Author’s Note: This article is cross-posted from my Substack.
How does Leronlimab work?
Leronlimab is a humanized monoclonal antibody that antagonistically binds to the CCR5 receptor to block activation of immune cells and lower the release of cytokines. The development of Leronlimab started with mouse antibodies that bind to CCR5. Unfortunately, mouse antibodies can’t be directly imported into humans since they are attacked by the immune system as foreign invaders. That’s where next-level genetic engineering comes in. Researchers looked at the genes for human antibodies, identifying ones that were closest to the genes for the antibody that the mice produce. They then took the segment of DNA from the mouse antibody that coded for the antigen binding site and stitched that into the human antibody gene. (The antigen binding site is the key part of the antibody allows it bind to the CCR5 receptor). The result is a chimeric or humanized antibody which can be mass-produced in bacteria.
As alluded to, the specific place where these antibodies bind is the CCR5 (Chemokine Receptor Type 5) receptor, a “G Protein coupled” receptor that resides on the surface of cells, in particular immune cells such as macrophages. When the receptor is stimulated, calcium channels open up and Ca++ ions move into the cell, causing activation (movement) of the macrophages.
Leronlimab was originally developed to treat HIV, because the HIV virus uses the CCR5 receptor to get into cells. (By blocking the receptors, the HIV virus could be blocked.) Despite being under study since 2007, Leronlimab is still not FDA-approved for HIV, although it appears to be getting close. To treat HIV, it is given as a once-weekly at-home injection. Researchers have found many other uses, however. For instance, when Leronlimab blocks the CCR5 receptors on breast-cancer cells, it prevents them from moving around so that the cancer can’t move to other parts of the body, which makes the cancer easier to treat. Note that Leronlimab is not yet FDA-approved for any of these possible applications, so off-label use for COVID-19 is impossible.
In the case of COVID-19, infection by the SARS-CoV-2 virus induces stressed endothelial cells to produce CCL5. When CCL5 reaches T-cell and macrophage cells in lymph nodes and binds to their CCR5 receptors, it induces those cells to become activated and then move towards the source of the infection along the CCL5 gradient. Unfortunately, in severe COVID-19, the immune response can be so strong that it leads to tissue damage. CCL5 also induces the production of inflammatory cytokines including TNF and IL-6.
What do we know about the efficacy of Leronlimab?
CytoDyn Inc. published a press release on January 28th, 2020, announcing that it was beginning to evaluate Leronlimab’s use for COVID-19. In that press release, CytoDyn clearly explained the mechanism of action described above, noting that clinical experience in China found that many patients who died from COVID-19 did not die from the virus but from an overactive immune response causing inflammation and the infamous “cytokine storm”.
A study published in preprint form on May 5th, 2020, looked at 10 terminally ill COVID-19 patients on ventilators at the Montefiore Medical Center in Manhattan. The experimenters administered 700 mg of Leronlimab to each patient. Within three days they found that found that IL-6 had decreased in all of the patients, reaching healthy levels in two weeks. After two weeks six patients had recovered while four died (a 40% mortality rate). At that time the mortality rate for ventilated patients was said to be “as high as 88%” in New York City. So, while there was no control group in this study, one can argue there was an observed reduction in mortality here. While the results on reduced mortality are weak due to a lack of a suitable control, the biomarkers studied all showed a reduction of immune response. The researchers found a reduction of new immune cells manufactured in the bone marrow and a return of platelet cell counts towards normal levels. The researchers also found that the concentration of virus in the blood (viremia) decreased. In a TEDx talk, one of the authors, Dr. Bruce Patterson, claims that Leronlimab was responsible for the drop in blood virus concentration. He said this:
“Leronlimab restored CD8 T-cells and increased Granzyme A to better clear virally infected cells. It also inhibits Treg cells and repolarizes macrophages which both enhance the immune response against infected cells.”
I honestly do not understand these details or know how well they are empirically supported by this or other studies.
The mild-to-moderate trial did not meet its primary efficacy endpoint, but in a post hoc analysis in the subset of subjects with more severe disease, a higher proportion of Leronlimab-treated subjects (50%; 24/48) versus placebo-treated subjects (21%; 5/24) showed improvement in National Early Warning Score 2 – a risk score for “rapid clinical deterioration requiring critical care intervention” (p = 0.0223).
The severe-to-critical trial also did not meet its primary endpoint — considering all patients, the difference in Day 28 mortality between Leronlimab and placebo was not statistically significant (N=384, 2:1 split, p > 0.05). (Update: a commentor pointed out that the placebo group ended up being younger and was small, so unfortunately they missed statistical significance. You can see all the details here.).
However, the researchers then analyzed patients on invasive mechanical ventilation or ECMO. They found that if Leronlimab was added to the standard of care, then on the 14th day there was a reduction in mortality of 82% (p=0.0233, N=62) and an average reduction in the length of stay of 5.5 days (p=0.005, N=62). They also found a 400% improvement on a 7-point ordinal scale for COVID-19 severity when compared with standard of care.
There have been several clinical reports and anecdotes about patients on ventilators or ECMO who rapidly recovered after receiving a single dose of Leronlimab (see here (N=1), here (N=4), here (N=1), and here (N=1)). A somewhat larger observational study with N=23 patients reported that after 30 days, 74% no longer required hospitalization. Six out of the seven patients that required ventilation survived. The biomarker results were somewhat mixed – while the researchers found evidence of reduced immune activation in the patients who received Leronlimab, they also found that the inflammatory marker CRP didn’t decrease until after two doses were given. Another small study on N=3 lung transplant patients with COVID-19 found a decrease in CRP after one week.
On March 29th, 2021, the Phillippines’ FDA began issuing compassionate use authorizations on a per-patient basis and for up to one year. Incidentally, one of first two patients was a former President of the Phillippines. In April compassionate use authorizations were given to 28 critically ill patients.
Why hasn’t the FDA acted?
CytoDyn’s failure to reach either their primary or secondary endpoints in their Phase II/III trial on critically ill patients is undoubtedly a major blow. The company has not yet applied for an Emergency Use Authorization (EUA), and it seems this failure is the reason why. (News reports from August 2020 saying that company had applied for an EUA turned out to be incorrect.) CytoDyn is moving forward, however, and has filed a new protocol with the FDA that will study four doses given over four weeks to critically ill COVID-19 patients.
The use of any immunomodulator like Leronlimab is clearly a double-edged sword. It makes sense that it would only be helpful in the most severe cases. This is what the two clinical trials showed – they showed a significant effect on mortality for patients on ventilators and no statistically significant effect on other patients. Unfortunately the analysis of the patients on ventilators was a post-hoc analysis, which is frowned upon in science due to the possibility of data dredging. So clearly the science is not settled here.
Let’s consider this from an ethical point of view. Patients who are in ICUs and on ventilators have a high chance of dying. Inflammation macrophage activity, and excess cytokines are implicated in many COVID-19 deaths. There is strong evidence, going back over a decade, showing that Leronlimab decreases inflammation, macrophages, and cytokines. Leronlimab is known to be a very safe drug (prior to 2020 no serious side effects have been found in nine clinical trials with more than 800 patients). Even if Leronlimab only saves 20% of those to whom it is given, then one can argue we have an ethical obligation to do so. It is a somewhat expensive drug (for HIV patients getting weekly therapy, it costs about $2000 per dose; another source suggests it would cost about $1100). However, keeping someone in the ICU costs around $3,000-$10,000 per day. So in addition to saving lives, Leronlimab could also save money as well by reducing the amount of time patients need to spend in the ICU. This could lead to second-order life-saving effects in places where ICU beds are in short supply.
“I believe that if there is a drug that can help someone who is on a ventilator or ECMO and it can save them, then whatever small population that is, it is useful — that is my opinion. I have no financial interest or commercial interest or any other interest of any sort with them (CytoDyn).”
I agree. While the evidence is not conclusive, we have good reason to believe Leronlimab can help very critically ill COVID-19 patients such as those on ventilators or ECMO. There are likely gains from receiving Leronlimab for such patients and very little downside, especially if the patient is considered terminally ill. So not allowing doctors access to Leronlimab risks many unnecessary deaths. The drug should be an especially impactful tool in places like Brazil and India, where there are currently shortages of ICU beds and ventilators.
Dan Elton, Ph. D., is Director of Scholarship for the U.S. Transhumanist Party. You can find him on Twitter at @moreisdifferent, where he accepts direct messages. If you like his content, check out his website and subscribe to his newsletter on Substack.
For an overview of the possibilities of Leronlimab to save the lives of critically ill COVID-19 patients, watch this brief video by Random Ryman.
A Summary of Daniel P. Carpenter’s “Reputation and Power” – A Titanic Book on the History of the FDA
Note from the Editor: In a conversation on Clubhouse that I hosted, entitled “Is the FDA moving too slowly with vaccine approvals?”, Willy Chertman articulated a number of nuanced points about the FDA. He had recently finished reading Reputation and Power, an 856-page book on the history of the FDA. I asked Willy to organize his notes on the book so that the USTP membership could learn his key takeaways from the book and learn more about the history and role of the FDA. Willy graciously accepted my request. I have edited his notes somewhat for length and made some minor copyedits. A few key takeaways are bolded.
– Daniel C. Elton, Director of Scholarship, United States Transhumanist Party, April 2, 2021
Reputation and Power Organizational Image and Pharmaceutical Regulation at the FDA by Daniel P. Carpenter 856 pgs. Princeton University Press, 2010
Reputation and Power is a very deep dive into the history of the FDA and the reputational universe that it inhabits and creates. The gist of the book is that reputation management is the best lens to understand the FDA, not “public interest” versus “regulatory capture”. The political and regulatory power of the FDA is bound up inextricably with how Congress, the pharmaceutical industry, academic medicine, and consumer-protection groups view it. By virtue of the size of the market it regulates and its pre-market approval power, the FDA is likely the most powerful regulatory agency in the world.
Because of the length of the book and the variety of topics it covers, I’ve split this book summary into two parts. The first half covers the history of the FDA and the second half covers the themes and lessons I learned from the book. Though Carpenter covers up to about 2010, time constraints meant that this summary only covers up to 1992. Hopefully future posts will cover the remaining material.
The origin story of the FDA in popular political mythology begins with thalidomide, but Carpenter does an excellent job showing how the FDA started as an obscure branch of the USDA, originating with the Pure Food and Drug Act of 1906. In the early 1900’s the FDA had nothing but the ability to confiscate dangerous drugs or compounds from the market. Later, in a pattern that will repeat itself, forces within and without the FDA made good use of the dictum “Never let a crisis go to waste.”
The context is that the early 1900s were a stupendous time to be a patent medicine salesman– a synonym for charlatan. Apart from aspirin, it’s not clear that any patent medicine of that time ever turned out to be effective. Medicines to lull your baby to sleep relied on opium or alcohol, and sulfonamide antibiotics were not invented until the 1930s, and even then their manufacturing process was initially unreliable . Yet the patent medicine trade was booming. In an interesting historical irony, John D Rockefeller, through his foundation’s funding of the Flexner Report, which birthed medical education as we know it, ended the traveling medicine salesman/huckster-doctor profession – which his own father had been in.
The Pure Food and Drug Act of 1908 required accurate labeling of products and also gave the FDA the power to seize and destroy products that violated the law. Importantly, this did not give the FDA the power of pre-market approval, which is its most important power today. Though the FDA was prohibited from directly lobbying for more authority, many in the agency and their Progressive congressional allies believed the FDA was weak and underfunded relative to the growing pharmaceutical industry it was supposed to regulate. In 1935, New York Senator Copeland had tried to pass legislation that would strengthen the FDA, aided by women’s political organizations and the Consumers Research group, but his attempt had failed in the House.
There had been previous small-scale pharmaceutical disasters, but the Sulfonamide Elixir stood out for scale and the media attention that it garnered. The leading role that the FDA eventually took in handling the disaster, as well as the relationship with the media that it cultivated, also made this disaster special. This is the beginning of the sidelining of the American Medical Association (AMA), which had previously been one of the centers of organized medical power.
People became seriously ill from its consumption, and by late October 1937, at least seventy-three of these had died. The FDA, assisted by state and local health officials and the American Medical Association, commenced an effort to secure as much of the compound as possible before any more was consumed.
The media ran stories of heroic FDA officials working late into the night trying to confiscate a dangerous drug, and the story re-surfaced whenever another death was reported. The cherry on top of this story was a report released by the Secretary of Agriculture, the Campbell-Wallace Report:
‘A few simple and inexpensive tests,’ the sort that would be performed by the company before marketing and analyzed in a pre-market review process by the FDA, would quickly have evinced the elixir’s “toxic properties.” Translation: with a pre-market review process, none of this would have happened.
In February 1938, Copeland’s S.3073 was again considered in the Senate. Women’s groups and public-health leagues now lobbied intensively for its passage, and their rhetoric made clear the centrality of the Wallace report in the new deliberations.
Contrary to the theory of regulatory capture, large pharmaceutical firms, who might have expected to benefit from a regulatory moat, did not advocate for the 1938 Food, Drug, and Cosmetic Act. Instead, it was Progressive politicians pressured by consumer protection groups, women’s groups, and forces within the FDA that advocated for it.
The 1938 Food, Drug, and Cosmetic Act gave birth to modern pharmaceutical regulation: The four enumerated powers—(1) pre-market review and notification, (2) prohibition (or withdrawal authority), (3) labeling regulation, and (4) compulsory disclosure of all drug contents (active and inactive)—have become assumed and core legal features of pharmaceutical markets
While the 1938 act did not contain an efficacy provision, Carpenter shows how this was effectively smuggled into drug regulation anyways, with officials saying:
It has been emphasized that there is no arbitrary standard of safety; it is a relative matter in which the toxicity of the drug must be weighed against the therapeutic benefits which its use will bring about.
In the 1940’s and 1950’s the FDA gradually raised the standards for drug approval, and its Division of Pharmacology drew many talented pharmacologists from academia. Throughout the FDA-cultivated “reputational ambiguity”.
The simultaneous ambiguity and fear-provoking stance of investigational regulation was, in part, FDA officials’ manner of expressing and maintaining the agency’s gatekeeping role, even as they did not fully comprehend…
Though a Randomized Controlled Trial was not yet an explicit requirement for drug approval, the FDA gradually raised the bar on the required toxicity, stability, and drug metabolism studies. As pharmacology refined its methodology, the FDA required more and more from drug companies, viewed amateur physician-directed trials with more suspicion, and by being the central gatekeeper of pharma, made the whole field more rigorous and scientific.
The FDA used a variety of carrots in addition to the “stick” of gatekeeper:
From the beginnings of the Eisenhower administration and probably earlier, FDA officials acted intentionally, strategically, and with foresight to establish numerous committees of liaison to the professions. Agency officials established not just medically specialized “advisory committees” of the sort that became institutionalized in the late twentieth and twenty-first centuries, but also more temporary committees that helped the FDA recruit and retain allies and consultants.
The Administration cultivated relationships with academic luminaries in pharmacology, and many of their promising students became part of it. Dr. Frances Kelsey, a Professor of Pharmacology at South Dakota State University who had done important research on the teratogenic effects of drugs on animal fetuses, was an archetypical example. She had come highly recommended to the agency, and though she developed a reputation as being a more exacting drug reviewer than most, the agency as a whole had become more cautious over the decades.
Thalidomide, marketed as Contergan in Europe, was being widely used there as a sedative, and the company (Merrell) submitted a drug application to the FDA. Kelsey held up the application due to safety concerns, even in the face of vigorous company complaint, and was vindicated when it was later tied to an outbreak of birth defects in Europe.
This might have remained the stuff of obscure industry history if the antitrust subcommittee led by Senator Estes Kefauver had not leaked the details of the story to the reporter Morton Mintz. Kefauver, who had been leading high-profile hearings on the “drug industry” and had been trying to shorten their drug patent periods as well as incentivize generic drug prescription, gave Morton Mintz key data about the Thalidomide saga as well as Frances Kelsey’s role in it.
1962 Amendments and After…
The Drug Amendments of 1962 were opposed by the Pharmaceutical Manufacturers Association, but the FDA’s star was ascendant with the Thalidomide crisis having shown its worth.
At their core, the Amendments contained three provisions governing pharmaceutical regulation (table 4.1). They first required affirmative evidence of “effectiveness” and “safety,” evidence in the form of “adequate and well-controlled investigations,” before any “new drug” could enter into interstate commerce. Second, they required designation of a medicine as an Investigational New Drug during its period of experimentation (and submission of the IND to the agency), and empowered the Administration to nullify this status (and hence development of the drug) if research protections for patients were not being observed, if the clinical trial protocol was not sufficiently rigorous, if pregnant women were being exposed to teratogens, or if any evidence of research as commercialization emerged. Third, they required the Administration to lay out and enforce new procedures to protect the interests and rights of patients in medical research.
The impact of the law was significant: Before 1960, there are no references to phased trials in the American and European medical literature, and there is no reference to a “Phase 3” study in Western medical literature before 1964. In the early 1960s, reports of “Phase 1” and “Phase 2” experiments appear haltingly, then rapidly near the end of the decade (table 4.2). What is more, American researchers and doctors began to reflect systematically on the relationship between earlier phases and later phases.
In the 1960’s, as the FDA continued to gain in power, it met with some moderate resistance from organized medicine. These incidents illustrate the reputational politics that the FDA is sensitive to: when comments by Frances Kelsey at a medical conference were taken to indicate that patients always had to be informed that they might receive a placebo, a leading clinical trialist at Harvard, Henry Beecher, wrote to the FDA Commissioner. In another incident, the FDA’s General Counsel William Goodrich implied that medical journals might be liable for misleading advertisements, which prompted a prominent Cornell pharmacologist Walter Modell, who had previously been an ally of the FDA, to publicly rebuke them.
In both cases, to varying degrees, those statements were publicly walked back by the FDA.
Sometimes public dissent against the FDA could damage one’s career, even for the most credentialed academic, as Louis Lasagna’s advocacy for combination antibiotics demonstrated:
Lasagna’s advocacy for Panalba was risky and vocal, and it marked the beginning of a steady decline in his status among medical academicians. Lasagna’s name was golden in the 1950s, when he had authored pathbreaking papers on the placebo response and clinical trial design, when he had founded the nation’s first clinical pharmacology department at Johns Hopkins, and when he had testified in support of efficacy standards at the Kefauver hearings in 1960.
…The diverging paths of Louis Goodman and Louis Lasagna marked the splintering audiences of the Food and Drug Administration as well as the agency’s enduring scientific legitimacy. In the status-conscious world of academic medicine, Louis Lasagna never fully recovered from the Panalba battle.
An important feature of FDA history in the 60’s and 70’s was the congressional hearing. Because of changes in how congressional committee chairs were chosen, congressional hearings became more important in this period. The obligation of FDA officials to appear before Congress when requested and to testify was an important check on its power and a venue where its public reputation was maintained.
Criticism from an industry-friendly senator could strengthen the FDA’s image as pharma policeman while an FDA whistleblower like John Nestor testifying to its regulatory inadequacy could force less accommodation with the drug industry by effectively shaming the FDA into more stringency.
Congressional hearings seemed, at least in the 1970s, to be the strongest check on FDA behavior. When Senator Gaylord Nelson read The Doctor’s Case Against the Pill, and started hearings into the FDA’s approval of it, and its widespread use, the end result was, after much criticism from prestigious physicians, scientists, and consumer safety advocates, the creation of the patient-package-insert. (see chapter 9)
An illustration of how the FDA sought to collaborate with other scientific institutions can be seen in how it dealt with medications that had been approved before 1962 and the formal recognition of an efficacy standard. Thousands of drugs had been approved in the 1940s and 1950s on the basis of evidence that were wholly inadequate by 1962 FDA standards. These drugs had now been incorporated into clinical practice for many years, and so any FDA action on them would be seen as doubly intrusive by physicians. To strengthen their position and reduce their workload, the FDA collaborated with the National Academy of Sciences to evaluate these old drugs.
The 1970s probably marks the peak of the FDA’s power, as a series of court decisions endowed the Administration with the authority to issue rules with “the force of law” and creating “a presumption in favor of agencies that claimed legislative rulemaking authority”. When the FDA does not want to create formal rules, which require an elaborate process, it also uses “nonbinding” guidance documents which are, in reality, quite binding:
Because the Administration has the ultimate say over whether and when a new drug will be marketed, its mere suggestions and intimations induce compliance even where they are not backed by legal authority. The agency’s use of Federal Register policy statements and “guidance documents” (nonbinding statements of policy that are not customarily published in the Federal Register but are published under the auspices of the FDA itself) permits its officials to avoid the more costly and elaborate process of formal rulemaking, while still gaining acquiescence with its regulatory wishes.
With its arsenal of new authorities and the powers that flowed from them, the Administration began in the 1960s and 1970s to exercise vast sway over the medical marketplace. Familiar over-the-counter remedies and doctor-prescribed pills vanished. The place of the general practitioner in drug development waned to the point of disappearance, as companies could no longer rely upon doctors’ casual observations or observations of patient histories to buttress claims of safety and effectiveness.
Though there were occasional media critiques of the FDA in the late 1960s, the 1970s and 1980s were really the beginning of a sustained critique of the FDA from the right. This came from many quarters: business-friendly publications like the Wall Street Journal, prominent economists like Sam Peltzman who were quantitatively assessing regulatory impact on innovation in various industries, and industry organizations. In 1974, the American Enterprise Institute played a key role by launching the AEI Center for Health Policy Research, which brought together pharmacologists, industry officials, and economists. The “drug lag”, coined in 1972, was the time between a drug being introduced in Europe vs the US, and along with the cost-benefit analysis of regulation, was a key critique of the administration. A sign of the success of these critiques was that while top FDA officials publicly rejected the premise of the drug lag, inside the administration, increased attention was paid to the drugs that had already been approved in peer countries.
Even as libertarian-aligned think tanks, academics, and newspapers criticized the FDA for being too cautious, the opposite critique was sustained by consumer-protection groups throughout this period.
No voice more cogently or passionately articulated the case for rigorous drug safety standards than that of physician-activist Sidney Wolfe, and no arrangement better amplified the concerns of Wolfe and his allies than the committee systems of the U.S. House and Senate. Wolfe helped to found the Health Research Group, a subsidiary of Ralph Nader’s Public Citizen, in 1971.
Wolfe had no formal role in the Administration, but by careful use of administrative procedures like FOIA requests and citizen petitions, combined with journalist connections, he could push the FDA into action when it was reluctant. The whole section on him is worth excerpting:
Wolfe’s principal weapon was his threat to the Administration’s consumer protection image. The credibility of this threat depended on a set of strategies by which Wolfe and his organization could embarrass the agency, extract data from it, influence the FDA’s decision agenda, or (less commonly) induce courts to force the agency to take a given action.
First, he was adept at using administrative procedures refined in the 1970s, including Freedom of Information Act (FOIA) requests and citizens’ petitions, to pry important drug safety and procedural information out of the agency, or to place contentious and uncomfortable items on the Administration’s agenda. Second, Wolfe exploited the public comment period of the FDA’s advisory committee meetings on drugs, an opportunity that offered a public venue albeit with brief appearances. Third, Wolfe appeared regularly at congressional committee hearings as an invited guest, and his ties to committee chairs and their staff gave him indirect access to committee powers (replete with tools for discovery). In the 1970s and 1980s, Wolfe worked partially in tandem with subcommittee chairmen ranging from Lawrence Fountain, Henry Waxman, and Ted Weiss in the House to Senators Edward Kennedy and Abraham Ribicoff.
Fourth, Wolfe maintained ties to journalists over a period of several decades (Morton Mintz, Christine Russell, Philip Hilts, and others). He used these journalists to publicize actions (such as the taking of surveys of FDA medical officers) that would otherwise not have received much public attention. Finally, Wolfe and his organization shrewdly used lawsuits and the threat of legal action to induce rulemaking and jar the agency into action. The strategies of administrative maneuvering, advisory committee testimony, appearances at congressional hearings, and media access became much more pivotal to Wolfe’s leverage over the FDA after 1979, when a federal judge limited the right of Nader’s group to sue agencies on behalf of the general public.
A clear demonstration of the conservative sentiment of the times was the backlash against the FDA when it attempted to regulate supplements more stringently:
In August 1973, the Administration published fourteen final regulations and five proposed rules that governed the labeling of foods and food supplements.
Led by Wisconsin Senator William Proxmire, Congress in 1976 passed an amendment to the 1938 Act which extended the “generally recognized as safe” (GRAS) exemption for vitamins and minerals to dietary supplements. The “Proxmire Amendment” prevents the Administration from restricting the potency of a vitamin or mineral supplement based on either of two criteria: (1) food misbranding charges or (2) on the premise that the supplement would qualify as a drug if it surpassed the agency’s desired level of potency. For almost two decades, FDA officials largely backed off from rule-making on supplements.
In the late 1990s, the FDA again attempted to regulate supplements and faced a similar legislative rebuke.
Overall, though the FDA faced some setbacks when it attempted to regulate supplements, it survived the conservative turn in the 1980s with its power and reputation mostly intact, an impressive achievement for such a powerful regulatory agency. In some ways, the criticism from the libertarian perspective may have strengthened the FDA’s reputational position:
[I]t would be wrong to conclude that the persistence of criticism and scrutiny has undermined the agency’s reputation and power. It is certainly plausible that criticism has depleted morale, and on occasion publicity and hearings have weakened its leadership.
For those who have paid attention to the increasing polarization of US politics over the last 20 years, this may sound familiar – criticism from your enemies can be a reliable signal to your allies that you’re on their side. In a similar way, pharma and libertarian criticism of the FDA may strengthen its reputational position in the views of consumer-protection groups and allied groups.
AIDS and Cancer
The “drug lag” criticism was a long-lasting and effective critique of the FDA, but Carpenter seems to argue that the most significant reforms of the FDA were really brought about by inter-agency squabbles over cancer drugs and the moral outcry of the HIV epidemic. The interactions of AIDS activists and the FDA are probably more well-known than the turf battle between the National Cancer Institute (NCI) and the FDA, but it appears that the latter may have been more influential.
NCI-supported investigators were developing combination chemotherapies that were very promising, modeled after the lucky discovery of platinum’s anticancer potential by physicist Barnett Rosenberg. From 1975 to 1977 Robert S. K. Young, an FDA medical reviewer, repeatedly took issue with the study protocols of combination chemotherapy trials and halted several trials. A prominent MD Anderson oncologist, Emil Freireich, retaliated by reading out a list of complaints about FDA interference into NCI-funded trials at an important meeting of President Ford’s Cancer panel. Benno Schmidt, the chairman of the panel and a prominent official in Ford’s Administration, agreed with him. Young’s supervisor William Gyarfas stuck by his subordinate.
Young overreached when in a 1977 Advisory Committee he attempted to more aggressively regulate the clinical trials of combination chemotherapy and effectively eliminate dosage variation in chemotherapy without preclinical studies. The Committee voted against his proposal, and this caught the attention of Richard Crout, then-head of the Bureau of Drugs. Crout met with the head of NCI and basically admitted his subordinate had overreached, and they worked on a series of protocols to relax FDA restrictions for terminally ill patients.
While this might have been the end of the bureaucratic conflict, the NCI had decided to escalate:
House Health Subcommittee chairman Paul Grant Rogers (D-FL) released a December 3, 1976 letter from the American Cancer Society calling for full “NCI control over the testing of new anticancer drugs, instead of FDA control” for nonprofit research sponsors. This transfer of power would be accomplished, as ACS representative Nathaniel Polster hoped, by amendments to the National Cancer Act. While NCI officials were largely silent about the ACS proposal, M. D. Anderson’s Freireich was not. He openly called for deep “structural changes” so that the “FDA can never again shut [down cancer research].”
This would be a huge escalation. If the NCI succeeded in wresting control over regulation of a specific disease, it would set a precedent for continued piecemeal diminishment of FDA authority:
And to Administration officials concerned about the maintenance of their authority over clinical trials, the ACS-NCI proposal raised the specter of debilitation by precedent. Once an exception for one category of illness was carved out of the FDA’s power over clinical research, it was feared, demands from representatives of other diseases would soon follow. As if to confirm the FDA’s premonitions, Solomon Garb of the Citizens’ Committee for the Conquest of Cancer seized upon the NCI-FDA dispute and called for ending FDA power over any clinical trial in which patients have “poor prognoses.” Garb’s remarks introduced a different and more formidable voice to the growing chorus of criticism, in part because the Citizens’ Committee was an amalgam of union, scientific, corporate, scientific, and civic leaders…
This proposal didn’t come from a fringe libertarian or anti-government organization but from respected sources. The NCI and the FDA eventually came to agreement:
DeVita and Crout settled on a new procedure whereby “stop orders” for NCI-sponsored trials for terminally ill patients could be issued only by the Bureau of Drugs chief (Crout himself at the time) or the deputy chief (Marion Finkel, at the time). The two groups later agreed to use the nation’s forty comprehensive cancer centers to mediate the surveillance of research protocols. The new arrangement embedded meaningful victories for both sides. For the Institute, the new procedures effectively bypassed Robert Young and, more notably, William Gyarfas, Director of the Oncology Drugs Division. NCI officials and their grantees would now deal more directly with Crout and Finkel, who were more trusted within oncology networks. And the Institute’s détente with the FDA helped it to buttress claims that it was being “dominated”…
The Administration would retain full control over cancer trials. The NCI would now officially acknowledge and defer to the IND regulations, and in so doing it would develop a “Master Plan” of drug development…
By January 1979, the dispute had issued in a document with odd legal status but firm organizational commitments (figure 6.1). An informal procedure for resolving FDA-NCI disputes appears to have been worked out in April 1979. The procedure entailed four steps: (1) first devolving disputes to the lowest managerial level deemed suitable for negotiation—the Associate Director of the Bureau of Drugs (at that time, Finkel) and the Director of the NCI’s Cancer Treatment Division (DeVita), then (2) to negotiations between the Bureau of Drugs head (Crout) and the NCI Director, then (3) to negotiations between the FDA Commissioner and NIH head, and (4) finally, determination by FDA Commissioner himself if none of these previous options produced a resolution. The memorandum bound neither agency legally. It was rather an informal institution founded in a political equilibrium, a mutual wish to avoid the spectacle of open, public conflict among two agencies whose reputations generally benefited from being out of the public eye.
While the NCI and FDA struggle would lead to a durable compromise between the two agencies, the Laetrile saga would come closest to threatening FDA power, and yet ultimately affirm it. From a libertarian perspective it is darkly amusing that the drug that came closest to breaking the FDA’s stranglehold was the charismatic but ultimately useless drug Laetrile.
Laetrile had been developed by an Ernst Krebs (of no relation to the Krebs cycle) who had failed out of medical school and whose father, incidentally, was also a conman physician. At various times its supporters described it as vitamin B17, as a relative of cyanide, and as amygdalin. NCI scientist Dean Burk had developed a molecular model that was supposed to demonstrate Laetrile’s anti-tumor activity and a San Francisco foundation applied to the FDA for an IND for experimentation.
Their IND was ultimately rejected by the FDA, which cited problems with the sponsors and monitors of the trial and its design. The key difference between the FDA’s rejection of Laetrile and its previous policing of quack medicines was the FDA exerting its power on the IND stage. This was a rhetorically powerful difference.
What most bothered many Laetrile supporters and their distant sympathizers was not the absence of Laetrile from the drug marketplace, but the absence of a permit for testing. Appropriating the juridical metaphor of a “fair trial,” they linked a populist ethic of self-medication to issues of justice and to more progressive norms of academic and intellectual freedom, the liberty of research and exploration of ideas. … By pressing the case for a total ban, by publicizing its seizures, and by assisting with state and federal prosecutions of Laetrile distributors, the Administration had resurrected a face that had been nearly invisible since the 1950s: the FDA as police.
Newspapers ran headlines criticizing the FDA for overreach. Organizations for therapeutic freedom sprung up across the country and a bill sponsored by Representative Steve Symms that would repeal the efficacy provisions of the 1962 amendments attracted over 100 sponsors. Several states passed laws legalizing Laetrile. The anti-FDA sentiment was nearly mainstream: Time Magazine, The Wall Street Journal, and the New York Times all ran editorials with some support for Laetrile proponents, or at least criticized the FDA’s overreach.
From the FDA’s perspective, several court cases were going in an unwelcome direction. Lower courts had issued an injunction against seizure of Laetrile, had decided that the FDA had the duty of showing lack of safety, not the sponsor affirmative proof of safety, and that the FDA had not exercised due process in its Laetrile ban. Since the regulatory power of the FDA was inextricably bound up with its flexible ability to issue rules and the affirmative requirement of drug sponsors to show safety and efficacy, these rulings were a threat to the FDA. In recognition of this enormous pressure, the FDA Commissioner did two contradictory things: one, he affirmed his agency’s judgement that Laetrile was ineffective and dangerous; two, he granted an IND to the NCI for Laetrile. In a PR coup for the Laetrile camp, they also testified before Congress to the Health and Scientific Research Subcommittee. The ability of the agency to offer different faces to different audiences is a recurring theme of Carpenter’s, who views it as key to the FDA’s long-term success.
In June 1979, in Rutherford vs United States, The Supreme Court reversed the Tenth Circuit, which had previously ruled that the FDA could not regulate drugs given to terminally ill patients. It was a powerful affirmation of the FDA’s regulatory authority. Though at this point the FDA could have likely dropped the Laetrile IND for any number of reasons, the FDA issued a conditional approval for Laetrile’s IND, which was set to be tested at rigorous NCI-affiliated institutions that the FDA trusted.
The Supreme Court decision, followed by the very public death of actor Steve McQueen, who had pursued a number of alternative medicine therapies including Laetrile after a mesothelioma diagnosis, led to the gradual decline of Laetrile’s political power. The FDA post-Laetrile had its legal power affirmed over every part of medicine: terminally ill patients, cancer patients, whether a given drug was even a legitimate experimental drug, etc.
Like the NCI and FDA power struggle, the AIDS crisis resulted in substantial concessions by the FDA. Unlike the former, the AIDS crisis played out much more publicly, and instead of bureaucratic warfare, the battle was a reputational one. The primary strategy of AIDS activists was to attack the FDA’s good name– instead of a public health agency and “protector of the American consumer” they sought to cast it as a villain who was killing AIDS patients through its slow and inflexible procedures. Until the 1990s AIDS was a slow death sentence, and in the early 1980s it was still poorly understood, with an official announcement by HHS Secretary Margaret Heckler that AIDS was caused by HIV occurring only in 1984. Retroviruses had only been discovered in 1970, and there were no targeted therapies for them until the HIV antiretrovirals.
An important advantage that AIDS activists had was that decades of organizing had left the gay community with many highly effective and experienced community activists. Many of them went on to form important groups: the most prominent of them were Gay Men’s Health Crisis, AIDS Foundation, Project Inform, and ACT-UP. Gay men were also highly concentrated in urban centers and in some places, like San Francisco, had achieved some degree of political power. Nancy Pelosi, a rising star in the Democratic Party, was sympathetic to many gay activist groups and a Congresswoman. All of these resources would eventually be mobilized against the FDA.
A key event was the story of HPA-23 and Rock Hudson. Rock Hudson, a movie star who had been diagnosed with AIDS in 1984, died of AIDS in 1985. Newsweek reported that before his death he had traveled to Paris to receive an experimental HIV treatment, HPA-23, which was being given there, though under poorly controlled conditions and with little good evidence. The FDA had banned even its experimental use in the US because of severe liver toxicity concerns; it then reversed course and allowed testing in 1985, likely due to the Newsweek story. Well-done trials in 1986 in the US later demonstrated severe toxicity and no efficacy, vindicating the FDA’s earlier caution.
The first effective treatment for HIV was azidothymidine (AZT), which was being developed by Wellcome, a reputable drug company that had substantial experience with the FDA. To the FDA’s credit, the AZT path to approval was remarkably quick: the company first started investigating AZT in June 1984 for possible HIV activity in-vitro; notified the FDA in April 1985, submitted an IND in June 1985, the FDA approved it in a week, and the first clinical trial (Phase 1) began in July 1985.
Phase 2 trials which had begun in February 1986 were halted early in September 1986 due to clear signs of treatment success, and AZT was officially submitted to the FDA for approval in December 1986. Eileen Cooper, a rising young star at the FDA, was in charge of reviewing it, and had been reviewing the AZT data for months before the official submission date. Even before the most militant AIDS activists had begun pressuring the FDA, she had been discussing with others on ways to speed and streamline the approval process.
She took two important steps. First, in September 1986 she had released AZT for compassionate use to 4000+ AIDS patients, which likely saved many lives. Second, she sought the support of the FDA’s Advisory Committee on Ineffective Drug Products in a January 1987 meeting, which would symbolically back up the FDA’s decision to approve AZT on the basis of a single prematurely ended clinical trial. This would achieve two contradictory goals: the rapid release of a likely effective drug to suffering patients; and satisfy the consumer-protection and public-health voices that generally urged caution.
Thus, even before much of the publicized anti-FDA activism, the FDA had demonstrated flexibility and speed in approving AZT. However Larry Kramer, a prominent playwright and activist in the gay community, viewed this as grossly inadequate, and penned a 1987 essay in the NYTimes attacking the FDA. Carpenter is skeptical of Kramer’s specific claims:
Kramer’s essay is shot through with inaccuracy and hyperbole. Of the therapies he mentions, only ddC (zalcitabine) emerged as a recognizably and broadly effective treatment for HIV/AIDS in the ensuing two decades—and its development had been accelerated by the Administration at the very time that AIDS activists were expressing strong doubts about it. Furthermore, many who perceived organizational problems at the agency—including journalists at the New York Times but also the George H. W. Bush administration—saw less a malady of bureaucracy and more a deficiency of resources. Like other AIDS activists, moreover, Kramer was equating the FDA with the Reagan administration when in fact much of Reagan’s and his administration’s ignorance of or indifference to AIDS was unrelated to FDA policy or regulations… Yet for all of its shortcomings and simplifications, and indeed because of them, Kramer’s essay was politically effective because it projected a simple, accessible, and forceful threat to the FDA’s reputation. Like much of the portraiture emerging from AIDS activists, it recast the Administration in terms and symbols diametrically opposed to those fashioned by Young, Cooper, and Tabor in the review and approval of AZT. In some ways, the FDA was being cast as a generalized but faceless bureaucracy, as an inefficient, an “intransigent,” “callous,” and inaccessible organization. In other ways, it was the Administration’s very gatekeeping power—over drugs themselves (the NDA process) and over clinical trials (IND approvals)—that was under attack. By serving as a “bottleneck,” a public health agency dedicated to consumer protection was lengthening the “roll-call of death.” Instead of raising genuine and substantive issues regarding clinical trial design with AIDS drugs, the Administration was in Kramer’s depiction imposing classic “red-tape” constraints upon medical research, nitpicking research protocols, shuffling words and sentences.
Beyond criticizing the FDA, local activists and physicians also directly subverted the traditional placebo-controlled trials:
Doctors would lie about their patients’ previous disease status to secure patient enrollment in a trial. Activist physicians and health-care workers would examine a pill to expose its placebo content. Once a placebo was identified, activists and patients would substitute the genuine treatment for the research subject, using supplies procured underground.
In California activist Martin Delaney ran an unofficial trial with “Compound Q”, distributing it to patients that had failed to respond to other drugs and bypassing the FDA entirely. Part of the project’s explicit aim was to push the FDA harder against its traditional approach to drug development.
Activists like Delaney and Kramer also personalized their criticism of the FDA by singling out Ellen Cooper, the medical reviewer for AZT (and the FDA’s unofficial point-person for HIV drugs), attacking her in the New York Times and in ACT-UP manuals. The peak of activist militancy was probably the October 1988 Rockville demonstration against the FDA. More than 1000 activists gathered in front of the FDA and displayed a banner that read, “Federal Death Administration”. Of note, these protests occurred after the AZT approval. Media coverage followed the protest, and the FDA responded by hosting a press release which effectively restated the new procedures that Ellen Cooper had developed for AZT. This announcement made newspaper headlines, though activists viewed it as a publicity stunt, not as a substantive change.
The most substantive change was probably the “Subpart E” regulation, which would allow for the possibility of a single expanded Phase 2 Trial sufficing to prove safety and efficacy for certain debilitating diseases. Again, this formalized the process that AZT had undergone, and this and other changes had actually been foreshadowed by the FDA’s behavior with cancer therapeutics. This is a recurring observation by Carpenter – phase shifts in FDA behavior are usually preceded by more subtle but similar behavior years or decades before. AZT had sped through the FDA approval process faster than any drug before – but it followed the template of cancer drugs before it. Continuity, not revolution, is the running theme of the FDA’s history.
ACT-UP was very strategic: some elements of conservative politics had long wished for a repeal of the 1962 Kefauver-Harris Amendments, but ACT-UP made sure to maintain “organizational and rhetorical distance” from those groups, which likely preserved their credibility with other forces. ACT-UP overplayed their hand in 1991. With the looming threat of another protest, ACT-UP demanded a 30-day review of DDI, which was undergoing the reformed approval process that incorporated surrogate endpoints (CD4 counts) and a historical controls of the patient’s previous history. Though they received a letter from the FDA Commissioner in response, the approval took more than 30 days, and so ACT-UP staged another protest. It was a dud in comparison to the 1988 protest, with many fewer protesters and little media attention.
This was likely because the FDA had neutralized much of the group’s criticisms by moving quite quickly with approvals and liberally allowing treatment INDs (which allow “compassionate use” of drugs outside of trial settings). The FDA had also begun reaching out to less militant AIDS groups and invited activists into Advisory Committee meetings. In a move reminiscent of how the FDA recruited prestigious academics in the 1950s and 1960s, the FDA waved the “carrot” of being a (partial) insider to neutralize opposition. Another factor may have been a changing media narrative that argued (apparently without evidence) that Reagan-era cuts were the reason for FDA slowness, which exonerated the FDA of blame.
The unofficial buyer’s clubs popularized in film were treated deferentially by the FDA in comparison to Laetrile sellers decades before. It tread lightly, likely in fear of invoking the “FDA as policeman” image.
Something inconvenient for the libertarian and AIDS activist critique of the FDA was the “medical reversal” on the DDC/DDI/AZT combination therapy. After DDC and DDI were approved in 1992 on the basis of surrogate endpoints showing boosted T-cell counts, follow-up studies failed to show benefit relative to AZT alone, and the combination was more toxic than AZT alone. This led to an internal debate in the AIDS-treatment-activist sphere. Here is one account, from Treatment Action Group, an organization that successfully pushed for stricter AIDS drug standards instead of continued loosening of regulatory standards. For a book-length treatment on the loosening of regulatory standards in the cancer world, and the consequences that followed, read “Malignant” by Vinay Prasad.
A less visible but likely more important event in FDA history was the Lasagna Committee, which was announced in 1988, and gathered many of the FDA’s critics.
Rhetorically, Administration personnel claimed from the late 1980s onward (with great plausibility) that drug review delays were primarily a matter of staffing. Internally, FDA leaders looked at the oncology drug division as an exemplar of what quick NDA review could look like, as many of its reviews were completed in less than a year. Oncology drug reviewers were quietly transferred to the anti-viral division, and new medical reviewers were hired. In the late 1980s and early 1990s, drug review times for new molecular entities – perhaps the single most important quantitative measure on which the Administration was judged in pharmaceutical politics – began to decline appreciably
In 1992 FDA Commissioner David Kessler, patient advocates, pharma industry representatives, congressional committee chairs, and President Bush’s staff agreed to the Prescription Drug User Fee Act, which informally bound the FDA to review time goals and effectively taxed drug companies per drug application. To the degree that FDA staffing was the rate-limiting step on drug approval, this would speed approval, but critics said it eroded the FDA’s willingness to push back against shoddy drugs. I am not sure how to evaluate that claim, but I don’t understand the mechanistic claim – the user fees tied the FDA to a review timeline, but it didn’t mandate approval or penalize rejection. Carpenter writes that it might have eroded FDA culture by tying it financially to pharma, but this seems somewhat implausible, because it did not tie funding to any drug in particular, or any particular target of “X% of drugs must be approved”.
FDA in the 2000s
Briefly, the FDA in the 2000s has been described as becoming increasingly lax on drug approval, particularly in cancer. This is covered in-depth in Malignant by Vinay Prasad. The Vioxx scandal, in which Merck was viewed as having concealed the fact that patients taking Vioxx were experiencing higher rates of cardiovascular complications, and in which the FDA seemed to take quite a long time to remove Vioxx from the market, also damaged the FDA’s reputation. In 2004 the FDA was widely viewed as having ignored science for political reasons when it kept Plan B (emergency contraception) prescription-only instead of making it OTC. Here is one perspective on that.
Scott Gottlieb, who had been a high-level FDA official before being Commissioner but also worked for the AEI (the leading think tank criticizing the FDA), had been anticipated to be a highly de-regulatory FDA Commissioner. I can’t find sources for this claim, but my impression is that Gottlieb has generally acquired a good bipartisan reputation and did not oversee a radical shift in FDA direction. He also won praise for moving somewhat aggressively against flavored vapes, which are widely viewed (rightly or wrongly) as a growing public health threat.
Approval is Final
Because approval of a drug is so symbolically powerful, and effectively stakes the FDA’s reputation to a given drug, the FDA only does so very deliberately. It is a social technology that reduces the immense complexity of an IND application (consisting of clinical trials, endless manufacturing and absorption data, etc.) into a binary YES/NO that physicians and nurses can rely upon. Reversing a decision is reputationally damaging, and the FDA has occasionally faced criticism from consumer-protection groups and even internal FDA employees that it is too unwilling to withdraw unsafe drugs from the market. This is problematic when drugs are approved based on surrogate endpoints instead of clinical endpoints, or when safety problems emerge after approval, as with Vioxx.
Carpenter comments on this:
It is interesting in light of these conflicts that, in the wake of the Vioxx tragedy of October 2004, higher FDA officials (including many long-term careerists) engaged in an organizationally motivated embrace of the status quo by defending randomized controlled trials and by disparaging pharmacoepidemiology. For different reasons, Deputy Commissioner Scott Gottlieb, CDER officials Sandra Kweder, Robert Temple, and others did not want to cede more control of the pharmaceutical market to David Graham and his colleagues at ODS. Yet it was also an extension of the familiar, an area where the agency had already developed capacity. Clinical trials have advantages when they are randomized and placebo-controlled. They also have drawbacks. Often tests are done on homogeneous patient populations, among patients who differ in many ways from the patients who will utilize the drugs in clinical situations. Clinical trials usually have an endpoint, and can often be too brief to allow analysts to detect whether the drug is inducing adverse events, particularly for toxicity, hepatotoxicity (or liver damage), and cardiovascular outcomes.
On Pressuring the FDA through Reputation
The FDA is responsive to both reputational and political pressure. The former is best thought of as arguing with the FDA on its own ground, which can be done from multiple perspectives. Patient advocacy groups can push the FDA to approve cancer drugs on less evidence; “thought-leader” physicians can sing the praises of an innovative drug and call the FDA slow; FDA whistleblowers can testify before Congress that the FDA is too deferential to pharma; consumer-protection groups can call the FDA’s approval based on a surrogate endpoint “reckless”. All these approaches seek to push the FDA in one direction or another, but fundamentally accept the legitimacy of the FDA and especially in the case of those pushing for more regulatory caution, hearken back to some idealized version of the FDA as a rhetorical device. In the early 2000’s, as the FDA was perceived to have relaxed its regulatory standards, especially on cancer, this occurs more often, with long-time FDA critics like Sydney Wolfe unfavorably compared the current FDA to the old FDA.
A recent example of reputational pressure was Eric Topol’s open letter to the FDA in October 2020 that criticized the emergency approvals of convalescent plasma, hydroxychloroquine, and remdemisvir, and pressured the FDA Commissioner to delay approval of a Covid-19 vaccine. Though many have criticized his actions, its method is illustrative: Topol, who has immense reputational power in academic medicine through decades of leading large clinical trials, publicly attacking Merck during the Vioxx scandal, and having critiqued the FDA in the past for its lack of action on Vioxx, was well-positioned to push the FDA to be more cautious. In addition, the emergency approvals Topol criticized (with the possible exception of Remdemisvir, and maybe Convalescent Plasma if you play with subgroup analysis….) seemed to have been regulatory bets that did not pan out, which left the FDA in a weak position. The politicization of hydroxychloroquine in particular made Topol’s arguments extremely appealing among the reputational audience (large medical journals, elite media, etc.) that the FDA caters to, which all dislike Trump. The combination of a weakened FDA and a strong attacker were the likely reasons for Topol’s success (and in the view of Alex Tabarrok and many others, the rest of the US’s disaster, since any delay in vaccine approvals likely cost many lives). Here an in-depth read on this.
The pro-regulatory counter to the previous paragraph is that vaccine approval was only an obviously good idea in retrospect and that vaccine hesitancy would rise with a rushed process. I think both of those claims are wrong, and I think Ezra Klein argues this well in a recent piece.
Political pressure takes the form of more direct action: Congressional committees can ask FDA officials to justify their actions and have public hearings that embarrass an agency that prefers less public attention. They can threaten FDA funding and if they’re playing hardball, threaten legislative action that directly alters FDA authority.
The challenges to FDA practice which resulted in sustained reform are those that combine both approaches, along with policy solutions that can be proposed at the right political moment. Conservative think tanks had long wished to tie some FDA funding to drug approvals and hold the FDA to a deadline and when conservatives made sustained and substantial gains in the 1980s and 1990s, the FDA, first informally and then through legislative change, moved in that direction.
Sustained media attention also seems to be important for pushing the FDA, but is not essential. The NCI-FDA disputes were not as high-profile as the 1980s AIDS activism but effected reform that was just as important.
An important but vague “audience” that the FDA defers to is the medical community as a whole. This might be thought of as the “elite consensus” in medicine. By directly incorporating respected medical scientists and doctors onto Advisory Committees, the FDA accedes to this audience but also partially neutralizes it. Pharmaceutical companies seek to use this in their favor as well by recruiting big-name academic stars to head clinical trials or research divisions and thereby “borrow” some of their reputation. A sustained critique of the FDA from these directions would also likely be a powerful pressure. For instance, if Advisory Committees repeatedly disagreed with the FDA in one direction, they could likely shame it into changing course.
Theoretically this might be strengthened if a sitting Congressman/woman then called a hearing to directly ask FDA officials about controversial decisions or if sympathetic media ran pieces highlighting this discrepancy. This would be a direct reputational attack on the FDA and a veiled political threat because it would raise the specter of legislative reform of the FDA with enough political attention.
Regulatory Caution is Often Proven Right
As disappointing and non-contrarian as it is to agree with a large, slow-moving government bureaucracy, my impressionistic summary of Reputation and Power along with background knowledge from Ending Medical Reversal and Malignant is that the FDA has usually been proven right in its caution. Approvals based on surrogate endpoints sometimes work, but in Malignant Vinay Prasad makes a strong argument that this often doesn’t speed approvals and that a substantial number of drugs approved on surrogate endpoints are never properly followed up on. Low regulatory standards in cancer drugs have led to a proliferation of low-value treatments approved on the basis of surrogate endpoints that don’t predict clinical (a.k.a. useful) endpoints and that may not actually provide any benefit outside of carefully selected clinical-trial participants. (Editorial Note: For a counterargument, see this post and linked SSRN article on “Type II” errors at the FDA).
A full argument that strict regulation is required for medical innovation is too long for this paper, but Ending Medical Reversal is an excellent argument along these lines. Here is a summary of it. I fully agree with Cowen and Tabarrok that the FDA was far too slow during COVID-19, but I think the libertarian critique of the FDA (usually) goes too far.
The FDA is More Powerful Than You Think
– Apart from holding pre-market approval power over a drug, the FDA also intensely regulates drug experimentation in the first place. It also regulates drug labeling. By virtue of regulating a drug’s intended use (which has substantial effects on insurance coverage) it also informally regulates medical practice in general. And in a decentralized fashion, by being able to disqualify Institutional Review Boards (IRBs), it also regulates clinical research on a fine-grained level.
This IRB-mediated power means the FDA can effectively ban individual physicians or entire institutions from research.
To the degree that overly-cautious IRB’s (who are in turn fearful of FDA attention) constrained Human Challenge Trials, this seems like an under-appreciated cost of the FDA and one that has not previously faced any sustained challenge. The lack of a constituency that is visibly harmed by overly cautious IRBs makes developing political pressure on this more challenging, but this seems valuable.
The FDA and COVID-19 Vaccines
As a thought exercise, it is worth considering what a successful attack against Topol on the vaccine delay question might have entailed. Academic stars in medicine that argued for faster vaccine approval, in contradiction to Topol, would have been rhetorically effective. A less politically polarized COVID-19 response in general would have neutralized the specific anti-Trump claims that Topol made.
Not being in an election year and so proximal to November 2 would have removed the incentive for anti-Trump individuals and institutions to view an early vaccine approval as a Trump victory and likely alleviated some concerns that the vaccines were being “rushed through.” Elite media that favored faster approval and that continually raised vaccine approval salience would not have so favorably amplified Topol’s open letter.
There were some prestigious names contra Topol on vaccines like Walid Gellad but few or none with Topol’s star-power and connections. The prominent economists who pushed for faster approval were all, fairly or not, associated with a deregulatory perspective, which likely made their arguments less credible to the FDA. If the FDA had not burned their credibility on hydroxychloroquine early on, they would have been less vulnerable to Topol’s reputational attack. The somewhat Rationalist-aligned academics and institutions that consistently pushed for vaccine approval and human challenge trials have no cachet in the medical community, and so cannot effectively engage in this reputational battle as insiders.
Willy Chertman is a 4th-year medical student at University of Miami who studied biology and political science as an undergraduate at the University of Miami. When not in school, he reads and tweets about medical research and health policy at @willyintheworld and on substack at https://willyreads.substack.com.
Dan Elton, Ph. D., is Director of Scholarship for the U.S. Transhumanist Party. You can find him on Twitter at @moreisdifferent, where he accepts direct messages. If you like his content, check out his website and subscribe to his newsletter on Substack.
To Maryland Governor Larry Hogan: Liberate Vaccine Doses from the FDA! – Article by Dan Elton and Edward Hudgins
Note from the Authors: This was an op-ed we wrote in the first week of February 2021. Unfortunately, no newspaper wanted to publish it. We first submitted it to the Baltimore Sun, which promptly turned it down. We then submitted it to the Capitol Gazette, The Washington Times, and The Washington Examiner but never heard back from any of them. Sadly, this op-ed is just as relevant today as when we first wrote it almost two months ago. Since it was written, the evidence for the safety and efficacy of the AstraZeneca vaccine has only gotten stronger. An observational study of millions of people in Scotland published in early March found that a single dose of the AstraZeneca vaccine offers ~94% protection against hospitalization, outperforming Pfizer’s vaccine, which offered ~85% protection. Last week AstraZeneca reached an endpoint in the Phase III trial in the United States that the FDA requested, finding an efficacy of 76%, very similar to the previous Phase III trial result (70%). Despite all this, there has been no action from the FDA,and millions of AstraZeneca doses remain languishing in factories in Baltimore, Maryland and West Chester, Ohio as thousands of American taxpayers that are desperate for them die every day.
~ Daniel C. Elton and Edward Hudgins, March 31, 2021
If Maryland Governor Larry Hogan acts immediately and decisively, he can save thousands of Marylanders from suffering and death from COVID-19. A facility in Baltimore produces the very effective AstraZeneca vaccine and has stockpiled millions of doses. But the U.S. Food and Drug Administration, headquartered in suburban Maryland, which must certify all vaccines and medical treatments before patients can reap their benefits, is holding those doses hostage to its antiquated, bureaucratic red tape. Hogan should act now to liberate the vaccine to save the lives of Marylanders.
Over a year into the pandemic, over 8,200 Marylanders have died, and some 410,000 have suffered from COVID-19. Marylanders have suffered from a chronic shortage of the FDA-approved Pfizer and Moderna vaccines. AstraZeneca is approved in the E.U. and 19 other countries. So as our morgues fill up, what’s the FDA’s excuse for delay?
The AstraZeneca vaccine has passed Phase I and Phase II efficacy trials, which were published in the medical journal The Lancet in July and November 2020. A Phase III peer-reviewed study that was conducted in three other countries indicates the vaccine has an efficacy of 70 percent, ranging from 62 percent to 90 percent with different dosages. Most importantly, the vaccine showed a 100-percent efficacy at preventing COVID-19 hospitalizations and deaths. The AstraZeneca vaccine was also the first shown in a scientific study to reduce transmission. And unlike the two already-approved vaccines, it requires only regular rather than ultra-cold refrigeration. It has been given to over one million people in the U.K. without safety issues detected, yet FDA has requested that AstraZeneca redo most of their Phase III trials using patients from the U.S.
Some media outlets have reported that AstraZeneca’s vaccine “may not work” in the elderly. Unfortunately, AstraZeneca’s Phase III data published so far does not allow for efficacy to be determined for those older than 65. However, Phase I & II trials showed a similar immune response after the second dose across all age groups, including those over 65, so there are good reasons to believe the efficacy should be similar for the elderly. Even if the efficacy is much lower, because the elderly are at such high risk it still makes sense to give them the vaccine in order to save lives. This was shown clearly by Oxford bioethicists Jonathan Pugh and Julian Savulescu, who ran some numbers to show the grave consequences of denying the vaccine to the elderly. It is also true that recent results show the AstraZeneca vaccine is not very effective against the South African variant at preventing mild forms of COVID-19. However, the current study only addressed mild illness and AstraZeneca’s vaccine gives a similar immune response to Pfizer’s vaccine, which has been shown to protect strongly against hospitalization from the South African variant. The World Health Organization recently released guidance recommending the rollout of the vaccine not be halted due to this finding and that the vaccine be given to all age groups.
The U.S. government has already contracted for 300 million doses of the vaccine, costing taxpayers over $1 billion. Yet with thousands dying daily and many more suffering from COVID-19 across the county, the FDA projects they won’t approve the vaccine until late April.
Since FDA won’t certify the AstraZeneca vaccine immediately, Governor Hogan should act. He might invoke emergency authority to simply take possession of enough of the AstraZeneca vaccine supply in the Baltimore factory producing it to meet Maryland’s needs. But this would likely be unnecessary. He should request that the facility release the vaccine and inform them that the state will likely be able to guarantee no adverse repercussions from the FDA. After all, during the past decade over 40 states passed “Right To Try” laws that allowed terminally ill patients to access safe treatments not certified by FDA for efficacy. The only “repercussion”: in 2018 Congress passed bipartisan legislation, signed by President Trump, recognizing the state’s authority to do so.
But in parallel, Hogan should call on President Biden to issue an executive order suspending the need for final FDA certification in this exceptional case.
Or Biden, backed strongly by the Maryland Congressional delegation, could request Congress pass emergency legislation creating a Free To Choose Medicine track parallel to FDA’s normal, slow certification process, on which COVID vaccines, tested safe and promising in Phase II or III trials, could be accessed by individuals, with informed consent. Such a track was created in 1992 for AIDS treatments, saving the lives of thousands of sufferers.
Or Biden could request Congress pass a reciprocity law certifying for the use of Americans any COVID treatment approved in other advanced countries. Rep. Chip Roy (TX-21) and Sen. Ted Cruz, (R-TX) have introduced legislation allowing for reciprocal approval of drugs approved in other trusted countries. This proposal could be focused to allow access to COVID vaccines.
Since AstraZeneca is produced in Maryland and the FDA headquarters is also in Maryland, Hogan is in an ideal position to be the hero, shake things up, and break the bureaucratic walls separating citizens from a lifesaving medication.
Ed Hudgins is founder of the Human Achievement Alliance and a science policy researcher. He can be reached at firstname.lastname@example.org. Dan Elton is Director of Scholarship at the US Transhumanist Party. You can reach him via direct message on Twitter (@moreisdifferent).
A List of Possible FDA Reforms – Compilation by Dan Elton
I have ranked these according to my own perception of which have the most support among DC bureaucrats and members of congress.
Improving transparency. During the COVID-19 pandemic the public has been kept in the dark regarding how key decisions were made, such as the decision to issue an EUA for hydroxychloroquine, the decisions that pushed Pfizer’s EUA from early November to late December, and the decision to require additional Phase III data from AstraZeneca which delayed their EUA by at least 3-4 months. Currently the FDA keeps much of the information relevant to decision making confidential. In theory Freedom of Information Act (FOIA) requests can be used to obtain some information, but in practice FOIAs are slow-walked, may require litigation, and take years to resolve. There are many possible ways to increase transparency at the FDA, some of which are outlined in this recent article in STAT News. 18 specific recommendations can be found in this journal article from 2018. One of people referenced as a top candidate for FDA Commissioner, Joshua M. Sharfstein, is a poor choice when it comes to implementing other reforms but has been a leading voice calling for more transparency.
Reciprocity. If a drug/medication is approved by a regulatory agency in a different country which has equivalent standards to the FDA (for instance agencies in the UK or Japan, the European Medicines Agency (EMA), or Health Canada), it should automatically be approved by the FDA (and vice versa). Reciprocity would save both taxpayers and companies a lot of time and money. Imagine if the AstraZeneca vaccine had been approved on January 1st, a few days after the UK approved it. It’s easy to see that tens of thousands of lives would have been saved, especially when you consider it would have been given to the most at-risk first! In 2015 Senators Mike Lee and Ted Cruz introduced the RESULT Act, which is primarily focused on implementing reciprocity.
Making the agency independent from the executive branch. It’s hard to insulate the FDA from political concerns as long as Congress controls the FDA’s purse, but it could at least be removed from direct interference from the executive branch by making it an independent agency like the FCC or Federal Reserve. There seems to be wide support behind this idea right now and recently four former FDA commissioners all endorsed this idea in an interview.
Rolling reviews. It should not take 3-4 weeks from the submission of an EUA application until a decision is made, especially when thousands are dying every day while waiting for vaccines. According to Dr. Marty Makary, a professor of public health policy at the Johns Hopkins Bloomberg School of Public Health who has conducted over a hundred clinical studies, the FDA “could have done the approval in 24-48 hours without cutting any corners”. Likewise, the approval of drugs and therapies after Phase III trials have reached an endpoint should not take 6 – 18 months. While the FDA does engage in a back and forth with companies prior to when they submit their paperwork for an EUA or approval, they do not use rolling reviews. Due to their rolling review systems other countries like the UK were able issue EUAs for COVID-19 vaccines faster than the FDA. Rolling reviews should be the norm, and the submission and analysis of trial data should made as streamlined and as efficient as possible without compromising the integrity of the analysis.
Tiered approvals. Doctors who want to provide new drugs to at-risk patients currently have to wait 5-10 years for lengthy Phase III trials to conclude and then another 6 – 18 months for the FDA to carry out their review of the trial data. Tiered approvals would allow a lower level of approval after just Phases I and II, freeing up treatments to those who need them most. The centrist Niskanen center has a white paper which suggests four levels of approval (see also their op-ed in The Hill).
Expansion of Right-to-Try. Federal right-to-try legislation was passed in 2018. However, it is very restrictive, and patients need to have met a number of strict requirements before they can try new medications and treatments, greatly limiting its utility.
Treating aging as a disease. Currently it is illegal to market an FDA-approved product as a treatment for aging. Even though aging is a harmful biological process, it is not considered a legitimate “indication” for a drug or therapy by the FDA. In other words, the FDA doesn’t view aging as a “disease” and therefore anti-aging treatments fall outside their mandate. Some specific aspects of aging are also not considered as legitimate indications. The FDA is currently operating in an inconsistent way as some conditions which are due to the aging process can are considered legitimate targets, such as osteoporosis and menopause, but others, like sarcopenia (age-related muscle loss /frailty), are not. Many experts, including David Sinclair, have spoken out about this issue. Some companies have found ways to get around the FDA’s restrictions, such as by using certain metabolic markers to track the degree of damage from aging. However, the impossibility of getting FDA approval for therapies that directly slow down or repair the damages from aging greatly dis-incentivizes industry R&D investment in this area. Fortunately, with advanced gene and stem-cell therapies on the horizon, the Congress and the FDA have already taken a few steps towards being able to review and approve anti-aging drugs and therapies. The 21st-Century CURES Act, for instance, mandated the creation of the Regenerative Medicine Advanced Therapy designation at the FDA.
Challenge trials in emergency situations. Many people, including a group of legislators, lobbied the FDA to give companies the go-ahead to do challenge trials, but there was no action. Thousands of volunteers for COVID-19 challenge trials signed up with 1daysooner.org but were unable to participate as they had wished to. As a result, data on vaccine efficacy was obtained much slower than it could have been.
Use of the proactionary principle for all drug & therapy approvals. The FDA should publish a transparent, quantitative, scientifically informed, and structured cost-benefit analysis for each regulatory action performed, which estimates the expected quality-adjusted life years (QALYs) saved versus risk of QALYs lost for both the action and inaction. The analysis should be made public, ideally sometime before the decision goes into effect. Crucially, the analysis should enumerate the risks and benefits of granting an approval and the risks and benefits of not granting it. See Max More’s overview of the proactionary principle and his chapter in The Transhumanist Reader, where he presents not just a principle but an entire framework for rational decision making. The key reform here is to make it mandatory that decision making at the FDA be highly structured and quantitative so it under less sway from political concerns and cognitive biases. If such a framework for rational decision making was in place it’s unlikely the FDA would have decided to delay Pfizer’s Emergency Use Authorization (EUA) from early November to December 11th, a decision which cost tens of thousands of American lives.
Free to Choose Medicine with a Trade-off Evaluation Database. In brief, Free to Choose Medicine would create an additional track after Phases I and II to allow doctors to prescribe new therapies to at-risk patients who are unable or unwilling to participate in a Phase III trial. Patients in the Free-to-Choose Track would be mandated to submit data to a trade-off evaluation database, creating a trove of valuable real-world data (this could be genetic, biomarker, and adverse events data, for instance). See this excellent podcast interview with Bart Madden for more information.
Dan Elton, Ph. D., is Director of Scholarship for the U.S. Transhumanist Party. You can find him on Twitter at @moreisdifferent, where he accepts direct messages. If you like his content, check out his website and subscribe to his newsletter on Substack.
Forecasting Whole-Brain Connectomics – A Kurzweilian Approach – Article by Dan Elton
Editor’s Note: In this article, U.S. Transhumanist Party Director of Scholarship Dr. Daniel C. Elton describes the recent advances in mapping the connectomes of various organisms, as well as the technological advances that would be needed to achieve effective human whole-brain emulation. Given extensive discussion of these subjects among U.S. Transhumanist Party members, including at the Virtual Enlightenment Salon of September 27, 2020, with Kenneth Hayworth and Robert McIntyre, it is fitting for the U.S. Transhumanist Party to feature this systematic exploration by Dr. Elton into what has been achieved in the field of connectomics already and what it would practically take for human whole-brain emulation to become a reality. As Dr. Elton convincingly illustrates, this possibility is still several decades away, but some steady progress has been made in recent years as well.
~ Gennady Stolyarov II, Chairman, United States Transhumanist Party, March 7, 2021
The connectome of an organism is a map of all neurons and their connections. This may be thought of as a graph with the neurons as nodes and synaptic connections as edges. Here we take the term ‘connectome’ to refer to the graph and the underlying electron microscopy images of the neurons, which contain much more information. However, to successfully simulate an organism’s brain using a connectome, more information will be needed. Retrieving a detailed scan of an entire brain and mapping all the neurons is a prerequisite for whole-brain emulation. In their landmark 2008 paper, “Whole Brain Emulation: A Roadmap“, transhumanists Anders Sandberg and Nick Bostrom construct a detailed “technology tree” showing the prerequisite technologies for realizing whole brain emulation:
In this article, we focus on the “scanning” component along with part of the “translation” component, namely neuronal tracing. By plotting technological progress on a logarithmic plot, similar to how Kurzweil does, we attempt to forecast how many decades away we are from being able to scan an entire human brain (and trace/segment all neurons to determine the connectome). Of course, while Kurzweilian projections have been known to hold (most famously for Moore’s law), we caution that the start of a logistic function can look like an exponential function. In other words, exponential trends can and often do plateau. As any investment advisor would say, “past returns are no guarantee of future results”.
The complete connectome of the nematode worm (Caenorhabditis Elegans) was published in 1986. A complete set of images of the fruit fly (Drosophila melanogaster) was published in 2018. However, all of the neurons and their connections have not yet been segmented or traced. In January 2020 researchers published the connectome of the central brain of the fruit fly, containing 25,000 neurons, which to my knowledge is the largest connectomics dataset published to date.
I thought it would be fun/interesting to plot the progress of connectomics over time and try to extrapolate out any trend observed. So, I did a literature search for all studies to date which either traced or segmented neurons and marked out synapses in electron microscopy data:
 D. D. Bock, et al. “Network anatomy and in vivo physiology of visual cortical neurons”, Nature471 (7337) (2011) 177–182. doi:10.1038/nature09802. [link]  K. L. Briggman, M. Helmstaedter, W. Denk, Wiring specificity in the direction-selectivity circuit of the retina, Nature 471 (7337) (2011) 183–188. [link]  D. J. Bumbarger, M. Riebesell, C. Rodelsperger, R. J. Sommer, System-wide rewiring underlies behavioral differences in predatory and bacterial-feeding nematodes, Cell 152 (1-2) (2013) 109–119. [link]  C.-Y. Lin, et al., A comprehensive wiring diagram of the protocerebral bridge for visual information processing in the drosophila brain, Cell Reports 3 (5) (2013) 1739–1753. [link]  S. ya Takemura, et al., A visual motion detection circuit suggested by drosophila connectomics, Nature500 (7461) (2013) 175–181. [link]  M. Helmstaedter, K. L. Briggman, S. C. Turaga, V. Jain, H. S. Seung, W. Denk, Connectomic reconstruction of the inner plexiform layer in the mouse retina, Nature500 (7461) (2013) 168–174. [link]  N. Kasthuri, et al., Saturated reconstruction of a volume of neocortex, Cell162 (3) (2015) 648–661. [link]  A. A. Wanner et al., 3-dimensional electron microscopic imaging of the zebrafish olfactory bulb and dense reconstruction of neurons, Scientific Data 3 (1). [link]  K. Ryan, Z. Lu, I. A. Meinertzhagen, The CNS connectome of a tadpole larva of Ciona intestinalis (l.) highlights sidedness in the brain of a chordate sibling, eLife 5 (2016) [link]  S.-y. Takemura, et al., A connectome of a learning and memory center in the adult Drosophila brain, eLife6 (2017). [link]  K. Eichler, et al., The complete connectome of a learning and memory centre in an insect brain, Nature548 (7666) (2017) 175–182. [link]  C. S. Xu, et al., A connectome of the adult drosophila central brain (preprint) [link]  L. K. Scheffer, et al., A connectome and analysis of the adult drosophila central brain, eLife9 (2020). [link]  J. S. Phelps, et al., Reconstruction of motor control circuits in adult drosophila using automated transmission electron microscopy, Cell184 (3) (2021) 759–774.e18. [link]
Next I plotted most of the data for the number of neurons versus the date of publication:
Next I did linear regression on the (year, log(# neurons)) data which is equivalent to fitting an exponential function to the data. (The reason for fitting the data in this way was to avoid the bias that occurs when fitting an exponential function with least-squares regression that leads to the larger values on the y axis being fit more accurately than smaller ones.) After doing the linear regression I extrapolated it forward in time.
The projection for the fruit-fly connectome (2024) seems about right. If anything, we may see it slightly sooner. It will be interesting to see how much longer it will take before we have physically realistic models of the fruit fly and fruit-fly behavior. U.S. Transhumanist Party member Logan T. Collins has advocated for building biophysically and behaviorally realistic models of insects to better understand nervous systems. For one thing, interesting neuroscience experiments may be performed on a simulated “virtual fly” much faster and easier than on a real fly (for instance, certain neurons may be removed or manipulated, and the effects on the virtual fly’s behavior observed). A project to produce the mouse brain connectome is underway, and again, the date extrapolated to — 2033 — seems plausible if the funding for the project continues. Beyond that though, I have very little idea how plausible the projections are!
Here are some numbers that show the challenges just with scanning the entire brain (not to mention segmenting/tracing all the neurons accurately!).
Assuming an isotropic voxel size of 20 nm, it is estimated that storing the images of an entire human brain would require 175 exabytes of storage. It seems we are approaching hard drives which cost about 1.5 cents per gigabyte. Even at those exorbitantly low prices, it would still cost $2.6 billion to store all those images!
The volume of the human brain is about 1.2 x 10^6 cubic millimeters. The Zeiss MultiSEM contains either 61 or even 91 electron beams which scan a sample in parallel. According to a Zeiss video presentation from April 8th, 2020, it can scan a 1×1 mm area at 4 nm resolution in 6.5 minutes. Assuming a slice thickness of 20 nm, a single such machine would require 742,009 years to scan the entire brain!
Dan Elton, Ph. D., is Director of Scholarship for the U.S. Transhumanist Party. You can find him on Twitter at @moreisdifferent, where he accepts direct messages. If you like his content, check out his website and subscribe to his newsletter on Substack.
USTP Director of Scholarship Dan Elton’s Letter to the FDA’s Vaccine Committee Meeting on the Emergency Use Authorization of the Johnson & Johnson Vaccine
The public can comment on the FDA’s committee meeting tomorrow (February 26th) to discuss the Emergency Use Authorization for the Johnson & Johnson / Janssen vaccine candidate. Members of the public can submit comments via an online system here or via the mail. Attached is my letter. The main theme is transparency.
To the VRBP Advisory Committee:
I am writing to request the FDA exhibit full transparency and show their cost-benefit calculations which justified such a long delay in approving the J&J/Janssen vaccine. Taxpayers deserve decisions that are made on the basis of rational cost-benefit analysis informed by the best science and data available. There is an incredible fog around key decisions that have greatly affected Americans during the COVID-19 pandemic – such as the FDA’s decisions that made it hard for at-home tests to be approved, HHS & FDA decisions not to pursue or support human challenge trials, and the FDA’s deadly decision to delay approvals of life-saving vaccines, most shockingly the AstraZeneca vaccine. With 2,000 – 3,000 Americans dying every day and millions of Americans desperate for life-saving vaccines (as evidenced by long lines across the country) it is only fair that taxpayers know the reasons for the FDA’s delays.
In a relentless pursuit of safety the FDA has ironically ignored the greatest safety concern to the American people – the SARS-CoV2 virus, and many have died needlessly as a result. Beyond normal expected utility based utilitarian calculations, the proactionary principle(s), developed by philosopher Max More and extended by Steve Fuller and others provide a good blueprint for conducting rational cost benefit analysis. It is my belief that the procedures the FDA have used to decide if and when to approve this vaccine have not utilized even the most rudimentary cost-benefit analyses, and lives have been lost as a result. I am open to changing my mind, however, if the FDA can produce a cost-benefit calculation that informed their decision making.
The interim Phase III collection period for the Janssen vaccine ended January 22 and they submitted their EUA application on February 4th. The American people have had to wait 22+ days for the EUA to be granted. Between February 4th – 26th, around 52,500 Americans will have lost their lives to COVID-19 (extrapolating the death rate forward 2 days from February 24th). In that time, countless others will have suffered under the ravages of the disease and the numerous sequela of “long COVID”. Even among those who have been lucky enough not to have their bodies invaded by the virus, most have suffered brutal economic and psychological effects from the pandemic.
As economist Tyler Cowen points out, it is a fallacy to think that manufacturing is the main bottleneck to getting life-saving vaccines to American people. Millions of doses of both the Pfizer and Moderna vaccines were available when the FDA finally approved them, showing that FDA approval was a larger constraint than manufacturing. While J&J may not have as many vaccines produced by February 26th as Moderna & Pfizer did at their EUA, if an expectation of an earlier EUA had been set by the FDA the company would have had a stronger incentive to ramp up production. It is incorrect to view the manufacturing and approval as independent – both are linked, with the timeframe set for one affecting the timeframe for the other. In economic terms, the elasticity of manufacturing to demand is not zero. Production of J&J’s vaccine began long ago so they could provide vaccines for their Phase I/IIa trial which began on July 22, 2020. While the company has faced production setbacks, a GSA report (GAO-21-265) estimates they will have 2 million doses available on February 26th.
The government of South Africa announced on February 10th that they would start administering the J&J vaccine to frontline health care workers. Now imagine if the FDA had made the J&J vaccine available just two weeks prior and assume that 2 million doses could therefore be distributed two weeks earlier as a result. At the current monthly rate of deaths, the average american has a 1/9,410 chance of dying from COVID-19 every 2 weeks. The risk of dying from the J&J vaccine, by contrast, based on the Phase I/II data and our prior knowledge about similar vaccines, is at most 1/1,000,000 (likely an overestimate). Assuming the vaccine is 100% effective at preventing death from COVID-19 (a safe assumption based on the current science), delivery of 2 million J&J vaccines 2 weeks earlier could save 212 lives and reduce suffering in many more. However, this number is obviously an underestimate because the vaccines will be distributed to the elderly and those with pre-existing conditions first, who have a 10x – 100x higher chance of dying from COVID-19 than the average American. So, the true number of lives that would have been saved is in the ballpark range 2,120-20,120.
The FDA’s decision to delay approval of the AstraZeneca vaccine by demanding additional American Phase III trial participants represents an even more egregious decision which surely cost thousands of Americans their lives. To be respectful of the purpose of the meeting at hand, however, I have restricted my discussion here to the J&J vaccine alone.
I ask that the FDA produce a cost-benefit analysis and clearly explain the reasons for the following decisions:
The reason the FDA did not allow the J&J vaccine to be made available via the FDA’s Expanded Access Program after excellent Phase I/II safety & immunogenicity data was published The Lancet on January 13th, 2021. (side note: see this article in STAT)
The reason the FDA did not recommend and/or advocate that those with a high risk of dying from COVID-19 obtain the J&J vaccine via the Right-to-Try pathway prior to EUA.
The reason the FDA, in October, created a requirement for a median 2 month follow up period in Phase III trials.
The reason the FDA decided not to recommend J&J use challenge trials to demonstrate the efficacy of their vaccine in a faster manner.
The reason the FDA decided not to allow pre-distribution of the J&J vaccine prior to EUA to speed up distribution.
The reason the FDA did not implement rolling reviews for the J&J vaccine.
The reason the FDA decided it needed 22 days to review J&J’s EUA application.
For each point, a cost-benefit calculation should be provided including a list of costs and benefits to the action vs the opposite action, ideally expressed in terms of quality-adjusted life years (QALYs) saved or lost.
Finally, I ask that in their communications and messaging the FDA focus on the efficacy of the J&J vaccine against hospitalization and death, especially against the South African variant, so Americans are informed first and foremost about the most important benefits of this vaccine.
Daniel C. Elton, Ph.D.
Dan Elton, Ph. D., is Director of Scholarship for the U.S. Transhumanist Party. You can find him on Twitter at @moreisdifferent, where he accepts direct messages. If you like his content, check out his website and subscribe to his newsletter on Substack.
How We Can Judge the Safety and Efficacy of New Vaccines Prior to Phase III Data and Why We Must – Article by Dan Elton
A common refrain we hear from public intellectuals about vaccines prior to Phase III data is “we don’t know anything about the safety or efficacy of vaccine X”. This attitude is both false and misleading to the public, instilling uncertainty and fear about vaccines. To see why it is false, consider if a normal vaccine safety study was done, but by coincidence all of the vaccines were given in hospital rooms that were painted blue. Could we conclude on the basis of such a study whether the vaccine would be safe if administered in rooms painted red? Yes, we can, and we should. We can utilize two forms of reasoning to conclude that the vaccine is safe if given in red rooms, even though we have no data on the matter. The first form of reasoning roughly approximates the way an ideal Bayesian statistical reasoner would function to compute what is called a “prior probability distribution”. Under this form of reasoning, we consider the millions of doses of similar vaccines (called the “reference class”) that have been administered. For instance, we might consider the vaccines developed for very similar coronaviruses like SARS and MERS. We note that if the color of paint did affect the safety of those vaccines, this would have likely been detected over the course of prior studies and over the course of millions of doses given previously. Of course, there is a chance the correlation might have been missed. To figure out how big that is, we can go a level deeper and consider a reference class of “things people might notice or fail to notice in medical studies”. We can conclude that for prior vaccines, if such correlations existed they would generally be picked up. On the basis of this and the fact that no such correlation was ever discovered in the reference class of prior vaccines we can conclude that the probability of vaccines like the COVID-19 vaccine being dependent on the color of paint is very small.
The second type of reasoning, which happens to be much more straightforward in this situation, is what the physicist David Deutsch calls “reasoning from our best explanation of the world”. According to the philosopher of science Karl Popper, we should reason using our explanatory theories of the world which have survived the most rounds of attempted falsification, and which have the highest degree of falsifiability (this rules out non-testable explanations like “vaccines work via invisible ghosts”). In more prosaic terms, this simply means reasoning using the best scientific theories which make predictions in the domain under consideration. We note that our best theories of vaccine function do not anywhere depend on the color of paint in the room. Instead they depend on things like T-cells, binding affinities of molecules, the concentrations of certain molecules in the body, etc. So, we decide that the vaccine is safe regardless of the color of paint in the room where it is administered.
Both of these forms of reasoning are valid and both are foundational to science, rationality, and human progress. Both of these types of reasoning can be used to say that vaccines under development are likely to be safe and effective before any data comes in. It’s why a reporter who interviewed numerous top scientists reported that they all told him that “they expected the vaccines were safe and effective all along.” Yet instead of proudly sharing this important knowledge with the public, we rarely hear scientists say publicly that they expect the vaccines are safe and efficacious. Instead, they hedge, saying “we have to wait until the data comes in”. This is unethical both on Kantian grounds (they are lying) and on consequentialist grounds, because it leads to undue caution and the public being afraid of vaccines.
Unfortunately, there is little incentive for scientists to tell the truth about what the likely risks and benefits are with new vaccines before full Phase III data is published. If, for instance, one or two people suffer severe side effects in a Phase III trial (which is rare, but has happened) a scientist who said they suspected it was “very safe” might receive harsh criticism for making a premature assessment. On the other hand, the same scientist will get no pushback for saying “we need to wait for data to make a judgement”. Indeed, they are likely to even be praised for exhibiting the virtues of “caution, prudence, and scientific skepticism”. Moreover, under no scenario should someone be allowed to get a vaccine until the full data comes in, even though it’s fine to allow people to sign up for studies where they have a 50-50 chance of getting the vaccine. Not very consistent, eh?
Activities which are likely to pose a significant risk to nature shall be preceded by an exhaustive examination; their proponents shall demonstrate that expected benefits outweigh potential damage to nature, and where potential adverse effects are not fully understood, the activities should not proceed.
The principle starts off OK but dives into serious error in the last line. The issue is that the precautionary principle only focuses on the potential adverse effects of proceeding and ignores the potential adverse effects of not proceeding, i.e., the effects of delay. As should now be clear in the case of the COVID-19 vaccines, not proceeding can sometimes be much more deadly than proceeding! There is often a high but unclear risk to not proceeding, and a low but unclear risk to not proceeding. (Picture two probability distributions, both wide (unclear) but one with a mean that is distinctly higher than the other). That’s where the precautionary principle throws expected utility theory (cost-benefit analysis) out and says we cannot proceed. The Nobel Prize-winning physicist Freeman Dyson stated the issue as follows:
“The Precautionary Principle says that if some course of action carries even a remote chance of irreparable damage to the ecology, then you shouldn’t do it, no matter how great the possible advantages of the action may be. You are not allowed to balance costs against benefits when deciding what to do.” — Freeman Dyson, Report from the 2001 World Economic Forum
Imagine an alternative world in which our society and government was not under the sway of the precautionary principle. In this alternative world, scientists would give their truthful assessment of new vaccines to the public, stating that they are likely safe and effective, using one or both of the reasoning methods mentioned above. In such a world, given the clear potential harms of inaction, the public would be allowed to purchase new vaccines if they wanted, if the companies manufacturing them were comfortable doing so, and if they were fully informed prior to their decision that they were taking an unapproved product that carries potential risks but also potential benefits. Initially, only a few people would purchase the vaccines, perhaps on the basis of Phase I results. These would be folks like those who injected themselves with a DIY vaccine over the summer, and the tens of thousands who were willing to participate in clinical trials as early as last spring. Companies would be incentivized to survey those who took the vaccine and collect self-reported data on their outcomes, which is very cheap and easy to do. After a few months going by without any of those people keeling over and dying, and with very few (likely none) of those people getting hospitalized for COVID-19, more people would feel comfortable getting the vaccine. Things would quickly snowball, with more and more people becoming willing to get the vaccine. During this time the distribution system would have been stood up and become operational, with on-site stockpiles building up ahead of the FDA’s Emergency Use Authorization (currently, the FDA does not allow hospitals to stockpile unapproved vaccines ahead of their EUA). To present this case in its strongest form, in a future post I plan to estimate how many lives would have been saved, assuming many vaccines had become available to those who wanted them last March or August. However, I hope it’s easy to see that thousands of lives would have been saved in this alternative world.
Our inaugural book review of 2020 covers Hacking Darwin by Jamie Metzl. As a happy coincidence, David Wood of the London Futurists recently had Metzl speak to his group, and you can watch a recording of the event here. This book is an exploration of how we might genetically engineer our children, why we might want to do so, and what the consequences might be.
The fact is, some people are already “hacking Darwin”. The first “test-tube baby” was born in 1978. This set the stage for preimplantation genetic testing, which became popular in the 1990s and widely used today. But “hacking Darwin” had already been occurring earlier due to genetic testing. A striking example Metzl discusses is the rapid decrease in Tay-Sachs disease in the Ashkenazi jewish community. Tay-Sachs is a genetic disorder which has devastating effects on the nervous system. By age 2, children with Tay-Sachs start to experience seizures and decline in mental functioning. Sadly, most die in agonizing pain by the age of five. About one in twenty seven Ashkenazi Jews carry the Tay-Sachs genes. Remarkably though, since the 1980s, the prevalence of the disease among Ashkenazi Jews has been very low, due to extensive genetic testing and family planning. Marriages between people who have tested positive for the disease were discouraged, and when they do occur, the couples tended to adopt rather than risk having a child born with the disease. The result was a great reduction in needless suffering, which is hard to argue against.
One of the major objections to genetic engineering is that it is “unnatural”. Metzl points out that a better term is “unfamiliar”. He points out that many things that seem natural are actually very “unnatural” – for instance, if you went back a few thousand years, you wouldn’t find anything resembling today’s corn or bananas – they are human concoctions from centuries of selective breeding. It seems that the queeziness people feel, which they label as due to “un-naturalness” is actually just due to unfamiliarity, which naturally invokes anxiety. History shows us that any radical technology or new idea naturally experiences widespread pushback. But history also shows that acceptance of a radical new idea or technology can be remarkably fast notwithstanding.
In-vitro fertilization provides an interesting case study of how public opinion can shift. Initially it was demonized, but public acceptance of it rapidly changed over the course of only a few years.
The next technology that will come down the pipeline, according to Metzl, is iterated embryo selection. Embryos are already inspected visually to select the one that is least likely to result in a miscarriage, and as noted in some cases preimplantation genetic testing is performed to check for a few genetic illnesses. This process can be scaled up and improved dramatically. Instead of having 10-15 eggs fertilized, a hundred might be, and instead of just doing visual checks, the genome of each embryo might be sequenced to screen out certain genetic disorders and select for certain traits. The process could also be “iterated”, using induced pluripotent stem cells (IPCs) from the embryos to create new gametes (eggs & sperm) which could be combined to create new embryos.
The benefits of expanding IVF and embryo selection could not only eliminate unnecessary suffering but also result in large financial savings which will allow money to be redistributed elsewhere in our healthcare system. The current cost of taking care of the current number of people born with genetic diseases each year was roughly estimated by Metzl to be $48 billion, spread over 37 years into the future.
The cost of sequencing is dropping dramatically (see Fig. 1). This is allowing for larger genome-wide association studies (GWASs). Using big data, statistical methods, and machine learning, many outcomes can be predicted by analyzing the many genes which can influence most traits. Already, the height a child will grow to can be predicted to within an inch (assuming they get adequate nutrition) by analyzing thousands of genes.
Two major types of enhancements which will benefit our offspring are discussed in length by Metzl – increased intelligence and increased healthspan, and it’s worth discussing some of his main findings here. (Other possible enhancements he notes are increased empathy, supersensory capabilities, increased physical stamina and strength, increased beauty, increased ability to extract nutrition from foods, and better ability to tolerate mircrogravity and radiation.)
Regarding intelligence, the Minnestota Family Twin study found that 70% of IQ is genetic. More recent works put the number somewhat lower (about 50%), but a surprising amount is hereditary, and the variance due to genetics is significant (about 15 points of IQ in each direction). The rest seems to be largely due to things like childhood nutrition and having a rich environment as a kid. Higher IQ provides many benefits. Among them is a better ability to adapt to change and work in a dynamic environment where you constantly have to learn new skills. Statistically, people with lower IQ tend to work jobs with a regular routine, such as service positions. Currently, those with low IQ can still have a great life (there’s no evidence IQ correlates with happiness), and low-IQ people can learn a trade where there is reliable demand, become very good at it, and be valued by society. With the advent of AI and robotics, this is rapidly changing, and the risk of large-scale technological unemployment is real. Metzl asks, in light of this, is it really fair that we are trusting the economic wellbeing of our children to the genetic lottery of sexual recombination? It’s already not easy to compensate for a bad draw in the genetic lottery. Additionally, if other parents are doing it, why would any parent want to risk their child being far behind their peers? According to Metzl, the choice will be clear for parents in the future.
The second major area where genetic engineering will have an effect is aging. The diseases of aging were not something evolution cared much about, so there are likely genetic hacks that are possible but were just never selected for – it’s an area ripe for optimization. For a glimpse of what is possible, Metzl has us consider the naked mole rat, a species which is remarkable in many ways (click here for a full list of ways this species is special). Most notably, naked mole rats don’t exhibit the normal signs of aging, and they don’t get cancer. Thus, as odd as it may seem, the naked mole rat is the subject of intense research, and this humble species even serves as a sort of touchstone increasing the confidence of venture capitalists investing in longevity biotech startups in Silicon Valley. According to Metzl, “Calico, Google’s San Francisco–based life-extension company, maintains one of the world’s largest captive colonies of naked mole rats to see if it can uncover biomarkers of aging and unlock the secrets of naked mole rat longevity.”
It seems that genetic engineering will eventually be accepted as the ethically superior way of creating children – no one will want to leave something as important as the health and economic wellbeing of their children to blind chance. Human beings naturally crave control and certainty where possible — that’s why we give our kids vaccines and parents spend thousands of dollars on prophylactic dental procedures such as orthodontics or the removal of wisdom teeth. Yes, there will always be some hold-outs who will want to stick with “traditional conception”, but after reading Metzl’s book I can’t help but think that eventually the numbers will be quite small. Consider, for instance, that even the Amish use modern medicine.
The scientific and technological path to a much more healthy world, with much less suffering and longer, healthier lives is clear. There are straightforward steps we can take to reduce congenital ailments, for instance. However, there’s a real chance we may delay even this for decades, causing much needless suffering. Part of the reason is that any discussions of the subject immediately bring up a lot of cultural baggage from the horrible legacy of eugenics. The horrors of eugenics form an unfortunate negative emotional halo around any discussion of genetic engineering. While the eugenics movement is largely dead, the subject is so important that Metzl rightly devotes a large part of the book to it. Concerns about a re-emergence of the horrors of eugenics are legitimate, but conflation of what is being proposed with those horrors is not. Eugenicists advocated forced sterilization, whereas nobody is proposing that today. Instead, all that is being proposed is that parents have a choice in how their children are conceived. However, there is a real concern that parents will voluntarily choose children with certain biases, such lighter skin and heterosexuality. There are also concerns that the creation of genetically engineered “super children” would lead to a caste system of some sort, leading to a highly in-equitable society where the non-genetically-engineered are constantly discriminated against and made to feel unworthy. Metzl acknowledges each of these risks as real, but he also points out that none of the scenarios are inevitable and asks the reader to consider the benefits of genetic engineering as well, some of which we previously discussed. He notes that our current world is already very unequal in terms of genetics. Might a bit more genetic inequality be acceptable, Metzl asks, if the children created make enormous contributions to the arts and sciences which benefit all of humanity? Regarding whether a caste system might form, Metzl suggests that we must work to ensure the technology is widely distributed (at one point I recall he suggests insurance companies might have an incentive to provide genetic engineering as it would reduce health costs later on). A bigger horror, Metzl suggests, is not genetic inequality, but perfect genetic equality – the creation of a uniform generation of cookie-cutter children, where misfits and non-neurotypicals (which have historically contributed so much) have been selected out. Each of these concerns are real, and Metzl doesn’t try to argue otherwise.
While ethical concerns may stifle the development of genetic engineering, a different scenario is a genetic arms race. In other areas such as AI, China is making more aggressive investments in genetic technology – a “$9 billion, fifteen-year investment to improve national leadership in precision medicine”. Metzl points out that the Chinese seem to have far fewer hang-ups around the subject and are blazing full steam ahead.
While the author is sympathetic to genetic engineering, the book presents a balanced treatment and never waxes too polemical. The first part of the book is mostly about the science. The later sections, on the ethical concerns and the genetic arms race scenario, are the most thought-provoking and are parts I may re-listen to at some point. Overall, this book is a very timely and thought-provoking introduction to the subject.