Letter To FDA Commissioner McClellan Opposing Use of Surrogate Endpoints for Approval of Cancer Prevention Drugs

This letter was mailed to the FDA commissioner on June 26, 2003. It is an open letter that went to various medical reporters.

June 26, 2003

Dear Dr. McClellan:

The undersigned consumer advocacy organizations write to express our alarm at the behind-the-scenes efforts by Dr. Andrew von Eschenbach and Dr. Anna Barker to undermine the FDA's drug approval requirements.(1) Their proposal to use surrogate endpoints for the approval of cancer chemoprevention drugs should be rejected by the FDA.

Because these potentially harmful drugs will be given to healthy people, it is all the more imperative that the FDA not relax its approval standards. In fact, manufacturers of chemoprevention agents should be required to prove that their drugs reduce cancer-specific mortality as well as all-cause mortality. The need to address all-cause mortality for drugs given to healthy people is best illustrated by the first 20 years of cholesterol research. Randomized controlled trials showed that the reduced rate of cardiovascular mortality in healthy but high-risk men given cholesterol-lowering drugs was offset by a higher rate of overall mortality. (2)

There are many examples of surrogate endpoints that eventually proved to be wrong. Because postmenopausal hormones could reduce cholesterol, this was thought to be a good surrogate for heart disease prevention-until the Women's Health Initiative showed they caused more cardiovascular events.(3) The validity of surrogate endpoints-even for cancer treatment drugs-has been controversial for over 15 years.(3) That controversy will only be exacerbated in the context of a drug for the treatment of non-invasive lesions and "precancers," given the fact that so many resolve spontaneously or remain dormant..(4)

There is much to be learned from the 1998 approval of tamoxifen for "prevention," once the drug halved the breast cancer incidence in the P-1 Trial. Now, women are justifiably concerned about the safety of taking an anti-cancer drug with potentially fatal side effects simply because a doctor deemed them high risk. (5) Several of the undersigned pointed out to the FDA's Oncologic Drug Advisory Committee that the P-1 Trial's failure to prove tamoxifen can reduce breast cancer mortality left the lingering question of whether the drug merely delays the onset of breast cancer.

It is shocking to learn that federal employees-particularly two who head the NCI-are meeting behind closed doors with a representative of the drug industry to influence drug approval policy and to change the product liability laws. Any change in the product liability laws will almost certainly have long-lasting implications in many arenas. We look to the FDA to take the proper steps to follow its mandate and protect the public's interest.

Sincerely,

Maryann Napoli
Center for Medical Consumers
Judy Norsigian
Boston Womens Health Collective

Barbara Brenner
Breast Cancer Action, San Francisco

Sharon Batt
Women and Health Protection, Canada

Deborah Forter
Massachusetts Breast Cancer Coalition
Cindy Pearson
National Women's Health Network

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(1) Goldberg, P. NCI Deputy Barker Hits FDA, Calls for New Incentives for Pharmaceutical Industry. The Cancer Letter, May 30, 2003.
(2) Moore Thomas J. Heart Failure. New York: Touchtone Books/Simon & Schuster, 1989
(3)Rossouw JE et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
(4) Raffle AE et al. Detection rates for abnormal cervical smears: what are we screening for? Lancet 1995;345:1469-73
(5) Port ER et al. Patient reluctance toward tamoxifen use for breast cancer primary prevention. Ann Surg Oncol 2001:8:580-5.