Category: Regulations

F.D.A. Should Allow Physicians and Parents the Freedom to Give Preterm Infants Probiotics

Substantial observational evidence shows that the status of a person’s microbiome can have a large effect on the person’s health. We still have a lot to learn about which bacteria are helpful and the details of how they help. But patients must act under uncertainty, or in the case of the preterm infants discussed in the passages quoted below, physicians and parents must act under uncertainty. Given the current evidence and the uncertainty, the F.D.A. is arrogantly wrong to ban probiotics.

(p. A5) For years, hospitals around the world have tried to protect prematurely born babies from life-threatening gut disease by giving them probiotics. Then . . . [in Oct. 2023], American hospitals stopped.

The Food and Drug Administration had linked an infant’s recent death to one of the products. It warned doctors about using them in preterm infants without getting agency permission first, and pushed Abbott Laboratories and another major manufacturer, Infinant Health, to stop selling them.

. . .

Neonatologists in the U.S. and other developed countries have learned to help smaller and smaller babies stay alive. As they treat tinier babies, the medical challenges mount, including a swift-onset disease known as necrotizing enterocolitis, or NEC.

. . .

To help prevent NEC, nearly all neonatal units in Australia and New Zealand give probiotics, as do a majority in several European countries. About 40% in the U.S. did before the FDA’s actions, according to recent surveys and neonatologists’ estimates.

Nearly all of the products consist of live bacteria intended to help create a healthy community of microbes in the gut. Scientists don’t know exactly how they work, but suspect they prevent harmful bacteria from overwhelming the bowels.

. . .

Neonatal units across the U.S. halted use of the probiotics because popular versions were no longer available and the FDA warned doctors against using probiotics for preterm babies outside of clinical trials.

“I was stunned,” said Jennifer Canvasser, who started a NEC patient advocacy group after her infant son died 10 years ago, weakened by the disease. “To think about families having one potential less way to prevent this devastating disease is just concerning.”

Probiotics supporters say the FDA disregarded the evidence favoring probiotics for preterm babies, saying that they likely save hundreds of infants for every one probiotic-caused infection, which can be treated with antibiotics.

An analysis of more than 100 studies involving more than 25,000 premature infants, published . . . [in Oct. 2023] in the journal JAMA Pediatrics, found that probiotics containing multiple strains of bacteria were associated with reduced deaths and NEC.

For the full story see:

Liz Essley Whyte. “Discord Arises Over Treating Preemie Babies.” The Wall Street Journal (Saturday, Nov. 17, 2023 [sic]): A5.

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

(Note: the online version of the story was updated Nov. 16, 2023 [sic], and has the title “Doctors, FDA Fight Over Giving Probiotics to Premature Babies.” The passages quoted above omit the subheadings that appear in the print, but not the online, version of the story.)

The analysis published in JAMA Pediatrics and mentioned above is:

Wang, Yuting, Ivan D. Florez, Rebecca L. Morgan, Farid Foroutan, Yaping Chang, Holly N. Crandon, Dena Zeraatkar, Malgorzata M. Bala, Randi Q. Mao, Brendan Tao, Shaneela Shahid, Xiaoqin Wang, Joseph Beyene, Martin Offringa, Philip M. Sherman, Enas El Gouhary, Gordon H. Guyatt, and Behnam Sadeghirad. “Probiotics, Prebiotics, Lactoferrin, and Combination Products for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis.” JAMA Pediatrics 177, no. 11 (2023): 1158-67.

For a useful discussion of how current medical protocols, especially the over-prescription of antibiotics, harm the microbiome, see chapter 3 of:

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

Health Insurance Firms Tell Regulators Surgery Prices Are Lower than What They Actually Charge, Undermining Price Transparency

Insurance firms that negotiate low prices with hospitals will be viewed more favorably by regulators, legislators, and the public. So they have a substantial incentive to inaccurately report prices as lower than they are. For true transparency, prices would need to be reported by those with no incentive to fudge the figures. Would that be hospitals, doctors, Consumer Reports, or academic economists?

(p. A11) How much does a new hip cost in New York? The answer isn’t at all clear, despite Gov. Andrew Cuomo’s efforts to improve price transparency.  . . .

. . . Michael Frank, a 52-year-old Westchester County executive . . . had his left hip replaced in 2015. The Manhattan hospital charged roughly $140,000. The insurance company paid a discounted rate of about $76,000, . . .

. . .

After hearing his story, I told Mr. Frank what I thought was an odd twist: I’d recently had two hips replaced, six months apart, at the same hospital that had treated him.

. . .

Eventually I learned that the hospital had charged $175,000 for my right hip and $180,000 for the left. The insurance company had paid discounted rates of $75,000 and $77,000.

. . .

In 2009, New York’s then-attorney general, Andrew Cuomo, announced the creation of a nonprofit organization called FAIR Health. Its mandate is to provide consumers accurate pricing information for all kinds of medical services.

I found the FAIR Health website and queried its database. It reported that the out-of-network price for a hip replacement in Manhattan was $72,656, close to what Mr. Frank’s and my insurance companies had paid. The problem: We were both in-network, and FAIR Health estimated that cost as only $29,162.

Something didn’t make sense, so I called FAIR Health. “Maybe you had complications,” the spokesperson suggested. Happily, I hadn’t. I was discharged from the hospital each time in under 24 hours, with no issues and no need for a home health aide. How many data points did FAIR Health use to calculate its price estimate? I was told “4,500 in Manhattan over the last six months.” Who submitted these prices? “The insurance companies.”

. . .  Rather than relying on insurers, it might be more effective if FAIR Health collected pricing information directly from hospitals and doctors. That way the data would be less susceptible to selective reporting or massaging. That’s what happened in the early 2000s, when class-action lawsuits revealed the main pricing database was being manipulated to the advantage of insurance companies.

For the full commentary see:

Steve Cohen. “You Can’t Put a Price on a Hip Replacement, and That’s a Problem.” The Wall Street Journal (Saturday, July 14, 2018 [sic]): A11.

(Note: ellipses added.)

(Note: the online version of the commentary has the date July 13, 2018 [sic], and has the title “Heard on the Street; New Biden Law Won’t Kill Drug Cures. It Will Reshape Them.” In the next to last paragraph quoted above, the second quoted sentence appears in the online, but not the print, version of the commentary.)

The So-Called “Inflation Reduction Act” Reduces Incentives to Develop Small Molecule Drugs and Drugs for Seniors

A recent blog entry suggested that the so-called “Inflation Reduction Act” “creates an incentive for Pharma firms to develop many middling drugs rather than a couple of blockbuster drugs.” In the passages quoted below from a different David Wainer commentary, he suggests that the Act also incentivizes pharma firms to reallocate development funds away from drugs for seniors and away from biologics. He assumes that the reallocation is “unintended” rather than based on the government believing that seniors matter less than others, or that biologics deserve more funding than the previous semi-free market allocated to biologics.

(p. B14) . . . the Inflation Reduction Act, . . . requires the federal government to negotiate prices for some drugs. Merck Chief Executive Officer Robert Davis was just one of many to warn it will be “highly chilling on future innovation.”

The 274-page legislation passed in 2022 doesn’t look likely to be a massive damper on innovation, but it will surely have an impact on how capital is allocated. When companies look at their R&D budgets, they will have to consider the law’s ramifications.

. . .

. . ., there is no arguing with the fact that the bill is reshaping many incentives drug companies face. For example, critics of the law point out that it eliminates the incentive to conduct additional research once a drug has been approved—a common strategy to extend patent protection for a drug—because prices are negotiated after nine years for small-molecule drugs and 13 years for biologics. As Kirsten Axelsen, a visiting scholar at the American Enterprise Institute explains, many oncology medications are first approved for severely ill patients and over time those drugs are tested for patients in earlier stages of the disease.

“Thanks to that, we’re now able to hold back the progression of cancer so that many of the major cancers have five-year survival rates of longer than 90%,” says Ms. Axelsen, who is also a policy adviser to law firm DLA Piper.

. . .

The law . . . could shift investment toward drugs that target the general population and away from seniors. That is because it only empowers Medicare to negotiate prices, leaving the commercial market wide open.

. . .

Perhaps the most serious concern is that the law picks winners and losers by favoring biologic drugs over small molecules, which face price reductions four years sooner than their larger molecule counterparts.

Small molecule drugs are chemically derived and simpler to make and can usually be taken orally by patients. These drugs—think medicine cabinet essentials like aspirin or statins—dominated the pharmaceutical industry during the 20th century. Biologics, therapies that are extracted from living organisms, are usually given through an injection and, because of their higher price tags, make up the bulk of today’s top-selling drugs. While biologics are at the cutting edge of medicine, discoveries of new small-molecule drugs continue to be made.

Eli Lilly’s CEO, David Ricks, noted in a recent earnings call that “it sends a signal to investors” that small molecules “aren’t wanted and are worth a lot less.” That could tip the scales toward more development in biologics, a likely unintended consequence of the law.

MIT’s Professor Lo says that is like effectively creating a tax on small molecules, or a subsidy for larger ones.

For the full commentary see:

Wainer, David. “Heard on the Street; Drug Industry’s Secret Weapon: ‘Guided Missiles’.” The Wall Street Journal (Saturday, Jan. 7, 2023 [sic]): B14.

(Note: ellipses added.)

(Note: the online version of the commentary has the date January 6, 2023 [sic], and has the title “Heard on the Street; New Biden Law Won’t Kill Drug Cures. It Will Reshape Them.” In the next to last paragraph quoted above, the second quoted sentence appears in the online, but not the print, version of the commentary.)

Regulators Wanted to Renege on Promise to Clinical Trial Volunteers Who Got the Placebo

Everyone agrees that those who receive the placebo in a randomized double-blind controlled trial (RCT) are losers in the clinical lottery. The question is whether the epistemic gain from RCTs justifies the pain for the losers? I am not a fan of Fauci, but his proposed solution to the dilemma in the case discussed below seems plausible, if we assume (as I do not) that RCTs are a necessary condition for all actionable medical knowledge and yet we still attempt to treat clinical trial volunteers ethically. My even better solution is to allow all willing volunteers to take the experimental drug, with no-one receiving a placebo. Then use some Bayesian updating technique to gather information from the comparison of results for study participants who volunteered to take the drug, with results for study participants who did not volunteer to take the drug. The study would not be blind, but useful information could be obtained, for instance if no one who takes the drug suffers from the disease, but many who do not take the drug, do suffer from the disease. In that case we have evidence that the drug is effective.

(p. A7) In October [2020], Judith Munz and her husband, Scott Petersen, volunteered for a coronavirus vaccine trial. At a clinic near their home in Phoenix, each got a jab in the arm.

Dr. Petersen, a retired physician, became a little fatigued after his shot, and developed redness and swelling on his arm. But Ms. Munz, a social worker, didn’t notice any change. “As much as I wanted it, I couldn’t find a darned thing,” she said. “It was a nothing burger.”

She knew there was a 50-50 chance that she would get the vaccine, developed by Johnson & Johnson. Judging from her lack of symptoms, she guessed she had received the placebo.

At the time, Ms. Munz thought that anyone who had received the placebo would get the real vaccine as soon as the trial showed it was safe and effective. She looked forward to the peace of mind it would bring. But last month, she was asked to sign a modified consent form indicating that people who got the placebo might have to wait up to two years to get the vaccine, if they got one at all.

Ms. Munz found the form vague, confusing and, most of all, unfair. “You put yourself out there with that risk,” she said. “I am owed that vaccine.”

. . .

But on Wednesday [Dec. 2, 2020], 18 leading vaccine experts — including a top regulator at the Food and Drug Administration — argued that vaccinating placebo groups early would be disastrous for the integrity of the trials. If all of the volunteers who received placebo shots were to suddenly get vaccinated, scientists would no longer be able to compare the health of those who were vaccinated with those who were not.

“If you’re going to prioritize people to get vaccinated, the last people you should vaccinate are those who were in a placebo group in a trial,” said Richard Peto, a medical statistician at the University of Oxford. Mr. Peto and his colleagues laid out their concerns in a new commentary in The New England Journal of Medicine.

. . .

Yet the prospect of giving people something useless in the face of a life-threatening disease has always been fraught. Even Jonas Salk balked at the idea of giving people placebos when researchers designed a trial to test his new polio vaccine in 1953.

“I would feel that every child who is injected with a placebo and becomes paralyzed will do so at my hands,” he complained. The study, Dr. Salk declared, “would make Hippocrates turn over in his grave.”

. . .

Dr. Fauci sketched out one possible way to balance the obligation owed to people who took the placebo against the need for more data from the trials. Vaccine makers could give everyone who got the placebo the vaccine — while also giving everyone who got the vaccine the placebo. None of the trial participants would know which order they got the doses. The trial could therefore continue to be blinded.

. . .

After learning that it may take two years before Johnson & Johnson will provide her with the real vaccine, Ms. Munz, who is 68, is considering trying to get Pfizer or Moderna’s version as soon as she’s eligible thanks to her age.

“I’ll drop out, which I can do, and I’ll get the vaccine,” she said.

Holly Janes, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, and her colleagues are preparing for this kind of erosion. She and her colleagues are now working on statistical methods to squeeze the most insight out of the trials no matter what their fate.

“It won’t be ideal from a purely scientific vantage point, because we lose the direct comparison between vaccine and placebo,” she said. “But we’re trying to strike a balance between doing what some would argue is right for the participants, and maximizing the public health value that comes out of these trials.”

For the full story see:

Carl Zimmer and Noah Weiland. “Should Volunteers Who Got Placebo Be First to Get the Real Thing?” The New York Times (Thursday, December 3, 2020): A7.

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

(Note: the online version of the story was updated Dec. 18, 2020 [sic], and has the title “Many Trial Volunteers Got Placebo Vaccines. Do They Now Deserve the Real Ones?”)

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.)

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.)

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.)

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.