Are Your Medicines Safe And Effective?

Big Brains Podcast | University of Chicago

Teaser/Abstract

"When a patient gets a medication from their doctor or nurse practitioner, they assume that somebody has looked very carefully at this drug and determined that it is indeed effective for the purposes for which it's being given to you and that it's reasonably safe. I frankly think a lot of us doctors believe that that's all kind of taken care of as well."

Source: Big Brains podcast, University of Chicago Podcast Network, Episode published June 26, 2025. Host: Paul Rand.

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SUMMARY

In this Big Brains episode, Dr. Jerry Avorn — Harvard Medical School professor and author of Rethinking Medications: Truth, Power, and the Drugs You Take — walks host Paul Rand through the central arguments of his book in accessible, often startling detail. The conversation covers the FDA's accelerated approval pathway and its drift from emergency tool to standard practice; the use of surrogate endpoints in cancer drug approvals; the Aduhelm Alzheimer's disaster; phenylephrine, the decongestant that doesn't decongest; who actually designs and pays for the clinical trials used to approve drugs; why US drug prices are structurally untethered from any measure of value; and what patients can do in the examining room to protect themselves. The transcript is extensive, candid, and exceptionally useful for the "Ask Jerry" AI knowledge base.

BACKGROUND

Both physicians and patients operate under a foundational assumption: that the FDA has carefully reviewed every approved drug and determined it to be both effective and reasonably safe. Dr. Avorn argues this assumption is no longer reliably true. Over roughly the past decade, under sustained pharmaceutical industry pressure, the FDA has grown more permissive — approving drugs based on laboratory measures rather than demonstrated patient benefit, and allowing approved drugs to remain on the market even when follow-up studies fail to confirm the original surrogate endpoint's clinical meaning.

The problem traces to a well-intentioned 1990s decision. Before 1962, drugs didn't need to be proven effective before sale. In 1962, landmark legislation required manufacturers to demonstrate efficacy before marketing. Then the AIDS epidemic hit, and the FDA created an "accelerated approval" pathway under which drugs could reach the market based on surrogate measures — lab tests or imaging findings that seemed likely to correlate with patient benefit — with manufacturers required to complete follow-up studies confirming real-world clinical benefit afterward. For desperate AIDS patients with no alternatives, this was rational. The problem, Dr. Avorn explains, is what happened next: the pathway was progressively applied to conditions far removed from its original context, and the follow-up study requirement became largely unenforceable. Today, more than half of all new drugs in the US reach the market through some form of expedited review using lower evidentiary standards. Even when follow-up trials fail to confirm benefit, drugs typically remain on the market, because the FDA has very limited practical authority to force a manufacturer to withdraw a product.

KEY FINDINGS

Surrogate endpoints and the cancer drug problem. Progression Free Survival (PFS) — the period during which cancer imaging or lab values do not worsen — has become a widely used surrogate endpoint for oncology drug approval. The appeal is intuitive: if a patient's disease isn't getting worse on imaging, that seems like a good thing. But PFS often does not predict actual patient survival. In a 2022 paper in JAMA, Dr. Avorn and colleagues examined cancer drugs approved on surrogate markers and found that in nearly every case, once the drug entered the market, it remained there — even when follow-up trials were never completed, and even when completed trials failed to confirm any real benefit for patients. Once a drug is approved, it is extremely difficult to remove.

Phenylephrine: the decongestant that doesn't decongest. Pseudoephedrine (Sudafed) was a genuinely effective over-the-counter decongestant, but became restricted because it could be chemically converted to crystal methamphetamine. Manufacturers replaced it with phenylephrine under the same Sudafed brand name. Study after study has since demonstrated that phenylephrine does not work for nasal congestion. The FDA has been unable to remove it from the market. Millions of Americans are spending money annually on a product sold under a trusted brand name that has no decongestant effect.

Aduhelm: the FDA's worst decision. Aduhelm (aducanumab), an Alzheimer's drug developed by Biogen and approved by the FDA in 2021, is Dr. Avorn's central case study in regulatory failure. The drug required intravenous infusions every other week, carried serious risks including brain swelling and brain bleeding, was initially priced at $56,000 per year, and — critically — did not improve cognition or even slow cognitive deterioration in patients with Alzheimer's disease. Its manufacturer's own statistician had previously concluded there was no evidence of clinical benefit from the accumulated trial data. The FDA's outside advisory committee, after reviewing the evidence, found no support for approval. The FDA nonetheless approved the drug based on its ability to lower amyloid levels in the brain — a surrogate measure that had never been established as a reliable predictor of cognitive benefit. Three advisory committee members resigned in protest, including Dr. Aaron Kesselheim, Dr. Avorn's Harvard colleague. Medicare ultimately refused to cover the drug outside of clinical trials, a virtually unprecedented step. Multiple major health systems, including Harvard's, declined to prescribe it. The drug was subsequently withdrawn, but Dr. Avorn notes its successor — Leqembi (lecanemab), from the same two companies — is now on the market at $26,000 per year with similarly modest clinical benefit and similar risks.

Who actually designs drug trials. A widespread misconception is that the FDA tests drugs for safety and efficacy. It does not. The FDA delegates trial design, funding, and conduct to the drug manufacturers themselves, then reviews the submitted data. Dr. Avorn argues this arrangement creates structural bias: manufacturers design studies to surface benefits and minimize visible harms. The Vioxx case is his primary illustration — Merck's arthritis painkiller was on the market for five years, during which time Americans spent $2.5 billion per year on it collectively, and it caused tens of thousands of heart attacks and strokes. Researchers detected cardiovascular risk signals as early as 2001. Merck resisted disclosure until its own randomized trial, which it had funded for other purposes, confirmed the risk in 2004. Merck ultimately paid approximately $5 billion in legal settlements. Dr. Avorn argues that if independent researchers, with meaningful patient input, designed clinical trials rather than manufacturers, the public would save far more than the apparent cost of funding those trials.

The R&D argument doesn't hold. The pharmaceutical industry's standard justification for high US drug prices is the cost of research and development. Dr. Avorn acknowledges a grain of truth but identifies two significant problems. First, a substantial proportion of foundational drug development is funded by NIH — taxpayer dollars — not by manufacturers. He cites Xtandi (enzalutamide), a highly effective drug for metastatic prostate cancer that was developed entirely at UCLA using federal funding, then licensed to a chain of companies that now sell it to Americans at two to six times the price paid in other wealthy countries. Second, the government has a legal right under the Bayh-Dole Act to "march in" on patents for federally funded inventions when they are not made available at reasonable prices — a right that has never once been exercised.

Drug pricing is structurally untethered from value. The United States is the only wealthy country in which drug prices are set entirely by manufacturers without meaningful government counterpressure. Every other comparable country uses some form of health technology assessment — evaluating how much better a new drug is for patients and negotiating prices accordingly. In the US, Congress explicitly prohibited Medicare from negotiating drug prices when Part D was enacted in the early 2000s — the provision was championed by Congressman Billy Tauzin, who subsequently became head of the pharmaceutical industry's lobbying organization. Dr. Avorn observes that while the Trump administration has used anti-pharma rhetoric, pharmaceutical stock prices rose on the day of Trump's most prominently anti-pharma speech — a signal, he argues, that markets understood the rhetoric as unlikely to produce meaningful change. He is particularly blunt: proposed most-favored-nation pricing requires congressional action that will not occur, and the NIH cuts and CDC scientist firings occurring simultaneously undermine the public health infrastructure that produces the drugs of the future.

IMPLICATIONS

For patients: Dr. Avorn offers four concrete recommendations for the clinical encounter.

The brown bag review: periodically bring every medication — prescriptions from all doctors, over-the-counter drugs, supplements, herbal remedies — in a bag to your primary care physician. Patients frequently take multiple formulations of the same drug class without realizing it (Motrin, Advil, ibuprofen, and Aleve are all essentially the same class), and a common blood pressure medication class (ACE inhibitors) causes chronic cough in approximately 15% of patients — a side effect frequently misattributed to allergies, asthma, or acid reflux.

Ask what the drug is for and how success is defined. What condition is this treating? What number or outcome are we trying to reach? How will we know when we've gotten there?

Ask how long you need to take it. Some drugs (blood pressure medications, diabetes drugs) are typically lifelong. Others (antibiotics, opioids) should be taken for the shortest time needed. Patients are not born knowing the difference, and doctors often assume they do.

Ask about affordability and alternatives. Is there a generic? A biosimilar? A therapeutically similar drug that costs substantially less? Is this drug better than existing alternatives or just newer?

For the system: Dr. Avorn argues for a conditional approval model — under which drugs with promising but unproven surrogate endpoint data could enter the market for a limited, supervised period at a price reflecting their unproven status, with mandatory re-evaluation in two to three years. If the drug demonstrates real clinical benefit, full approval and full pricing follow. If not, it is withdrawn. This preserves access for desperate patients while ending the current system in which manufacturers gain full market access and full pricing on the basis of lab tests, then face no meaningful consequences for failing to complete promised follow-up studies.