Who’s Watching the Chicken Coop? The FDA’s Flawed Drug-Approval Process
I recently attended a conference entitled “What Evidence is Essential for New Medical Products?” held at the American Association for the Advancement of Science in Washington, D.C., that probed the vexing dilemma of balancing the duty of the Food and Drug Administration (FDA) to assure the safety and efficacy of new drugs and medical devices versus the demand of patients for faster access to potentially life-saving cures.
The dilemma is best illustrated by the following “Tale of Two Drugs.” When the AIDS epidemic first swept the country and the world in the 1980s, AIDS activists successfully pressured the government to speed up the drug approval process for AZT (zidovudine), a process that usually took many years before drugs came to market. Those suffering with AIDS were literally dying in the streets. Robert Yarochoan, an FDA official at that time, told the conference audience of the dramatic response of both the FDA and the pharmaceutical company Burroughs-Wellcome to expedite the approval of AZT. Countless lives were saved as a result.
The other tale also deals with a deadly disease that is ravaging the world—tuberculosis (TB) that is resistant to the usual antibiotics used to treat it. Jerry Avorn spoke about what appeared to be a promising drug called bedaquiline. In the laboratory, bedaquiline appeared to kill multi-drug resistant TB germs. Usually, the next step in the drug-approval process would be small-scale clinical trials where the drug is tested in actual patients suffering from the disease. This vital step in the drug approval process was skipped in order to bring a potentially life-saving drug to market quickly. Tragically, when the drug was used for the first time by real patients, it ended up having a fatality rate five times that of more standard drugs for multi-drug resistant TB.
Similar problems exist for medical devices. Devices, such as pens to inject insulin, that are very similar to devices that are already approved and on the market, only have to pass a cursory review to assure that they are essentially equivalent. Truly new devices or ones that are substantially different from existing ones must go through an intensive approval process, more like new drugs, in which they must prove both their safety and efficacy. Astonishingly, only 1 percent of devices go through this intensive review process according to medical journal editor Dr. Rita Redberg.
Dr. Redberg informed the conference about WINGSPAN, an implantable filter that was supposed to protect against second strokes. FDA did not require the device to go through the intensive review and the device turned out to increase strokes and death. Even worse, it remains on the market and more than 11,000 devices are still being implanted every year.
Stories like this illustrate the dangers of rushing drugs and devices to market. Pharmaceutical and medical device manufacturers continue to ratchet up the pressure on the FDA to expedite the approval process, both by directly lobbying FDA, and by enlisting the support of many patient advocacy groups and lawmakers. At present, more than half (56%) of newly approved drugs used an expedited-approval pathway. (Darrow JJ, Avorn J, Kesselheim AS. New FDA breakthrough-drug category—implications for patients. N Engl J Med 2014;370:1252–8)
Congresswoman Rosa DeLauro (D-CT) spoke passionately about the dangers to patients in the present system, and has submitted a letter to FDA about her grave concerns about the proposed new accelerated drug approval guidelines. At the conference she also pledged to support giving the FDA the resources it needed to safeguard the nation’s drug supply.
Dr. Peter Lurie, associate commissioner of FDA, defended the agency, noting that just because FDA approved a drug didn’t mean doctors needed to prescribe it. But we know that drug company marketing strategies go into high gear once a drug is approved. Doctors then face intense pressures from industry, as well as pressure from patients who have been urged to “ask their doctors” on television ads about the latest drugs.
A number of other ideas emerged from the conference that offered more promise as a means of dealing with these dilemmas. In Europe, drugs that have been approved but where there is more uncertainty about their safety and effectiveness are labeled with a black triangle. Such a system could be used by FDA, which already mandates black box warnings to alert doctors to particularly dangerous side effects.
The FDA gives some new drugs a “conditional approval” and then requires the company to provide more data, but many companies fail to provide the data and there is no penalty. In some countries, however, where the government is the major purchaser of drugs, it pays the manufacturer a lower rate for the drug until it can produce convincing data about the safety of the drug. This provides a powerful financial incentive for drug companies to make good on their promise of more data. Public programs like Medicare and Medicaid could do this same in this country. The FDA should also consider including “sunset provisions” along with any conditional approval—the approval would end unless the additional data on safety and efficacy were provided in a specific timeframe.
Dr. Bernie Good from the Veterans Administration reported that the VA protects veterans by taking into account safety data when it decides whether to place a drug on the VA formulary. New drugs that have not undergone the full rigorous testing are less likely to be placed on the formulary. Medicaid programs also consider safety when deciding what to include in their list of approved drugs. This is not true for the Medicare program for the elderly, but is an idea worth pursuing.
Most importantly, the FDA must be given the financial resources it needs to do its job without depending on industry fees, which now pay for a large percentage of the costs of the drug approval process. The temptation is just too great for the agency to cut corners to avoid biting the hand that feeds it. While the FDA needs to have a good working relationship with industry, its mission is to serve the public’s best interests. That mission must never be compromised.
Stephen R. Smith, M.D., M.P.H., Community Catalyst physician consultant