Category: Regulations

F.D.R.’s Wage Controls Created a Wedge Between Patients and Doctors, With Awful Unintended Consequences

Under F.D.R.’s wage controls, firms competed for workers through perks, like healthcare benefits, since they could not legally compete by offering higher wages. That resulted in the first middlemen (in this case firms) between the customers (patients) and the suppliers (doctors). The result of adding the middlemen, and also adding a variety of regulations, is a “market” that is opaque, inefficient, and slow to innovate. Rather than drain the swamp, the response has been to add more middlemen (Medicare, Medicaid, Obamacare, and Pharmacy Benefit Managers, aka PBMs), that have only thickened the mire.

(p. B11) The roots of today’s fragmented system can be traced back to a quirk in U.S. history. Unlike most high-income countries, which created centralized government systems to ration care in the 20th century, the U.S. followed a different path shaped by historical circumstances. During World War II, wage controls prompted employers to offer health insurance as a tax-free benefit to attract workers.

Medicare and Medicaid, followed decades later by Affordable Care Act exchanges, were added over time to cover those who couldn’t get insurance through their job, creating a highly decentralized and convoluted system.  . . .

. . . the pressure to increase their earnings means insurers have looked for ways to overbill the government and skimp on patient care, always staying a step ahead of regulators. In recent years, they have become vertically integrated conglomerates, controlling doctors, pharmacies and payment-processing systems.

. . .

One of the most frustrating aspects of the system is a tactic called prior authorization, a process requiring providers to obtain insurer approval before delivering certain services. While that might be disagreeable, there is little public data on how often insurers deny care. This lack of transparency allows insurers to wield prior authorization aggressively, particularly when expensive treatments are recommended.

For the full commentary see:

David Wainer. “How to Fix Health Insurance.” The Wall Street Journal (Saturday, Dec. 21, 2024): B11.

(Note: ellipses added.)

(Note: the online version of the commentary has the date December 20, 2024, and has the title “How American Health Insurance Got So Infuriating.”)

Almost $2 TRILLION in Compliance Costs for Biden’s 1,213 New Regs over 10 Years

I am queasy about Trump’s tariffs but hopeful about his deregulation. Besides attacks on freedom of speech, regulations are currently the most binding constraint on innovation and flourishing in the U.S. I hope that the tariffs will be a bargaining ploy that in the long run will result in less protectionist policies for both us and our trading partners. But even if my hope is dashed and higher tariffs become a sustained policy, I believe (but cannot prove) that heavy regulations are the greater evil.

(p. A13) By the time Mr. Biden left office, his administration had issued 1,213 new regulations, according to the American Action Forum. The Washington think tank tracks federal regulations, their cost and added paperwork hours on its Regulation Rodeo website. Mr. Biden’s red tape will result in $1.9 trillion in compliance costs over the first 10 years the new rules are in effect, according to AAF.

By comparison, in Mr. Trump’s first term, his administration issued slightly more regulations—roughly 1,340—but many reduced costs to businesses and consumers. In total, they cost only $64.7 billion, less than 4% of Mr. Biden’s total.

Mr. Biden’s regulatory regime was far more expensive than even Barack Obama’s. Over two terms, the Obama administration issued 2,997 regulations, at a price tag of $870.5 billion. That’s less than 46% of the regulatory cost Mr. Biden racked up in four years.

For the full commentary see:

Karl Rove. “Trump Sets Out to Break Burdensome Rules.” The Wall Street Journal (Thursday, Jan. 23, 2025): A13.

(Note: the online version of the commentary has the date January 22, 2025, and has the same title as the print version.)

Tainted Sulfa Drugs Led Feds to Mandate Drug Safety Tests

Note that the impetus for the creation of mandated drug licensing was an episode of tainted sulfa drugs. The motive of the mandate was to assure safety. The later impetus for the strengthening of mandated drug licensing was the thalidomide episode. Again the motive was to assure safety.

Economists annoyingly emphasize trade-offs. If we stuck to regulation for safety, we could vastly reduce the costs of drug development, allowing more and faster drug innovation.

A case can even be made for doing away with safety regulation. Firms have incentives to produce safe drugs, and private certifying organizations provide information, for instance Consumer Reports. And there are many examples of F.D.A.-approved drugs that turned out to be unsafe (e.g., Vioxx). Mandated safety regulations reduce consumer freedom to choose, and slow the amount and speed of new cures. Mandated efficacy regulations reduce them even more.

(p. C6) Between the late 1930s and the late 1940s, every major class of antibiotics was developed, as William Rosen meticulously recounts in “Miracle Cure: The Creation of Antibiotics and the Birth of Modern Medicine.” Rosen’s highly informed retelling captures the drama of scientists’ quest, against long odds, to find and produce bacteria-killing drugs—and the egos, ambitions, brilliance and resolve that drove them.

. . .

It is a strength of “Miracle Cure” that Rosen places its many tales of discovery in their larger contexts, explaining for instance the near-complete lack of drug-safety regulation that prevailed when the Tennessee-based S.E. Massengill Co. began selling Elixir Sulfanilamide in October 1937. To make the drug more palatable, the company’s chief chemist had dissolved it, along with raspberry flavoring, in a toxic chemical also used in brake fluid. At least 73 people died. The Federal Food Drug and Cosmetic Act became law the following year. Companies would no longer be able to market new drugs without government licensing. And the government would have to ensure that they were safe.

This book is not for the casual reader. At some points Rosen gets into weeds so thick that only aficionados will find a way through. Still, it’s an important contribution to a still-germane yet fast-receding history. And it’s all the more impressive that Rosen, formerly a book editor and publisher, wrote it as he was battling his own intractable disease. An aggressive cancer took his life in April 2016. He left behind a history worth reading.

For the full review see:

Meredith Wadman. “Medicine’s Age of Wonders.” The Wall Street Journal (Saturday, May 20, 2017 [sic]): C6.

(Note: ellipsis added.)

(Note: the online version of the review has the date May 19, 2017 [sic], and has the same title as the print version.)

The book under review is:

Rosen, William. Miracle Cure: The Creation of Antibiotics and the Birth of Modern Medicine. New York: Penguin Books, 2018.

Dog Health Insurance Is Simpler and More Transparent Than Human Health Insurance

Why is dog health insurance simpler and more transparent than human health insurance?

Dog healthcare is mostly provided in a true marketplace, while human healthcare is provided in a hyper-regulated mishmash of market and government. Because there are more regulations and more risks of malpractice for human healthcare, more and more providers work for large healthcare firms. It’s much easier to have a small independent veterinary practice than a small independent human healthcare practice. So we find more competition in veterinary practices, resulting in prices that are lower and more transparent.

For humans the mega-providers gain with lack of transparency. Insurers are vertically integrated with hospitals, doctor practices, and obscure middlemen called Pharmacy Benefit Managers (PBMs). I would like to confirm my strong guess: few dog health insurance firms own veterinary practices.

(p. A24) I rushed around the patient as he lay motionless with his eyes closed in the emergency room. He was pale and sweaty, his T-shirt stained with vomit. You didn’t have to be a health-care worker to know that he was in a dire state. The beeps on the monitor told me his heart rate was dangerously slow. I told the man that he was going to be admitted to the hospital overnight.

After a pause, he beckoned me closer. His forehead furrowed with concern. I thought he would ask if he was going to be OK or if he needed surgery — questions I’m comfortable fielding. But instead he asked, “Will my insurance cover my stay?”

This is a question I can’t answer with certainty. Patients often believe that since I’m part of the health-care system, I would know. But I don’t, not as a doctor — and not even when I’m a patient myself. In the United States, health insurance is so extraordinarily complicated, with different insurers offering different plans, covering certain things and denying others (sometimes in spite of what they say initially they cover). I could never guarantee anything.

. . .

The killing of Brian Thompson, the chief executive of UnitedHealthcare, the country’s largest health insurer, has reignited people’s contempt for their health plans. It’s unknown if Mr. Thompson’s tragic death was related to health care, and the gleeful responses have been horrifying. But that reaction, even in its objectionable vitriol, matters for how it lays bare Americans’ deep-seated anger toward health care. Around the country, anecdotes were unleashed with furor.

Among these grievances is the great unknown of whether a treatment recommended by a doctor will be covered. . . .

Unsurprisingly, despite my platitudes, my patient did worry. Instead of resting on the stretcher, he and his wife began calling his insurance company. To keep him from leaving, I tried to be more persuasive, even though I didn’t know what kind of health plan he had: “I’m sure your insurance will pay. I’ll document carefully how medically necessary this admission is.” I added that social workers and other advocates could also assist in sorting out his insurance once he was admitted. And worst-case scenario, if they couldn’t, I crossed my fingers that the hospital’s charity care would help.

I said what I could to get him to stay, but I understood why he wanted to be certain. The average cost of a three-day hospital stay is $30,000.

. . .

My one family member with solid insurance is my dog. He got elective surgery recently, and I was astounded by the straightforward nature of his insurance. Once we meet the deductible, everything is simply covered by 80 percent. This is clearly described in a packet I received when I first signed him up. It’s an imperfect comparison to insurance for humans — I pay in full first, then get reimbursed — but it’s incredible to think that insurance for pets and possessions is easier to navigate and more consumer-friendly than insurance for people.

For the full commentary see:

Helen Ouyang. “What I Know About Americans’ Anger at Health Care.” The New York Times (Thursday, December 12, 2024): A24.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Dec. 8, 2024, and has the title “What Doctors Like Me Know About Americans’ Health Care Anger.”)

Allow Those with Skin in the Game to Help Find Quicker Cures

The New York Times devoted more than two and half full pages to the article that I quote from below. Very very few articles receive that much space. The story is meant to inspire and it does. Linde has a terrible genetic disease, as did her mother and grandmother, as do her two sisters, and as might her two daughters. She is uncredentialled, but determined. She reads scientific articles, gives talks at scientific meetings, creates a foundation to raise funds, and with her sisters gave samples from her skin to create cell lines that can be used for research to find a cure. Linde, both literally and figuratively, has skin in the game.

In the article, victims of the disease wish that there were more clinical trials to test more possible cures. If the price of clinical trials were lower, more of them would be supplied. One way to reduce the price would be for the F.D.A. to only mandate testing for safety, not to mandate testing for efficacy. After all, it was concerns over the safety, not the efficacy, of thalidomide, that first accelerated the F.D.A.’s clinical trial mandates. Testing only for safety (Phase 1 and Phase 2 clinical trials), would hugely reduce the price, resulting ultimately in more and quicker cures.

(p. A1) Linde Jacobs paced back and forth across her bedroom, eyeing the open laptop on the dresser and willing the doctor to appear. Her husband was dropping off their older daughter at school. Their younger daughter was downstairs, occupied by a screen. Linde wanted to be alone when she learned whether she carried the family curse.

Linde’s mother, Allison, had died just four weeks before, after a mutant gene gradually laid waste to her brain. In her 50s, Allison transformed from a joyful family ringleader into an impulsive, deceptive pariah. She drove like a maniac on cul-de-sacs. She pinched strangers, shoplifted craft supplies and stole money from her daughter.

Now, on this morning in September 2021, Linde would find out if she had inherited the same vile genetic mutation.

. . .

The doctor finally popped up on the computer. Wasting no time on pleasantries, she shared her screen and zoomed in on one line of laboratory paperwork: POSITIVE.

. . .

Soon, Linde’s husband, Taylor, pulled into the garage and opened the car door. He could hear her sobbing.

. . .

Linde looked at Taylor. “I don’t want you to feel stuck with me,” she said.

(p. A12) Leaving had never crossed his mind. Allison’s miserable experience, he told Linde, did not have to be hers. “You have all this time,” he said. “Do something about it.”

Even as they spoke, scientists were working on projects that might one day help her. Some had discovered how to cure grave conditions with gene editing. Others were tinkering with patients’ skin cells to test experimental drugs. And pharmaceutical companies were developing new Alzheimer’s therapies, one of which happened to target the rare defect in Linde’s brain.

Linde didn’t know any of that yet. But she decided to take Taylor’s advice. She would use the time she had, somehow, to find influential scientists and make them care about what was happening to her — and what might happen to her girls.

Linde and Taylor scoured the internet for any scrap of hope about treating frontotemporal dementia, or FTD. There was little to read.

Taylor remembered a Netflix documentary about a new way to edit genes. The method, called CRISPR, had cured some children with sickle cell disease. He searched “FTD treatment CRISPR” and found the website of Dr. Claire Clelland, a neurologist at the University of California, San Francisco. She had collected skin cells from patients with FTD, reprogrammed them into neurons and tried to edit the faulty genetic code within.

The website listed a phone number. Taylor called and left a message — a Hail Mary, he figured.

Within a day, Dr. Clelland responded by email. “Happy to help if I can,” she wrote.

. . .

(p. A13) “Could I ask a question?” one young scientist said. How much risk, she wondered, was Linde comfortable taking on an experimental treatment? Editing genes with CRISPR was new, after all, and could come with serious side effects.

“Sign me up, patient zero, sounds good,” Linde said.

“What choice do I have,” she added, “if I don’t want the same future for myself as my mom had, and her mom?”

When she wasn’t working or coaching her daughter’s soccer team, Linde threw herself into the scientific research on MAPT — a niche but growing subfield. The gene provides the instructions for cells to make tau, a protein in the brain.

One day she came across news of a project investigating how tau can go awry. She wrote to the scientist leading the work, Dr. Kenneth Kosik of the University of California, Santa Barbara, describing her family and asking to talk.

Dr. Kosik was sitting in his home office when her note landed in his inbox. “It was the second time in my life that I realized, I’ve got to get back to this person in, like, a nanosecond,” he recalled.

. . .

Dr. Kosik told Linde that an elite group of researchers, known as the Tau Consortium, would gather in Boston in a few months for its annual meeting. Dr. Clelland would be there, as would other “Michael Jordans” in the field. We should try to get you there, he said, so the scientists can be reminded of the human toll of tau-related diseases.

A few weeks later, Linde received an invitation to be the keynote speaker. Jenica and Ashlyn could come, too.

She texted her sisters, “Holy shit.”

One morning in Boston in June 2023, Linde and her sisters got all dolled up, only to arrive in a grand hotel ballroom filled with 100 scientists in oxfords and sneakers.

Dr. Kosik introduced Linde to the members of the Tau Consortium. Too nervous to look anyone in the eye, she stared at a screen showing her slides and read from her prepared remarks.

“You will notice the lack of credentials following my name,” she began. But she said her life had brought her other titles: Caregiver. Jail-Bailer. Carrier. She was the heartbeat, she said, of the cells they studied.

. . .

After the Boston talk, Linde received a flurry of invitations to tell her story. She was interviewed on YouTube by Emma Heming Willis, the wife of the actor Bruce Willis, the most famous person known to have frontotemporal dementia. She came face to face with monkeys that carried MAPT mutations in Madison, Wis. And though she detested the crowds and grime of big cities, she flew to places like Philadelphia and Washington, D.C., to at-(p. A14)tend scientific meetings.

Linde, who by then had moved to River Falls, Wis., always returned home exhausted. But the trips were also fortifying. Learning about the latest research quelled her anxiety — and her husband’s.  . . .

During her travels, Linde met other families with MAPT mutations. They were all frustrated by the lack of clinical trials for their genetic glitch, especially because several promising treatments were in the pipeline for other dementia genes. Linde and the others started a global survey of people with MAPT mutations. If an opportunity came along for a clinical trial, they would make it as easy as possible for scientists to find volunteers.

. . .

A few months later, Linde and the group started a nonprofit, called Cure MAPT FTD. They have since found more than 500 people with confirmed or possible MAPT mutations in 10 countries, all of whom have expressed interest in participating in future clinical trials.

In March of this year, Linde got an astonishing offer from Dr. Clelland. Along with collaborators at Washington University and the Neural Stem Cell Institute in New York, she wanted to collect skin cells from Linde and her sisters and turn them into clusters that divide infinitely, known as cell “lines.”

“We propose to make new lines that can be shared with academics and also with industry so that people can do drug screening” and CRISPR projects, Dr. Clelland wrote.

. . .

Based on what happened to Allison and Bev, Linde figures she has at least 10 more years before she starts showing symptoms. But there’s no guarantee; some MAPT carriers begin to change in their 20s. Whenever Linde tells a joke a little too loudly, or has a dulled emotional response to a dramatic event, she worries: Is this tau?

That anxious metronome never shuts off. It compels her to fill any moment of downtime reading the latest study or sending another email. She has spent thousands of dollars and hundreds of unpaid hours on travel. But sometimes, like when she finds herself alone in a hotel room, FaceTiming her daughter about a rough day at school, she questions whether these scientific pursuits are really the best way to run out the clock.

. . .

Dr. Clelland said designing a CRISPR molecule that could precisely excise the MAPT mutation from a cell’s genome was not the hard part. The major unsolved challenge is delivering those molecular scissors into the brain. Still, she and her colleagues at U.C.S.F. have set an ambitious goal of getting MAPT therapy into clinical trials within four years.

For the full story see:

Virginia Hughes. “A Mother’s Race to Beat a Genetic Time Bomb.” The New York Times (Wednesday, December 25, 2024): A1 & A12-A14.

(Note: ellipses added.)

(Note: the online version of the story was updated Jan. 2, 2025, and has the title “Fighting to Avoid Her Mother’s Fate, for Her Daughters’ Sake.” I have omitted a few subhead titles that appear in both the online and print versions.)

Mainstream Approach to Alzheimer’s Is Built on Doctored Data

Widespread fraud among highly credentialled, and richly financed, medical researchers results in fewer and slower cures. Many millions of dollars are required to bring a major drug to market, much of it due to the hyper-costly and mandated Phase 3 randomized double-blind clinical trials. There are more good ideas than can received such financing. The intense competition creates a temptation to cut various corners, as the book review quoted below emphasizes.

Aaron Rothstein, the reviewer of Piller’s Doctored book, emphasizes the sad revelation of widespread fraud. But in an earlier entry on this blog, I quoted an essay of Piller’s that suggests that Piller also has something substantive to say about how to cure Alzheimer’s. The current system is broken, vastly reducing the diversity of approaches to curing important diseases like Alzheimer’s. Piller suggests that the ruling clique among Alzheimer’s researchers may in effect be silencing other approaches that could bring us a better faster cure.

Rothstein downplays this substantive aspect of Piller’s book. (It probably reflects too much cynicism on my part to wonder how close Rothstein himself is to the ruling clique?)

I look forward to reading Piller’s book, both for what it has to say about widespread fraud and for what it has to say about Alzheimer’s. Doctored is scheduled for release in a few days, on February 4, 2025.

(p. C9) In 2023 my colleagues and I were preparing to enroll patients in a clinical trial of a new drug that promised to mitigate brain damage in stroke victims. The National Institutes of Health, a governmental organization that funds billions of dollars of research every year, had committed $30 million to the trial. The drug was, in part, the brainchild of Berislav Zlokovic, a neuroscientist at the University of Southern California.

Then, suddenly, the NIH paused the trial. Charles Piller, an investigative journalist for Science magazine, had published an article alleging that multiple papers from Dr. Zlokovic, including many supporting the new drug, contained seemingly altered data. Though Dr. Zlokovic disputed some of the concerns, this news stunned us. We might have put patients at risk, while offering groundless hope. A fraud of the sort Mr. Piller described would violate the basic ethics of clinical trials and overturn the presumption of trust on which the practice of medicine relies.

I thought of this episode often as I read Mr. Piller’s “Doctored,” which brings together his long-form journalism about neuroscience-research malfeasance, including that alleged of Dr. Zlokovic. Though the book sometimes attempts to do too much—diving into scientific theories about the causes of Alzheimer’s, for example—its strength lies in Mr. Piller’s dramatic and damning investigation of scientific transgression. The author’s reporting is largely based on the research of Matthew Schrag, a Vanderbilt neurologist who uses technical expertise to identify episodes of misconduct.

. . .

Mr. Piller thoroughly double checks Dr. Schrag’s work. He asks researchers and image analysts to confirm Dr. Schrag’s findings, and they concur.

. . .

“Doctored” demonstrates how some of the most accomplished and elite scientific gatekeepers may have lied, cheated, squandered trust and endangered lives. How did this happen? The temptations of ego and fame perennially entice humans, but our system of peer review, grant funding and administrative oversight is meant to check these temptations.

The scientific publication process does not contain all the safeguards one might expect. Peer reviewers do not always see the original data from authors. Thus they trust that numbers or images in a manuscript accurately reflect the experiment. And determining whether an image is fraudulent requires skilled image analysis that peer reviewers may not possess. Furthermore, digging for such mistakes is costly: It takes time away from other research, from teaching, from seeing patients and from home life.

What can be done about this? Making raw data available to peer reviewers and giving them time to review articles could help. Mr. Piller suggests a less professionally incestuous relationship between researchers, the Food and Drug Administration, the NIH and pharmaceutical companies could reduce favoritism in funding. A major overhaul of the finances and administrative swell of our system would help, as well.

For the full review see:

Aaron Rothstein. “Medical Promise Betrayed.” The Wall Street Journal (Saturday, Jan. 25, 2025): C9.

(Note: the online version of the review has the date January 24, 2025, and has the title “‘Doctored’ Review: Medical Promise Betrayed.”)

The book under review is:

Piller, Charles. Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s. New York: Atria/One Signal Publishers, 2025.

Surgeons Respond More to Individual Incentives Than to Group Incentives

Medicare introduced a new billing code that reimburses surgeons more for repairing hernias that are at least 3 cm long. As a result the percent of repaired hernias that were less than 3 cm dropped from 60% to 49%. It is probably not too hard for surgeons to justify this change. Probably surgeries on hernias just under 3 cm, are just as hard to do as surgeries on hernias that are just above 3 cm. So probably it seems arbitrarily unfair to reimburse more for the slightly larger ones. So look at the close calls closer until you find an angle where one that on first glance was less than 3 cm, now appears to be more than 3 cm.

On the other hand, consider the response when Blue Cross Blue Shield in Michigan offered to pay more to urology group practices that had more patients on active surveillance for prostate cancer. (A growing consensus suggests that most low-risk prostate cancer patients would be better off with active surveillance, rather than quick prostate surgery by urologists.) The response by Michigan urologists–no change in the percent of prostate cancer patients on active surveillance.

Why the difference? I suggest that surgeons, like other people, respond more to individual incentives than to group incentives. A person who responds to group incentives bears the costs themselves, but shares the benefits with others who may be free-riders. If the incentive is individual, no one free rides.

I became aware of the recent academic articles on how incentives do or don’t influence surgeons by reading:

Millenson, Michael L. “It’s Money That Changes Everything (or Doesn’t) for Surgeons.” Forbes.com, Jan. 26, 2025 [cited Jan 27, 2025]. Available from https://www.forbes.com/sites/michaelmillenson/2025/01/26/its-money-that-changes-everything-or-doesnt-for-surgeons/ .

The academic article showing that individual incentives matter to some surgeons is:

Hallway, Alexander, Erin Isenberg, Ryan Howard, Sean O’Neill, Jenny Shao, Leah Schoel, Michael Rubyan, Anne Ehlers, and Dana Telem. “Medicare Coding Changes and Reported Hernia Size.” JAMA (published online on Jan. 16, 2025).

The academic article showing that group incentives don’t seem to matter to surgeons is:

Srivastava, Arnav, Samuel R. Kaufman, Addison Shay, Mary Oerline, Xiu Liu, Monica Van Til, Susan Linsell, Corinne Labardee, Christopher Dall, Kassem S. Faraj, Avinash Maganty, Tudor Borza, Kevin Ginsburg, Brent K. Hollenbeck, and Vahakn B. Shahinian. “Physician Payment Incentives and Active Surveillance in Low-Risk Prostate Cancer.” JAMA Network Open 8, no. 1 (Jan. 8, 2025): e2453658-e58.

At Age 84 Scolnick Has the Passion to Persevere at Curing His Son’s Illness

Many of those with the passion to persevere in overcoming the necessary and unnecessary (regulatory) obstacles to medical innovation, do so because they have a sense of urgency due to skin in the game–they or a relative is directly affected by the disease they are passionate to cure. Dr. Edward Scolnick whose story I quote below, is a great example. In the story, we find another example, Ted Stanley, who donated $100 million to Scolnick because Stanley’s son is also suffering mental illness. And perhaps an indirect example? Rienhoff does not directly have skin in the game, but he is playing a key role because of Scolnick’s passion, and Scolnick’s passion is due to his skin in the game.

If we want more cures we will reduce the unnecessary (regulatory) obstacles so that those with less skin in the game (and so less passion to persevere) will also innovate.

[“Skin in the game” has been emphasized by Taleb in his book with that title.]

(p. A1) Dr. Edward Scolnick figures he needs five, maybe 10 more years to solve one of the brain’s greatest mysteries.

Scolnick, 84 years old, has spent most of the past two decades working to understand and find better ways to treat schizophrenia and bipolar disorder, mental illnesses suffered by tens of millions of people, including his son.

“I know I can crack it,” said Scolnick, a noted drug developer who spent his career plumbing the building blocks of DNA for new treatments.

Long before his latest quest, Scolnick spent 22 years at Merck, mostly as head of the drug giant’s laboratory research. He led development of more than two dozen medicines, including the first approved statin to lower cholesterol, an osteoporosis treatment and an anti-HIV therapy.

. . .

(p. A9) In 2021, Scolnick learned that a group of scientists analyzing DNA from thousands of people with schizophrenia had found mutations in 10 genes that substantially increased the risk of developing the illness. They estimated that a mutation on a single gene, called Setd1a, raised the risk 20-fold.

“It got my blood boiling,” Scolnick said. He began pursuing an emerging class of treatments called LSD1 inhibitors, hoping to develop a new drug. Scolnick enlisted Dr. Hugh Young Rienhoff Jr., who recently developed an LSD1 inhibitor to treat blood disorders.

. . .

Rienhoff anticipates testing a new drug for safety as early as next year, first in animals. He said he saw Scolnick’s passion about fielding a breakthrough treatment but didn’t fully understand why until Scolnick shared about his son’s lifelong struggles with mental illness.

Jason Scolnick, 54, said his doctor has been regularly fine-tuning his medications for bipolar disorder over the years to minimize their debilitating side effects. Using the drugs currently prescribed for schizophrenia or bipolar disorder is like undergoing chemotherapy, he said. “There’s no guarantee it will work and it makes you feel terrible, but the cancer will feel worse or kill you.”

There remains a long road ahead for any new medicine. It takes more than a decade, on average, to get a drug from the research lab through government approvals to patients.

. . .

After leaving Merck, Scolnick was hired in 2004 by the Broad Institute of MIT and Harvard to lead research on psychiatric disorders. He fostered ties with Ted Stanley, a memorabilia entrepreneur whose son also suffered with mental illness. In 2007, Stanley gave $100 million to launch the Stanley Center for Psychiatric Research at the Broad, headed by Scolnick for five years.

. . .

Scolnick and Rienhoff had sat together at a Blackstone dinner years earlier. During the meal, Scolnick shared stories with his table companions about Merck’s development of Crixivan, the anti-HIV drug. “I was hearing a piece of history,” Rienhoff said, “not just HIV history.”

Scolnick became emotional describing how the drug developers, facing various obstacles, wrestled with whether or not to keep going. He pushed for the study to continue, given the urgency. At the time, AIDS was killing tens of thousands of people a year in the U.S.

“I said to Ed, ‘You are thinking like a doctor not a scientist,’” Rienhoff said. “That was the beginning of our relationship.”

. . .

Rienhoff has a team of chemists making and testing compounds at labs in the U.S. and abroad.

“I am optimistic something will come of this,” Rienhoff said. “I can do it, but I wouldn’t have done it if not for Ed. I am, really, doing this in a way for Ed.”

. . .

Biotech company Oryzon Genomics in Spain is developing LSD1 inhibitors for cancer and other conditions. Columbia University researchers tried Oryzon’s drug in mice and found it reversed cognitive impairments caused by the Setd1a genetic mutation connected to schizophrenia. Oryzon is running a small trial in Spain of the LSD1 inhibitor in patients with schizophrenia.

Dr. Joseph Gogos, who led the Columbia research, said it was possible such treatments would be approved for people.

Scolnick is more certain—of both a revolutionary new treatment and his living to witness it.

“Before I die, we will see new medicines, new diagnostics, better outcomes for patients burdened by schizophrenia or bipolar illness,” he said. “I will not be happy to die. But I will die happy that my life helped.”

For the full story see:

Amy Dockser Marcus. “Aging Scientist Races Against Time.” The Wall Street Journal (Friday, Nov. 29, 2024): A1 & A9.

(Note: ellipses added.)

(Note: the online version of the story has the date November 26, 2024, and has the title “A Scientist’s Final Quest Is to Find New Schizophrenia Drugs. Will He Live to See Them?”)

Patients Are Too Patient About the Time They Waste in Worthless Healthcare

Healthcare appointments are often too numerous, too time-consuming, too stressful, and too harmful. Journalist Paula Span, often citing the words and research of MD Ishani Ganguli, presents this as an outrageous revelation. Dr. Ganguli tells us “there are opportunity costs” and “you don’t have infinite time, energy and attention” (Ganguli as quoted in Span 2024, p. D3). Outrageous it is, but to few of us is it a revelation. Patients know because they experience. If they are smart (I am often stupid) they will stifle their complaints so they do not annoy their care-givers. But care-givers know also. Those implementing the time-wasting or onerous practices are not evil. But they often do not have the incentive, or sometimes even the power, to change.

Every time I go into a doctor’s office, I am weighed. I always ask, “Do you want me to take my shoes off?” The nurse or medical assistant always shrugs and says they do not care. If my weight mattered, shouldn’t it be taken consistently, either always with shoes on or shoes off? I have had my weight taken countless times but I cannot remember a single time when the doctor mentioned the weight measure from earlier in the appointment. Prescription lists are endlessly requested, even by those who do the prescribing. Many lab tests are done out of the inertia of routine. In many hospitals sleeping patients are interrupted by a “care-giver” who comes in and performs a routine task, like asking them how much pain they are feeling. The “care-giver” records the answer and departs, taking no other action, but in the meantime diminishing the healing sleep of the patient. Tasks of this sort must be damaging to the morale of the care-giver. They signed up to do good, not to do harm. But they must do harm to follow the mandated protocol, or they risk being punished.

Why do these practices continue? Because they have been done in the past. No one will be rewarded for dropping them, and the care-giver who fails to do them is at risk of being criticized or punished. In a non-entrepreneurial, litigious, and highly regulated system, much that is done is not done for the benefit of the patient. It is done for CYA (“Cover Your Ass”).

But hope abides. We could deregulate healthcare. Then doctors could tell their nurses to only take the patient’s weight when it is actually needed. Hospital entrepreneurs could tell staff to only ask patients of their pain when they are awake and complaining of pain. Options in healthcare would be more diverse. But some of the options would actually make sense. Care-givers providing options that make sense would expand their own practice and be imitated by others. We would have better care and less wasted time.

The commentary by Paula Span, mentioned above, is:

Paula Span. “Too Much Time Spent on Doctors.” The New York Times (Tuesday, November 26, 2024): D3.

(Note: the online version of Span’s commentary has the date Nov. 23, 2024, and has the title “So Many Days Lost at the Doctor’s Office.”)

An academic article co-authored by Ganguli presents empirical evidence on how much time patients spend in healthcare activities:

Ganguli, Ishani, Emma D. Chant, E. John Orav, Ateev Mehrotra, and Christine S. Ritchie. “Health Care Contact Days among Older Adults in Traditional Medicare: A Cross-Sectional Study.” Annals of Internal Medicine 177, no. 2 (Feb. 2024): 125-33.

In an academic op-ed piece, Ganguli justly laments how the healthcare system often wastes patients’ time, sometimes even resulting in worse health. She uses the example of the severe cardiac side-effects from the eight weeks of Monday through Friday radiation that her 81-year-old father was given for his recently discovered prostate cancer:

Ganguli, Ishani. “How Does Health Care Burden Patients? Let Me Count the Days.” New England Journal of Medicine 391, no. 10 (Sept. 7, 2024): 880-83.

Keep Raging at “the Dying of the Light”

I still remember as an undergraduate at Wabash College reading in our intro psychology textbook of an experiment in which a dog was put in a box. Every time the dog tried to leap out of the box, he received an electric shock. Eventually the electric current was turned off. But the dog never again tried to leap. Are we like the dog, too discouraged by past constraints, so that we are resigned to accept the Biblical limit of “three score and 10” (Psalm 90:10)?

But there is a paradox. Kloc cites an article claiming a very high market value for expanded lifespans. But then where are the voters urgently demanding that medical entrepreneurs be unbound? Where are the citizens demanding that regulators stop mandating Phase 3 clinical trials? Citizens with a sense of urgency can make a difference–see the Act-Up movement in the early years of AIDs. When will they?

(p. 1) The longevity industry is coming off perhaps its best run on record. The expected span of an American life has increased by about three decades since 1900 — to around 78 as of 2023. But for many people, even 78 years just won’t do.

The Methuselah Foundation, a biomedical charity, for example, wants to “make 90 the new 50,” and scientists at one biotechnology firm have argued that, unencumbered by disease, the body could potentially make it all the way to age 150. Even more optimistic estimates put the number closer to 1,000.

​​Whatever the maximum human life span may be, people appear increasingly determined to find it — in particular men, who are more inclined to favor radically extending life, maybe even indefinitely. Last year, nearly 6,000 studies of longevity made their way onto PubMed, a database of biomedical and life sciences papers; that’s almost five times as many as two decades ago.

Along with the creation of dozens of popular podcasts and a sizable supplement industry, that zeal has led to efforts to preserve organs, search out life-extending diets and even try to reverse aging itself.

. . .

(p. 24) Researchers at Harvard and Oxford recently tried to gauge that interest in the marketplace today. They estimated that the total value of any scientific breakthrough that added another decade to global life expectancy would be worth $367 trillion.

For the full story see:

Joe Kloc. “Gilgamesh, Ponce and the Quest to Live Forever.” The New York Times, First Section (Sunday, January 19, 2025): 1 & 24.

(Note: ellipsis added.)

(Note: the online version of the story has the date Jan. 18, 2025, and has the title “The Centuries-Old, Incredibly Male Quest to Live Forever.”)

When Kloc mentions estimates of possible human lifespan “closer to 1,000” he links to a Scientific American interview with João Pedro de Magalhães, professor of biogerontology at England’s University of Birmingham. João Pedro de Magalhães believes that in principle humans could live to 1,000:

Gifford, Bill. “How Old Can Humans Get?” Scientific American (July 31, 2023). Available from https://www.scientificamerican.com/article/how-old-can-humans-get/.

When Kloc says that some “even try to reverse aging itself” he links to:

Poganik, Jesse R., Bohan Zhang, Gurpreet S. Baht, Alexander Tyshkovskiy, Amy Deik, Csaba Kerepesi, Sun Hee Yim, Ake T. Lu, Amin Haghani, Tong Gong, Anna M. Hedman, Ellika Andolf, Göran Pershagen, Catarina Almqvist, Clary B. Clish, Steve Horvath, James P. White, and Vadim N. Gladyshev. “Biological Age Is Increased by Stress and Restored Upon Recovery.” Cell Metabolism 35, no. 5 (2023): 807-20.

Kloc also links to estimates of the economic value of extending lifespans by one year, and by a decade, as given in:

Scott, Andrew J., Martin Ellison, and David A. Sinclair. “The Economic Value of Targeting Aging.” Nature Aging 1, no. 7 (July 2021): 616-23.

“Rage, rage against the dying of the light” is a line from Dylan Thomas’s poem “Do Not Go Gentle Into That Good Night.”

Ozempic 25 Years Sooner Would Have Saved and Improved Many Lives

Apparently Ozempic had been discovered in the late 1980s and could have been on the market roughly 25 years ago. Pfizer decided that the likely potential revenues were not sufficient to justify the huge costs. But what if the costs had not been so huge? For instance what if we adopted the proposal suggested by Milton Friedman, and advocated by me, to stop mandating hyper-expensive Phase 3 clinical trials to prove efficacy? (The mandates to prove safety through Phase 1 and Phase 2 trials would be retained.) With lower costs, Pfizer might have moved forward. Or if Pfizer had not, some other firm probably would have entered the breach sooner. If Ozempic had been available sooner, by now it would be much cheaper. Many lives would have been saved that have been lost. Other lives would have been healthier and happier.

(p. A26) They called 2023 the year of Ozempic, but it now seems GLP-1 drugs might define an entire decade — or an even longer era. The game-changing drugs, which mimic the hormone GLP-1, offer large benefits for not just diabetes management and especially weight loss but also, apparently, heart and kidney and liver disease, Alzheimer’s and dementia, Parkinson’s and addiction of all kinds. And perhaps because of widespread use of the drugs, the obesity epidemic in America may finally and mercifully be reversing.

But of all the things we learned this year about GLP-1s, the most astonishing could be that the revolution might have started decades earlier. Researchers identified the key breakthrough for GLP-1 drugs nearly 40 years ago, it turns out, long before most Americans had even heard the phrase “obesity epidemic.”

This summer, a former dean of Harvard Medical School, Jeffrey Flier, published a long personal reflection that doubled as an alternate history of what may well be the most spectacular and impactful medical breakthrough of the century so far. In 1987, Flier co-founded a biotech start-up that pursued GLP-1 as a potential treatment for diabetes, not long after it had first been identified by researchers who’d also found that the hormone enhanced insulin secretion in the presence of glucose.

The startup obtained worldwide rights to develop GLP-1 as a metabolic therapy from a group of those researchers, based at Massachusetts General Hospital. They even generated clinical results that suggested it might have promise as a weight-loss drug as well — only to have Pfizer, which had agreed to fund the research, withdraw its support, without providing the researchers with an especially satisfying explanation. Instead, Pfizer told Flier and his partners that the company didn’t believe there would be a market for another injectable diabetes treatment after insulin. Well, Flier tells me, “they were wrong.”

. . .

. . . Flier’s memoir is not just a lament for what might have been. In the aftermath of the pandemic emergency, as citizens and officials alike have embraced a more libertarian attitude toward public health, there’s been a similar drift in the public conversation about drug discovery and development. Operation Warp Speed is often held up as a new model — calls for an Operation Warp Speed 2.0 have been followed by those for an Operation Warp Speed for everything — . . .

Many of the same reformers will complain about all the red tape at the F.D.A. and C.D.C., tallying up huge mortality costs imposed by slow-moving government, arguing for human challenge trials in which individuals volunteer to take untested drugs and be deliberately infected and even talking about the invisible graveyard of unnecessary regulation and delay.

This is all fine and good — there are surely lots of things those agencies can speed up. And in recent years, reformers of various stripes have lobbied some worthy additional proposals into the biomedical zeitgeist — for a system based not on patents but on huge and direct cash prizes for medical breakthroughs, for instance, or one helped along by advance market commitments or benevolent patent extensions. Just last week the researchers Willy Chertman and Ruxandra Tesloianu published “The Case for Clinical Trial Abundance,” an invigorating manifesto for drug development reform.

. . . in focusing on government bureaucracy as the major biomedical bottleneck, we are seeing just one piece of the picture and overlooking what is perhaps the central challenge of research and development — that it is, at present, so complicated that difficulties or bad decisions at any stage can stifle the whole decades-long process, distorting the actual medical and public-health functions of drug development in countless ways.

For the full commentary see:

David Wallace-Wells. “We Could Have Had Ozempic Years Ago.” The New York Times, SundayOpinion Section (Sunday, Jan. 5, 2025): 11.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Dec. 25, 2024, and has the title “Pfizer Stopped Us From Getting Ozempic Decades Ago.”)

Dr. Flier’s published “memoir” mentioned above is:

Flier, Jeffrey S. “Drug Development Failure: How GLP-1 Development Was Abandoned in 1990.” Perspectives in Biology and Medicine 67, no. 3 (Summer 2024): 325-36.

“The Clinical Trial Manifesto” mentioned above is the introductory essay in the compilation referenced below. Another essay that looks promising in the compilation is “Unblocking Human Challenge Trials for Faster Progress.”

Chertman, Willy, and Ruxandra Tesloianu, eds. The Case for Clinical Trial Abundance: A Series of Short Papers Outlining Reform Possibilities for Our Nation’s Clinical Trials. Washington, DC: The Institute for Progress (IFP), 2024.