A big medical story last year was the FDA's November revocation of the accelerated approval of the drug Avastin for advanced breast cancer. Regulators' rationale was that the drug "used for metastatic breast cancer has not been shown to provide a benefit, in terms of delay in the growth of tumors, that would justify its serious and potentially life-threatening risks. Nor is there evidence that use of Avastin will either help women with breast cancer live longer or improve their quality of life."
The FDA's "accelerated approval" mechanism is intended to be a "quick-on, quick-off the market" way for medicines to reach patients. Introduced almost two decades ago, accelerated approval permits the FDA to issue what amounts to a limited, or conditional, approval of a new drug to treat a "serious or life-threatening disease" for which there is an "unmet medical need." It works to the advantage of drug companies and needy patients alike.
Accelerated approval has two defining characteristics. First, it can be based on clinical trials that do not yet show an improvement on a definitive health endpoint such as increased longevity, reduction in the incidence of heart attacks or cancer cure, but merely on a "surrogate endpoint" that is thought to correlate with clinical benefit. Examples of surrogate endpoints are the shrinking of a tumor or improvement in a laboratory value such as "good" cholesterol.
Second, the drug sponsor (company) must perform confirmatory trials to prove that the medicine is effective in meeting a definitive endpoint, at which time the approval is converted to a standard, unconditional approval. If the studies fail to provide such confirmation, the FDA can pull the drug from the market, or remove a specific indication for which accelerated approval was initially granted, as in the case of Avastin.
Until June 2010, the FDA had never withdrawn any of the 90 or so drugs on the market that had been given accelerated approval; Mylotarg, a leukemia drug originally approved in 2000, was pulled by Pfizer at the request of the FDA after post-marketing studies showed no clinical improvement and a greater number of deaths in the Mylotarg-treated patients compared with the control group.
Avastin received accelerated approval for the treatment of metastatic breast cancer in 2008 on the basis of a single clinical trial which showed that when used with another drug, it slowed tumor progression and extended patients' lives on average by about five months. In two subsequent post-marketing trials, Avastin was paired with different chemotherapy drugs than in the original trial and performed even less well, prolonging patients' lives on average by no more than three months. The FDA's decision to revoke the indication for breast cancer leaves it approved for certain types of colon, lung, kidney and brain cancer; and at physicians' discretion it can be used "off-label" for breast cancer. However, the presence of an indication on the FDA-approved labeling is important to patients because it increases the likelihood that insurance companies will pay for the drug.
Some have argued that the Avastin case suggests that the accelerated approval process recklessly allows drugs on the market without sufficient evidence of efficacy, but that viewpoint fails to consider the real cost in lives as a result of the FDA's indolent "regular" approval process. The initial approval of Avastin for advanced breast cancer and the subsequent revocation of that indication on the basis of new data show that accelerated approval mechanism works as it was intended.
The essence of the "quick-on, quick-off" accelerated approval pathway is that the standard for approval is lenient but confirmation of efficacy is required. The vast majority of drugs marketed after accelerated approvals are found in subsequent studies to be safe and effective. And given that only medicines for "serious or life-threatening diseases" and that address an "unmet medical need" are eligible for this pathway, accelerated approval has offered significant benefits to patients for almost 20 years by making important medicines available far earlier than would otherwise be the case.
There is a new wrinkle in the Avastin saga, however. Two recent clinical studies may reopen the debate about the value of the drug for breast cancer. They found that when Avastin was given along with chemotherapy before surgery to certain women with early-stage breast cancer, the drug helped to make tumors disappear. In one clinical trial, 34% of women given Avastin plus chemotherapy for a few months before surgery had no sign of cancer in their breasts when doctors operated, versus 28% of women given chemotherapy alone. In the other trial, more than 18% of the patients on Avastin plus chemotherapy had no cancer in their breasts or lymph nodes at surgery versus 15% of those on chemotherapy alone. The data on survival are not yet available.
Thus, although the revoked indication was for advanced breast cancer, the new findings suggest it might be useful in situations in which the cancer has not widely spread.
The question is, then, could the new studies provide the rationale for another accelerated approval of Avastin, this time for early stage breast cancer? We don't see why not.
Henry I. Miller, a physician and molecular biologist, is the Robert Wesson Fellow in Scientific Philosophy and Public Policy at the Hoover Institution; he was the founding director of the Office of Biotechnology at the FDA. Jeff Stier is a Senior Fellow at the National Center for Public Policy Research and directs its Risk Analysis Division.