After 30 days, I can repost my Wall Street Journal op-ed here.
Month: October 2026
Finding a Disease Mechanism, and a Drug to Block It, Does Not Always Work
Many medical researchers think that the only route to progress is through basic research, and even then, progress may only consist of incrementally longer life or modest reductions in side-effects. For instance Dr. Paul Marks, who was influential in Nixon’s war on cancer, believed Nixon should only fund basic science, by which he meant cell genetics, and that such research would probably not cure cancer, but only help us to better manage it. Some medical researchers (e.g. Prasad and Cifu 2015; Raza 2019) have criticized this approach as “reductionism.” Others (e.g., Devita and Devita-Raeburn 2015; Prasad and Cifu 2015; Raza 2019) support a pluralistic approach–any method that yields major advances, especially cures, is okay.
Those who advocate basic science seek mechanisms of disease, and when they think they have found one, they seek a chemical that will interfere or block that mechanism. The article quoted below tells the illuminating story of scientists who identified inflammation as a major mechanism of atherosclerosis and found a drug (ziltivekimab) that interferes with that mechanism. They then tested it using the “gold standard”: a large-scale, double-blind randomized controlled trial (RCT). But to their “shock” they found that cardiovascular death rates were not lower for those taking the drug than for those taking a placebo.
The ultimate goal is cures. Finding a mechanism, and a chemical that blocks it, can be one path to a cure. But that path sometimes leads to a dead end. So we should allow researchers to follow other paths as well.
(p. D4) Novo Nordisk stunned the cardiology world last week when it announced that a large study it was running on an experimental drug for heart disease had failed. The drug, widely expected to be a blockbuster, was no better than a placebo.
The drug, ziltivekimab, reduces inflammation, which is generally thought to be a cause of atherosclerosis. Stopping that inflammation was hoped to be a way to save lives.
Now the drug’s failure is raising a troubling question. Is inflammation really a cause or is it just a marker of atherosclerosis, the way gray hair is a marker of aging?
Cardiologists had mixed reactions to the news. Dr. Sanjay Kaul, a cardiologist at Cedars Sinai, quoted Thomas Huxley on X: “The great tragedy of science — the slaying of a beautiful hypothesis by an ugly fact.”
Dr. David Maron of Stanford, who is president of the American Society for Preventive Cardiology, said the result “comes as a surprise and a big disappointment.”
But he added, something could have been wrong with the study: Perhaps it just wasn’t the right drug to target heart disease inflammation, or maybe patients in the trial were too sick to be helped by anti-inflammatory medications. There is too much evidence, he said, from pathology studies of plaques in arteries, animal studies, epidemiology and other clinical trials, to toss out the inflammation hypothesis.
“Inflammation is more than a marker of disease, it is a cause of the disease,” Dr. Maron said.
The Novo Nordisk study, called Zeus, involved more than 6,300 patients with heart disease or advanced kidney disease. They also had high levels in their blood of a marker of inflammation known as C reactive protein, or CRP. And they had high levels of interleukin-6, or il-6, a chemical that causes inflammation.
The drug did what it was supposed to do. It made il-6 levels plunge. CRP levels fell in concert.
With those signals indicating that inflammation was controlled, it seemed only logical that heart disease complications and cardiovascular death rates would drop, too. But that didn’t happen.
“I think we’re all in a state of shock,” said Dr. Martha Gulati of Houston Methodist, past president of the American Society for Preventive Cardiology.
For the full story, see:
(Note: the online version of the article has the date Aug. 6, 2026, and has the title “A Promising Heart Drug Fails, Challenging a Long-Held Theory of Disease.”)
When U.S. Firms Do the Hard Discovery of Disease Mechanisms, Chinese Firms Cash in With Quick Development of “Fast Followers”
The most binding constraint in drug development is identifying a mechanism by which the disease works, and targeting a weak point through which the mechanism can be slowed or shut down. Since this is the hardest, scarcest part of drug development, firms that achieve it should be rewarded. If they are, then we would find more resources going into searches for mechanisms of disease, and ultimately achieve more effective therapies and even cures. But Chinese firms are increasingly alert to U.S. firms’ advances in mechanism discovery. “After Novo Nordisk published landmark results in February 2021 showing strong results for its weight-loss drug semaglutide, at least 16 Chinese programs targeting the same mechanism filed for clinical-trial approval or dosed patients in China within 18 months, according to the biopharma market-intelligence firm Sleuth, and at least 62 such Chinese programs have launched through June 2026” (Martinez 2026, p. A10).
When Chinese pharma firms learn of the discovery of a new mechanism they are quickly developing, and running trials on, “fast follower” drugs that make use of the same mechanism, but affect the mechanism with a slightly different chemical entity. They can run the trials more quickly, partly because their government and scientific institutions tolerate, and even encourage, them to cut corners in a variety of ways (Ritchie 2020, p. 70). They can then gain fast approval of their fast follower drugs, receiving a larger part of the rewards from the therapy than the firms that achieved the hardest part by discovering and proving the mechanism.
As long as this system continues, it creates a perverse incentive for firms to be fast followers, rather than discoverers of fundamental mechanisms. It also creates a perverse incentive for firms discovering new mechanisms to practice secrecy rather than transparency.
Small mission-oriented startups are the most likely source of the discovery of new mechanisms. But they are also the most resource-constrained, and the least able to conduct large trials. Secrecy will make it harder for them to raise funds, making it harder for them to survive, let alone thrive. The situation for the small firms is all the worse because the FDA requires large Phase 3 double-blind randomized clinical trials, which are especially hard for small firms to fund and execute.
My musings above were informed and stimulated partly by the article:
(Note: the online version of this article has the date July 9, 2026, and has the title “U.S. Biotechs Are Keeping More Secrets to Beat Copycats in China.”)
The book I reference above on Chinese RCTs is:
Ritchie, Stuart. 2020. Science Fictions: How Fraud, Bias, Negligence, and Hype Undermine the Search for Truth. Metropolitan Books.
The Burdens of Prior Approval Still Bedevil Our Over-Regulated Semi-Socialist Healthcare System
In June 2025 many healthcare insurance companies promised to reduce the burden of requirements for prior authorization for treatments. Prior authorization delays treatment, increases uncertainty, and burdens patients and healthcare providers with substantial costs in time and effort to fill out paperwork. As of May 2026, surveys of doctors, administrators, and patients still found prior authorization requirements to be a burden, many not detecting a noticeable change.
This is consistent with what Dr. Ben Goldacre has observed about big pharma firms. When patients or policy makers complain about some practices, such as lack of transparency in reporting clinical trials that fail to support a new drug, the firms promise to take action, and policy makers move on to other issues, thinking that the complaint has been resolved. But often the firms do not deliver on their promises, which amount to “fake fixes” (Goldacre 2013, pp. 47, 54, 299, 333, and 343). Letting our guard down based on the “false reassurance” (Goldacre 2013, pp. 47 and 54) of their promises, no one holds them responsible.
What is true of big pharma firms may also be true of healthcare insurance firms.
The problem is not that the firms are led by evil people, but that perverse incentives lead good people to do bad things. The perverse incentives are an unintended consequence of a baroque system built largely with good intentions.
For the article documenting the continuing burden of prior authorization rules, see:
(Note: the online version of the article has the same date as the print version, and has the title “Medical Care Delays for Approval Persist, Despite Insurers’ Promises.”)
Goldacre’s book, that I praise above, is:
Goldacre, Ben. 2013. Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients. New York: Farrar, Straus and Giroux.