An important but obscure aspect of the Food and Drug Administration's regulation of drugs has been in the news in recent months. Called "accelerated approval," this "quick-on, quick-off" mechanism for medicines to reach the marketplace can work to the advantage of drug companies and needy patients alike.
Introduced almost two decades ago, accelerated approval permits the FDA to issue what amounts to a limited, or conditional, approval of a new drug that is intended for a "serious or life-threatening disease" and for which there is an "unmet medical need."
Such an 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.
Until June, however, the FDA had never withdrawn any of the 90 or so drugs on the market that had been given accelerated approval; Mylotarg, a leukemia drug originally approved in 2000, was pulled by Pfizer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.
In July, an FDA advisory committee met to consider whether the FDA's accelerated approval for the drug Avastin to treat advanced breast cancer should be revoked in light of new data. The drug, which acts by cutting off the blood supply to tumors, is also approved (via the regular approval process) for colon, kidney, lung and brain cancer, and is the world's best-selling cancer medicine.
Avastin received accelerated approval for the treatment of advanced breast cancer in 2008 on the basis of a single clinical trial, which showed that when used with another drug, it slowed tumor progression but extended patients' lives on average by only 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 advisory committee voted 12 to 1 in July to recommend that regulators revoke the approval for breast cancer. (Because it is approved for treatment of other cancers, Avastin would remain on the market and at physicians' discretion could be used "off-label" for breast cancer; but off-label, a hugely expensive treatment â€” a wholesale cost of $88,000 for a typical breast cancer patient â€” would be less likely to be covered by insurance.)
The FDA is likely to accept this recommendation, which would be entirely appropriate; 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.
It is worthy of emphasis that the vast majority of drugs marketed after accelerated approval are found in subsequent studies to be safe and effective. And given that only medicines for "serious or life-threatening diseases" that address an "unmet medical need" are eligible for this pathway, accelerated approval has offered huge benefits to patients for almost 20 years by making important medicines available far earlier than would otherwise be the case.
The various commentaries that followed the advisory committee's recommendation on Avastin were not consistently on point. A July 25 New York Times editorial, for example, raised the thorny issues of cost and cost-effectiveness. It suggested that the FDA should revoke the approval for Avastin in part because of the drug's high price tag. The Times, perhaps mistaking itself for a health economics journal, opined that "the cost of Avastin has always seemed outrageously high for the medical benefits it confers" and praised Britain's National Institute for Health and Clinical Excellence for concluding that the cost of Avastin was "too high for the limited and uncertain benefit it may offer patients." (The institute is the entity that rations healthcare in Britain.)
We are sympathetic to the need for sensible allocation of medical resources. But the FDA has a narrow mandate â€” the assessment of the safety and efficacy of drugs. Determinations of cost-effectiveness and questions of reimbursement lie outside its expertise and mandate and must be decided by other agencies and in other forums.
Amid controversies such as the one over Avastin, we should not lose sight of the fact that accelerated approval works.
Henry I. Miller, a physician and fellow at Stanford University's Hoover Institution, was an official at the FDA from 1979 to 1994. He is the author of "To America's Health: A Proposal to Reform the FDA." Jeff Stier is an associate director of the American Council on Science and Health.