AAOS Bulletin - June, 2005

Do benefits of FDA outweigh its risks?

By James H. Herndon, MD

For years, it was assumed that the United States had the “safest” drug supply in the world, due to the vigilance and oversight of the U.S. Food and Drug Administration (FDA).

In recent months, however, the safety of our drug supply has been called into question. Even FDA staff members are saying that the agency is “virtually defenseless” and “incapable” of protecting the public from dangerous drugs.

As a strong advocate for patient safety issues, I am deeply troubled by the path the FDA has taken over the past several years and the impact that recent decisions on the safety of COX-2 inhibitors and other non-steroidal anti-inflammatory drugs (NSAIDs) may have on the patient-physician relationship. The FDA needs to implement major reforms to correct the current imbalance between being responsive to drug industry interests and being responsible for drug safety.

The FDA has a three-pronged mission: to promote and protect the public health by helping safe and effective products reach the market in a timely way, to monitor products for continued safety after they are in use and to help the public get the accurate, science-based information needed to improve health. But the passage of the Prescription Drug User Fee Act, which introduced FDA “user fees,” put the emphasis on getting drugs to market. User fees, which are paid by pharmaceutical companies, are used to hire more reviewers and make other changes to speed up the approval process. As a result, the agency has neglected both postmarket surveillance and public safety.

Impact of user fees

User fees today total more than $200 million annually and account for more than half the money the FDA spends on the review process.1 The FDA’s Office of New Drugs has more than 800 scientists who focus on initial new drug approvals, compared to just 14 who handle post-approval oversight in the Office of Drug Safety. As a result, the priority review drugs, supported by user fees, are coming to the market much faster, with a median approval time of just 6.7 months in 2003.2 At the same time however, the drug review process was being compromised by the deadlines imposed by the Prescription Drug User Fee Act.

According to an internal survey conducted by the Office of Inspector General of the Department of Health and Human Services, 18 percent of respondents admitted that they had “been pressured to approve or recommend approval” of a drug, despite their reservations on its safety, efficacy or quality. More than half (58 percent) said that they were not given enough time “to conduct an in-depth, science-based review” of drugs assigned to priority review.3

Postmarket controls

Although nearly 80 percent of new drug approvals include a requirement that the company conduct postmarket studies, more than two thirds of these studies have never been started.4 But side effects associated with long-term use only become apparent after release. Likewise, rare side effects are often not observed in clinical trials because of the small number of patients involved, but would become evident after wide-scale marketing.

Unfortunately, once a drug has been approved for sale, the FDA has no legal authority to penalize companies for not conducting the studies and must negotiate label wording with the company. It has done little to prevent companies from promoting “off-label” uses of drugs and has allowed companies to keep negative studies about their drugs secret. For years, “black box warnings” have been distributed through the Physician’s Desk Reference. The black box warning is the strongest warning available for prescription drugs, generally reserved for those drugs that may have serious or life-threatening risks.

As a result, both physicians and patients find it difficult to assess the risk-benefit ratio of a drug. Initial studies, on which the FDA bases its decision to approve a drug, are usually small and short-term and may not reflect the risks that a large-scale, long-term study may reveal. Direct-to-consumer advertising encourages patients to demand new drugs, and too many physicians readily acquiesce to those requests.

Effect on physicians, patients

The FDA’s actions also have an impact on the patient-physician relationship. The FDA’s failure to disclose in advance that many of those who sat on the advisory panel convened in February to judge the safety of COX-2 and NSAIDs had ties to the pharmaceutical market (and 10 had ties with the makers of the drugs being reviewed) is just one example. When the connections were revealed, the panel’s decision came into question. It may have been, as some suggested, a vote between those who had safety concerns as their first priority and those who had patient pain relief as their main priority, but the lack of disclosure made it seem that the panel was in industry’s “pocket.”

The FDA’s actions put both physicians and patients at risk. Patients are at risk from unknown or unidentified (as yet) side effects; physicians may be at risk for prescribing drugs that they didn’t realize had adverse effects. When adverse effects later occur, what happens to the physician-patient relationship? Does the patient lose trust in the physician’s judgment or feel betrayed by the medical profession? Does the physician become potentially liable for an adverse effect? The answers to these questions will unfold in the courts over the next several years.

What next?

Reform at the FDA is long overdue. Although several “baby steps” have been proposed, the agency needs to address the deeper issues of conflict of interest, lack of attention to safety issues and lack of authority in compelling industry to heed its recommendations. The proposed new Drug Safety Oversight Board does not have the authority to regulate direct-to-consumer advertising, mandate label language or establish deadlines for completing safety studies.

An independent agency is called for, with the authority and resources needed, and with a primary commitment to ensuring the safety of the American public, rather than satisfying industry. This new agency must have the authority to conduct postmarket surveillance. It must also be empowered to make companies perform required postmarket approval studies and to pull a drug from the market when safety concerns are identified.

James H. Herndon, MD, is chairman emeritus, department of orthopaedic surgery, at Partners Healthcare System, Inc. and second past president of the AAOS. He can be reached at jherndon@partners.org

1. Okie, S. “What Ails the FDA?” N Engl J Med 2005;352:1063-1066

2. Ibid.

3. Office of Inspector General. FDA’s review process for new drug applications: a management review. March 2003. (OEI-01-00590.) (Accessed April 25, 2005, at http://www.oig.hhs.gov/oei/reports/oei-01-01-00590.pdf)

4. Food and Drug Administration. Report on the performance of drug and biologics firms in conducting postmarketing commitment studies: availability. Fed Regist 2004;69(50):12162-12164

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