The Trouble with Trump’s Pick to Run the FDA

Dr. Marty Makary, Donald Trump’s nominee to head the Food and Drug Administration, is a contrarian.

Near the end of the Johns Hopkins professor of medicine’s latest book, Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health, he asks, “Can diabetes be more effectively treated with a cooking class instead of prescribing insulin? Can we lower high blood pressure by improving sleep quality and reducing stress instead of throwing antihypertensive medications at people? Can we discuss school lunch programs, not just bariatric surgery and Ozempic?”

Alone among Trump’s health care appointees, Makary has escaped criticism on Capitol Hill and in the mainstream media. If the Senate confirms him, his penchant for questioning conventional wisdom could unleash the FDA to pursue the positive public health aspects of Robert F. Kennedy Jr.’s agenda, requiring greater regulation of the nation’s food supply.

But while the FDA’s role in food oversight is essential, it is less than half the agency’s mandate. Its main job is ensuring the safety and efficacy of drugs, biologicals, medical devices, and vaccines. Based on his book’s questionable use of medical evidence, Makary could push to change evidentiary standards at the divisions of the FDA that grant approval for those crucial aspects of health care. That would mean undermining public trust in an agency once considered the gold standard for regulators worldwide.

Makary has often criticized the medical and regulatory establishment throughout his career, accusing them of “groupthink” and being prone to drawing conclusions not justified by evidence. Yet, he can be just as guilty of cherry-picking evidence to justify preconceived conclusions as those he accuses. Like the vaccine-skeptic slated to become his boss, he could do far more harm than good.

While the CDC and Surgeon General have nominal responsibility for public health, Congress gave neither the power to make changes in policy. The CDC only issues recommendations. Implementation is voluntary and left to the states. The Surgeon General occupies the medical bully pulpit but otherwise lacks authority.

The FDA, on the other hand, has the power to prevent market access for unsafe or ineffective drugs, vaccines, and medical devices. It ensures safe manufacturing processes for the products it regulates. It protects the public from food-borne illnesses. It issues nutritional advice and drug labeling guidelines. It polices false medical claims on packaging and in advertisements. It safeguards about one in every four products that eventually reach the market.

To carry out that broad mandate, the agency leans heavily on the scientific judgments of its in-house employees, most of whom are well-trained physicians, scientists, and statisticians. Their jobs entail evaluating the scientific studies behind manufacturers’ claims that their new drugs and devices are safe and effective, almost all provided by industry-funded clinicians. They also must monitor and respond to post-marketing surveillance studies that identify harms not seen in the short-term clinical trials used for regulatory approval. Agency scientists frequently rely on the advice of independent outside experts, who are supposed to be free from financial relationships with companies whose products they are reviewing.

Having served on several FDA advisory committees as a consumer representative, I know from personal experience that the agency’s regulators offer a far more objective review of the scientific evidence than the drug, medical device, and food industry-funded clinicians and scientists hired by companies seeking product approvals. When the science is unclear, they are slow to act. But when outside pressure is intense (especially from companies or patient advocacy groups), they sometimes approve products that lack sufficient evidence. One need look no further than recent drug approvals for Alzheimer’s disease or Duchenne’s muscular dystrophy, both approved on questionable evidence, to see how far the FDA has slipped from its once-vaunted reputation.

The need to carefully evaluate the science before leaping to conclusions makes Makary’s book a thought-provoking yet disturbing read. He lays the blame for several public health fiascos on advice offered in the 1990s by medical professional societies. He documents how the advice to families not to expose toddlers to peanuts until age three (from the American Academy of Pediatrics) and that addiction is not a threat from short-term use of opioids (from the American Pain Society) were based on expert opinion, not rigorous studies. Both have since been withdrawn.

With contempt, he dismisses the weakness of the evidence behind long-standing recommendations to avoid cholesterol-laden and high-fat foods, much of which has been either walked back (dietary cholesterol) or become highly nuanced (avoiding saturated fats, not all fats). Makary takes sides in the media-fueled debates over hormone replacement therapy for menopause and the use of silicone-filled breast implants, coming down in favor of their widespread use despite controversies about their safety.

In short, he routinely sides with contrarians in scientific debate, including the use of school lockdowns early in the pandemic. He frequently deploys the epithet “groupthink” at those with whom he disagrees, including the research choices of the National Institutes of Health, the guidelines offered by many medical professional societies, the advice provided by the CDC, and the choices made by many practicing physicians who blindly follow their advice.

Yet he does not apply his contrarian mindset to two groups that are usually the target of journalistic accounts of medical mistakes: the pharmaceutical and medical device industries, which are the main targets of contrarians on the left. These two industries depend on favorable judgments from the FDA he hopes to lead. They also provide nearly half its budget through user fees, which is a blatant conflict of interest.

A book about medical blind spots contains just two paragraphs questioning pharmaceutical industry actions. Makary criticizes Purdue Pharma for promoting the use of Oxycontin without mentioning that the company funded the clinicians who formed the American Pain Society, which wrote guidelines touting opioids for minor pain. The British-born surgeon also criticizes the massive price increases on EpiPens (its maker, Mylan, goes unnamed) in response to the peanut allergy epidemic.

It is a curious oversight. While Makary digs deep in the medical literature to find studies that justify his opinions, he avoids mention of the hundreds of medical journal studies published throughout his quarter-century career that document the pernicious effects of industry’s role in financing medical research, clinical practice guidelines, patient advocacy groups, continuing medical education, and physician marketing. He ignores how industry-funded research supported the extensive use of drugs and devices beyond the indications included on the FDA-approved label, often causing great harm in the process.

Had the FDA nominee looked past that blind spot, he would have found many stories that would have fit nicely with the central theme of his book. Off-label drug promotion by industry has been responsible for some of the worst medical disasters of the past three decades.

For instance, throughout the 1990s and into this century, Amgen, the nation’s largest and most profitable biotech firm, promoted the overuse of its Epogen in dialysis patients. The company gave financial support to researchers whose studies proved that greater use of Epogen elevated their red blood cell counts and gave patients more energy. The company also funded the creation of guidelines by the National Kidney Foundation that promoted the off-label use of the drug for that purpose. The side effects were overlooked. The result? An excess of heart attacks and strokes among an already vulnerable population led to a black box warning from the FDA. The NKF eventually withdrew the guidelines.

Nor does Makary mention the better-known Vioxx case, where Merck heavily promoted the use of its high-priced, anti-inflammatory alternative to generic ibuprofen for minor aches and pains despite clear signals in the drug’s clinical trials that it raised the risk of heart attacks and strokes. Tens of thousands of people died from Vioxx before it was finally pulled from the market by Merck, which paid close to $5 billion to settle claims made by aggrieved families.

One of the most disturbing aspects of Makary’s book is his inconsistent use of medical evidence, a habit that seators should scrutinize at his confirmation hearing. He is quick to critique the quality of studies used to justify the expert opinions he questions but enthusiastically embraces studies that use even lower levels of evidence when they suggest potential upsides from the therapies he supports.

This double standard is on full display when he derides research indicating health risks associated with taking hormone replacement therapy (HRT) to relieve symptoms of menopause. There is no question HRT benefits women experiencing hot flashes and vaginal dryness. But for over two decades, HRT has carried a label based on the Women’s Health Initiative (WHI). This NIH-funded clinical trial compared more than 20,000 post-menopausal women taking hormones to two similarly sized groups taking other non-hormonal therapies. The trial also compared the hormone-taking group to a much larger “matched cohort” that was not in the trial.

The FDA warning states women taking an estrogen/progestin combination drug experience “increased risks of stroke, deep vein thrombosis, pulmonary embolism, and myocardial infarction.” The trial “also demonstrated an increased risk of invasive breast cancer.” It is that latter finding that draws fire from Makary.

Makary correctly points out that the trial’s finding that HRT increased the risk of breast cancer was problematic. The range of data points in the original study, known as the confidence interval, straddled the line between statistical significance and insignificance. (In statistics, “significance” refers to the likelihood that the results are correct, not that there is a major effect.) The data showed a trend indicating increased cancer risk, but no conclusive proof.

Since breast cancer is always a hot-button issue, the interim results led the organizers, over the protests of some of its participating clinicians, to stop the trial and hold a press conference. The widespread publicity triggered an immediate drop in HRT use and an ongoing reluctance to begin estrogen supplementation to relieve symptoms of menopause.

More than two decades later, Makary interviewed the primary organizers and authors of the study, who reluctantly confirmed his critique of the original study. “The finding (on breast cancer) is very borderline,” Dr. JoAnn Manson, a professor of medicine at Harvard Medical School and the study’s leader, told him. Yet earlier this year, Manson and 18 co-investigators published an updated review of the clinical implications of the WHI in JAMA based on a 2020 study that included longer follow-up. It found elevated cancer risk, and this time, it was statistically significant.

After critiquing the original breast cancer finding, Makary makes broad claims for the health benefits of HRT, including delaying the onset of Alzheimer’s disease; preventing cardiovascular disease and heart attacks; and reducing colon cancer risk. “Women taking estrogen have a 35% lower incidence of Alzheimer’s,” he declares. What evidence does he cite? A 1996 study of 8,877 women in a southern California retirement community mailed a general health survey in 1981, less than half of whom had died by 1995. The researchers then examined death records and found 248 mentioning Alzheimer’s or other forms of dementia, with about 35% more mentions in women who had not taken HRT than in the group that had.

This type of research is known as an observational study of matched cohorts, which is a much less trustworthy source of medical evidence than randomized clinical trials like the WHI. The possibility that unmeasured or unidentified variables such as underlying health conditions or family history will confound the results is enormous. The best one can say about conclusions drawn from observational studies is that they offer clues for further research but are inadequate for making definitive claims about efficacy.

Makary’s claim that HRT reduces the risk of heart disease is based on another observational study called the Nurses Health Study, published in 1991 and updated in 2000. This frequently criticized study recorded the self-reported health habits, treatments, and outcomes of over 70,000 nurses over two decades. “Heart disease is the leading cause of death in American women. HRT reduces that risk by about 50%,” he declares.

Yet in 2015, the Cochrane collaboration (“a highly respected group of experts who conduct extensive scientific reviews,” to use Makary’s description from another section of his book) found “no evidence that hormone therapy provides any protective effects against death from any cause, and specifically death from cardiovascular disease, non-fatal heart attacks or angina, either in healthy women or women with pre-existing heart disease.”

The Cochrane group further concluded HRT increased risk of stroke for post-menopausal women.”

The recent update of the WHI, a randomized controlled clinical trial, again found no cardiovascular benefits. The study, which appeared this past May in JAMA, showed HRT significantly increased the risk of stroke and blood clots. The overall incidence of heart disease among women also increased, although that finding was not statistically significant.

And, as for Makary’s major claim that HRT presented no risk of cancer, this latest WHI study confirmed the trial’s original suspicion about just that. Except this time, the findings were statistically significant. “At 20-year follow-up, [estrogen plus progestin] compared with placebo significantly increased breast cancer incidence” by 28 percent, the study showed. If taking estrogen alone, there was a slight decrease in breast cancer risk, but that was a statistically insignificant finding.

The bottom line: The overall risk of developing cancer from HRT is small and is more significant in older women. That is why the WHI investigators still suggest short-term HRT for women under 60 is an appropriate therapy for relieving menopause symptoms if they aren’t already at risk of developing heart disease or cancer.

Debate over HRT isn’t the only medical arena where Makary takes sides on controversial issues based on studies that are far from conclusive. Water fluoridation “may be affecting our intelligence,” Makary warns, citing a Canadian study that compared IQ test results in young children in two communities: one with fluoridated water and one without. This matched cohort study measured the IQs of just 512 children in the two communities. It found a statistically significant decrease of four IQ points in boys aged 3 to 4 but no decrease in girls.

One doesn’t have to be a contrarian to know any number of confounding variables may have skewed the results of this small study. Yet Makary concludes, “We should be open to reversing this practice” of fluoridating water.

The book is peppered with definitive statements about medical outcomes based on such sketchy evidence. In a chapter on childbirth practices, he appropriately condemns America’s extraordinarily high rate of C-section deliveries. He also criticizes induced labor by pointing to a randomized controlled trial published in the New England Journal of Medicine that showed women with low-risk pregnancies who had labor induced at 39 weeks (full-term) had fewer complications than those who waited beyond their due date for labor to begin. “The study made its claim of superiority by adding unrelated outcomes together — outcomes that were not statistically significant by themselves,” he writes.

But then, he laments how these “cold medical practices” (excessive use of C-sections and induced labor) have soured expectant mothers on modern medicine and caused thousands to turn to home births. Parents who “glamorize home births and medical-free deliveries ignor(e) the real risks such decisions entail… Home deliveries triple the risk of infant mortality.”

That shocking claim, which would certainly turn me off to birthing at home if I were an expectant mother, sent me rushing for the footnotes. There were none. So, I searched the medical literature and found a 2010 meta-analysis (an analysis using pooled data from a group of studies on the same subject) in the American Journal of Obstetrics and Gynecology that made that claim. It reviewed data from over one-half million planned hospital or planned home deliveries. However, only 1 of the 12 studies used for the meta-analysis was a randomized controlled trial. The rest were observational studies, some with some without matched cohorts. The low quality of the evidence was blasted by letter writers to the Journal.

I also found a subsequent review of that meta-analysis that warned, “the authors’ conclusions should be treated with some caution as they did not reflect all the evidence presented in the review.” In an echo of Makary’s critique of the Women’s Health Initiative, the critique pointed out that the meta-analysis showed no statistical difference in the two groups in perinatal infant mortality (deaths up to 7 days after childbirth).” The alleged “tripling” was only in neonatal infant mortality (deaths up to 28 days after childbirth), which logic suggests would include more deaths not associated with childbirth itself. The critique also pointed out that the data on neonatal infant deaths came from trials that included fewer than 50,000 births — less than a tenth of the meta-analysis’ total review population.

Makary goes to great lengths throughout his latest book to appear as a voice of reason. He asks government officials, guideline writers, and practicing clinicians to be more humble when making limited evidence recommendations. He wants NIH to fund more research on practices that challenge conventional wisdom. He questions the peer review practices at medical journals, pointing to the 10,000 annual retractions identified by Retraction Watch (Full disclosure: its founder, Dr. Ivan Oransky, has edited magazine articles I’ve written). He laments the absence of respect for contrarian researchers who challenge “groupthink.” “Today, more than ever,” he writes, “organized medicine is finding ways to limit and stifle scientific debate.”

Science is always contested terrain. But today, despite the backlash against the Covid-era shutdowns and the growth of vaccine hesitancy fed by disinformation about safety, the primary contest is not between skeptical contrarians and the medical establishment. It is between scientists backed by companies with a financial interest in the outcome of medical research and their regulators.

Industry and the self-interested physician specialists it funds play an outsized role in generating medical evidence and writing clinical practice guidelines. Industry-funded research dwarfs that of the NIH. Outcomes and conclusions that ought to be based on an objective interpretation of facts can be biased by any number of factors, ranging from the researchers’ preconceived ideas to the study’s structure to who funded their efforts.

Moreover, best medical practice is an always-changing target, hopefully for the better. New paradigms can and often do replace yesterday’s conventional wisdom. But those changes usually come slowly and only when more rigorous investigations follow up studies whose statistical validity only hints at the need for change.

It is those higher standards of evidence that the FDA has traditionally adhered to when approving new technologies, issuing guidelines and warnings, or removing unsafe products from the market. The 18,000-person watchdog agency needs its next leader to adhere to those standards. Based on Blind Spots, Dr. Makary still needs to show he will follow those standards when he appears before the Senate for confirmation.

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