1. 1 The Chemoprevention of Sporadic Colorectal Cancer Issues Surrounding a Benefit/Risk Analysis in Clinical Trials Mark Avigan MD CM Medical Officer Division of Gastrointestinal and Coagulation Drug Products Center for Drug Evaluation and Research

2. 2 Overview of Presentation Public health concerns Considerations for clinical trial design –Efficacy –Current treatment modalities, endpoints, duration –Safety Current treatment vs new therapy Criteria for FDA approval Unresolved issues to be addressed by Advisory Committee

3. 3 Chemopreventive treatment should not replace colonoscopic screening and surveillance if CRC suppression is not as effective Patients who avoid colonoscopic examinations because of chemopreventive treatment may be increasing their CRC risk Risk attached to treatment of many may outweigh the benefit to few Public Health Concerns

4. 4 Benefits for Different Uses ‘ Adjunctive’ CRC prevention (colonoscopy+drug) – An additive effect : reduction of risk for CRC and mortality – A relaxation of screening/surveillance guidelines ‘ Alternative’ CRC prevention (drug only) – Elimination of colonoscopy associated AEs, discomfort and cost – Drug safety profile superior to colonoscopy without compromising CRC risk reduction Treatment of non-compliant patients – CRC risk reduction must outweigh drug AEs

5. 5 Efficacy Study Population Endpoints –Reduction in the frequency of: polyps, colon cancer, mortality Concomitant treatment modalities –Screening / surveillance colonoscopy –Medications with possible chemopreventive properties used by patients for other illnesses Duration of Rx –Expected occurrence interval –Durability of polyp suppression

6. 6 Is Adenoma Recurrence a Useful Surrogate for CRC Risk? Most small adenomatous polyps do not progress to malignancy – Probability that a small adenoma contains high grade dysplasia/malignant changes in the US is small (< 1%) Average transition time from small adenoma to invasive cancer > 10 years In the National Polyp Study, the % of patients with recurrent small or medium adenomas was over 30% (N. Engl. J. Med., 1993)

7. 7 Measurement of Efficacy Cumulative lifetime incidence of lesions FAP 100% (adenomas) 100% (CRC) Sporadic 60% (adenomas) 6% (CRC) Numbers Needed to Treat to detect a 50% reduction of lesions FAP 2,000 pt-yr (adenomas) 2,000 pt-yr (CRC) Sporadic 3,000 pt-yr (adenomas) >30,000 pt-yr (CRC)

8. 8 Screening and Surveillance Colonoscopy (As Therapy) Incidence of CRC was reduced between 76% and 90% (Results of National Polyp Study) (N. Engl. J. Med., 1993) Approximately 95% of colonoscopies examine the entire colorectum Summary: Colonoscopy is benchmark for other CRC prevention modalities

9. 9 Factors Influencing Efficacy Poor compliance during long-term chronic administration Lack of sufficient duration of treatment of patients Rebound of adenomatous neoplastic growth despite continued chemoprevention treatment Administration of ineffective doses or reversal of efficacy due to other concomitant medications or medical conditions

10. 10 Safety Population Examples of chemopreventive agent safety issues – Aspirin – Cox-2 inhibitors Power calculations

11. 11 Safety: Study Population Geriatric patient susceptibilities – Severe drug toxicity – Drug-drug interactions Potential for drug toxicity related to chronic administration Reduction of adenoma growth but dysplasia and CRC changes may continue

12. 12 Aspirin – Serious upper GI complications after age 65: 16/10 4 pt-yr (Ann. Int. Med., 2001) – Prevention of cardiovascular events may be more important than possible chemoprevention Cox-2 inhibitors – VIGOR study: 5X MIs in patients treated with rofecoxib 50 mgs qd vs naproxen 500 mg bid: 74/10 4 pt-yr vs 15 /10 4 pt-yr (FDA Advisory Committee Meeting, Feb 2001) – Safety issues raised by VIGOR require further study Safety Issues: Aspirin and Cox-2 Inhibitors

13. 13 Issues Surrounding Safety Incidence of drug-induced SAEs and mortality < chemopreventive benefit – Benefit related to reduction in CRC linked mortality Serious complications associated with colonoscopy Clinical studies should be powered to adequately study these effects

14. 14 * Rate per 10,000 pt-yr

15. 15 Number Needed to Treat (NNT) Chemoprevention –10,000/15 = 700 treated for one cancer prevented –700 healthy people at risk for each person who benefits Treatment of Disease (best case) –1 treated for one therapeutic effect –1 person at risk for each person who benefits

16. 16 Ability to Detect Drug Toxicity: Low Background Rate If 10,000 pt-yr per group with no events, then risk < 3 in 10,000 Therefore risk (at worst) is comparable to benefit

17. 17 Ability to Detect Drug Toxicity: High Background Rate If 10,000 pt-yr with 100 events per group –Difficult to detect drug effect –Confidence interval wide ( ± 14 per 10,000) –14 (extra AEs) ~ 15 (cancer prevented) Uninformative study –Can’t distinguish no harm from big harm –Need 70,000 pt-yr per group

18. 18 Benefit/Risk CRC suppression limited to a small % of treated patients Since colonoscopy is effective the potential benefit of ‘adjunctive’ treatment is smaller Co-administered drugs (e.g. low dose aspirin) may also have chemopreventive effects Adequate safety powering must take into account background SAE rates and treatment duration

19. 19 FDA Approved Chemopreventive Agents Tamoxifen Indicated for women at high risk for breast cancer Breast Cancer Prevention Trial randomized over 13, 000 women to 5 year treatment arms Approval granted for a 44% reduction in incidence of invasive breast cancer over median period of 4.2 years

20. 20 Celecoxib Indicated for reduction of colorectal adenomas in FAP Granted Accelerated Approval status (21 CFR 314 Subpart H) –Serious or life-threatening illness –Meaningful therapeutic benefit over existing treatments –Surrogate endpoint acceptable if likely to predict clinical benefit Calculated benefits to treat FAP and sporadic CRC are very different

21. 21 Unresolved Issues Significance of clinical benefits of treatment Clinical design requirements –Patient enrollment, role of adenomatous polyps as endpoints, duration of treatment and powering for safety Data analysis requirements –Approaches to study dropouts and uncontrolled safety information Benefit/risk analysis requirements