Challenge trials are becoming more accepted

Challenge trials, also called human infection trials, are clinical trials in which e.g. a vaccine is tested on participants who have volunteered to be infected with the disease the vaccine is meant to prevent. It's been a source of controversy.  But maybe open letters have some effect after all?  

The NYT has the story:

Would You Get Sick in the Name of Science?  Since the pandemic, drug trials that purposely make people vomit, shiver and ache have become a research area of growing interest. All that’s needed: brave volunteers. By Brent Crane

"challenge trials have become an area of enthusiasm since the Covid-19 pandemic. Funding for trials has poured in. Countries including India, Canada and Australia are beginning to develop the capacity for conducting them. Some researchers have found it easier to recruit volunteers, who are willing to shiver, sweat, puke and ache all in the name of helping others (and earning a little cash).

...

" Researchers have found that challenge trials can be used to observe not just immune responses but also transmission and infection. And by the standards of disease research, they are nimble; the whole process can take as little as a few months. This is in contrast to the years it often takes to run a traditional trial requiring thousands of research subjects to naturally become infected with a disease.

...

" In April 2020, 35 U.S. congressional members wrote a letter calling on regulators to permit challenge trials for Covid-19 vaccines. Three months later, 177 prominent scientists, including 15 Nobel laureates, joined their call. But opponents argued that the risks of infecting volunteers with a poorly understood virus were too great. The National Institutes of Health, Food and Drug Administration and Centers for Disease Control and Prevention all refused to allow them. At least one trial, in the Netherlands, was scuttled because of the perceived risk.

"And yet, instead of torpedoing the field, the pandemic “revitalized” it, said Dr. Christopher Chiu, an immunologist at Imperial College London. In 2021, after months of deliberation, the world’s first Covid-19 challenge trial began at Imperial College London — one of two that took place between 2021 and 2022 for Covid-19 — and interest grew from there.

"In 2020, while locked down in his Brooklyn apartment, a former corporate lawyer named Joshua Morrison stumbled upon an early draft of the Journal of Infectious Diseases article arguing for Covid challenge trials. That March, Mr. Morrison and two others founded an advocacy group in Washington, D.C., as a place to organize potential volunteers for Covid-19 challenge trials. As a nod to the speed of challenge trials, they called it 1Day Sooner. Within months, the organization had tens of thousands of sign-ups.

"1Day Sooner went on to promote challenge trials for maladies including norovirus, hepatitis-C and shigella, a bacteria that can cause dysentery."

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Here are all my posts on challenge trials

Scientists deliberately gave women Zika--challenge trials for diseases whose incidence has dropped too far for conventional clinical trials

 Nature has the story (despite the somewhat inflammatory headline).

Scientists deliberately gave women Zika — here’s why. ‘Human challenge’ results suggest that such trials could be used to test vaccines when Zika incidence is low.  by Mariana Lenharo, Nature, 21 October 2023

"For the first time, scientists have deliberately infected people with Zika virus to learn whether such a strategy could help to test vaccines against the pathogen.

The virus can cause severe birth abnormalities in babies born to parents infected during pregnancy. It also has been associated with neurological problems in adults, although those cases are rare. But infected study participants had only mild symptoms, and none became pregnant during or immediately after the trial. The results raise hopes that ‘human challenge’ programmes — in which volunteers are exposed to a pathogen in a controlled setting — could make it feasible to test vaccines at a time when Zika incidence is low.

“This is a great scientific gain in terms of the development of a vaccine,” said Rafael Franca, an immunologist at the Oswaldo Cruz Foundation in Ribeirão Preto, Brazil. The results are scheduled to be presented today at the annual meeting of the American Society of Tropical Medicine and Hygiene in Chicago, Illinois.

...

"In 2022, after a long process to address ethical concerns around the study, Durbin and her team recruited 28 healthy women, aged 18 to 40, who were neither pregnant nor lactating. All agreed to be admitted to a research facility and remain there until they were no longer infectious; they stayed at the unit for 9 to 16 days. They were tested for pregnancy several times before receiving the virus, to avoid the risk of congenital problems associated with Zika, and were counselled to use birth control for at least two months after the study.

Hope for smaller trials

The researchers injected 20 participants with one of two strains of Zika virus and eight with placebo. All of the participants who received the virus were infected; of those, 95% developed a rash — a common symptom of Zika — and 65% had joint pain. None of the placebo recipients had those symptoms.

Durbin says the findings indicate that the two strains of Zika administered in the trial can be safely and effectively used to infect participants in a Zika vaccine trial. She estimates that the controlled human infection model could be used in a phase III clinical trial for vaccine efficacy with as few as 50 to 100 participants. “With the challenge model, where you have 100% of infections, you could get an efficacy result with many fewer people” than in a conventional trial, says Durbin.

...

The new study represents a turnaround in the thinking about challenge trials. In early 2017, a report by researchers convened by the National Institute of Allergy and Infectious Diseases and the Walter Reed Army Institute of Research concluded that the risks of a human-infection study for Zika, at that time, surpassed the potential benefits.

...

But “from that time to now, we learnt a lot,” says Palacios. “Now we know that the risk of the virus being transmitted to another person through sexual relationships is limited and something that can be controlled,” he says. And regulators have signalled that they might consider data from human challenge trials in vaccine development, “in particular for those diseases that don’t have enough incidence to test in the field.”

Despite the low number of Zika cases, researchers say that it’s important to continue the efforts to develop a vaccine, because the virus might make a comeback. “Infections are much lower than they were during the epidemic in 2016. However, they are still occurring,” says Neil French, an infectious-disease specialist at the University of Liverpool, UK, who is involved in a Zika vaccine-development project. “The justification for a vaccine remains strong.”

Support for hepatitis C human challenge studies, in The Lancet Gastroenterology & Hepatology

 Here's a call for action, in The Lancet Gastroenterology & Hepatology:

Joint statement in support of hepatitis C human challenge studies by Harvey J Alter, Eleanor Barnes, Mia J Biondi, Andrea L Cox, Jake D Eberts, Jordan J Feld, T Jake Liang, Josh Morrison, Charles M Rice, Naglaa H Shoukry, David L Thomas, Jennifer Van Gennip, Charles Weijer, on behalf of other signatories †, Published:September 20, 2023 DOI:https://doi.org/10.1016/S2468-1253(23)00314-X

"We, the 121 undersigned, believe that human challenge studies among adult volunteers will be critical in the development of hepatitis C vaccines.

...

"Despite the advent of safe and highly effective direct-acting antiviral (DAA) treatments, the ongoing toll of hepatitis C remains high among low-income and middle-income countries and vulnerable populations such as people who inject drugs. Millions of new infections occur annually, outpacing cures in some regions,1 with progress further disrupted by the COVID-19 pandemic. Without a change in strategy and the development of new tools, we will not reach the ambitious goal set out by WHO of elimination of viral hepatitis as a public health threat by 2030. This will require an effective hepatitis C vaccine—“the best insurance for the future”, as highlighted by a recent announcement of the White House national hepatitis C elimination programme.2

...

"Human challenge studies for a hepatitis C vaccine could accelerate vaccine development dramatically. The effort to establish the model and test an initial vaccine candidate could take as little as 3 years. If that candidate fails, subsequent studies to test others could provide evidence of efficacy as quickly as 1 year.

"It is only because of the remarkably effective treatments that we can now consider human challenge studies for hepatitis C. With DAAs, cure rates of people without cirrhosis are reliably over 98%, with highly effective salvage regimens for the few who do not respond to a first course of therapy.5,  6 We are confident that in the era of DAAs, human challenge studies can be done in accordance with the highest ethical and safety standards. Healthy volunteers providing fully informed consent would be infected for at most 6 months before treatment and would be free to go about their lives with the right to request treatment and withdrawal from a study at any time. Acute infection causes no or few symptoms in most, and unlike in most challenge studies, where the risk of transmission necessitates quarantine of participants, the risk of passing hepatitis C to others is very low in day-to-day life.

"The impact of a vaccine would be enormous: reducing transmission, preventing cirrhosis, and most importantly, markedly reducing the rate of liver cancer, the world's second-most deadly cancer in terms of total fatalities.7 The global success of hepatitis B vaccine in achieving these goals exemplifies the importance of an effective hepatitis C vaccine. With the prospect of such a significant advance, we have confidence that people will volunteer to participate in hepatitis C challenge studies, and with such a strong team of experts worldwide, we are confident this approach will lead to the development of a successful hepatitis C vaccine."

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† Here's the full list of 121 signers of the letter

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1Day Sooner has a related web page with some background: https://www.1daysooner.org/hepatitis-c-open-letter

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Earlier related posts:

Monday, May 15, 2023

Eliminating Hepatitis C, now that there's a cure (even though it's expensive)

Saturday, August 26, 2023

Challenge trials for a Hepatitis C vaccine

Sunday, November 1, 2020

What do we know about the effects of payments to participants in challenge trials for vaccines, and other public spirited activities?

Challenge trials for a Hepatitis C vaccine

 The Journal Clinical Infectious Diseases has a special supplement on challenge trials (human infection trials) of a Hep C vaccine (now that Hep C is a curable disease):

Volume 77, Issue Supplement_3, 15 August 2023

Controlled Human Infection Model for HCV Vaccine Development

SUPPLEMENT ARTICLES

Controlled Human Infection Model for Hepatitis C Virus Vaccine Development: Is It Time to Be Real? 

T Jake Liang and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Page S215, https://doi.org/10.1093/cid/ciad343

• Hepatitis C virus (HCV) elimination has been a goal of the public health and scientific communities since its identification in 1989. Despite the advance and availability of highly effective antiviral regimens to treat HCV infection, it is unlikely that global HCV elimination can be achieved without an effective preventive vaccine. Because of the lack of appropriate animal models for preclinical testing and the perception that highly effective treatments would suffice in addressing the global burden of HCV, HCV vaccine development has not been a high priority. To accelerate vaccine development, the concept of a controlled human infection model (CHIM) for HCV has been proposed, in which healthy human volunteers would be deliberately infected with HCV for the purpose of testing the efficacy of candidate vaccines. This concept of challenge studies is not new and has been applied to more than 25 infectious agents, including the cholera vaccine, for which all efficacy data that served as the basis for regulatory approval were obtained from CHIM studies. Without a CHIM strategy, HCV vaccine development may not be feasible. In a recent phase 2 randomized controlled trial, over 900 people who inject drugs were screened to enroll 548 individuals to receive a T-cell–based HCV vaccine candidate or placebo. After a monumental effort that took over 6 years to complete, the trial documented 75 incident HCV infections overall, with only 45 included in the final analysis, and showed no protection against initial infection or progression to chronicity with the vaccine. While this study demonstrated that vaccine testing in the at-risk population can be done, future testing of additional HCV vaccine candidates using a similar pathway may be impractical in light of the duration and cost. With the ability to cure those who do not clear the virus, HCV CHIM is now a conceivable approach that could be a critically important, if not necessary, intermediate stage of vaccine development. HCV CHIM could de-risk vaccine candidates, accelerate development, reduce cost, and allow the selection of more promising candidates for further testing in larger clinical trials. CHIM may conceivably be used for larger phase 2/3 efficacy trials as a basis for clinical approval. In developing such a model, many challenges and questions must be addressed. In this Supplement issue, we, the editors of this Supplement commissioned various articles written by respective subject matter experts who provide their perspectives and opinions on these challenges and questions, ranging from the source of viral inoculum and the safety of transient HCV infection to the perspective of potential volunteers and the ethics of CHIM. While we strive to be data-driven and evidence-based, some of the opinions represent the views of the authors of each article and may be controversial. Ultimately, we hope these perspectives will enable fulsome discussion about the feasibility of HCV CHIM and lead to the development of well-designed clinical protocols.

  Supplement sponsorship. This article appears as part of the supplement “Controlled Human Infection Model for HCV Vaccine Development,” sponsored by Toronto General Research Institute, United States National Institutes of Health, Johns Hopkins University, the Canadian Institutes of Health Research (CIHR), and the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of CIHR (HPC-178912) and the Public Health Agency of Canada.

• View article

Ethics of Controlled Human Infection Studies With Hepatitis C Virus 

Annette Rid and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S216–S223, https://doi.org/10.1093/cid/ciad382

• Global elimination of hepatitis C virus (HCV) will be difficult to attain without an effective HCV vaccine. Controlled human infection (CHI) studies with HCV were not considered until recently, when highly effective treatment became available. However, now that successful treatment of a deliberate HCV infection is feasible, it is imperative to evaluate the ethics of establishing a program of HCV CHI research. Here, we evaluate the ethics of studies to develop an HCV CHI model in light of 10 ethical considerations: sufficient social value, reasonable risk–benefit profile, suitable site selection, fair participant selection, robust informed consent, proportionate compensation or payment, context-specific stakeholder engagement, fair and open collaboration, independent review and oversight, and integrated ethics research. We conclude that it can be ethically acceptable to develop an HCV CHI model. Indeed, when done appropriately, developing a model should be a priority on the path toward global elimination of HCV.

• View article 
• Supplementary data

Volunteering for Infection: Participant Perspectives on a Hepatitis C Virus Controlled Human Infection Model 

Jake D Eberts and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S224–S230, https://doi.org/10.1093/cid/ciad350

The perspectives of former challenge study participants and a survey of other potential volunteers can inform the design of hepatitis C virus controlled human infection models, including on topics such as transparency, volunteer safety and risk, and compensation.

• Ethical human subjects research requires participants to be treated safely and respectfully, yet much bioethical debate takes place without participants. We aim to address this gap in the context of controlled human infection model (CHIM) research. Based upon our own experience as study participants, and bolstered by a survey of 117 potential hepatitis C virus CHIM participants, we present ideas to inform efficient, ethical, and scientifically useful study design. We advocate for full protocol transparency, higher compensation, commitment to the rapid dissemination of study results, and proactive efforts to detail risk-minimization efforts as early as possible in the recruitment process, among other measures. We encourage researchers to proactively partner with volunteer advocacy organizations that promote collective representation of volunteers to maximize their agency, and guard against ethical issues arising from healthy human subjects research.

• View article 
• Supplementary data

First Do No Harm? Modeling Risks and Benefits of Challenge Trials for Hepatitis C Vaccine DevelopmentGet access

Alyssa Bilinski and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S231–S237, https://doi.org/10.1093/cid/ciad379

• Background

  In 2019, about 58 million individuals were chronically infected with hepatitis C virus. Some experts have proposed challenge trials for hepatitis C virus vaccine development.

  Methods

  We modeled incremental infections averted through a challenge approach, under varying assumptions regarding trial duration, number of candidates, and vaccine uptake. We computed the benefit-risk ratio of incremental benefits to risks for challenge versus traditional approaches. We also benchmarked against monetary costs of achieving incremental benefits through treatment.

  Results

  Our base case assumes 3 vaccine candidates, each with an 11% chance of success, corresponding to a 30% probability of successfully developing a vaccine. Given this probability, and assuming a 5-year difference in duration between challenge and traditional trials, a challenge approach would avert an expected 185 000 incremental infections with 20% steady-state uptake compared to a traditional approach and 832 000 with 90% uptake (quality-adjusted life-year benefit-risk ratio, 72 000 & 323 000). It would cost at least $92 million and $416 million, respectively, to obtain equivalent benefits through treatment. BRRs vary considerably across scenarios, depending on input assumptions.

  Conclusions

  Benefits of a challenge approach increase with more vaccine candidates, faster challenge trials, and greater uptake.

• View article 
• Supplementary data
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  Earlier:

  Monday, May 15, 2023

  Eliminating Hepatitis C, now that there's a cure (even though it's expensive

  and here are my posts on challenge trials (and Covid vaccines).