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 21^st 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 

A child of unconventional, British-born parents, raised in the bucolic countryside of Vancouver Island, British Columbia, her relentless pursuit of science began in a love of animals, carrying her through two Canadian universities to a University of Chicago PhD in pharmacology and tenuous postdoctoral positions investigating the pituitaries of whales and armadillos. The research sent her to sea with grudging whalers and to inhospitable deserts by night. She married fellow pharmacologist Ellis Kelsey, followed him for his work, and became a mother of two daughters. Lack of paid opportunities for a woman scientist sent her commuting to medical school in Chicago where she obtained an MD degree in 1950 at age 36, while her husband kept the home and family together. She was working as a G.P. locum tenens and as an editor for JAMA. After a stint in South Dakota, the family relocated to Washington in 1960 where she began her lengthy career in the FDA, rising through the ranks to positions of prominence. Not long after the move, her stance on thalidomide earned her the Distinguished Federal Service Award of 1962, presented by President J​ohn​​ ​F. Kennedy. It also brought widespread admiration, mountains of fan mail, several other honours, and the resentment of male colleagues. Ellis died suddenly in 1966, but she kept working into her 90s, taking on the public-health challenges of other notorious “remedies” seeking approval. Kelsey’s fame eventually subsided but rose again in 2015 with late honours and her death at 101 years of age.  

Cheryl Krasnick Warsh​,​ who lives and works on Kelsey’s parental home of Vancouver Island, has given us a wonderful biography. With many previous publications in gender history and the history of alcohol and other drugs, Warsh is well placed to handle this vast and ​multifaceted​​ ​topic, sensitive to the misogyny of Kelsey’s century and with expertise on the nature and fortunes of licit and illicit substances.  

In twenty short chapters, Warsh divides this long life into three ​​segments– before​,​ during, and after thalidomide– and identifies her subject in three different ways. She describes “Frankie’s” early years in simple prose, reminiscent perhaps of Gertrude Stein or Emily Carr. Quirks and disputes in the Oldham home become evidence of a high-functioning, dysfunctional family. As a young woman, “Frances Oldham” delved into science studies at what would become University of Victoria and McG​i​ll in Montreal but made the ​trip ​back home every summer. She slipped into the laboratory of distinguished pharmacologist E.M.K. Geiling at the University of Chicago, when he believed the applicant was male. Despite his initial skepticism, Geiling fostered her career and supervised her doctorate. In 1937, she worked on the lethal side-effects of elixir sulfanilamide and determined that the solvent was responsible. At that time, she also became interested in researching harmful effects of pharmaceuticals on pregnancy and explored the legal protections (or lack thereof) for their consumers. With Geiling and Ellis Kelsey, Frances Oldham wrote a pharmacology textbook, one of the first in America, that went into four editions. These experiences, her medical degree and the work with JAMA were excellent preparations for her concerns about thalidomide. Now she was “Dr Kelsey,” one of two in the same home. 

Kelsey first doubted the value of this new drug when the side effect of peripheral nerve damage seemed to have been excluded from the incomplete applications and their inadequate trials. Further delay allowed for the early reports of fetal damage (coming from newspapers rather than manufacturers) to add to the concerns. While she succeeded in blocking the approval of thalidomide, it had managed to make its way into the US anyway, in the form of free samples given to practitioners sloppily engaged as researchers in shoddy “clinical trials.” Warsh carefully tracks the resultant American harm through reports of at least 56 damaged or dead infants documented in a survey of city health officers in 1962—probably merely the tip of an iceberg. She also probed the tragedy’s impact on attitudes to abortion, respect for the disabled, and increasing caution over medications. 

Beyond the thalidomide story, this biography provides a good sense of the evolving field of pharmacology and interesting chapters on the thorny history of several famous drugs–Krebiozen, laetrile, dimethyl sulfoxide (DMSO), artificial sweeteners, and diethylstilbestrol (DES)–and the harmful impact of Xrays on the pregnant belly. Kelsey found support from other women scientists, in particular Barbara Moulton and Helen Taussig​,​ who became her friends. 

Warsh has tapped into a wealth of sources—extending well beyond the numerous publications, FDA documents, and newspaper reports. She interviewed Kelsey, aged 99, in 2014 and spoke with her colleagues, daughters and other family members. She made excellent use of the personal papers, sorted by the pharmacologist herself with the help of FDA historian John Swann; they contain more than 78,000 items and occupy more than 100 feet of shelving in the Library of Congress. Moreover, Warsh follows the court decisions, changing legislation and rules governing not only drug approvals but ​also ​the ordering of female lives in terms of employment and reproductive freedoms. Yet she handles all this information with a deft light touch, accessible language and playful humour.  

A great read about a great scientist and a fascinating era in biomedical science. 

Frances Oldham Kelsey, the FDA, and the Battle Against Thalidomide
Warsh, Cheryl Krasnick
Oxford University Press. 
New York, 2024-03-15

Photos of Frances Oldham Kelsey from Wikicommons

Cheryl Krasnick Warsh Interviewed at Library of Congress