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Regulatory Considerations

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Presentation on theme: "Regulatory Considerations"— Presentation transcript:

1 Regulatory Considerations
Edwin Rock, MD, PhD Office of Oncology Drug Products Food and Drug Administration

2 Outline FDA Requirements for Drug Approval ICH Regional Variations
Cancer Approval Endpoints

3 FDA Requirements for Drug Approval
Labeling 1906 Pure Food & Drug Act Safety Food, Drug, and Cosmetic Act (FDC) Efficacy FDC Amendments

4 FDA Accelerated Approval
Serious or life-threatening disease Improvement over available therapy Surrogate endpoint reasonably likely to predict clinical benefit Requires confirmation of benefit

5 Endpoints Supporting FDA Approval
Regular Approval (~Clinical Benefit) Longer life Better life, i.e. a favorable effect on Valid measure of how patient feels or functions Accepted surrogate Accelerated Approval (~Surrogate) Surrogate of better life Reasonably likely to predict clinical benefit

6 Oncology Surrogates at FDA
For Regular Approval Disease Durable complete response Acute leukemias Partial response (PR) Advanced breast Disease free survival (DFS) Adjuvant breast For Accelerated Approval Response rate with duration Solid tumors

7 ICH Regional Considerations: EU
New Medicines Legislation, 11/05 Conditional Marketing Authorization, 3/06 Approval Mechanisms

8 The New Medicines Legislation
11/05, Modifies EMEA Role Mandates Centralized Procedure for new treatments of cancer, AIDS, neurodegenerative diseases, diabetes, etc. Access to 27 countries in Europe (25 EU + Norway and Iceland) EMEA Marketing Authorisation Objective criteria of quality, safety efficacy Economic considerations, comparative efficacy remain excluded (Member State responsibility) Approval mechanisms Normal Exceptional circumstances Conditional (new)

9 Conditional Marketing Authorization
Scope and conditions Orphan drugs, emergency threats, serious, chronic, life-threatening conditions Public health interest; to fulfill an unmet medical need Applicant must demonstrate “presumed positive benefit/risk” of the product based on scientific evidence and pending completion of further studies (“specific obligations”) Quality and non-clinical safety data should be complete

10 Conditional Marketing Authorization Obligations and Compliance
Obligations and timeframes publicly available Clear information to patients and health professionals on conditional nature of authorization Authorisation valid for 1 year, renewable Assess compliance with timeframe for obligations Retain, modify obligations, or consider benefit-risk established If holder does not apply for renewal, authorization expires Suspend, revoke, withdraw or vary authorisation if a product viewed as harmful or lacking therapeutic efficacy

11 Models for conditional authorization
Basis for approval Confirmation Short-term “Soft endpoint” Long-term “Hard endpoint” Interim analysis of RCT Further analysis “Selective approval” (small effect in broad indication) Identify responders (restrict indication) Biomarker Exploratory (Phase II single-arm or randomized) Clinical outcome Randomized controlled trial (Phase III in the same or related indication)

12 Approval Mechanisms Normal Exceptional circumstances
Comprehensive data to assess risk-benefit balance In general, randomized active and placebo-controlled trials required Phase IV: “Follow-up” studies of (dose-response), therapeutic use Exceptional circumstances Comprehensive data cannot be provided (because of specific circumstances: rarity, medical ethics, state of scientific knowledge) Phase IV: “Specific obligations” to inform about the safe and effective use (normally not possible to assemble full data package) Conditional Marketing Authorization Can demonstrate positive benefit risk balance, based on preliminary evidence from an ultimately comprehensive development Phase IV: “Specific obligations” to provide missing data (intended to become a “normal” marketing authorisation)

13 Conditional vs. Exceptional
Conditional MA Exceptional circumstances Granted before all data are available Comprehensive data cannot be provided (e.g., too rare) Authorization valid for one year (renewable) Annual reassessment of the risk-benefit balance Obligations: Further clinical studies to verify benefit/risk balance Obligations: Specific procedures in particular concerning safety Data package: Initial + Obligations = Normal Initial + Obligations < Normal Approved under exceptional circumstances: MabCampath (alemtuzumab), Foscan (temoporfin), Glivec (imatinib), Onsenal (celecoxib), Taxotere (docetaxel), Trisenox (arsenic trioxide), Velcade (bortezomib), Zevalin (ibritumomab tiuxetan)

14 Patient Focused Drug Development
EU US Early Access Named Patient Basis Single patient IND Early Evaluation Accelerated Assessment Fast Track Early Distribution Conditional Authorization Treatment IND Early Approval Subpart H & E

15 Regulatory Considerations: Japan
Figure: Schwartsmann, G., et al Journal of Clinical Oncology 20 (18S): 47s-59s Local Phase 1 for PK/PD mandatory Bridging to western studies feasible

16 FDA Cancer Approval Endpoints
Historical Order When Introduced Effect Measured Benefit Measured Need for Blinding Tumor Shrinkage 1950s Drug Surrogate No Overall Survival 1980s Drug plus natural history Direct Symptom Palliation Drug in disease setting Yes Time to Event (PFS, TTP) 1990s

17 Time from randomization to death
Survival Time from randomization to death Strengths Unambiguous, daily assessment Not subject to investigator interpretation Limitations Requires large sample size, long follow-up Cross-over may wash out effect Trial design considerations Randomized trials required to show an effect Likelihood and magnitude of survival benefit

18 Radiographic Response Rate
Strength Treatment “entirely” responsible for tumor reduction (contrast survival or PFS w/ natural history component) Limitations Need for response duration component Issues: CR’s vs. PR’s vs. SD; burden of disease Not necessarily reflective of clinical benefit Trial design considerations Only endpoint reliably assessed in single arm trial Prospectively identified, acceptable response criteria Complemented by symptom improvement

19 Progression-Free Survival
Time from randomization to progressive disease or death Strengths Smaller size & shorter follow-up than for survival Differences not obscured by secondary therapy Deaths included as events Limitation Greater potential for bias than with survival endpoint Trial design considerations Randomized, blinded trials required to show an effect Must evaluate at baseline and regularly on follow-up: all patients with same tool / schedule / sites of disease

20 Symptom Palliation Strength
Patient’s perspective; direct measure of clincal benefit Limitations Missing data confound interpretation Multiple endpoints affect statistical power and plan Unblinded assessments invite observer bias Trial design considerations Randomized, blinded trials required to show an effect Requires hypothesis driven, valid instrument Associated tumor response supportive of clinical benefit

21 Patient Reported Outcomes in FDA Anticancer Product Approvals
Drug Year Domains # Photofrin 1995 Dysphagia 1 Gemzar 1996 Pain / PS / weight 2 Novantrone Pain Hycamtin 1998 SCLC symptoms (9) Amifostine 1999 Xerostomia Palifermin 2004 Mucositis

22 Trial Design Considerations
Randomization Enables convincing demonstration of effect Allows concomitant safety assessment Blinding Addresses measurement bias Incorporated at each step subject to bias Instrument characteristics Measured change should be clinically relevant Prospective statistical analysis plan

23 Cancer Approval Endpoints
Historical Order When Introduced Effect Measured Benefit Measured Need for Blinding Tumor Shrinkage 1950s Drug Surrogate No Overall Survival 1980s Drug plus natural history Direct Symptom Palliation Drug in disease setting Yes Time to Event (PFS, TTP) 1990s

24 Common reasons for rejection
Negative trials Claims based on exploratory subgroup analysis Non-inferiority without established control arm effect A posteriori defined non-inferiority margins Marginal activity with safety issues Lack of randomized control trial No appropriate historical control No dramatic activity

25 Outline FDA Requirements for Drug Approval ICH Regional Variations
Cancer Approval Endpoints

26

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