Yesterday I blogged about trying to speed up vaccine development and distribution by taking some of the risk out of it for pharma companies via an advanced market commitment, and today let's consider again one of the proposals being discussed for speeding up the testing process.
Here's a white paper proposing some steps to further consider and prepare for human challenge trials (aka controlled human infection studies) to speed up the testing of potential Covid-19 vaccines.It is put out by the organization 1 Day Sooner, which seeks to promote such trials, and has started assembling a list of volunteers in case challenge trials should become practical, to help vaccines become available sooner.
Evaluating use cases for human challenge trials in accelerating COVID-19 vaccine development
Linh Chi Nguyen , Christopher W Bakerlee, T. Greg McKelvey, Sophie M Rose, Alexander J Norman, Nicholas Joseph, David Manheim,, Michael R McLaren, Steven Jiang, Conor F Barnes, Megan Kinniment, Derek Foster, Thomas C Darton, Josh Morrison; for the 1Day Sooner Research Team
Abstract: Recently, human challenge trials (HCTs) have been proposed as a means to accelerate the development of an effective SARS-CoV-2 vaccine. In this paper, we discuss the potential role forsuch studies in the current COVID-19 pandemic. First, we present three scenarios in which HCTs could be useful: evaluating efficacy, converging on correlates of protection, and improving understanding of pathogenesis and the human immune response. We go on to outline the practical limitations of HCTs in these scenarios. We conclude that, while currently limited in their application, there are scenarios in which HCTs would be vastly beneficial and, thus, the option of using HCTs to accelerate COVID-19 vaccine development should be preserved. To this end, we recommend an immediate, coordinated effort by all stakeholders to (1) establish ethical and practical guidelines for the use of HCTs for COVID-19; (2) take the first steps toward an HCT, including preparing challenge virus under GMP and making preliminary logistical arrangements; and (3) commit to periodically re-evaluating the utility of HCTs amid the evolving pandemic.
Here's the main experimental design element:
"In HCTs, a relatively small number of healthy volunteer participants are administered a vaccine candidate or a placebo. However, unlike in conventional trials, consenting HCT participants are then administered an infectious dose of pathogen, and the outcomes of this infection is tracked. By challenging participants with pathogens under close observation in a clinical setting, HCTs can provide a unique opportunity to assess efficacy of a vaccine candidate."
And here are their concluding recommendations:
"To preserve the option to implement HCTs in scenarios such as this, we recommend an immediate, coordinated effort by all stakeholders to address the considerations outlined in this manuscript and make the necessary preparations. These include:
1. Convening experts to discuss the ethical and practical considerations associated with HCTs for COVID-19, concluding in a set of recommendations and guidelines for their use in the present pandemic and their role in the licensure process (which, notably, could provide guidance that is broadly useful in the event of future pandemics, too),
2. Taking the first practical steps toward an HCT, including preparing challenge virus under GMP and making preliminary arrangements with volunteers, vaccine developers, regulators, academic institutions, and clinical researchers to run HCTs in situations where they are expected to be highly useful,
3. Keeping informed of the evolving situation, periodically conducting a systematic reevaluation, and adjusting course based on the progress of the pandemic and the outcomes of the first drug and vaccine trials.
"HCTs have the potential to considerably shorten the COVID-19 pandemic, saving many lives and enabling economies and societies to return to normality. But we must act now to ensure this opportunity is not missed."
********
It's an admirably careful and balanced paper for one with a policy recommendation, and it sets the stage for a useful and timely debate.
As an experimenter, I have one reservation about the proposed controls. In the passage I quoted above, they said " healthy volunteer participants are administered a vaccine candidate or a placebo," i.e. the control is a placebo. That strikes me as potentially controversial given that the next step of the experiment is to infect the participants with Covid-19. I might prefer a study in which the control for one vaccine was a different potential vaccine, so that no subjects were (relatively) sure to contract the disease.
But this doesn't detract from the usefulness of the preparations they recommend: conducting further discussions, and taking initial practical steps.
********
Here is my earlier post on this subject:
Key criteria for the ethical acceptability of COVID-19 human challenge studies
WHO Working Group for Guidance on Human Challenge Studies in COVID-19
Authors: WHO
"Overview: This document aims to provide guidance to scientists, research ethics committees, funders, policy-makers, and regulators in deliberations regarding SARS-CoV-2 challenge studies by outlining key criteria that would need to be satisfied in order for such studies to be ethically acceptable."
*******
Here's a news story from CNN, complete with some anecdotes about the sometimes sketchy history of human challenge trials:
Thousands of people want to be exposed to Covid-19 for science
By Robert Kuznia
"Human challenge studies date all the way back to the first vaccine, for the highly lethal smallpox disease. The vaccine was developed in the late 18th century by physician Edward Jenner, who aimed to put a piece of folklore to the test: that milkmaids seemed to contract a milder form of the disease, called cowpox.
"In an experiment that today would warrant steep criminal charges, Jenner took pus from the scab of a milkmaid and inserted it into an incision on the arm of an 8-year-old boy. The child, James Phipps, developed a headache, chills and other mild symptoms, but when directly exposed to smallpox -- again through incisions on the arm -- he proved impervious."
**********
Here's an op-ed from the Washington Post, by the philosophers Richard Yetter Chappell and Peter Singer:
Pandemic ethics: The case for experiments on human volunteers
They conclude:
"We are ethicists, not medical or biological scientists. When it comes to factual beliefs about the pandemic, we defer to expert scientific opinion, as everyone should. But what we ought to do with the facts we have, and how we should go about seeking facts we still lack, are ethical questions. Ethicists have a crucial role to play in this debate.
"There is too much that we don’t know about covid-19. The longer we take to find it out, the more lives will be lost. (That’s why the website asking for vaccine volunteers is called “1 Day Sooner.”) If healthy volunteers, fully informed about the risks, are willing to help fight the pandemic by aiding promising research, there are strong moral reasons to gratefully accept their help. To refuse it would implicitly subject others to still graver risks."
***********
And here's a post from the Volokh Conspiracy (pointed out to me by Frank McCormick) focusing on the question of paying volunteers for human challenge trials:
The Moral Case for Testing Coronavirus Vaccines through "Challenge Trials" on Paid Healthy Volunteers
Doing so can potentially save many thousands of lives. And moral objections to this practice are weak. The issues here are very similar to the longstanding debate over whether we legalize organ markets. by ILYA SOMIN .
He concludes:
"Like others who risk their lives to benefit others, challenge trial volunteers deserve our gratitude, and proper compensation for their efforts. And there is no good moral justification for forbidding them to take those risks. To the contrary, we should move ahead with challenge trials as soon as feasible. Every day of delay could literally be a matter of life and death—a great many lives and deaths."
Here's a white paper proposing some steps to further consider and prepare for human challenge trials (aka controlled human infection studies) to speed up the testing of potential Covid-19 vaccines.It is put out by the organization 1 Day Sooner, which seeks to promote such trials, and has started assembling a list of volunteers in case challenge trials should become practical, to help vaccines become available sooner.
Evaluating use cases for human challenge trials in accelerating COVID-19 vaccine development
Linh Chi Nguyen , Christopher W Bakerlee, T. Greg McKelvey, Sophie M Rose, Alexander J Norman, Nicholas Joseph, David Manheim,, Michael R McLaren, Steven Jiang, Conor F Barnes, Megan Kinniment, Derek Foster, Thomas C Darton, Josh Morrison; for the 1Day Sooner Research Team
Abstract: Recently, human challenge trials (HCTs) have been proposed as a means to accelerate the development of an effective SARS-CoV-2 vaccine. In this paper, we discuss the potential role forsuch studies in the current COVID-19 pandemic. First, we present three scenarios in which HCTs could be useful: evaluating efficacy, converging on correlates of protection, and improving understanding of pathogenesis and the human immune response. We go on to outline the practical limitations of HCTs in these scenarios. We conclude that, while currently limited in their application, there are scenarios in which HCTs would be vastly beneficial and, thus, the option of using HCTs to accelerate COVID-19 vaccine development should be preserved. To this end, we recommend an immediate, coordinated effort by all stakeholders to (1) establish ethical and practical guidelines for the use of HCTs for COVID-19; (2) take the first steps toward an HCT, including preparing challenge virus under GMP and making preliminary logistical arrangements; and (3) commit to periodically re-evaluating the utility of HCTs amid the evolving pandemic.
Here's the main experimental design element:
"In HCTs, a relatively small number of healthy volunteer participants are administered a vaccine candidate or a placebo. However, unlike in conventional trials, consenting HCT participants are then administered an infectious dose of pathogen, and the outcomes of this infection is tracked. By challenging participants with pathogens under close observation in a clinical setting, HCTs can provide a unique opportunity to assess efficacy of a vaccine candidate."
And here are their concluding recommendations:
"To preserve the option to implement HCTs in scenarios such as this, we recommend an immediate, coordinated effort by all stakeholders to address the considerations outlined in this manuscript and make the necessary preparations. These include:
1. Convening experts to discuss the ethical and practical considerations associated with HCTs for COVID-19, concluding in a set of recommendations and guidelines for their use in the present pandemic and their role in the licensure process (which, notably, could provide guidance that is broadly useful in the event of future pandemics, too),
2. Taking the first practical steps toward an HCT, including preparing challenge virus under GMP and making preliminary arrangements with volunteers, vaccine developers, regulators, academic institutions, and clinical researchers to run HCTs in situations where they are expected to be highly useful,
3. Keeping informed of the evolving situation, periodically conducting a systematic reevaluation, and adjusting course based on the progress of the pandemic and the outcomes of the first drug and vaccine trials.
"HCTs have the potential to considerably shorten the COVID-19 pandemic, saving many lives and enabling economies and societies to return to normality. But we must act now to ensure this opportunity is not missed."
********
It's an admirably careful and balanced paper for one with a policy recommendation, and it sets the stage for a useful and timely debate.
As an experimenter, I have one reservation about the proposed controls. In the passage I quoted above, they said " healthy volunteer participants are administered a vaccine candidate or a placebo," i.e. the control is a placebo. That strikes me as potentially controversial given that the next step of the experiment is to infect the participants with Covid-19. I might prefer a study in which the control for one vaccine was a different potential vaccine, so that no subjects were (relatively) sure to contract the disease.
But this doesn't detract from the usefulness of the preparations they recommend: conducting further discussions, and taking initial practical steps.
********
Here is my earlier post on this subject:
Friday, May 8, 2020
Here's a similar in spirit paper, considering when and why human challenge trials might be appropriate, put out by the World Health OrganizationKey criteria for the ethical acceptability of COVID-19 human challenge studies
WHO Working Group for Guidance on Human Challenge Studies in COVID-19
Authors: WHO
"Overview: This document aims to provide guidance to scientists, research ethics committees, funders, policy-makers, and regulators in deliberations regarding SARS-CoV-2 challenge studies by outlining key criteria that would need to be satisfied in order for such studies to be ethically acceptable."
*******
Here's a news story from CNN, complete with some anecdotes about the sometimes sketchy history of human challenge trials:
Thousands of people want to be exposed to Covid-19 for science
By Robert Kuznia
"Human challenge studies date all the way back to the first vaccine, for the highly lethal smallpox disease. The vaccine was developed in the late 18th century by physician Edward Jenner, who aimed to put a piece of folklore to the test: that milkmaids seemed to contract a milder form of the disease, called cowpox.
"In an experiment that today would warrant steep criminal charges, Jenner took pus from the scab of a milkmaid and inserted it into an incision on the arm of an 8-year-old boy. The child, James Phipps, developed a headache, chills and other mild symptoms, but when directly exposed to smallpox -- again through incisions on the arm -- he proved impervious."
**********
Here's an op-ed from the Washington Post, by the philosophers Richard Yetter Chappell and Peter Singer:
Pandemic ethics: The case for experiments on human volunteers
They conclude:
"We are ethicists, not medical or biological scientists. When it comes to factual beliefs about the pandemic, we defer to expert scientific opinion, as everyone should. But what we ought to do with the facts we have, and how we should go about seeking facts we still lack, are ethical questions. Ethicists have a crucial role to play in this debate.
"There is too much that we don’t know about covid-19. The longer we take to find it out, the more lives will be lost. (That’s why the website asking for vaccine volunteers is called “1 Day Sooner.”) If healthy volunteers, fully informed about the risks, are willing to help fight the pandemic by aiding promising research, there are strong moral reasons to gratefully accept their help. To refuse it would implicitly subject others to still graver risks."
***********
And here's a post from the Volokh Conspiracy (pointed out to me by Frank McCormick) focusing on the question of paying volunteers for human challenge trials:
The Moral Case for Testing Coronavirus Vaccines through "Challenge Trials" on Paid Healthy Volunteers
Doing so can potentially save many thousands of lives. And moral objections to this practice are weak. The issues here are very similar to the longstanding debate over whether we legalize organ markets. by ILYA SOMIN .
He concludes:
"Like others who risk their lives to benefit others, challenge trial volunteers deserve our gratitude, and proper compensation for their efforts. And there is no good moral justification for forbidding them to take those risks. To the contrary, we should move ahead with challenge trials as soon as feasible. Every day of delay could literally be a matter of life and death—a great many lives and deaths."