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The FDA’s Defenses Against Political Pressure Are Beginning to Crumble. 

The FDA’s Emergency Use Authorization for convalescent plasma has set a disturbing precedent for vaccine approvals.

There is widespread anticipation of the availability of vaccines to prevent COVID-19 infections so that Americans can get their lives back to some semblance of normal.  Some three dozen vaccines, made with a variety of technology platforms, are now in clinical trials. Several of the more promising development programs have been accelerated by a White House crash program, “Operation Warp Speed,” which was launched in May.

It was no secret that there would be intense pressure on the FDA from a White House desperate for good news to provide an “October Surprise” in the form of a vaccine approval before the November 3rd election, even if that approval was premature.  Well, it seems UPS and other delivery partners are reportedly planning to perform test runs in September, in preparation for actually beginning to ship a coronavirus vaccine by November 1st.

We’re already seeing the manifestations of pressure on the FDA, as well as its effects. Without providing any evidence, on August 22nd, President Trump accused the FDA of deliberately delaying coronavirus vaccine trials: “The deep state, or whoever, over at the FDA is making it very difficult for drug companies to get people in order to test the vaccines and therapeutics,” the President tweeted, advancing the theory that bureaucrats throughout the government, including in the FDA, are conspiring against the President’s reelection.

He accused the agency of trying to delay a COVID-19 vaccine until after the fall election, tweeting, “Obviously, they are hoping to delay the answer until after November 3rd. Must focus on speed, and saving lives!” President Trump ended his tweet with a tag to the Twitter account of FDA Commissioner Dr. Stephen Hahn, whom he appointed to the job last year.

(Note: during my 15 years at the FDA, in both Democrat and Republican administrations, I never saw any evidence of actions intended to influence an election; nor do I today.)

The day after those tweets, accompanied by the fanfare of a presidential press conference, the FDA issued an Emergency Use Authorization (EUA) for convalescent plasma, the antibody-rich blood product taken from patients who have recovered from COVID-19. In theory, infusing a sick patient with the antibodies would neutralize the virus that’s present and spur recovery.

“The decision would have a stronger foundation if patients had participated in a randomized study that looked at whether patients who received plasma fared better than those who didn’t.”

Regulators took this action in spite of the fact that less than two weeks earlier, several top government health officials (Dr. Francis Collins, the director of the National Institutes of Health; Dr. Anthony Fauci, the government’s premier infectious disease expert; and Dr. H. Clifford Lane, the clinical director of the National Institute of Allergy and Infectious Diseases) had urged FDA to hold off, citing recent unconvincing data from the country’s largest study of convalescent plasma, conducted by the Mayo Clinic on more than 35,000 patients. The government scientists felt that the design of the study did not provide confidence that the product was efficacious, and that, therefore, the data were not strong enough to justify an EUA. Dr. Janet Woodcock, the head of FDA’s drug review division, who is currently on leave from the agency to work on Operation Warp Speed, told POLITICO as recently as August 21st that convalescent plasma has not been “proven as an effective treatment.”

Response to the FDA’s action was swift. Within hours after regulators issued the EUA, two former FDA commissioners wrote in an op-ed in the Wall Street Journal: “The decision would have a stronger foundation if patients had participated in a randomized study that looked at whether patients who received plasma fared better than those who didn’t.” Translation: on the basis of the available evidence, the issuance of the EUA was premature.

Moreover, because the EUA will make convalescent plasma widely available, the completion of the ongoing rigorous, randomized, well-controlled trials (which are ongoing in a number of research institutions) will be difficult or impossible. (With convalescent plasma available, why would anyone participate in a study in which he might get a placebo?)

It certainly appears that Dr. Hahn has capitulated to White House pressure. If that’s so, it could be part of a broader pattern—one that extends to the FDA’s sibling agencies, like the Centers for Disease Control and Prevention. That would be disturbing. Political expediency should not be permitted to trump science, especially where public health is concerned.

Food and Drug Administration.

Food and Drug Administration.

COMPROMISES AT THE EXPENSE OF PUBLIC TRUST

An action this week by the Centers for Disease Control and Prevention (CDC) may represent similar capitulation to pressure from above. New guidance on testing for the SARS-CoV-2 virus, released on Monday, August 24th, amended the agency’s guidance to recommend that people who have been exposed to the virus, typically defined as being within six feet of an infected person for at least 15 minutes, “do not necessarily need a test” if they do not have symptoms. This flies in the face of evidence that the time of highest virus shedding and infectivity is in the days shortly before symptoms emerge and would seem to represent an abandonment of any attempt at contact tracing and isolation of infected persons.  

Those criteria are extremely important because they emphasize that regulators do not intend to cut corners via “accelerated approval” based on “surrogate endpoints”—such as a vaccine’s ability to elicit antibodies to the virus—but short of actual prevention of infection.

The New York Times reported that, according to two (anonymous) government officials, the CDC changed its guidelines on instructions from higher up the food chain: “One official said the directive came from the top down. Another said the guidelines were not written by the C.D.C. but were imposed.” The change sounds suspiciously like, “If we do less testing, we have fewer cases.”

Interestingly, for months, Dr. Hahn, formerly the Chief Medical Executive of the MD Anderson Center in Houston, appeared to have been creating a bulwark against exactly this kind of political pressure. The first installment was an FDA policy statement, “Development and Licensure of Vaccines to Prevent COVID-19: Guidance for Industry,” published on June 30th. It specifies in great detail the criteria for FDA approval of coronavirus vaccines, but the overarching principle is simple: “the goal of development programs should be to pursue traditional approval via direct evidence of vaccine efficacy” in protecting humans from COVID-19—through clinical trials—and a vaccine must be at least 50% more effective than a placebo in preventing the disease. The clinical trials would also need to demonstrate that the vaccine is safe, of course.

Those criteria are extremely important because they emphasize that regulators do not intend to cut corners via “accelerated approval” based on “surrogate endpoints”—such as a vaccine’s ability to elicit antibodies to the virus—but short of actual prevention of infection. The guidance enables FDA Commissioner Hahn to fall back on that policy if he is pressured by his bosses to adopt a lower standard. He went out of his way to emphasize the FDA’s independence and integrity on July 21st, tweeting, “Americans should know that we are steadfast in maintaining our regulatory independence & ensuring our decisions for treatments & vaccines for #COVID19 are based on science & data. This is a commitment that the American public can have confidence that I will continue to uphold.” And, in a podcast interview with the editor of JAMA, Dr. Hahn repeated that theme: “Americans’ and the world’s public trust in the FDA is really important … People depend upon us every day of their lives, and we cannot do anything that would break that trust. That’s a solemn promise.”

In an August 7th article in JAMA, Dr. Hahn and two senior colleagues beat the drum yet again, promising “unequivocally” that “candidate COVID-19 vaccines will be reviewed according to the established legal and regulatory standards for medical products.” They added: 

While Operation Warp Speed is an important initiative and FDA has lent technical expertise around end point selection and safety considerations to this public-private partnership for vaccine development, there is a line separating the government’s efforts to focus resources and funding to scale vaccine development from FDA’s review processes, which are rooted in federal statute and established FDA regulations.

Dr. Peter Marks, the head of the FDA organization that evaluates vaccines, has also made his feelings on the subject known. Earlier this month, Marks told Reuters that the FDA’s evaluations would be guided by science alone and that if he were subjected to political pressure for a premature approval, “I could not stand by and see something that was unsafe or ineffective that was being put through.” He added, “You have to decide where your red line is, and that’s my red line. I would feel obligated [to resign] because in doing so, I would indicate to the American public that there’s something wrong.”

The companies working on vaccines, most of which are large and well-established, support the FDA officials’ position. “[The companies] are acutely aware of the political dynamic here,” and it would not make sense “to take a huge reputational risk not just for your vaccine but for all the products across your portfolio to benefit the president politically,” according to Rob Smith, the director of Capital Alpha Partners, a research firm (as quoted in the New York Times).

In sum, the message from Drs. Hahn and Marks to several audiences—their bosses at the Department of Health and Human Services and the White House, the public, and the vaccine industry—seemed to be clear: although regulators will streamline regulation and facilitate the development of COVID-19 vaccines, they won’t be stampeded into exposing Americans to inadequately tested, potentially dangerous products. 

And yet, there’s that dubious EUA for convalescent plasma, a disturbing precedent. I join my medical and scientific colleagues in hoping that Dr. Hahn will make good on his many promises to predicate approvals of therapeutics and vaccines solely on what he referred to as “established legal and regulatory standards.” Doing otherwise would break trust with a public that depends on the expertise and integrity of the FDA.

Henry I. Miller, a physician, molecular biologist, and Senior Fellow at the Pacific Research Institute. Henry was a research fellow at the National Institute of Child Health and Human Development, and the founding director of the FDA's Office of Biotechnology. He was the co-discoverer of a critical enzyme in the influenza virus. You can find him online or on Twitter at @henryimiller.

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