Regulations Discourage Search for Magic Bullet Cures

The so-called “Inflation Reduction Act” mandates that several of the biggest blockbuster drugs must have prices negotiated between Medicare and Pharma firms. As the commentary quoted below suggests, this creates an incentive for Pharma firms to develop many middling drugs rather than a couple of blockbuster drugs. Paul Ehrlich’s “magic bullet” may be impossible, but we will never know if no-one is trying to discover it.creates an

(p. B10) A true home run in the drug industry is when a company develops a mega-blockbuster that transforms its finances for years.

But with Medicare trying to bring costs down by targeting the industry’s most expensive drugs, a portfolio of medium-size moneymakers that can keep your name off the U.S. government’s naughty list can be a wise strategy.

That is at least one reason why big pharma is investing heavily in biotech companies developing antibody-drug conjugates. Known as ADCs, these treatments work like a guided missile by pairing antibodies with toxic agents to fight cancer. In short, they enable a more targeted form of chemotherapy that goes straight into the cancer cells while minimizing harm to healthy cells.

. . .

One reason most ADCs aren’t likely to become mega-blockbusters like Keytruda, a cancer immunotherapy that has earned 35 approvals across 16 types of cancer, is that they aren’t one-size-fits-all drugs. Instead, they are designed to target a specific protein that is expressed on the surface of a cancer cell. That means that each drug is made with an antibody targeting a subset of cancer. There are more than 100 ADCs being tested in humans by pharma and biotech companies.

For the full commentary see:

David Wainer. “Heard on the Street; Drug Industry’s Secret Weapon: ‘Guided Missiles’.” The Wall Street Journal (Friday, Oct. 27, 2023 [sic]): B10.

(Note: ellipsis added.)

(Note: the online version of the commentary has the date October 26, 2023 [sic], and has the title “Heard on the Street; ‘Guided Missile Drugs’ Could Be Big Pharma’s Secret Weapon.”)

Dr. Marty Makary Refuses to Stop Asking Questions

I am almost finished reading Marty Makary’s Blind Spots book that is discussed in the passages quoted below from a column by Pamela Paul. Makary writes with wit and clarity. But the thought-provoking examples are what make the book great. And the thought that the examples provoke is that medicine would progress more quickly to more cures if doctors had greater freedom in what they say, write, research, and prescribe.

Marty Makary has been named by President-Elect Trump to head the Food and Drug Administration (F.D.A.)

(p. A22) You probably know about the surge in childhood peanut allergies. Peanut allergies in American children more than tripled between 1997 and 2008, after doctors told pregnant and lactating women to avoid eating peanuts and parents to avoid feeding them to children under 3. This was based on guidance issued by the American Academy of Pediatrics in 2000.

You probably also know that this guidance, following similar guidance in Britain, turned out to be entirely wrong and, in fact, avoiding peanuts caused many of those allergies in the first place.

. . .

As early as 1998, Gideon Lack, a British pediatric allergist and immunologist, challenged the guidelines, saying they were “not evidence-based.” But for years, many doctors dismissed Dr. Lack’s findings, even calling his studies that introduced peanut butter early to babies unethical.

. . .

Finally, in 2017, following yet another definitive study by Lack, the A.A.P. fully reversed its early position, now telling parents to feed their children peanuts early.

But by then, thousands of parents who conscientiously did what medical authorities told them to do had effectively given their children peanut allergies.

This avoidable tragedy is one of several episodes of medical authorities sticking to erroneous positions despite countervailing evidence that Marty Makary, a surgeon and professor at Johns Hopkins School of Medicine, examines in his new book, “Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health.”

. . .

While these mistakes are appalling, more worrisome are the enduring root causes of those errors. Medical journals and conferences regularly reject presentations and articles that overturn conventional wisdom, even when that wisdom is based on flimsy underlying data. For political or practical reasons consensus is often prized over dissenting opinions.

“We’re seeing science used as political propaganda,” Makary told me when I spoke to him by phone. But, he argues, mistakes can’t be freely corrected or updated unless researchers are encouraged to pursue alternative research.

“Asking questions has become forbidden in some circles,” Makary writes. “But asking questions is not the problem, it’s the solution.”

For the full commentary see:

Pamela Paul. “Why Medicine Still Has Such Blind Spots.” The New York Times (Friday, September 20, 2024): A22.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Sept. 19, 2024, and has the title “The Medical Establishment Closes Ranks, and Patients Feel the Effects.” In the print version the word “caused” is emphasized by italics.)

The book praised in my opening comments and in Pamela Paul’s commentary is:

Makary, Marty. Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health. New York: Bloomsbury Publishing, 2024.

F.D.A. Regulation “Guaranteed Failure” of a Powerfully Effective Anti-Pain Drug That, Unlike Opioids, Is Nonaddictive

Christmas is a time of good will and hope. I should have worked harder to post an entry that exudes both. Instead I provide another example of how government regulation increases our pain.

(p. A19) Injectable Toradol IV/IM is a great drug. Many doctors, primarily in emergency rooms, use it daily. Yet most patients would rather swallow a pill than get a shot. Responding to this well-known preference, Syntex developed an oral version and submitted it to the FDA. The agency approved Toradol Oral in 1991 but gave it a label that essentially precluded its use—limiting the drug’s dosage to about a third of its effective amount, imposing a strict limit of five days of use, and mandating that the oral tablets follow an injection or intravenous dose of Toradol IV/IM.

The upshot? You could receive Toradol Oral from your pharmacist only after you had received it via an injection, say, from an emergency-room doctor. The requirement—along with the super low dose and limited duration—guaranteed failure.

. . .

Toradol IV/IM is well-established, relatively safe and works about as well as morphine to reduce pain. It’s also nonaddictive and abuse-proof because it doesn’t provide an opioid “high.” What we really need is an oral formulation with the proper dose for use at home, at work and while traveling. Such a drug could help alleviate the opioid crisis.

For the full commentary see:

Charles L. Hooper. “How the FDA Helped Fuel the Opioid Epidemic.” The Wall Street Journal (Wednesday, May 3, 2023 [sic]): A19.

(Note: ellipsis added.)

(Note: the online version of the commentary has the date May 2, 2023 [sic], and has the same title as the print version.)

Medicare Bureaucrats Let Pretty in Pink Boutique Defraud Taxpayers

Fraudsters are scamming the Medicare bureaucracy out of billions of taxpayer dollars. How boldly audacious the fraudsters are. They don’t even bother to give their fraudulent catheter supply firm a plausible name. Pretty in Pink Boutique? Are the fraudsters high, are they stupid, or do they take malicious pleasure in seeing how far they can go and still get away with it? And who is working for the Medicare bureaucracy? Are they simply bitter because they work for a bureaucracy that neither rewards competent hard work, nor punishes incompetent dereliction of duty? Does anyone in the government know the meaning of the phrase “due diligence”? Does anyone care? Congress creates the incentives and constraints and so is more responsible than the bureaucrats. The article quoted below gives one more example of why we flourish when free enterprise grows and government shrinks.

Yes I take this personally–my identity was stolen by fraudsters borrowing government Covid money in my name for an alleged potato farm. Of course the truth is more complicated than my rant implies. Bureaucrats can be conscientious and entrepreneurs can be corrupt. But I do believe that the incentives and constraints of government bureaucracy encourage corruption, or at least lethargic inertia. And the incentives and constraints of free enterprise encourage conscientious hard work and innovative dynamism.

(p. A1) Linda Hennis was checking her Medicare statement in January [2024] when she noticed something strange: It said a company she had never heard of had been paid about $12,000 for sending her 2,000 urinary catheters.

But she had never needed, or received, any catheters.

Ms. Hennis, a retired nurse who lives in a suburb of Chicago, noticed that the company selling the plastic tubes was called Pretty in Pink Boutique, and it was based in Texas. “There’s a mistake here,” Ms. Hennis recalled thinking.

She is among more than 450,000 Medicare beneficiaries whose accounts were billed for urinary catheters in 2023, up from about 50,000 in previous years, according to a new report produced by the National Association of Accountable Care Organizations, an advocacy group that represents hundreds of health care systems across the country. The report used a federal database of Medicare claims that is available to researchers.

The massive uptick in billing for catheters included $2 billion charged by seven high-volume suppliers, according to that analysis, potentially accounting for nearly one-fifth of all Medicare spending on medical supplies in 2023. Doctors, state insurance de-(p. A15)partments and health care groups around the country said the spike in claims for catheters that were never delivered suggested a far-reaching Medicare scam.

. . .

Catheters and other medical supplies are frequent targets of billing schemes. Last April [2023], the federal government brought criminal charges against 18 defendants who had submitted bills for nonexistent coronavirus tests and other pandemic-related services. And in 2019, the Department of Justice said it had broken up an international fraud ring involving more than $1 billion in phony billing for back and knee braces.

. . .

Patients and doctors who have been reporting mysterious catheter claims to Medicare for months say they are frustrated by a lack of communication from the government about whether billions of dollars have been lost to an ongoing billing scam.

One of the advocacy group’s members, Dr. Bob Rauner, runs a large network of doctors in Nebraska. In an interview, he said his patients had been collectively billed nearly $2 million in 2023 for phantom catheters. (He tracks such spending because his organization gets bonus payments from Medicare when patients have good health outcomes with low overall medical spending.)

. . .

The vast majority of the suspicious claims identified by the new analysis came from seven companies, many of which have shared executives, according to public documents and the advocacy group’s report. Only one of the businesses had a working phone number, and it did not return a request for comment. The other numbers were either disconnected, went to different businesses or, in one case, went to a previous owner.

Pretty in Pink Boutique is registered with Medicare to a street address of a house in El Paso. Its phone number goes to an auto body shop called West Texas Body and Paint, where an employee who answered a call from a reporter said the shop receives “calls all day, every day” from Medicare enrollees concerned about fraudulent bills.

Pamela Ludwig runs an unrelated business in Nashville that is also called Pretty in Pink Boutique. She has received so many catheter complaints that she added a page to her website explaining that her business was not part of any scam.

“I have people calling me, cussing, screaming,” Ms. Ludwig said. “They feel violated.”

For the full story see:

Sarah Kliff and Katie Thomas. “Billions in Claims for Catheters Suggest Medicare Billing Scam.” The New York Times (Saturday, February 10, 2024): A1 & A15.

(Note: ellipses, and bracketed years, added.)

(Note: the online version of the story has the date Feb. 9, 2024, and has the title “Staggering Rise in Catheter Bills Suggests Medicare Scam.”)

Dislodging Entrenched Special Interests Requires the Courage to Be the Target of Ill-Will

Many years ago, for reasons I forget, I listened to an interview posted online with Charlie Munger, who for decades was Warren Buffett’s sidekick at Berkshire Hathaway. One portion of Munger’s comments struck me as particularly insightful, so insightful, that I replayed that portion several times so I could write down a rough transcript of the comments. I am posting that rough transcript a few paragraphs below.

A lot of progress in healthcare, and in the world more broadly, depends on individual heroes who have the courage to be the target of ill-will in order to champion truth and virtue, against the powerful special interests that benefit from falsehood and corruption. Those who speak out are often cancelled and have their careers ruined. We remember a few of the names of those who eventually were vindicated. For example Ignaz Semmelweis was cancelled by the medical establishment for arguing that doctors should wash their hands before delivering babies. He eventually was vindicated and remembered, though long after he died of a beating in an insane asylum. Several much-more-recent examples can be found in Marty Makary’s thought-provoking Blind Spots. (Makary has been named by President-Elect Trump to head the Food and Drug Administration.)

Those like Semmelweis who suffered but were vindicated, are painful to ponder. How much more painful to ponder are those who fought the good fight but were never vindicated, and so are utterly forgotten? We justly honor the unknown soldier. We should find a way to also justly honor the unknown speaker of truth to power.

I cringe at Donald Trump’s occasional rudeness and bullying, but I hope that his courage to be the target of ill-will, allow him to succeed in unbinding the entrepreneurs who create breakthrough innovations.

Below is my transcript of a small portion of Charlie Munger’s comments at the University of Michigan in 2010. My memory is that Munger made his comments in answers to expansive questions from Becky Quick as part of a celebration to honor Munger’s donations to the University of Michigan. Munger’s story below is from health care, but the moral from the story applies much more broadly. (Munger’s interest in health care led him to chair the board of trustees of Good Samaritan Hospital in Los Angeles for over 30 years.)

And so there’s a lot of abuse in health care. And one of the ways you fix it is to, is for the people who have the power, they exercise it to prevent the abuse.

In a lot of places you have live and let live, in the hospitals it’s live and let live, because nobody wants to criticize anybody. That’s a huge mistake, a huge mistake.

In our leading academic hospitals (I’m sure this isn’t happening in Michigan); [1:41:03 of recording] but I have a friend whose daughter is head of infectious diseases and something at a medical school hospital, a great hospital.

And of course the doctors there are fishing the patients out of nursing homes, and bringing them in so they can walk by the beds, and bill them. And they are bringing in these terrible infections. And that takes a lot of treatment, and a lot of walks by the bed, and so on, and so on.

Of course the parents of this particular doctor recognize that she is sort of risking her life going through medical school because of the abuse of the system by some of the doctors in a hospital where nobody is stopping the abuse.

It’s like Burke said, for evil to triumph in the world, all that is necessary is that good men do nothing. And all over America some people are intervening to stop some of these abuses. And, and you have to identify them; you have to rationalize them; you have to be willing to take the ill-will.

I have a friend, this is another wonderful story on human nature, chief of the medical staff, southern California hospital.

A bunch of non-board-certified anesthesiologists, who came out of, I forget the sub-branch of medicine; but it’s not, it’s not chiropractic, but it’s . . . anyway they got in control of the anesthesia department of the hospital.

[1:42 of recording]

And he could see that they had created three totally unnecessary deaths and had covered up every single one. And he knew that this was just gonna to ruin his life. So he got rid of them all. Changed the whole system. He ruined families, he ruined incomes, he cleaned house. And he told me the story 20 years later, and I said what happened. And he said, to this day none of the people I cleaned out and none of their friends has ever spoken to me. He was willing to take all that ill will to do the Lord’s work, and do it right.

And you can say, why did he wait for the third death? Maybe he felt he needed that much horror to accomplish the fix.

But all over America, there are stories like that. That’s a GOOD story about human nature. That’s a story about wisdom and virtue triumphing; and of course they don’t always win.

Even in a bull fight, the bull sometimes wins.

[1:44 of recording– relevant segment over]

The interview with Munger is:

Quick, Rebecca (interviewer). “A Conversation with Charlie Munger.” University of Michigan Ross School of Business, Sept. 14, 2010.

(Note: at three places in the recording I roughly indicate in brackets the time into the posted recording, in case anyone wants to watch the video and check the accuracy of my rough transcript. Let me know if you find an error.)

The Marty Makary book that I praise in my initial comments is:

Makary, Marty. Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health. New York: Bloomsbury Publishing, 2024.

“More Than 60%” of Medicines Are Based on Chemicals First “Produced by Living Organisms”

Over millennia life (plants, microbes, fungi) developed toxins to protect them from predators. If humans can identify these toxins, they can use them to likewise protect themselves against diseases. Through serendipitous accident and random trial and error, over tens of thousands of years, indigenous peoples discovered and made use of some of these toxins. We should make use of this knowledge even though it is not certified by any randomized double-blind clinical trials performed by highly credentialed academics. Cassandra Quave, author of the essay quoted below, is working to do this, as is Berkeley professor Noah Whiteman, the author of Most Delicious Poison.

(p. C4) My team moved in unison to clip bits of plants, press them into sheets of paper and stuff them into large collection bags. Later, in my research lab at Emory University, we would test their chemical compounds against antibiotic-resistant pathogens. The possibility of developing new drugs from elements of nature such as our leaf clippings is important for everyone, but it’s personal for me; after losing my leg as a child, I nearly died as a result of postsurgical infection.

In recent decades, with the advance of high-tech methods for synthesizing molecules, the search for useful medical compounds from the natural world, especially plants, has faded. Fortunately, just as we’ve started to recognize the limits of artificial synthesis, even newer technology is now helping scientists like me to release more of nature’s medicinal secrets.

Plants have been the source of countless revolutionary medicines since the 19th century. Scientists derived aspirin from the willow tree, for instance, and morphine from opium poppies. They found quinine, the first treatment for malaria, in the bark of the Amazon’s fever tree (and more than a century later, scientists in China found that artemisinin from sweet wormwood was also a powerful anti-malarial agent). Many groundbreaking cancer drugs also came from plants—Taxol from the Pacific yew tree, vincristine from the Madagascar periwinkle.

Microbes found in soil and fungi launched a golden era of advances in antibiotics, starting with the discovery of penicillin in a mold in 1928. By the peak in the 1950s, scientists were isolating a wide range of antimicrobial compounds from microbes found in nature. But such work ended all too soon, as scientists stopped discovering effective new compounds.

Many of the drugs originally drawn from nature are now synthesized in pharmaceutical factories, using the blueprint of their chemical structures. Natural products (that is, chemicals genetically encoded and produced by living organisms) account for more than 60% of the pharmaceuticals that we possess.

Over the past 30 years, however, the focus on nature waned as scientists instead built large chemical libraries filled with tens of thousands of lab-made molecules. One hope was that the next antibiotic breakthrough would emerge from making and testing enough of these synthetic compounds. But that effort has fallen flat: Though other medicines have been developed in the lab, no new registered classes of antibiotics have been discovered since the 1980s.

For the full essay see:

Cassandra Quave. “Hunting for Medicines Hidden in Plants.” The Wall Street Journal (Saturday, November 20, 2021 [sic]): C4.

(Note: the online version of the essay has the same date and title as the print version.)

Quave’s essay is adapted from her book:

Quave, Cassandra Leah. The Plant Hunter: A Scientist’s Quest for Nature’s Next Medicines. New York: Viking, 2021.

The Noah Whiteman book I praise in my introductory comments is:

Whiteman, Noah. Most Delicious Poison: The Story of Nature’s Toxins―from Spices to Vices. New York: Little, Brown Spark, 2023.

Patients Who Benefit From a Drug in a Clinical Trial, Should Not Be Banned by the F.D.A. From Continuing the Drug After the Trial Ends

Especially for a fatal disease for which there is no known cure, like A.L.S., patients in a clinical trial who benefit from an experimental drug should not be banned by the F.D.A. from continuing to take the drug after the trial ends. Such a ban violates the liberty of free citizens. Such regulators appear arrogant and unsympathetic. If the regulator, or someone the regulator loves, had A.L.S., would the regulator discover a sense of urgency?

(p. A17) It’s hard to process what the doctor is saying: You have a disease that will rapidly paralyze you until it eventually suffocates you to death. But you are one of the lucky ones: You qualify for a clinical trial of a promising experimental drug. There is a 30% to 50% chance of receiving a placebo instead of the experimental therapy.  . . .  Still, you are grateful to qualify for the trial; most patients don’t.

Fortunately, the trial has a design that is friendly to patients, and so six months later, after the randomized portion is complete, all patients may receive the real drug as part of what’s called an “open label extension.” Without this, you may only get the placebo. And the access to the real drug may end once the trial is complete, even if it was helping you.

My husband, Mike Cimbura, was one of the 36 participants who received the drug NurOwn in a Phase 2 clinical trial for amyotrophic lateral sclerosis. Mike regained some function, but he was able to get only one dose before the trial ended. Mike and I fought for continued access to treatment and to improve an archaic regulatory pathway. He died waiting for change in 2019.

. . .

. . . patients need a more flexible regulatory process moving with urgency to help find treatments and cures for this deadly disease.

For the full commentary see:

Nicole Cimbura. “A Slow FDA Is Denying ALS Patients Their Only Hope.” The Wall Street Journal (Tuesday, April 27, 2021 [sic]): A17.

(Note: ellipses added.)

(Note: the online version of the commentary has the date April 26, 2021 [sic], and has the same title as the print version.)

“Epiphany” on a New Approach to Cure “Half of All Cancers”

Many health experts view immunotherapy as the most promising broad approach for curing cancers. Within the broad immunotherapy approach there are many sub-approaches–distinct approaches on how to activate the immune system against cancer. The article quoted below discusses a new sub-approach.

(p. D4) Within every cancer are molecules that spur deadly, uncontrollable growth. What if scientists could hook those molecules to others that make cells self-destruct? Could the very drivers of a cancer’s survival instead activate the program for its destruction?

That idea came as an epiphany to Dr. Gerald Crabtree, a developmental biologist at Stanford, some years ago during a walk through the redwoods near his home in the Santa Cruz mountains.

“I ran home,” he said, excited by the idea and planning ways to make it work.

Now, in a paper published Wednesday [July 26, 2023] in the journal Nature, Dr. Crabtree, a founder of Shenandoah Therapeutics, which is developing cancer drugs, along with Nathanael S. Gray, a professor of chemical and systems biology at Stanford, and their colleagues report that they have done what he imagined on that walk. While the concept is a long way from a drug that could be given to cancer patients, it could be a target for drug developers in the future.

. . .

In laboratory experiments with cells from a blood cancer, diffuse large B-cell lymphoma, the researchers designed and built molecules that hooked together two proteins: BCL6, a mutated protein that the cancer relies on to aggressively grow and survive, and a normal cell protein that switches on any genes it gets near.

. . .

BCL6, at one end of the dumbbell, guides the molecule toward cell-death genes that are part of every cell’s DNA and are used to get rid of cells that are no longer needed.

. . .

When the dumbbell, guided by BCL6, gets near the cell-death genes, the normal protein on the end of the dumbbell arms those death genes. Unlike other processes in the cell that can be reversed, turning on cell-death genes is irreversible.

. . .

The concept could potentially work for half of all cancers, which have known mutations that result in proteins that drive growth, Dr. Crabtree said. And because the treatment relies on the mutated proteins produced by the cancer cells, it could be extremely specific, sparing healthy cells.

For the full story see:

Gina Kolata. “A Key to Making Cancers Self-Destruct.” The New York Times (Tuesday, August 8, 2023 [sic]): D4.

(Note: ellipses, and bracketed date, added.)

(Note: the online version of the story was updated July 31, 2023 [sic], and has the title “Flipping a Switch and Making Cancers Self-Destruct.” Where the wording of the versions differs, the passages quoted above follow the online version.)

The academic article co-authored by Crabtree in Nature (published in July with an “issue date” of Aug. 10) and mentioned above is:

Gourisankar, Sai, Andrey Krokhotin, Wenzhi Ji, Xiaofan Liu, Chiung-Ying Chang, Samuel H. Kim, Zhengnian Li, Wendy Wenderski, Juste M. Simanauskaite, Haopeng Yang, Hannes Vogel, Tinghu Zhang, Michael R. Green, Nathanael S. Gray, and Gerald R. Crabtree. “Rewiring Cancer Drivers to Activate Apoptosis.” Nature 620, no. 7973 (Aug. 10, 2023): 417-25.

Effective Therapies Will Remain Banned When F.D.A. Mandates Costly Evidence of Long-Term Clinical Benefits, Rather than Frugal Evidence of Short-Term Biomarkers

How many therapies that would have cured diseases, or extended lives, or limited side effects or pain, are not available because their champions cannot afford the often astronomical costs of Phase 1, Phase 2, and Phase 3 clinical trials? Nobel-Prize-winning economist Milton Friedman favored eliminating the F.D.A., but as a more politically palatable step-in-the-right-direction, favored limiting F.D.A. mandates to approving safety through Phase 1 and Phase 2 clinical trials (and no longer mandating proving efficacy through Phase 3 clinical trials, which usually cost much more than Phase 1 and Phase 2 clinical trials, combined). Perhaps an even more politically palatable, but tinier, step-in-the-right-direction is proposed in the commentary quoted below. This modest step would allow in Phase 3 clinical trials the use of less costly biomarker “surrogate end-points” in place of far more costly clinical end-points, such as years of added life. In the case discussed in the article quoted below, the surrogate end-point was the percent of arginine in the patient’s blood.

(p. A17) Discovering treatments for rare diseases is a daunting task. Recruiting even a few dozen people for a clinical trial requires doctors and drug companies to identify a large share of the patient population. And since the market for such therapies is necessarily small, it’s nearly impossible to attract investment. So when news emerged about Aeglea BioTherapeutics’ ARG1-D therapy pegzilarginase, we could hardly believe it. Pegzilarginase is an enzyme engineered to lower the body’s levels of arginine. The randomized placebo-controlled study of pegzilarginase included 32 patients with ARG1-D.

The results speak for themselves. The amount of arginine present in blood plasma declined by 80% for patients on pegzilarginase. After only six months, 90.5% of patients who received pegzilarginase had normal arginine levels, and this was sustained over time. The data also suggested progressive improvements in motor function compared with a placebo. And most patients tolerated the therapy quite well.

These numbers were jaw-dropping. Which is why the FDA’s decision is incomprehensible.

The FDA even refused to look at Aeglea’s data. Instead, the agency demanded that the firm compile additional data suggesting pegzilarginase will produce a clinical benefit in addition to eliminating excess arginine. But for ARG1-D and other rare diseases, measuring clinical outcomes can take years, while measuring biomarkers likely to produce clinical benefits can take weeks.

. . .

Evaluating clinical benefits could force sick patients to remain in placebo groups for months. That the FDA would put its rigid rules before the convincing data we already have is unethical. If the FDA doesn’t correct its error soon, patients with ARG1-D will lose their best chance at full, productive lives.

For the full commentary see:

Stephen Cederbaum and Emil Kakkis. “The FDA’s See-No-Data Approach.” The Wall Street Journal (Wednesday, Sept. 27, 2023 [sic]): A17.

(Note: ellipsis added.)

(Note: the online version of the commentary has the date September 26, 2023 [sic], and has the same title as the print version.)

Those Open to the Unexpected Can Benefit from Serendipity

Serendipitous discoveries often involve seeing something unexpected and imagining a use for it. I am currently reading Mary Makary’s Blind Spots. To explain the inertia of the medical establishment, he points out that seeing our expectations contradicted is painful for us; it causes what Leon Festinger called “cognitive dissonance.” Cognitive dissonance causes stress. Most of us minimize the stress by denying or papering over the experiences that contradict expectations. It takes effort, often painful effort, to keep the contradiction in mind. One of my heroes is Oswald Avery, who discovered that the genetic material is DNA. Before he focused on DNA, he worked hard to understand the behavior of the Pneumococcus bacteria that cause pneumonia. Then Fred Griffith showed that only encapsulated Pneumococcus bacteria could cause pneumonia since unencapsulated Pneumococcus can be eliminated by the immune system, and showed further that unencapsulated Pneumococcus could acquire capsules, and become infectious. This transformation of the Pneumococcus contradicted Avery’s expectations, likely causing the him the stress, and the Graves disease, that paralyzed his research for six months (Barry 2005, pp. 421-422). But Avery did not suppress the contradiction. Eventually he pivoted (or if it takes six months I should say ‘eventually he painfully changed direction’) to the research that led to DNA as the genetic material.

(p. A15) Horace Walpole, who coined the term “serendipity” in a 1754 letter, believed that “the best discoveries are made while one is searching for something else,” according to Mr. Pievani. But blind luck, although often important, is not sufficient in itself, as emphasized by Louis Pasteur when he observed that “chance favors the prepared mind.”

“Serendipity” provides a catalog of serendipitous discoveries.  . . .

Mr. Pievani offers a useful and informative survey but sometimes layers his material so elaborately as to be off-putting. Early on, for example, we learn that “in 1762, Venetian playwright Carlo Gozzi, the anti-Goldoni who in the same year published the Turandot, which would inspire Giacomo Puccini, brought to the theater a fairy tale, The Deer King, which in the midst of the rococo revived the novella by Khusrau and Armeno, in particular the theme of the transmigration of souls from human to animal.” Huh? Aside from showcasing Mr. Pievani’s extensive learning, such digressions mostly demonstrate his need for a ruthless editor.

“Serendipity,” translated from the Italian by Michael Gerard Kenyon, is most intriguing when it focuses on people with prepared minds who didn’t merely find something they weren’t looking for but were in fact searching for something else when they had a breakthrough.

. . .

In 1928 Fleming, a microbiologist, had been growing Staphylococcus aureus in petri dishes. One day, upon returning from vacation, he noticed that one of the cultures had been accidentally contaminated with a Penicillium mold, which had mysteriously killed the surrounding bacteria. As a military doctor in World War I, Fleming had seen many soldiers die of bacterial infections, and he surmised that maybe this mold would help cure comparable illness.

. . .

. . ., without a prepared mind à la Pasteur, many key discoveries would have been missed. Mr. Pievani makes clear that “if you do not have predictions and expectations in mind, you will never be able to see that an accidental observation is incongruent and therefore potentially a harbinger of serendipity.” The author seeks to encourage what he calls an “ecology of serendipity” that facilitates scientific discovery. He has some suggestions, notably that one should be a “xenophile: love all things strange, all things different, foreign and new, the exceptions, the deviations.”

For the full review see:

Barash, David P. “BOOKSHELF; Progress By Accident.” The Wall Street Journal (Tuesday, Dec. 17, 2024): A15.

(Note: ellipses added.)

(Note: the online version of the review has the date December 16, 2024, and has the title “BOOKSHELF; ‘Serendipity’: Progress by Accident.” In both versions of the article, the names of works of literature and species of bacteria or mold, are italicized.)

The book under review is:

Pievani, Telmo. Serendipity: The Unexpected in Science. Translated by Michael Gerard Kenyon. Cambridge, Mass.: The MIT Press, 2024.

The book by Barry that I reference in my initial comments is:

Barry, John M. The Great Influenza: The Story of the Deadliest Pandemic in History. Revised ed. New York: Penguin Books, 2005.

Medicare Rewards Health Insurers for Overestimating Future Prescription-Drug Costs

I believe that the perverse incentives that Medicare creates for insurers, as described in the 2019 article quoted below, still exist. But I need to confirm my belief.

(p. A1) Each June, health insurers send the government detailed cost forecasts for providing prescription-drug benefits to more than 40 million people on Medicare.

No one expects the estimates to be spot on. After all, it is a tall order to predict the exact drug spending for the following year of the thousands of members in each plan.

However, year after year, most of those estimates have turned out to be wrong in the particular way that, thanks to Medicare’s arcane payment rules, results in more revenue for the health insurers, a Wall Street Journal investigation has found. As a consequence, the insurers kept $9.1 billion more in taxpayer funds than they would have had their estimates been accurate from 2006 to 2015, according to Medicare data obtained by the Journal.

Those payments have largely been hidden from view since Medicare’s prescription-drug program was launched more than a decade ago, and are an example of how the secrecy of the $3.5 trillion U.S. health-care system promotes and obscures higher spending.

Medicare’s prescription-drug benefit, called Part D, was designed to help hold down drug costs by having insurers manage the coverage efficiently. Instead, Part D spending has accelerated (p. A12) faster than all other components of Medicare in recent years, rising 49% from $62.9 billion in 2010 to $93.8 billion in 2017. Medicare experts say the program’s design is contributing to that increase. Total spending for Part D from 2006 to 2015 was about $652 billion.

The cornerstone of Part D is a system in which private insurers such as CVS Health Corp., UnitedHealth Group Inc. and Humana Inc. submit “bids” estimating how much it will cost them to provide the benefit. The bids include their own profits and administrative costs for each plan. Then Medicare uses the estimates to make monthly payments to the plans.

After the year ends, Medicare compares the plans’ bids to the actual spending. If the insurer overestimated its costs, it pockets a chunk of the extra money it received from Medicare—sometimes all of it—and this can often translate into more profit for the insurer, in addition to the profit built into the approved bid. If the extra money is greater than 5% of the insurer’s original bid, it has to pay some of it back to Medicare.

For instance, in 2015, insurers overestimated costs by about $2.2 billion, and kept about $1.06 billion of it after paying back $1.1 billion to the government, according to the data reviewed by the Journal.

. . .

If those big insurers were aiming to submit accurate bids, the probability that they would have overestimated costs so frequently and by such a large amount is less than one in one million, according to a statistical analysis done for the Journal by researchers at Memorial Sloan Kettering Cancer Center, who study pharmaceutical pricing and reimbursement.

Insurance companies use heaps of data to predict future spending. If truly unpredictable events were blowing up their statistical models, the proportion of overestimates to underestimates would be closer to 50/50, says Peter Bach, director of Sloan Kettering’s Center for Health Policy and Outcomes, which conducted the statistical analysis.

“Even expert dart throwers don’t hit the bull’s-eye every time. But their misses are spread around in every direction,” says Dr. Bach. “If they start missing in one particular direction over and over they are doing it on purpose.”

For the full story see:

Joseph Walker and Christopher Weaver. “Medicare Overpaid Insurers Billions.” The Wall Street Journal (Saturday, Jan. 5, 2019 [sic]): A1 & A12.

(Note: ellipsis added.)

(Note: the online version of the story has the date Jan. 4, 2019 [sic], and has the title “The $9 Billion Upcharge: How Insurers Kept Extra Cash from Medicare.”)