Life, Liberty, and the Pursuit of Health Experiments
The FDA needs better ways to address scientific uncertainty
Update May 7, 2024: today I wrote my Congressional delegation urging them to help move the Promising Pathway Act to the Senate floor. It’s not everything I’m asking for below, but it’s certainly a significant step in the right direction.
In an Atlantic article entitled “Americans Don’t Get to Have the Best New Covid Drug,” Rachel Gutman-Wei offers neutral coverage of the vexing story of Xocova—a Covid-fighting medicine Americans are currently forbidden to try, even though it has been in use in Japan for more than a year. Xocova works better than Paxlovid, is safer than Paxlovid, has fewer side effects than Paxlovid, and costs four times less than Paxlovid. Why is the US Food and Drug Administration (FDA), which is chartered with ensuring the safety and effectiveness of medicines, forcing Americans to resort to using medicines that are less safe and less effective? Isn’t it, in effect, an inversion of the FDA’s mission? In this article, I’ll look at the question through the lens of three policy proposals that could help the FDA better fulfill its charter. In tomorrow’s post, “Consumer Reports for Medicines,” I’ll drill down on economic issues.
Under current law, the FDA only has one option for communicating with the public about medicines: the agency can officially approve a medicine if it has been conclusively proven to be both safe and effective for the indication stated on the label. Proven safe and effective sounds good, but scientific proof is essentially a subjective line drawn on a continuum of degrees of confidence. The problem is as old as science itself; in 1616, the Inquisition ruled that Galileo’s heliocentric theory could not be marketed to the public because it was not yet proven safe and effective. Approval took 142 years.
Under current law, it’s illegal to buy or sell a new medicine while acceptable levels of “proof” are being garnered. There’s no way for the system to account for the public health consequences of the sales ban. If the approval process were generally quick, a brief marketing prohibition might not be a major problem—but Xocova was granted so-called “Fast” Track Designation nine months ago! Meanwhile, practically everybody I know caught Covid and a couple friends now have serious cases of long Covid. Xocova, in contrast to Paxlovid, has been shown to prevent long Covid. “Cautiously” banning Xocova for the past nine months has been making Americans less safe.
The FDA doesn’t directly test investigational new drugs; instead, it meticulously guides a stringent process in which the manufacturer iteratively self-tests their own product according to sometimes inscrutable FDA specifications. The FDA has unchecked power to dictate any terms it sees fit, with no public scrutiny or chance for appeal. Imagine if courts worked this way!
The thinking behind this article has been critiqued by friends who used to work for the FDA. My friends are caring, thoughtful people who are among the most brilliant scientists I know. The problem is that caring brilliant people are navigating a bureaucracy that is set up to prioritize the preservation of the FDA’s reputation for rigorous stringency above the overall goal of protecting public health.
Sound advice is the main thing we need from the medical-regulatory establishment. What we’re getting instead is a vetocracy that routinely defaults to snatching away lifesaving medicines. The problem can be solved with legislation that would make it easier for the FDA to openly acknowledge scientific uncertainty and allow people greater freedom to make safer health choices for themselves in a free market.
Legislative Proposal 1: Extend the Minor Use and Minor Species Animal Health Act (MUMS) to Humans
Although the FDA is only allowed to give either a red light or a green light to medicines used by humans, the 2004 Minor Use and Minor Species Animal Health Act (MUMS) enables the FDA to give veterinary medicines a metaphorical flashing yellow. Under the MUMS Conditional Approval track, veterinarians are authorized to use unproven medicines in animals if there’s a scientifically reasonable expectation that the medicine’s anticipated health benefits seem likely to outweigh its safety risks. Although MUMS has sometimes been slightly controversial, it has been working reasonably well for the past 20 years.
Expanding the Conditional Approval track to include humans would enable the FDA to evaluate the experience with Xocova in Japan and declare that there’s a scientifically reasonable expectation the drug will be similarly safe and effective in America. The Conditional Approval decision ought to take about as long as it takes to read Gutman-Wei’s Atlantic article—the drug’s safety and efficacy are pretty much self-evident. Under expanded “Major Use in Major Species” legislation, Xocova could be made immediately available while conclusive proof is being meticulously gathered in support of Full Approval. Conditional Approval would require post-market safety/efficacy monitoring, which could be used in support of an eventual Full Approval application. Somewhere, in an alternate counterfactual MUMS timeline, a couple of my friends don’t have long Covid right now.
The existing MUMS law already allows Shionogi to apply for Conditional Approval to use Xocova in animals. Coronaviruses are a serious problem for animals—both in terms of directly sickening or killing them, and in terms of creating reservoirs for the evolution of new strains that might infect humans. A recent study entitled “Neurologic Effects of SARS-CoV-2 Transmitted among Dogs” shows that Covid causes brain damage in experimentally infected beagles, just like it does in humans. It’s not clear why Shionogi hasn’t sought Conditional Approval to protect our pets. Maybe mum’s the word and they’re just not aware of the workaround? My friends who used to work for the FDA weren’t aware of MUMS.
Legislative Proposal 2: Acknowledging Scientific Uncertainty
A controversial new Alzheimer’s medication called Aduhelm is another example of the problems created by the proven-or-prohibited binary the FDA currently labors under for human medicines. Aduhelm can have life-threatening side effects and its benefits for reducing surrogate measures of Alzheimer’s disease are legitimately questionable. Under current law, the FDA has no flashing yellow option to convey that the benefits of Aduhelm might outweigh its risks, at least in certain subsets of individuals. Aduhelm was instead given a green light, implying it has been proven safe and effective. The lack of a flashing yellow option encourages false hope about how likely the dangerous monopoly extortion-priced treatment is to work.
Current law empowers the FDA to offer useful “definite-maybe” judgements about unproven food supplement products. Here’s an example of a Qualified Health Claim for a supplement product:
Limited scientific evidence shows that by consuming 500 mg each day of cranberry dietary supplement, healthy women who have had a urinary tract infection (UTI) may reduce their risk of recurrent UTI.
An issue with Qualified Health Claims is that product manufacturers are required to apply for pre-market approval, and the pre-approval process can take up to nine months. Rather than slogging through a long bureaucratic process with uncertain outcomes while a product sits in a warehouse, supplement manufacturers typically choose to refrain from making qualified claims on the label. In an effort to prevent manufacturers from making false claims about snake oil, the current pre-approval law effectively suppresses all claims, including appropriately hedged descriptions of areas of legitimate scientific uncertainty. Throwing the definite-maybe baby out with the false-claim bathwater makes it harder to communicate valid scientific findings.
The Acknowledging Scientific Uncertainty Measure (ASUM) would end the practice of attempting to police false-claim future-crime and would explicitly allow manufacturers to print appropriately hedged health claims on the label without pre-approval. Under the measure, the Federal Trade Commission (FTC) would retain its existing power to address fraudulent or deceptive labeling.
In a hypothetical embodiment of the new law, a mint tea product named Might Fight Covid™ could be sold without pre-market review. The label would be allowed to include links to peer-reviewed scientific literature indicating that mint-family herb products inhibit SARS-CoV-2 replication in cell culture, fight Covid in hamsters and mice, and safely prevent or alleviate Covid symptoms in human clinical trials. The packaging would also be allowed to state the product’s level of caffeic acid, which Trilling and colleagues report is the principal antiviral agent in mint-family herbs. If a preponderance of future publications show that mint-family herbs don’t fight Covid in humans, then the FTC could rule that the name Might Fight Covid™ is false advertising and could enforce a name change1.
In public discourse, many people seem to start with the assumption that science is a system for cataloging proven facts. It’s important to remember that science is actually a method for experimentally addressing areas of uncertainty. Scientists catalog evidence and make bets based on degrees of confidence. Unquestioned truths are the province of religion.
ASUM would require the FDA to indicate its degree of confidence for all official actions. In principle, the legislation could also be applied to other regulatory agencies, such as the Environmental Protection Agency. Critics of government regulations would undoubtedly seize upon the new level-of-confidence statements and crow “see, look—they’re not really sure!” Which is true. The silver lining of this problem is that it would help promote improved public understanding of how science actually works. Critics would be called upon to concede they’re “not really sure” either. Public debates are more productive if they revolve around relative likelihoods rather than unquestioned truths.
Legislative Proposal 3: The Seliger Right to Buy Law
A friend of mine moved to Thailand. Her cat, Murder Mittens, flipped out about the move, so my friend waltzed into a corner pharmacy and waltzed out with some Prozac. A week of Prozac helped Murder Mittens through a tough time. As far as my friend can tell, the freedom to casually buy Prozac doesn’t appear to be collapsing Thai society into a zombie apocalypse. The traffic in Bangkok is a disaster, but who knows—maybe without easy access to Prozac it would be worse!
The situation in Thailand contrasts with the US, where most of my loved ones haven’t even been able to obtain inferior Paxlovid. In America, doctors routinely veto Paxlovid prescriptions for healthy 70+ year-olds, pharmacies routinely veto valid prescriptions, and insurance companies routinely veto coverage of the $1400 monopoly-extortion cost. I’ve witnessed each of these things happening.
Some readers may note that we already have a Right to Try law. Some may also note that current law allows physicians to prescribe medicines off-label—meaning for uses that realistically might offer patients net benefit even though it’s not the specific purpose indicated on the medicine’s label. I refer such readers to Jake Seliger’s titanic struggle to obtain medicines that might save him from terminal head-and-neck cancer. Even for people at death’s door, the existing Right to Try and off-label prescription laws aren’t working in the real world.
The Seliger Right to Buy Law would create a mechanism where people would be given an option to sign a limited liability waiver affirming that they have been made aware of the results of available safety and efficacy testing. The law would apply to fully or conditionally approved prescription medicines, as well as FDA-authorized Investigational New Drugs. Under the liability waiver, the person would be allowed to buy the medicine. Drugs of abuse (e.g., opioids) would be excluded from the legislation.
Under Right to Buy, some people would undoubtedly make foolish decisions, as people sometimes do in all areas of life. But making the world a safer place for fools isn’t a strong argument for depriving everybody else of the right to make wise decisions for themselves. Moreover, revoking the controversial early-pandemic authorization of hydroxychloroquine didn’t stop fools from choosing it—all it did was encourage risky megadose lawlessness among fools. It’s as though we learned nothing from America’s disastrous experiment with prohibition of alcohol. It would obviously be better if people didn’t make the medically foolish choice to drink to excess, but Prohibition isn’t a safe or effective method for achieving such a goal.
I’ve been reflecting on the classic Ben Franklin quote: “Those who would give up essential Liberty, to purchase a little temporary Safety, deserve neither Liberty nor Safety.” If you ask my friends with long Covid, giving up the essential Liberty of choosing which medicines we put in our own bodies purchased us more than a little lasting Harm. If the Founding Fathers could have anticipated this state of affairs, I bet the Second Amendment would’ve included the right to bear medicine.
Tomorrow’s post: a fourth legislative proposal that would create new infrastructure for testing medicines.
Acknowledgements
I’m grateful to David Humphrey, Brad Queen, Andrew Rum, Jake Seliger, Chris Shiebler, Chris Tharrington, and my friends who used to work for FDA for helping me hammer out these ideas and for critical review of the article. I’m especially grateful to Jake for helping streamline the arguments with improved plain language.
Disclaimers
•The thinking behind this article comes from my experience as a professional vaccine developer. I receive licensing royalties for vaccines that are currently in preclinical development.
•I am not a licensed medical professional
•A few clarifying sentences have been added to the initial post in response to reader critiques (which I welcome!)
•This article is mirrored on my Medium account
Here’s an arbitrary example of the FTC appropriately policing unsupported medical claims: https://www.ftc.gov/system/files/warning-letters/covid-19-letter_to_herbal_arc.pdf