Peginterferon  2a/Ribavirin FDA Antiviral Drugs Advisory Committee Brian Murphy, MD, MPH, MS InterMune Submitted November 12, 2002 for Presentation November 14, 2002

Disclosure Presently serve as Vice-President Corporate Development/Hepatology at InterMune InterMune develops drugs in the HCV therapeutic area including interferons

What Information is Still Pending for the US Treating Community? Absolute number of US patients in the peginterferon  2a/ribavirin registration trial The withdrawal rate of US versus Ex-US patients in this registration trial Percentage response of US versus Ex-US patients enrolled in this registration trial Safety profile of US versus Ex-US patients enrolled in this registration trial

What Data Does the Treating Community Have Access to? NEJM Paper*:56% –On-therapy analysis –Used data from weeks EU Analysis**54% / 50% 54% was an on-therapy analysis Used data from week 60 50% was an intent-to-treat analysis Borderline statistical significance versus the comparator group; p = 0.057) Analyzed data per protocol *Fried MW, et al. NEJM, 2002; 347(13): **European Union Scientific Discussion: Pegasys; EMEA 2002

Impact of Patient Withdrawals: Absolute number of US patients NEJM EU DISCUSSION Total number of patients Number who completed follow-up (computed) Number withdrawn for insufficient response 3435 (computed) Number withdrawn for other reasons (%) 85 (19% reported) 96 (computed)

Clinical Questions: Absolute number of patients Did the withdrawal rate exceed that planned for the study? –Most studies plan for a 10-15% drop-out rate –Sample size power calculations are missing from the NEJM article; were detailed in the peginterferon  2b/RBV study article If the withdrawal rate exceeded the planned drop-out rate, are the results, including the safety data, significant? What was the absolute number of American patients that withdrew from the study? Is the baseline American presence more diminished by the withdrawal of US patients?

Treatment Response by Geographic Location: Peginterferon alfa-2b/RBV* Study Center Peginterferon Alfa-2b 1.5/RBV Intron A/RBV US169/346 (49%) 131/337 (39%) Non-US95/165 (57%) 100/168 (59%) *FDA Advisory Panel on Peginterferon alfa-2b

Age group (years) Anti-HCV positive (%) White African-American Mexican American Adapted from Centers for Disease Control and Prevention (M. Alter). MMWR. 1998;47(RR-19):4. Prevalence of HCV Infection, United States,

Prevalence (%) of Overweight/Obesity Among Males in US, * Overweight = BMI  25 Obesity = BMI  30 Caucasians African- American Hispanic Ages /2252.6/ /30.4 Ages / / /27 Ages  / / /29.7 *Flegal KM, et al. JAMA 2002; 288(14):

If the numbers are available, how should they be analyzed? Intent-to-treat (ITT) –Includes all patients randomized –Avoids comparing non-randomized cohorts –If similar centers, patient populations, and inclusion/exclusion criteria, can help health-care providers and their patients compare across studies if head-to-head trials are lacking –“Provides estimates of treatment effects that are more likely to mirror those observed in subsequent practice”* *Guidance for Industry, (E9) Statistical Principles for Clinical Trials; Center for Biologics Evaluation and Research, Sept. 1998, ICH

Roche Statement on Clinical Trial Analysis “Intent-to-treat versus on-treatment analyses: ITT analysis includes all patients assigned to each study group regardless of whether they dropped out of the study or switched therapies. On- treatment analysis includes only those patients who completed the study within their originally assigned groups. Therefore, on-treatment analyses fail to account for dropouts and switches, and their treatment success rates tend to be deceptively higher than those from similar ITT analyses” * * Evaluating Clinical Studies-What Clinicians Need to Know ; Roche Labs 2001

Conclusions (1) Global trial results may not be reflective of the American experience. For informed treatment decisions, the following American data would be valuable to know: –The absolute number of US patients in the study –US vs. Ex-US response rates by ITT analysis –US vs Ex-US safety parameters by ITT analysis –US vs Ex-US withdrawal rates by ITT analysis

Conclusions (2) To adequately compare data, we are in agreement with the ICH Guidelines that support the use of ITT analyses, and agree with the Roche position that data analyzed by other methods may lead to “deceptively” higher results.