Unique Challenges for Pharmaceuticals. Steven Galson, MD, MPH Director Center for Drug Evaluation and Research Institute of Medicine May 30, 2006

Transcription

1 Uniue Challenges for Pharmaceuticals Steven Galson, MD, MPH Director Center for Drug Evaluation and Research Institute of Medicine May 30, 2006

2 As we know, There are known knowns. There are things we know we know. We also know There are known unknowns. That is to say We know there are some things We do not know. But there are also unknown unknowns, The ones we don't know We don't know.

3 Outline: Challenges in Pharmaceutical Caveat Benefit/Risk Analysis Long regulatory lifecycle & changing underlying benefit/risk data Complexity of selecting ideal methodology Case examples Communication tools Ideal benefit/risk balance for therapeutic products Conclusion

4 Caveat Discussion of challenges does not mean FDA not supportive of change

5 Long regulatory lifecycle & changing underlying benefit/risk data

6 EFFICACY & SAFETY EFFICACY CHALLENGES SAFETY 1 KNOWLEDGE (Certainty) 0 Discovery PRECLINICAL DEVELOPMENT IND PHASE 1 PHASE 2 PHASE 3 NDA MARKET

7 EFFICACY & SAFETY CHALLENGES Data on which benefit/risk calculations can be made changes throughout lifecycle Currently, safety data growth dramatic after approval Shift to left of knowledge gained -earlier in lifecycle needed (CP to personalized medicine) Can future methodology capture changing reality? 1 0

8 Learning Wheel Dynamism of learning process presents challenges to development of B/R methods PHASE 3 & 4 METHODS DETECT UNDERSTAND CRITICAL PATH RESEARCH INDUSTRY & FDA APPLY PREDICT PRECLINICAL TOOLS

9 Complexity of selecting ideal methodology Case examples Quantification of Benefits Tarceva Quantification of Safety - Lotronex

10 Genomics: From Population to Individuals Tarceva (Erlotinib) a potent EGFR tyrosine kinase inhibitor EGFR (Epidermal Growth Factor Receptor) used as a biomarker can select likely responders allowing enrichment and a smaller study Non-Small Cell Lung Carcinoma

11 Biomarkers to Enrich Trials: Selection of Likely Responders Kaplan-Meier Curve for Overall Survival of Patients by Treatment Group

12 EGFR Positive Patients Selection of Likely Responders EGFR Negative Patients

13 Current pharmacogenomic examples bcr/abl or 9:22 translocation imatinib mesylate (Gleevec)* HER2-neu trastuzumab (Herceptin)** C-kit mutations imatinib mesylate (Gleevec)** Thiopurine S-methyltransferase mercaptopurine and azathioprine* UGT1A1-irinotecan (Camptosar)** Cytochrome P-450 (CYP) 2D6 5-HT3 receptor antagonists and codeine derivatives* *-FDA package insert information *-FDA-approved device

14 Quantification of Benefits Current methods look mostly at means Advances in genomics will allow focus on individuals in whom drug will have higher benefit/risk ratio B/R analysis for large market drugs much more prone to error than B/R for targeted therapies

15 Quantification of Safety or Risk Lotronex example Use pattern of drug after approval may not be reflective of clinical trials. This may fundamentally alter assumptions about safety and risk used to calculate (by any methodology) at point of approval

16 Lotronex (alosetron hydrochloride) Tablets Serotonin receptor antagonist Indicated for the treatment of certain women with severe, irritable bowel syndrome (IBS) Severe IBS is defined in terms of symptom freuency and restriction of daily activities

17 Premarket Safety Database Roughly 3000 Lotronex-treated patients Two randomized, double-blinded, placebocontrolled trials in women with IBS Dose-ranging studies; other ongoing studies Dose-dependent constipation Most common reason for treatment withdrawal Four cases of ischemic colitis Self-limited, all resolved

18 Early Postmarketing Experience Rapid exposure to a large population Only a third of prescribers were gastroenterologists IBS may be viewed as an interim diagnosis Potential for misdiagnosis of ischemic colitis Observed increased severity in labeled GI events Hospitalization, need for surgery, death No identifiable risk factors for ischemic colitis emerged from spontaneous reports Marketing stopped

19 Re-Assessment of Clinical Trial Data Nearly 12,000 Lotronex-treated patients Constipation Excess over placebo; most events occurred within 1 month Early stopping rules decreased likelihood of serious constipation? Ischemic Colitis Excess over placebo (2-5 cases/ 1000 exposed) More careful case ascertainment in later trials? No identifiable risk factors emerged Patients with urgency had high response rates

20 Overall Needs Assessment limit use to patients with most disabling IBS symptoms Stand to benefit the most May accept greater risk determine efficacy and safety of: Lower doses As needed doses vs. continuous dosing pharmacogenomic markers that could predict which patients might be at increased risk for adverse events

21 Lotronex (alosetron hydrochloride) Tablets Physicians must enroll in a Prescribing Program Patients must sign a Patient-Physician Agreement Pharmacists must provide patients with Medication Guide at time of dispensing Product labeling carries a Boxed Warning for serious GI adverse events: Ischemic colitis Serious complications of constipation

22 Challenges to proper assessment of risk side of benefit/risk Unexpected changes to benefit risk can result from: Inadeuate understanding of dose/response relationship at approval Lack of specificity of label & other roll-out strategies Even strongest predictive methodology can be defeated by knowledge gaps in development program Focus on better clinical trial design, dose/response, roll-out communication and proper drug use needed to effectively predict benefit/risk ratio using any method

23 Communication of Benefit/Risk We don t use communication tools well-suited to explaining benefit/risk

24 Shared Goal - Communicating the benefits and risks in a manner so that correct personal decisions can be made

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26 Expressing and communicating excess benefits and risks in the label of a new drug -legal document

27 Highlights Contents Overview Of New Drug Label High level ½page summary Cited or concisely summarized information accompanied by identifying numbers indicating where to find more detail Allows easy reference to full prescribing information Allows hyperlinks in electronic formats Reorders and reorganizes sections Freuently referenced information moved forward Safety information remains consolidated Establishes format reuirements Minimum 8-point font (trade labeling that accompanies drug product will have minimum 6-point font) Standardized bolding and white space Clarifies and updates reuirements

28 Example of Highlights HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Imdicon safely and effectively. See full prescribing information for Imdicon. IMDICON (cholinasol) CAPSULES Initial U.S. Approval: 2000 WARNING: LIFE-THREATENING HEMATOLOGICAL ADVERSE REACTIONS See full prescribing information for complete boxed warning. Monitor for hematological adverse reactions every 2 weeks for first 3 months of treatment (5.2). Discontinue Imdicon immediately if any of the following occur: Neutropenia/agranulocytosis (5.1) Thrombotic thrombocytopenic purpura (5.1) Aplastic anemia (5.1) RECENT MAJOR CHANGES Indications and Usage, Coronary Stenting (1.2) 2/200X Dosage and Administration, Coronary Stenting (2.2) 2/200X INDICATIONS AND USAGE Imdicon is an adenosine diphosphate (ADP) antagonist platelet aggregation inhibitor indicated for: Reducing the risk of thrombotic stroke in patients who have experienced stroke precursors or who have had a completed thrombotic stroke (1.1) Reducing the incidence of subacute coronary stent thrombosis, when used with aspirin (1.2) Important limitations: For stroke, Imdicon should be reserved for patients who are intolerant of or allergic to aspirin or who have failed aspirin therapy (1.1) DOSAGE AND ADMINISTRATION Stroke: 50 mg once daily with food. (2.1) Coronary Stenting: 50 mg once daily with food, with antiplatelet doses of aspirin, for up to 30 days following stent implantation (2.2) Discontinue in renally impaired patients if hemorrhagic or hematopoietic problems are encountered (2.3, 8.6, 12.3) DOSAGE FORMS AND STRENGTHS Capsules: 50 mg (3) CONTRAINDICATIONS Hematopoietic disorders or a history of TTP or aplastic anemia (4) Hemostatic disorder or active bleeding (4) Severe hepatic impairment (4, 8.7) WARNINGS AND PRECAUTIONS Neutropenia (2.4 % incidence; may occur suddenly; typically resolves within 1-2 weeks of discontinuation), thrombotic thrombocytopenic purpura (TTP), aplastic anemia, agranulocytosis, pancytopenia, leukemia, and thrombocytopenia can occur (5.1) Monitor for hematological adverse reactions every 2 weeks through the third month of treatment (5.2) ADVERSE REACTIONS Most common adverse reactions (incidence >2%) are diarrhea, nausea, dyspepsia, rash, gastrointestinal pain, neutropenia, and purpura (6.1). To report SUSPECTED ADVERSE REACTIONS, contact (manufacturer) at (phone # and Web address) or FDA at FDA-1088 or DRUG INTERACTIONS Anticoagulants: Discontinue prior to switching to Imdicon (5.3, 7.1) Phenytoin: Elevated phenytoin levels have been reported. Monitor levels. (7.2) USE IN SPECIFIC POPULATIONS Hepatic impairment: Dose may need adjustment. Contraindicated in severe hepatic disease (4, 8.7, 12.3) Renal impairment: Dose may need adjustment (2.3, 8.6, 12.3) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling Revised: 5/200X

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30 Lack of unanimity about ideal benefit/risk balance for therapeutic products Better methodologies & communication tools will not be panacea

31 Benefit/Risk is in the eyes of the beholder: FDA evaluates benefits/risks for the population Benefits Risks Provider evaluates benefits/risks for a patient Benefits B B B B B BB RRR Risks Patient evaluates benefits/risks in terms of personal values

32 Societal issues in benefit/risk decisionmaking The best methodology and communication methods will only take us so far: SSRI Accutane Public understanding of the limits of science Science literacy

33 Conclusions Pharmaceutical product benefit/risk balancing, a multidisciplinary challenge: Drug development science Communications Societal issues Successful adoption of methodological improvements would benefit drug development enterprise, practitioners and patients