When the Food and Drug Administration (FDA) was created in 1930, its mission was to ensure the safety of prescription medications. In 1962, with the passage of the Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act, the FDA also became responsible for certifying drug effectiveness. Positive results in one or more randomized double-blind clinical trials became the gold standard for approval. Thus, patients were assured that when their doctor prescribed a “hot” new drug that had appeared on the market, it had met the FDA’s rigorous safety and effectiveness criteria.
Yet, sixty-three years later, near the beginning of Rethinking Medications (2025), Dr. Jerry Avorn writes:
“In 2021, the Food and Drug Administration (FDA) gave its approval to Aduhelm, a new drug for Alzheimer’s disease that didn’t work, could cause brain damage, and was poised to cost the nation each year a sum the size of NASA’s annual budget. How did the world’s once best prescription drug regulatory body fall so low” (p. 31)
The FDA not only approved Aduhelm but did so over an almost unanimous negative vote of its scientific advisory panel. What had happened to the promise of safety and effectiveness? Jerry Avorn MD, founder and director of Harvard’s Division of Pharmacoepidemiology and Pharmacoeconomics, argues that the Aduhelm approval resulted from a longstanding decline in the FDA’s regulatory standards, a slippery slope greased by social, political, and especially pharmaceutical industry pressures. Rethinking Medications is a comprehensive assessment of the pharmaceutical industry, the FDA, and their complex relationship in the 21st century. Much of the book addresses three core issues: Does a new drug work? Is it safe? And what should it cost? Other chapters deal with education, patient empowerment, and the specific examples of psychedelics and pain killers.
According to Avorn, the FDA’s rigor began to break down during the late 1980s when the agency initiated an accelerated or “fast track” review process in response to the AIDS epidemic, a reasonable change in light of the rapid spread of this incurable and deadly disease. (pp. 30-32) Initially, “fast track” approval involved greater FDA monitoring and quicker action but still required evidence of clinical effectiveness. In the case of AIDS, a hematological marker, CD4 T-cell count, was highly correlated with clinical outcome, which made it an excellent index of effectiveness.
However, not long afterward, the FDA opened its accelerated approval pathway to medications for chronic, progressive diseases and to use a favorable change in such surrogate markers (e.g. blood tests or images) as substitutes for clinical improvement. For example, in the case of Alzheimer’s disease, reduction in the number of amyloid plaques was considered a sufficient reason to approve Aduhelm, though the study had not documented symptom reduction or slower decline in functioning. While some surrogate markers are good predictors of outcome (e.g. Hb A1c in diabetes), most markers used for chronic disease drug approvals lack strong predictive evidence.1
However, the accelerated track includes a presumed fail-safe mechanism. The pharmaceutical company is required to complete a long-term confirmatory study to confirm clinical effectiveness. By 2022, more than half of new drug applications were being processed in the expedited track, and over 80% of these were approved.
(p. 77) The confirmatory study requirement, even if honored by the companies, allowed medications to be prescribed for years before a negative finding might cause approval to be revoked. According to Avorn, the increasing use of surrogate markers as endpoints tells the industry, “You can market your drug if it makes a lab test look better in a short study, compared to a placebo. We won’t be on your case too much about those confirmatory follow-up studies.” (p. 37) [Avorn engages in hyperbole here. Aduhelm was shown to be ineffective and withdrawn from the market in 2024.]2
Avorn next addresses the safety of newly approved drugs. Serious side effects must be recognized, if possible prior to approval. However, according to the author, the profit motive sometimes outweighs evidence of significant harm. He discusses the case of Vioxx (Merck Pharmaceuticals, 1998), a COX-2 inhibitor approved because it had fewer GI bleeding side effects than other NSAIDs. Several studies subsequently showed that patients taking Vioxx had almost double the number of myocardial infarcts and strokes of those taking other NSAIDs. Nonetheless, Merck rigorously disputed this evidence for several years before finally removing Vioxx from the market in 2004. Largely as a result of the Vioxx scandal, Congress passed the FDA Amendments Act in 2007, which introduced several safeguards for ensuring drug safety. These included (a) creating a nationwide system for monitoring adverse effects, (b) preventing companies from hiding clinical trial results by requiring that all trials be registered in a federal registry, and (c) insisting that companies complete follow-up studies after the drug has been approved. (pp. 167-170)
In 2007, a far more widespread safety failure was still a decade from being revealed. When Oxycontin was approved in 1995, the FDA believed the long-acting form of oxycodone would result in less abuse potential, since the drug would be absorbed slowly without an immediate “rush” to promote abuse. This belief had a theoretical basis, but there were empirical findings that strongly suggested otherwise. Over twenty years later, a presidential commission (2017) “concluded that the FDA’s mishandling of the evaluation, approval, and use (of oxycontin) was an important cause of the nation’s opioid crisis” (p. 393).
Anyone who watches broadcast television today will find it difficult to believe that prior to 1997, essentially no prescription drug advertising appeared on television. In 1997, the Food and Drug Administration approved a new rule allowing pharmaceutical companies to state only “major risks” in their ads, rather than its previous requirement of a full list of all possible risks, contraindications, and side effects, which had effectively precluded direct-to-consumer advertising. The industry quickly learned how to package major risks into brief statements aired sotto voce at the end of their commercials under images of smiling patients picnicking in a park. Since then, ads for expensive new pharmaceuticals have spread like wildfire.
Aggressively promoted new drugs are mostly treatments for chronic, malignant, or degenerative diseases that require continued use over many months or years. The producers, in essence, have monopolies on these products because they are protected by patents from competition for a certain number of years. Without competition, companies are able to charge very high prices, which they justify as necessary to compensate for costs of research and development.
Avorn identifies several reasons to doubt that excessive R & D costs are a determining factor in pricing new drugs. First, many Big Pharma companies spend more on marketing, most of which is direct-to-consumer advertising on TV and other media, than they do on research and development. Thus, much of the actual “investment” is spent in devising ways to convince consumers that new is better.
Secondly, most newly approved medications are not innovative, but rather modifications of existing drugs for which the patents will soon expire. The manufacturer seeks to have a replacement drug with a claimable advantage (e.g. fewer side effects, fewer daily doses) sufficiently different to be patented and approved before it loses patent protection on a profitable product. When generic versions of the product appear on the market costing up to 60% less than the original, the manufacturer attempts to maintain profits and market share by heavily promoting its “new, improved version.”
Third, “breakthrough” medications that employ a newly discovered mechanism, or work dramatically better than available alternatives, are generally the result of NIH-funded basic science and clinical trials performed by university faculty. While the Bayh-Dole Act (1980) allows universities to patent promising new drugs, only pharmaceutical companies have the ability to develop and market the drug commercially. When a company purchases the patent from its home university, the scientists and the university profit from the purchase, but lose control over the medication that results. Although Big Pharma does invest significantly in developing these drugs and bringing them to market, the basic research and initial clinical trials are supported by federal grants. “The largest engine driving the nation’s prodigious ability to bring new drugs to market is the hundreds of billions of taxpayer generated dollars in the National Institutes of Health and other public and philanthropic of biomedical discovery.” (p.197) Not Big Pharma.
Finally, retail prices for the same drugs in Canada, Europe, Australia, and Japan average about 60% lower than in the United States, even though their manufacturers presumably still make a profit. The real reason they set prices much higher in the United States is simply because they can. Most other countries have mechanisms to control drug prices based on realistic cost/benefit estimates.
Rethinking Medications is a compelling analysis of today’s pharmaceutical industry and its regulation by the FDA. Big Pharma is clearly the “heavy” in Avorn’s analysis. The FDA failures result from some combination of responsiveness to the need for new therapies in chronic diseases, inadequate resources and personnel to enforce the requirement for confirmatory studies, and the withholding of critical data by pharmaceutical companies. The FDA Amendments of 2007 corrected many of these problems, although the FDA’s fate under the Trump administration is yet to be seen. The prospects are not promising because the Department of Health and Human Services is directed by a man who aggressively promoted hydroxychloroquine as a treatment for Covid and doubts the effectiveness of vaccines.
Despite Dr. Avorn’s focus on failures and deficiencies, the reader should keep in mind that the American pharmaceutical industry does have a remarkable track record of producing innovative and effective medications. This, of course, does not justify the industry’s rampant profiteering and deceptive practices. It would require strong federal regulation, especially regarding pricing, to address these problems. Here again, the current administration’s anti-regulatory stance makes progress in the near future improbable.
Notes
1, Wallach JD, Yoon S, Doernberg H et al. Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments. JAMA, 2024; 331 1646-1654.
2, Two anti-amyloid monoclonal antibody medications, Legembi and Kisunla, have now been approved for treatment of early Alzheimer’s disease. Both have been shown to slow its progression by several months.
RETHINKING MEDICATIONS
Jerry Avorn MD
Simon & Schuster, 2025: 512 pages
Web image by Jaretuz
