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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

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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

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• 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

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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

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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

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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)

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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)

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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

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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

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Safety

• Population

• Examples of chemopreventive agent safety issues

– Aspirin– Cox-2 inhibitors

• Power calculations

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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

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• Aspirin– Serious upper GI complications after age 65: 16/104 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: 74/104 pt-yr vs 15 /104 pt-yr (FDA Advisory Committee Meeting, Feb 2001)

– Safety issues raised by VIGOR require further study

Safety Issues:

Aspirin and Cox-2 Inhibitors

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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

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Treatment Compared toPossibleBenefit

CRC Risk * NL (3X)

Chemopreventionand colonoscopy(adjunct)

colonoscopy missed lesions 4 (11)

Chemoprevention(alternative)

colonoscopy

missed lesionsand avoidedAEs ofcolonscopy

7 (14)

Chemopreventionnone(noncompliant)

all cancers 15 (45)

* Rate per 10,000 pt-yr

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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

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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

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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

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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

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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

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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

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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