial

6 Regulatory Use and Acceptance of Biomarkers Vast number of biomarkers are in clinical use and accepted by regulators ( traditional ) Question is regulatory use and acceptance of new biomarkers, for example, molecular diagnostics: how does this occur? Over many decades, new biomarkers proposed by individual drug sponsors in the context of a drug development program a nonpublic setting Vast majority of new biomarkers accepted this way, including many companion diagnostics Exceptions include HIV and cancer (RECIST criteria) More recently, FDA has established a qualification program that can lead to a new, publically-available accepted biomarker Consortia or other groups can submit data Acceptance published in Guidance: 12 new biomarkers so far Biomarker can then be used in any development program within COU

7 FDA has Aggressively Supported Development of New Biomarkers through Regulatory Policy and Guidance 2005 Guidance on PG Data Submissions Concept Paper on Drug-Diagnostic Co-Development 2007 Companion Guidance on PG Data Submissions* Guidance on PG Tests and Genetic Tests for Heritable Markers 2008 ICH E15 Definitions in Pharmacogenetics/Pharmacogenomics 2010 ICH E16 Qualification of Genomic Biomarkers Guidance on Qualification Process for Drug Development Tools 2012 Guidance on Clinical Trial Designs Employing Enrichment Designs* 2013 Guidance on Clinical PG: Premarketing Evaluation in Early Phase Clinical Studies Rule: Orphan Subsets of a Common Disease 2014 Guidance on in vitro Companion Diagnostic Devices Guidance on Laboratory Developed Tests* In Process Guidance on Drug-Diagnostic Co-development ICH E18 Genomic Sampling Methodologies *draft 7

8 Companion Diagnostics When a new drug requires a diagnostic for use, generally should be an already FDA-approved diagnostic or approved at time of drug approval (co-development) Problem: multiple drugs with similar targets developed with different assays, read-outs not the same, use in clinic may vary Problem: lab may use LDT that does not measure exact same analytes Becoming more acute as multiple therapies that target small subsets are approved

9 Multiple Companion Diagnostic Approvals Drug Trade Name (Generic Name) Lynparza (olaparib) Erbitux (cetuximab); Vectibix (panitumumab) Exjade (deferasirox) Gilotrif (afatinib) Gleevec/Glivec (imatinib mesylate) Herceptin (trastuzumab) Herceptin (trastuzumab); Perjeta (pertuzumab); Kadcyla (ado-trastuzumab emtansine) Mekinist (tramatenib); Tafinlar (dabrafenib) Tarceva (erlotinib) Xalkori (crizotinib) Zelboraf (vemurafenib) As of Mar 2015 Device Trade Name BRACAnalysis CDx therascreen KRAS RGQ PCR Kit DAKO EGFR PharmDx Kit Ferriscan therascreen EGFR RGQ PCR Kit DAKO C-KIT PharmDx INFORM HER-2/NEU PATHVYSION HER-2 DNA Probe Kit PATHWAY ANTI-HER-2/NEU (4B5) Rabbit Monoclonal Primary Antibody INSITE HER-2/NEU KIT SPOT-LIGHT HER2 CISH Kit Bond Oracle Her2 IHC System HER2 CISH PharmDx Kit INFORM HER2 DUAL ISH DNA Probe Cocktail HER2 FISH PharmDx Kit HERCEPTEST THxID BRAF Kit cobas EGFR Mutation Test VYSIS ALK Break Apart FISH Probe Kit COBAS 4800 BRAF V600 Mutation Test

10 COMMITTEE QUESTIONS

11 Ethical Issues in Precision Medicine? Regional harmonization of policies on DNA collection for future exploratory use--global heterogeneity; similarly for return of incidental findings from sequencing When does studying patients less likely to benefit, e.g., marker negative patients, become unacceptable; when is equipoise lost? Appropriate use of invasive procedures for exploratory IVD or biomarker development

12 What Specific Recommendations for Report? Promotion of analytical quality, transparency of methods, and reproducibility in the discovery research enterprise Establishment of a unified biomarker taxonomy and respective evidentiary criteria Routine specimen collection and analysis in clinical trials and other studies Concrete framework on how to balance need to assess biomarker utility with efficiency of drug development for targeted subsets

13 Additional Questions? What systems can be developed to characterize differences in performance or concordance of tests for the same analyte (cleared, approved or LDT)?

14 Changes in Regulatory Environment over Months? Transition to sequencing approaches for companion diagnostics rather than individual drug-test pairs Consolidation of the clinical trial infrastructure to facilitate uniform molecular screening and efficient enrollment of rare subsets More clarity on approval pathways for biomarker defined subsets Increased use of data from clinical practice to generate and, in some cases, confirm hypotheses about molecularly defined subsets and drug responsiveness

15 Coordination of Regulatory Oversight of Molecularly-Targeted Therapies Between CDER and CDRH? Yes, and continuing to be refined Coordinated reviews more challenging in early development phases given unclear diagnostic codevelopment intent/outcomes and short timelines in PDUFA If coordinated advice needed, sponsor should alert FDA It is my impression that CDRH is under-resourced for this activity