Art Diamond – Page 2 – artdiamondblog.com

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.”)

With Age, Many Cells Contain Cancerous Mutations That Never Develop Into Cancer

Encouraging non-cancerous mutations that compete for resources with cancerous mutations is a novel approach for curing some cancers, but there are many other novel and plausible approaches. Cancer is a complicated and diverse disease; maybe we will eventually see “cancer” as many different diseases. We have too much uncertainty to mandate one centrally planned approach. Plus citizens have the right to keep the money they earn and to choose how to spend that money. We should keep taxation and regulations low so that diverse funders can follow their judgements to fund diverse approaches. [Most of what I just wrote, I also wrote for an earlier entry.]

(p. D3) Cancer is a disease of mutations. Tumor cells are riddled with genetic mutations not found in healthy cells. Scientists estimate that it takes five to 10 key mutations for a healthy cell to become cancerous.

Some of these mutations can be caused by assaults from the environment, such as ultraviolet rays and cigarette smoke. Others arise from harmful molecules produced by the cells themselves. In recent years, researchers have begun taking a closer look at these mutations, to try to understand how they arise in healthy cells, and what causes these cells to later erupt into full-blown cancer.

The research has produced some major surprises. For instance, it turns out that a large portion of the cells in healthy people carry far more mutations than expected, including some mutations thought to be the prime drivers of cancer. These mutations make a cell grow faster than others, raising the question of why full-blown cancer isn’t far more common.

“This is quite a fundamental piece of biology that we were unaware of,” said Inigo Martincorena, a geneticist at the Wellcome Sanger Institute in Cambridge, England.

. . .

Dr. Martincorena and his colleagues reported their findings on Thursday [Oct. 18, 2018] in the journal Science.

By examining the mutations, the researchers were able to rule out external causes for them, like tobacco smoke or alcohol. Instead, the mutations seem to have arisen through ordinary aging. As the cells divided over and over again, their DNA sometimes was damaged. In other words, the rise of these mutations may just be an intrinsic part of getting older.

. . .

The study . . . raised questions about efforts to detect cancer at its earliest stages, when cancer cells are still rare, Dr. Kennedy said: “Just because someone has mutations associated with cancer doesn’t mean actually they have a malignancy.”

Given the abundance of cancer mutations in healthy people, why isn’t cancer more common? Dr. Martincorena speculated that a healthy body may be like an ecosystem: Perhaps clones with different mutations arise in it, compete for available space and resources, and keep each other in check.

If so, fighting cancer might one day be a matter of helping harmless clones outcompete the ones that can lead to deadly tumors.

For the full commentary see:

Zimmer, Carl. “Matter; Delving Into a Cancer Paradox.” The New York Times (Tuesday, October 23, 2018 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Oct. 18, 2018 [sic], and has the title “Matter; Researchers Explore a Cancer Paradox.”)

The academic article in Science co-authored by Martincorena and mentioned above is:

Martincorena, Iñigo, Joanna C. Fowler, Agnieszka Wabik, Andrew R. J. Lawson, Federico Abascal, Michael W. J. Hall, Alex Cagan, Kasumi Murai, Krishnaa Mahbubani, Michael R. Stratton, Rebecca C. Fitzgerald, Penny A. Handford, Peter J. Campbell, Kourosh Saeb-Parsy, and Philip H. Jones. “Somatic Mutant Clones Colonize the Human Esophagus with Age.” Science 362, no. 6417 (Oct. 18, 2018): 911-17.

Medical Researchers Have Incentive to Exclude Older Patients from Clinical Trials

As human beings, medical researchers would like to offer experimental therapies to whoever needs them and is willing to take the risks and uncertainty of new frontiers. But as practical medical researchers medical researchers know their careers depend on the success of their clinical trials, and the success of their clinical trials depends on the number of patients who thrive on the new therapy. So their personal incentive is to cherry-pick clinical trial enrollees, picking only the most robust who are most likely to thrive. The solution? Allow medical researchers to be both human beings and medical researchers. Allow them to give the therapy to those at high risk, based on their cumulative experience and judgement. Not all sound actionable knowledge arises from randomized double-blind clinical trials.

(p. A5) Many cancer trials cap enrollment at age 65. Even when trials for older people are available, oncologists are reluctant to enroll elderly patients because frailties might make them less resilient against side effects from toxic treatments, according to a 2020 study in an American Cancer Society journal. People over 70 represent a growing share of the cancer-patient population but are vastly underrepresented in clinical trials, the study said.

“How can we make decisions for people over 70 if people over 70 are not included in the trials that we use to base our decision making?” said Dr. Mina Sedrak, deputy director of the Center for Cancer and Aging at City of Hope, a cancer center near Los Angeles and an author of the paper.

. . .

The Food and Drug Administration guidelines recommend “adequate representation” of the elderly in cancer trials, including people over age 75. The Journal of the National Cancer Institute in December 2022 published a series of papers presented at a workshop focused on how to improve trial enrollment of older people.

Researchers have developed geriatric assessment tools that try to predict patients’ survival chances based on more than age alone. Professional groups are also working to try to address gaps. Despite these efforts, enrollment of older patients still lags behind, cancer doctors said.

. . .

To participate in many trials involving transplants, patients would have to undergo the more intense chemotherapy whether randomly assigned to receive an experimental treatment or the standard of care. That makes it harder to incorporate older patients into randomized trials, cancer doctors said.

For the full story see:

Amy Dockser Marcus. “Cancer Patient Contests Age Limit for Clinical Trials.” The Wall Street Journal (Monday, Jan. 9, 2023 [sic]): A5.

(Note: ellipses added.)

(Note: the online version of the story has the date Jan. 8, 2023 [sic], and has the title “71-Year-Old Cancer Patient Broke Trial Age Limits for a Chance at a Cure.”)

A preface to the “series of papers” about how to improve trial enrollment of older people,” mentioned above, is:

St. Germain, Diane, and Supriya G Mohile. “Preface: Engaging Older Adults in Cancer Clinical Trials Conducted in the National Cancer Institute Clinical Trials Network: Opportunities to Enhance Accrual.” JNCI Monographs 2022, no. 60 (Dec. 2022): 107-10.

When a Therapy Fails in a Clinical Trial, Is That the Fault of the Therapy or of the Trial?

When a proposed therapy fails in a clinical trial is that because the therapy can’t work, or is it because the trial itself was flawed? It is far from written in stone how a clinical trial should be set up. Should the therapy be given by pill or intravenously? In what doses? How often, for how long? At what stage of the disease? Because Stage 3 clinical trials are so expensive and difficult to implement, some therapies may have only one shot to succeed. How many therapies that could have helped some people, will never do so, because the researchers had bad luck, or less skill, in implementing the trial? This problem could be reduced the regulatory mandate to requiring only the Stage 1 and Stage 2 clinical trials, that mainly establish safety (as opposed to the much-more-expensive Stage 3 that mainly establishes efficacy). That way researchers who lacked the deep pockets of the researchers discussed in the article quoted below, could still more often afford multiple shots at designing a trial that would succeed at identifying what therapy, applied to which patients, in what modalities, might cure them, or at least lengthen their lives, or reduce their symptoms. Some of the greatest advances in medicine occurred in an environment of quick trial and error, as when medicine has to be precticed on the battlefield of war, or when Emil Freireich improvised new ingredients for his chemo cocktail to cure some children of childhood leukemia or when Freireich’s protégé Vincent DaVita did the same to cure some adults of Hodgkin’s lymphoma. Ideally I would eliminate all mandates, both to enhance liberty, and to speed trial-and-error therapies. But here I suggest eliminating only Stage 3 clinical trials, not because I think that is ideal, but (following Milton Freidman) because I suspect that policy reform may be the best that is politically feasible. We would maximize trial and error adjustments by eliminating all mandated clinical trials. In the vast majority of decisions in life we make judgements without the benefit of a clinical trial. And such judgements usually are effective and improve with experience. [Gary Klein persuasively makes this point through a multitude of examples, in his tour de force Sources of Power.] What is done in life generally, can also be done in medicine in particular, bringing us more cures, faster.

(p. D4) “There is no reason why cancer vaccines would not work if given at the earliest stage,” said Sachet A. Shukla, who directs a cancer vaccine program at MD Anderson Cancer Center. “Cancer vaccines,” he added, “are an idea whose time has come.” (Dr. Shukla owns stock in companies developing cancer vaccines.)

That view is a far cry from where the field was a decade ago, when researchers had all but given up. Studies that would have seemed like a pipe dream are now underway.

“People would have said this is insane,” said Dr. Susan Domchek, the principal investigator of a breast cancer vaccine study at the University of Pennsylvania.

. . .

“We had this trial, 63 patients, Stage 4 cancer. They had failed all therapies,” Dr. Finn said.

. . .

In their initial studies, it became clear to Dr. Finn and her colleagues that the cancers were too far advanced for immunizations to work. After all, she notes, with the exception of rabies, no one vaccinates against an infectious disease in people who are already infected.

“I said, ‘I don’t want to do that again,’” Dr. Finn said. “It is not the vaccines. We have to look at different patients.”

Now, she and her colleague at Pittsburgh, Dr. Robert Schoen, a gastroenterologist, are trying to prevent precancerous colon polyps with a vaccine. But intercepting cancer can be tricky.

They focused on people whose colonoscopies had detected advanced polyps — lumps that can grow in the colon, but only a minority of which turn into cancer. The goal, Dr. Schoen said, was for the vaccine to stimulate the immune system to prevent new polyps.

It worked in mice.

“I said, ‘OK, this is great,’” Dr. Schoen recalled.

But a recently completed study of 102 people at six medical centers randomly assigned to receive the preventive vaccine or a placebo had a different result. All had advanced colon polyps, giving them three times the risk of developing cancer in the next 15 years compared to people with no polyps.

Only a quarter of those who got the vaccine developed an immune response, and there was no significant reduction in the rate of polyp recurrences in the vaccinated group.

“We need to work on getting a better vaccine,” Dr. Schoen said.

. . .

Dr. Domchek said she can envision a future in which people will have blood tests to find cancer cells so early that they do not show up in scans or standard tests.

“To paint a grand future,” she said, “if we knew the tests predicted cancer we could say, ‘Here’s your vaccine.’”

For the full story see:

Gina Kolata. “New Hopes for a Cancer Vaccine.” The New York Times (Tuesday, Oct. 11, 2022 [sic]): D4.

(Note: ellipses added.)

(Note: the online version of the story has the date Oct. 10, 2022 [sic], and has the title “After Giving Up on Cancer Vaccines, Doctors Start to Find Hope.” Where the wording of the versions differs, the passages quoted above follow the online version.)

Gary Klein’s main book that I praise in my initial comments is:

Klein, Gary A. Sources of Power: How People Make Decisions. 20th Anniversary ed. Cambridge, MA: The MIT Press, 2017.

New Evidence American Indians Were Eating a Lot of Mammoth Meat During the Time When Mammoths Became Extinct

Scientists once thought that the extinction of megafauna like mammoths was due mainly to climate change. But the extinction in America coincided with the arrival of humans, leading some to argue that early indigenous American Indians killed off the mammoths. This goes against the politically correct stereotype that American Indians were mostly peace-loving environmentalists.

A recently published article provides additional evidence. Using a skull from the Clovis period, roughly during the period when mammoths became extinct, the authors were able to conclude from the young child’s “isotopic signature” that two-thirds of the child’s diet came from his mother’s breast-milk, and one third mainly from the meat of large mammals like mammoths. They could also infer that the mother had a diet high in mammoth meat. Summarizing the academic article in The New York Times, columnist Carl Zimmer says: “a study analyzing the ancient bones of a young child who lived in Montana suggests that early Americans hunted mammoths and other giant mammals to oblivion” (p. D3).

I am not criticizing the early American Indians. If I had been alive back then and I could obtain nutrition for me and my family by slaughtering a few mammoths, I would have tried to do so. But we are making a mistake if we reject American exceptionalism in part on the basis of a false and sanctimonious claim that the indigenous American Indians acted on morally superior environmental values.

My musings above are based partly on the commentary:

Carl Zimmer. “Mammoth: It’s What Was for Dinner.” The New York Times (Tuesday, December 10, 2024): D3.

(Note: the online version of the story has the date December 4, 2024, and has the title “Mammoth: It’s What Was Once for Dinner.”)

The academic article that is the basis for Zimmer’s commentary is:

Chatters, James C., Ben A. Potter, Stuart J. Fiedel, Juliet E. Morrow, Christopher N. Jass, and Matthew J. Wooller. “Mammoth Featured Heavily in Western Clovis Diet.” Science Advances 10, no. 49 (2024): eadr3814.

Will Cancer Die from a Magic Rifle Bullet or From Magic Shotgun Pellets?

We dream of a magic bullet that can cure all cancer. But will all “cancer” continue to be seen as one unified disease, with potentially one common cure? Or will we see many diseases, many causes, and many cures? [The idea of a “magic bullet” against a disease was born from the great Paul Ehrlich who found one of the first effective antibiotics (not to be confused with the the more recent environmentalist Paul Ehrlich who is famous for losing his bet with the great Julian Simon).]

(p. D3) A new study, published [online on] Wednesday [Oct. 2, 2019] in the journal Nature, found that fungi can make their way deep into the pancreas, which sits behind your stomach and secretes digestive enzymes into your small intestine.

. . .

One particular fungus was the most abundant in the pancreas: a genus of Basidiomycota called Malassezia, which is typically found on the skin and scalp of animals and humans, and can cause skin irritation and dandruff. . . .

The results show that Malassezia was not only abundant in mice that got pancreatic tumors, it was also present in extremely high numbers in samples from pancreatic cancer patients, said Dr. Berk Aykut, a postdoctoral researcher in Dr. Miller’s lab.

. . .

Administering an antifungal drug got rid of the fungi in mice and kept tumors from developing. And when the treated mice again received the yeast, their tumors started growing once more — an indication, Dr. Aykut said, that the fungal cells were driving the tumors’ growth.

. . .

The new study also sheds light on how fungi in the pancreas may drive the growth of tumors. The fungi activate an immune system protein called mannose-binding lectin, which then triggers a cascade of signals known to cause inflammation. When the researchers compromised the ability of the lectin protein to do its job, the cancer stopped progressing and the mice survived for longer.

For the full story see:

Knvul Sheikh. “Fungi May Have a Role In Pancreatic Cancer.” The New York Times (Tuesday, October 8, 2019 [sic]): D3.

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

(Note: the online version of the story has the date Oct. 3, 2019 [sic], and has the title “In the Pancreas, Common Fungi May Drive Cancer.” Where the wording of the versions differs, the passages quoted above follow the more detailed online version.)

The study in Nature mentioned above is:

Aykut, Berk, Smruti Pushalkar, Ruonan Chen, Qianhao Li, Raquel Abengozar, Jacqueline I. Kim, Sorin A. Shadaloey, Dongling Wu, Pamela Preiss, Narendra Verma, Yuqi Guo, Anjana Saxena, Mridula Vardhan, Brian Diskin, Wei Wang, Joshua Leinwand, Emma Kurz, Juan A. Kochen Rossi, Mautin Hundeyin, Constantinos Zambrinis, Xin Li, Deepak Saxena, and George Miller. “The Fungal Mycobiome Promotes Pancreatic Oncogenesis Via Activation of MBL.” Nature 574, no. 7777 (Oct. 10, 2019): 264-67.

Medical Mergers Can Reduce Competition and Raise Prices When Government Aids Incumbents or Fetters Entrepreneurs

The story quoted below gives useful evidence that in the recent past hospital mergers have generally resulted in higher prices. But the story is incomplete, creating the misleading impression that government antitrust action is clearly needed. My hypothesis: mergers can increase efficiency and lower patient prices, but only tend to do so when hospitals are constrained by the real or potential entry of entrepreneurial health providers. Unfortunately entry is currently very limited, often by government actions. Often new hospitals must acquire a certificate of need before they are allowed to exist.

Often, incumbent hospitals successfully object to those certificates. Federal subsidies differentially go to large incumbent hospitals. Federal Covid-relief funds went to large incumbent hospitals that used much of the funds to buy up other hospitals. Less directly, enormous government regulation creates a differential burden on the small new entrant that likely cannot afford the huge specialized staff to successfully navigate the voluminous opaque regulations.

If we want lower prices, government should allow mergers, but also stop creating constraints that discourage entry. Government should especially reduce the regulations that discourage medical entrepreneurship.

(p. D4) The nation’s hospitals have been merging at a rapid pace for a decade, forming powerful organizations that influence nearly every health care decision consumers make.

The hospitals have argued that consolidation benefits consumers with cheaper prices from coordinated services and other savings.

But an analysis conducted for The New York Times shows the opposite to be true in many cases. The mergers have essentially banished competition and raised prices for hospital admissions in most cases, according to an examination of 25 metropolitan areas with the highest rate of consolidation from 2010 through 2013, a peak period for mergers.

The analysis showed that the price of an average hospital stay soared, with prices in most areas going up between 11 percent and 54 percent in the years afterward, according to researchers from the Nicholas C. Petris Center at the University of California, Berkeley.

The new research confirms growing skepticism among consumer health groups and lawmakers about the enormous clout of the hospital groups. While most political attention has focused on increased drug prices and the Affordable Care Act, state and federal officials are beginning to look more closely at how hospital mergers are affecting spiraling health care costs.

During the Obama years, the mergers received nearly universal approval from antitrust agencies, with the Federal Trade Commission moving to block only a small fraction of deals. State officials generally looked the other way.

President Trump issued an executive order last year calling for more competition, saying his administration would focus on “limiting excessive consolidation (p. B1) throughout the health care system.” In September [2018], Congress asked the Medicare advisory board to study the trend.

. . .

Prices rise even more steeply when these large hospital systems buy doctors’ groups, according to Richard Scheffler, director of the Petris Center.

“It’s much more powerful when they already have a very large market share,” said Mr. Scheffler, who recently published a study on the issue in Health Affairs. “The impact is just enormous.”

For the full story see:

Reed Abelson. “When Hospitals Merge, Patients Often Pay More.” The New York Times (Wednesday, November 14, 2018 [sic]): B1 & B6.

(Note: ellipses added.)

(Note: the online version of the story has the same date as the print version, and has the title “When Hospitals Merge to Save Money, Patients Often Pay More.” Where the wording of the versions differs, the passages quoted above follow the online version.)

The article co-authored by Scheffler and mentioned above

Scheffler, Richard M., Daniel R. Arnold, and Christopher M. Whaley. “Consolidation Trends in California’s Health Care System: Impacts on Aca Premiums and Outpatient Visit Prices.” Health Affairs 37, no. 9 (Sept. 2018): 1409-16.

Some Medical Researchers Seek Patient Input on Execution of Studies

In the story quoted below some medical researchers are seeking patient involvement in studies, but I was disappointed to realize that the involvement is mostly superficial with the aim of getting patient agreement to be part of the study. The researchers in the story still see a big divide between patients and doctors. Doctors see patterns and create hypotheses to be tested. Patients, if they want, can stand by posters, and make minor suggestions on the execution of study design.

I suggest, more ambitiously, that patients sometimes, if allowed, can see patterns and create hypotheses. They have the incentive, the skin in the game. And sometimes they have direct experience on what works and what does not work.

(p. R6) Joel Nowak, a 66-year-old Brooklyn, N.Y., resident with metastatic prostate cancer, knows a lot about cancer research. Over the years, he has contributed blood, saliva and medical information to studies in hopes of helping investigators battle the disease.

But something has nagged at him. Almost always, Mr. Nowak says, investigators want data, “but you never hear from them again.”

Then he was asked to join a new endeavor that is trying to change that—by making participants into partners.

The Metastatic Prostate Cancer Project, launched by the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute in Boston, is trying to give participants a bigger stake in studies by asking them for input, inviting them to events and keeping them updated on progress.

. . .

Patients are . . . invited for a tour of the Broad Institute to see its gene-sequencing machines or to meet and share ideas with researchers, says Nikhil Wagle, director of the umbrella initiative.

Dr. Wagle thinks the approach has led to unusually fast and large enrollment. More than 4,000 people enrolled in the breast-cancer project and over 290 in the angiosarcoma initiative. In just a few weeks, more than 200 signed up for the prostate-cancer study.

. . .

Keeping participants up-to-date is another concern for researchers. It is an issue close to home for Corrie Painter, principal investigator of the angiosarcoma project at the Broad and one of the creators of all three of the institute’s cancer initiatives.

Dr. Painter draws on her experiences as a cancer survivor and research participant in shaping interactions with patients. She was diagnosed with angiosarcoma nearly eight years ago. Dr. Painter says that after her diagnosis, like many patients, she felt frustrated at being treated more “as passive recipients of care rather than part of the process of discovery.”

. . .

Meanwhile, some patients are taking the opportunity to play a larger role in shaping studies. Mr. Nowak, for one, joined a patient advisory council of the prostate-cancer project. Members communicate on videoconferences, email exchanges and in person. During a meeting at the Broad, researchers showed a prototype for the saliva kits that were going to be mailed to patients to collect samples.

The advocates told researchers to take “Metastatic Prostate Cancer Project” off the box. “There are a lot of men who don’t want other people to know they have cancer,” says Mr. Nowak.

For the full story see:

Amy Dockser Marcus. “Researchers Look to Enlist Patients as Partners.” The Wall Street Journal (Monday, Feb. 25, 2018 [sic]): R6.

(Note: ellipses added.)

(Note: the online version of the story has the date Feb. 25, 2018 [sic], and has the title “Medical Researchers Look to Enlist Patients as Partners.” The last two ellipses above indicate where I omit sentences that appeared in the longer online version, but not in the print version.)

Marcus’s story is related to her book:

Marcus, Amy Dockser. We the Scientists: How a Daring Team of Parents and Doctors Forged a New Path for Medicine. New York: Riverhead Books, 2023.

Large Medical Databases Would Allow Discovery and Testing of Causal Patterns of Diseases

After considerable effort, as of the writing of the article quoted below, Dr. Wagle has only been able to gather data on 375 of the roughly 155,000 metastatic breast cancer patients in the U.S. Many have long complained about the difficulty in obtaining and consolidating medical records. Exploring the reasons would take a longer article than the one quoted below. Part of the story is the Health Insurance Portability and Accountability Act of 1996 (HIPAA). It was passed to protect patient privacy, but it served as cover for medical institutions to stonewall patients, policy makers, and other medical institutions from obtaining information. The institutions make the process of obtaining medical information as slow, opaque, and onerous as possible. Partly this is a result of the general inefficiency of medical bureaucracy. Regulations limit competition among medical institutions and limit entrepreneurship, allowing inefficiencies to persist. To those who are mission-oriented within the bureaucracy, providing records may seem a lower priority than issues affecting current medical care. But also, restricting information may increase patient lock-in. Ceteris paribus, a patient may choose to stay at an institution that has long health records for the patient. Also, providing less information to third parties may make the institution less vulnerable to criticism and law suits.

Ideally, Dr. Wagle’s database would serve as a modern day version of the dusty hospital archives that Dr. William Coley pursued to find a pattern among the patients who had been spontaneously cured of their cancer in the late 1800s.

From personal experience I can say that getting patient information is easier now than it was 30 years ago, at least for the patient to obtain their own information.

An important side point is Dr. Wagle’s emphasis on the value of obtaining patient narratives, in addition to coded data. Narratives allow the discovery of additional causes or effects, beyond what the initial coders include in the coded data. Gary Klein makes this point in defending the value of what he calls “stories” (Klein 2017).

(p. D4) Dr. Nikhil Wagle thought he had a brilliant idea to advance research and patient care.

Dr. Wagle, an oncologist at the Dana Farber Cancer Institute in Boston, and his colleagues would build a huge database that linked cancer patients’ medical records, treatments and outcomes with their genetic backgrounds and the genetics of their tumors.

The database would also include patients’ own experiences. How ill did they feel with the treatments? What was their quality of life? The database would find patterns that would tell doctors what treatment was best for each patient and what patients might expect.

The holdup, he thought, would be finding patients. Instead, the real impediment turned out to be gathering their medical records.

. . .

Dr. Wagle is making data from medical records and patients’ experiences public as he gets them. After 2 1/2 years, though, he is disappointed by how little there is to share.

The patient who inspired his project had a lethal form of thyroid cancer. She was expected to die in a few months. In desperation, doctors gave her a drug that by all accounts should not have helped.

To everyone’s surprise, her tumors shrank to almost nothing, and she survived. She was an “extraordinary responder.”

Why? It turned out that her tumor had an unusual mutation that made it vulnerable to the drug.

And that got Dr. Wagle thinking. What if researchers had a database that would allow them to find these lucky patients, examine their tumors, and discover genetic mutations that predict which drugs will work?

. . .

Dr. Wagle decided to build a database, starting with metastatic breast cancer, his specialty. There are about 155,000 metastatic breast cancer patients in the United States. He would use social media, online forums and advocacy groups to reach out to patients for their records.

. . .

Startlingly, faxing “is the standard,” Ms. McGillicuddy said, for medical records requests.

The process can be frustrating. Fax numbers can be out of date. Some medical centers will not accept electronic patient signatures on the permission forms.

Sometimes, the medical centers just ignore the request — and the second request. In the end, Ms. McGillicuddy said, the project gets fewer than half the records it requests.

Then comes the laborious task of extracting medical information from the records and entering it into the database. A faxed medical record may be 100 or 200 pages long.

So far, the breast cancer project has received 450 records for 375 patients. (Each patient tends to have more than one record, because the women typically are seen at more than one medical center.)

For the full story see:

Gina Kolata. “Concealing New Cancer Treatments.” The New York Times (Tuesday, May 22, 2018 [sic]): D4.

(Note: ellipses added.)

(Note: the online version of the story has the date May 21, 2018 [sic], and has the title “New Cancer Treatments Lie Hidden Under Mountains of Paperwork.” Where the wording of the versions differs, the passages quoted above follow the online version.)

Gary Klein’s main book that I praise in my initial comments is:

Klein, Gary A. Sources of Power: How People Make Decisions. 20th Anniversary ed. Cambridge, MA: The MIT Press, 2017.