A human challenge study, also called a challenge trial or controlled human infection model (CHIM), is a type of
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
for a
vaccine
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. or other
pharmaceutical
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field an ...
involving the intentional exposure of the test subject to the condition tested.
Human challenge studies may be ethically controversial because they involve exposing test subjects to dangers beyond those posed by potential
side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s of the substance being tested.
[
During the mid 20th and 21st century, the number of human challenge studies has been increasing.] A challenge study to test promising vaccines for prevention of COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickly ...
was under consideration during 2020 by several vaccine developers, including the World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
(WHO), and was approved in the UK in 2021.
Over the second half of the 20th and the 21st centuries, vaccines for some 15 major pathogens have been fast-tracked in human challenge studies – involving about 30,000 participants – while contributing toward vaccine development to prevent cholera, typhoid
Typhoid fever, also known as typhoid, is a disease caused by ''Salmonella'' serotype Typhi bacteria. Symptoms vary from mild to severe, and usually begin six to 30 days after exposure. Often there is a gradual onset of a high fever over several d ...
, seasonal flu
Flu season is an annually recurring time period characterized by the prevalence of an outbreak of influenza (flu). The season occurs during the cold half of the year in each hemisphere. It takes approximately two days to show symptoms. Influen ...
, and other infections. Since the 1980s, challenge trials which reported about adverse events
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can ther ...
have had only 0.2% of patients with serious adverse events.
According to medical ethicists, methods of conducting clinical trials by human challenge testing have improved over the 21st century to satisfy ethical, safety, and regulatory requirements, becoming scientifically acceptable and ethically valid as long as participants are well-informed and volunteer freely, and the trials adhere to established rigor for conducting clinical research.[
]
Design
The intent of a challenge study is to fast-track the timeline for providing evidence of safety and efficacy of a therapeutic drug or vaccine, especially by compressing (to a few months) the usually lengthy duration of PhaseII–III trials (typically, many years). Following preliminary proof of safety and efficacy of a candidate drug or vaccine in laboratory animals and healthy humans, controlled "challenge" studies may be implemented to bypass typical PhaseIII research, providing an accelerated path to regulatory approval of the test compound for widespread prevention against an infectious disease
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
, such as COVID‑19.[
The design of a challenge study involves first, simultaneously testing a vaccine candidate for ]immunogenicity
Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:
* Wanted immunogenicity typically relates to vaccines, where the injectio ...
and safety in laboratory animals and healthy adult volunteers (100 or fewer)which is usually a sequential process using animals firstand second, rapidly advancing its effective dose into a large-scale PhaseII–III trial in low-risk, healthy volunteers (such as young adults), who would then be deliberately infected with the disease being tested against for comparison with a placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
control group.[ In a challenge study for a vaccine to prevent an infectious disease, participants would be closely monitored for signs of ]toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
and adequate immune response
An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...
, such as by producing substantial levels of antibodies against the virus causing the disease.[
]
Ethics
Awareness of the history of challenge trials is indispensable, including trials that were problematic or even connected to abuse. Special ethical issues can arise when a wealthy country finances and organizes these clinical trials in a less wealthy country.
Two commonly discussed general thresholds for risk to research participant are minimizing all risk after the infection and avoiding serious injury. Researchers typically customize other thresholds for each clinical trial.
Vaccines for viral infections
Challenge studies have been used to expedite evaluation of vaccines for several pandemic viral diseases, such as cholera, typhoid fever, malaria, influenza,[ streptococcal pharyngitis, ]tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, i ...
, shigella
''Shigella'' is a genus of bacteria that is Gram-negative, facultative anaerobic, non-spore-forming, nonmotile, rod-shaped, and genetically closely related to '' E. coli''. The genus is named after Kiyoshi Shiga, who first discovered it in 1 ...
, pertussis
Whooping cough, also known as pertussis or the 100-day cough, is a highly contagious bacterial disease. Initial symptoms are usually similar to those of the common cold with a runny nose, fever, and mild cough, but these are followed by two or t ...
, and dengue fever.
Other than expediting clinical evaluation of vaccine properties, advantages of using challenge studies for vaccine candidates include minimizing bias which is inherently part of traditional cohort studies
A cohort study is a particular form of longitudinal study that samples a cohort (a group of people who share a defining characteristic, typically those who experienced a common event in a selected period, such as birth or graduation), performing ...
, as both the exposure (timing of infection, virus challenge dose) and outcome (assessment of blood biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
s) are standardized.[ Disadvantages include high cost of conducting the trial at multiple locations and the complex management of infrastructure for a challenge trial, especially for obtaining national regulatory approval, organizing participants and trial personnel, and implementing laboratories with ]Good Clinical Laboratory Practice
Good clinical laboratory practice (GCLP) is a GxP guideline for laboratory samples from clinical studies.
Good clinical practice (GCP) does not define requirements for laboratories and good laboratory practice (GLP) focusses on pre-clinical analys ...
qualifications.[ Before beginning a challenge study, a vaccine sponsor must have demonstrated ]Good Manufacturing Practice
Current good manufacturing practices (cGMP) are those conforming to the guidelines recommended by relevant agencies. Those agencies control the authorization and licensing of the manufacture and sale of food and beverages, cosmetics, pharmaceut ...
standards for approval to use the candidate vaccine in humans, including expensive toxicology
Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating e ...
and immunogenicity
Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:
* Wanted immunogenicity typically relates to vaccines, where the injectio ...
testing. The vaccine sponsor may have required proof of safety and efficacy of adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to:
* Adjuvant therapy in cancer management
* Analgesi ...
s for delivering the vaccine, demonstrated what the effective vaccination schedule may be, and coordinated with international regulatory agencies and bioethicists for approval and eventual distribution, all requiring coordinated financing and planning.[
]
COVID-19
Human challenge studies are under consideration to hasten the development of a COVID-19 vaccine, including one proposal made by bioethicist Nir Eyal,[ and another by rubella vaccine inventor Stanley Plotkin with bioethicist ]Arthur Caplan
Arthur L. Caplan (born 1950) is the Drs. William F. and Virginia Connolly Mitty Professor of Bioethics at New York University Grossman School of Medicine and the founding director of the Division of Medical Ethics.
Caplan has made many contribut ...
.[ These authors propose that the multi-year duration and multinational location of a typical Phase III efficacy clinical trial will continue as usual, while people infected with COVID-19 will continue to suffer or die.][ As an alternative based on emerging results from COVID-19 vaccine challenge studies, regulatory agencies could allow early emergency use of the vaccine, while the challenge study continues collecting data for eventual licensure.][
In May 2020, a guidance document was issued by the WHO on criteria for conducting challenge clinical trials and providing clinical care for the participants.][ Following the challenge infection with or without the candidate vaccine, volunteers would be monitored closely in hospitals or clinics managed by physicians treating people with COVID-19 disease and with life-saving resources, if needed.][ Volunteering for a vaccine challenge study during the COVID‑19 pandemic is likened to the emergency service of healthcare personnel for COVID‑19-infected people, firefighters, or ]organ donors
Organ donation is the process when a person allows an organ of their own to be removed and transplanted to another person, legally, either by consent while the donor is alive or dead with the assent of the next of kin.
Donation may be for re ...
.[
]
References
External links
*
Let volunteers take the COVID challenge: Young, healthy, informed people should be allowed to participate in vaccine trials.
Conor Friedersdorf, ''The Atlantic'', 21 April 2020
1 Day Sooner
US-UK advocacy organization for human challenge studies of candidate COVID-19 vaccines (25,104 volunteers from 102 countries, as of late May 2020)
{{Medical ethics
Clinical trials by type
Human subject research