1DaySooner: Open Letter on Challenge Trials for COVID-19

Despite the checkered ethical history of Challenge Vaccine Trials (The Hideous Truths Of Testing the Hepatitis Vaccine On Humans), several scientist published an open letter to the NIH asking for them to be considered.

The Press release for 1DaySooner’s letter, released July 15, 2020.

Adrian Hill, Director of the Jenner Institute at the University of Oxford, writes that “Oxford’s Jenner Institute and 1Day Sooner are collaborating on work towards the production of a COVID-19 human challenge virus,” and “collaborative human challenge studies should be feasible and informative in the coming months.”

New York, NY— In an open letter to Dr. Francis Collins, Director of the National Institutes of Health (NIH), 15 Nobel Laureates are joined by over one hundred prominent figures and over two thousand 1Day Sooner challenge volunteers in advocating for the potential of challenge trials to accelerate COVID-19 vaccine development. The signatories come from a range of disciplines including epidemiology, medicine, economics, psychology, and philosophy.

“If challenge trials can safely and effectively speed the vaccine development process,” the letter states, “then there is a formidable presumption in favor of their use, which would require a very compelling ethical justification to overcome.”

The NIH, which has funded the work of 160 Nobel Laureates, has been at the forefront of medical research for decades. While the NIH has committed to producing the virus, Dr. Collins has stated that COVID-19 challenge trials are “on the table for discussion — not on the table to start designing a plan.”

In contrast, Adrian Hill, Director of the Jenner Institute at the University of Oxford and signatory of the open letter, writes in a public statement that “collaborative human challenge studies should be feasible and informative in the coming months.” This is the first public statement from a vaccine developer about their plans to conduct a COVID-19 human challenge trial.

As 1Day Sooner and Oxford’s Jenner Institute collaborate on human challenge trial preparation, it is essential that Dr. Collins and the NIH do not lag behind by neglecting preparation for these trials. As the signatories write, “we appeal to the government and foundation funders around the world to support this effort.”
https://1daysooner.org/open-letter-press-release

The text of the letter:

Dear Dr. Collins,

The COVID-19 pandemic must be fought urgently on many fronts, but it is hard to picture robust economic and social recoveries in the absence of a vaccine. We are writing to underscore the vast importance of human challenge trials as a method to help develop vaccines.

In April, thirty-five members of the US House of Representatives called upon U.S. regulators to consider allowing volunteers to be infected with the pandemic coronavirus to speed vaccine testing—in so-called human challenge or controlled infection trials. In addition, over a hundred vaccine candidates are already under development around the world, at least ten of which have moved into the clinical trial phase. In May, the World Health Organization published guidance supporting trials of that form, if done ethically, and in June published a draft laying out a practical roadmap for their implementation.

The undersigned urge the U.S. government (including, but not limited to the Coronavirus Task Force, the Department of Health and Human Services, the Food and Drug Administration, Centers for Disease Control and Prevention, National Institutes of Health, and Congress), its allies, international funders, and world bodies (e.g. the World Health Organization), to undertake immediate preparations for human challenge trials, including supporting safe and reliable production of the virus and any biocontainment facilities necessary to house participants.

Background

The rationale for human challenge trials is that they can greatly accelerate the development of a COVID-19 vaccine.

Human challenge trials can provide information much faster than conventional efficacy trials, which take months longer. In such trials, volunteers still receive the vaccine candidate or a control. Instead of resuming life as usual and waiting to “catch” a virus, volunteers are deliberately exposed to the pathogen under controlled conditions. Beyond being faster than conventional trials, a challenge test is likelier to conclude with interpretable results, e.g. should the presence of virus around the study site begin to fade over time.

If challenge trials can safely and effectively speed the vaccine development process, there is a formidable presumption in favor of their use, which would require a very compelling ethical justification to overcome.

Principles for an Effective COVID-19 Human Challenge Trial

Human research demands caution and oversight. Crucial protections must be extended to protect the health and autonomy rights of volunteers. Guidance from the World Health Organization clarifies that human challenge trials are ethical when they meet certain criteria. The following are some protections that should clearly be in place.

● Trial participants should be relatively young and in good health. The mortality risk of the coronavirus to 20-29 year-olds, healthy and unhealthy, is similar to that of living kidney donors , a relatively common procedure, similarly justified by the donor’s informed consent and the benefits to society. Excluding participants with preexisting conditions would lower the risk significantly.

● It is crucial that all trial participants be provided the highest quality medical care with frequent monitoring. A significant percentage of the population will likely become infected and their access to medical care may be limited. As a result, the guarantee of excellent medical care in the study means that infection would be safer in the controlled, medically supervised, and isolated conditions of a challenge trial.

● Ethical and scientific review must be of the highest quality. In the U.S., that would mean not only the usual FDA and IRB review but a vigorous public discussion and perhaps even an additional, independent ethics and science taskforce representing, among others, challenge volunteers.

● The autonomy of the volunteers is of paramount concern. This means that the informed consent process must be robust (e.g. no children, no prisoners, multiple tests of comprehension). It also means that the wish of informed volunteers to participate in the trial ought to be given substantial weight. Providing some input over trial development and procedure to those interested in becoming volunteers (e.g. in the design of isolation conditions) could both enhance their agency and improve study design. Decades of psychological research on highly altruistic behaviors has demonstrated that a large, and likely growing, fraction of the general population is willing to undergo meaningful risks to benefit others due to genuinely altruistic motivation rather than insensitivity to risk, psychopathology, or other ethically concerning motives.

If done properly, live Coronavirus human challenge trials can be an important way to accelerate vaccine development and, ideally, to save the lives of millions around the world as well as help rescue global economies. We strongly recommend that production of the unattenuated virus begin immediately consistent with good manufacturing practices for potential use in trials that balance risks and benefits and respect the safety and autonomy of volunteers. It is also vitally important that there is both full transparency on the vaccine development and trial process and a diverse group of trial participants necessary to provide a broadly effective and universally available vaccine. We appeal to the government and foundation funders around the world to support this effort.
US Open Letter — 1Day Sooner

There are 125 signatories, including 15 Nobel Laureates:

Nobel Laureates
19. Mario Capecchi, Distinguished Professor in the Department of Human Genetics, University of Utah School of Medicine
20. Carol Greider, Professor of Molecular Biology and Genetics, Johns Hopkins University School of Medicine
21. Oliver Hart, Lewis P. and Linda L. Geyser University Professor, Harvard University
22. Lou Ignarro, Professor Emeritus, UCLA School of Medicine
23. William G. Kaelin, Jr., Professor of Medicine, Howard Hughes Medical Institute, Harvard Medical School
24. Barry Marshall, Clinical Professor and UWA Brand Ambassador, The University of Western Australia
25. Craig Mello, Distinguished Professor in RNA Therapeutics, University of Massachusetts Medical School
26. Paul Modrich, James B. Duke Professor of Biochemistry, Duke University
27. Edvard Moser, Professor of Neuroscience, Kavli Institute for Systems Neuroscience, Norwegian University of Technology and Science
28. May-Britt Moser, Professor of Neuroscience, Kavli Institute for Systems Neuroscience, Norwegian University of Technology and Science
29. Sir Richard Roberts, Chief Scientific Officer, New England Biolabs
30. Michael Rosbash, Professor of Biology and Investigator, Howard Hughes Medical Institute, Brandeis University
31. Alvin Roth, The Craig and Susan McCaw Professor of Economics, Stanford University
32. Jack Szostak, Alex Rich Distinguished Investigator, Massachusetts General Hospital
33. Arieh Warshel, Dana and David Dornsife Chair in Chemistry, Distinguished Professor of Chemistry and Biochemistry, University of Southern California

What do you think about this letter?

It is persuasive if not compelling to me. The parallel with living kidney donors is of strong personal interest, since a member of my family donated a kidney to a stranger. (This was a living donation. My family member has lived for ten years with one kidney.)

What I very much dislike is the emphasis on Nobel Laureates. Some Nobel Laureates are buffoons and some are ethically challenged. The world should not care whether Nobel Laureates signed a letter about medical ethics.

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I’d like to understand the expected benefit, i.e. the accelerated timeline, in more detail. We are a week away from the first US phase 3 trial enrolling subjects. Given that a challenge study will take time to prepare, in terms of design, review, and generating materials, can it actually offer a substantial time savings compared to existed scheduled trials? If not, then I’m not sure that a challenge study can be justified on a utilitarian basis.

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It may be a cynical take, but after many years observing science, my suspicion is that Nobel Laureates as a population are enriched for the ethically challenged.

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For me, “months longer,” if true, is compelling.

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Here is where the rubber meets the road. Which of the scientists here would sign the letter? Why? Which would not? Why not?

I would sign. The third bullet point alone is more than enough to reveal that the letter seeks to begin a serious and urgent process. The letter does not urge a particular outcome.

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The enhanced review process described could not (in my opinion) come close to being completed in shorter than 6 months.

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If that’s true then I assume it would erase any benefit. I’m skeptical that this is in fact true, since some very smart people, some of whom I know to various extents, have written and/or signed the letter.

Understood, and if that’s what we are really talking about, I’d have a hard time ignoring the potential benefits also. I take that comparison to be assuming both studies start administering doses on the same day, and I believe a challenge study would save months in that scenario. But similar to Art, it’s not clear to me a challenge study could begin as early as next Monday. At the same time, six months of review seems unlikely given the way everything else has been expedited.

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Here is the bullet I was speaking of:

Ethical and scientific review must be of the highest quality. In the U.S., that would mean not only the usual FDA and IRB review but a vigorous public discussion and perhaps even an additional, independent ethics and science taskforce representing, among others, challenge volunteers.

Maybe much or most of this has been done. And I could agree with a process that strives for this sort of process. But a “vigorous public discussion” or “additional, independent ethics and scientific task forces” cannot be tossed together in a flash. This is one of the many things that should have been addressed years, even decades, ago. We should be reviewing guidelines that were set in stone in calmer times, and not speeding a process that we all know cannot be rushed.

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Well, if you just inoculate a bunch of young people, send them home to self isolate, same as everyone else, as has become usual, and rely on follow up to detect vaccine effectiveness, I certainly can see that taking … f o r e v e r … to get results, depending on the cohort numbers. Infections seem to be lumpy in distribution. It could be, that for a good while, that no one is exposed to a cluster, or one group is just more compliant with physical distancing. Teasing out results from extraneous variables, such as direction stickers on supermarket floors, would either require very significant numbers or a long time or both.

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