A participant recently engaged in a five-month Phase 2 clinical trial for an experimental dengue drug at the Johns Hopkins University Center for Immunization Research (CIR), providing insight into the operational, ethical, and participant-centric aspects of human medical experimentation. The study involved intentional infection with a modified dengue virus, highlighting established ethical frameworks, risk assessment protocols, and ongoing debates surrounding participant compensation and motivations.
Introduction to Clinical Trials
Clinical trials are a mandatory component of drug development globally, requiring three phases of human testing to evaluate the safety and effectiveness of new medications before approval. Since its launch in February 2000, the U.S. government's ClinicalTrials.gov has registered over 500,000 trials. Annually, approximately $100 billion is invested in their operation; however, most trials do not culminate in new drug approvals.
Dengue Fever Context
Dengue fever is recognized as the world's most prevalent mosquito-borne viral illness, with the World Health Organization estimating up to 400 million infections annually. Projections indicate that climate change is contributing to an increased global burden of the disease. Despite its prevalence, dengue is classified as a neglected tropical disease, partly due to the absence of specific FDA-approved treatments for severe cases. The illness can be fatal, particularly when co-occurring with conditions such as malnutrition or HIV.
Phase 1 and 2 drug trials for diseases prevalent in lower-income countries are often conducted in the U.S. due to the availability of academic expertise and funding not always accessible in regions most affected by the disease. The trial in question was conducted in Baltimore, Maryland, an area where dengue cases are rare.
The Specific Clinical Trial
The participant enrolled in a five-month Phase 2 clinical trial at the Johns Hopkins University Center for Immunization Research (CIR). The study aimed to test an experimental drug, consisting of monoclonal antibodies, for its efficacy in preventing severe dengue infection. The trial design involved two cohorts: one group received the experimental drug or a placebo intravenously prior to viral administration, while the other received it several days post-exposure. Compensation for participation was stated to be up to $3,425 or approximately $3,500.
Participant Experience and Risks
Participants received either the experimental monoclonal antibodies or a placebo. The dosing day involved a five-hour process of intravenous infusions and multiple blood draws. Following this, participants were injected with a genetically modified DENV-3 serotype of the dengue virus, engineered to induce mild illness. Approximately one week post-injection, the participant experienced symptoms consistent with mild dengue, including flu-like illness, a full-body rash, body aches, and pain behind the eyes.
A key risk identified in the consent forms was antibody-dependent enhancement (ADE), a phenomenon where a prior dengue infection can increase the risk of severe disease upon subsequent infection due to imperfect antibodies. This risk factor is carried by the participant for life. The experimental monoclonal antibodies did not guarantee long-term dengue protection.
Informed Consent and Ethical Frameworks
Prior to participation, individuals underwent an extensive consent process. This included reviewing a comprehensive information packet detailing potential risks, participant rights, and a code of conduct. This was followed by an open-book test requiring a minimum score of 70% on the content. Anna P. Durbin, director of the CIR and the trial's principal investigator, described consent as an evolving process. She also noted that consent forms remain lengthy despite efforts to ensure comprehensive information while maintaining clarity.
Historically, medical research has included instances of unethical experimentation, such as Nazi experiments during World War II, the U.S. Tuskegee study (1930s-1970s) which withheld syphilis treatment from Black Americans, and the Willowbrook experiments (1956-1970) which intentionally infected children with mental disabilities with hepatitis.
In response to these abuses, the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research published the Belmont Report in 1978. This foundational document established three core ethical principles for human research:
- Respect for Persons: Mandates informed consent and participant autonomy.
- Beneficence: Emphasizes the philosophy of "Do no harm."
- Justice: Ensures fair distribution of research benefits and risks.
These principles led to U.S. regulations mandating that Institutional Review Boards (IRBs) evaluate the ethics of medical research involving human participants. IRBs engage in detailed discussions to scrutinize procedural ethics, evaluate risks, confirm mitigation strategies, and ensure participants are fully informed about procedures, compensation, sample use, withdrawal rights, and data privacy.
Risk Assessment in Clinical Trials
Nir Eyal, a bioethicist at Rutgers School of Public Health, outlined a three-stage process for calculating appropriate risk levels in clinical trials involving healthy individuals:
- Risk Minimization: Designing trials to minimize risks and maximize benefits, such as using genetically modified viruses engineered to induce mild illness.
- Societal Benefit Proportionality: Assessing if individual risks are proportionate to the potential benefits for society, even if there is no direct medical benefit to the participant.
- Absolute Risk Threshold: A debated stage concerning whether there should be an absolute upper limit of risk to an individual, regardless of societal benefit. Eyal has posited that, with proper informed consent and sufficient societal benefit, an upper limit on individual risk might not be necessary, suggesting properly informed individuals should be able to assume risks commensurate with societal benefit.
IRBs generally adopt a conservative stance on acceptable risks, influenced by the historical context of medical abuse. This cautious approach contributes to ongoing discussions regarding paternalism in clinical trial design.
Compensation and Participant Demographics
The participant received approximately $3,500 for 17 visits over five months. The level of compensation in clinical trials is a subject of ethical debate. Historically, review boards have been cautious about offering high payments, fearing that significant compensation could unduly influence individuals in financial need to participate.
Anna P. Durbin has advocated for higher pay, disagreeing with the restriction based on concerns about undue influence. Josh Morrison, president and cofounder of 1Day Sooner, an organization advocating for clinical trial participants, argues that restricting compensation due to this fear is "patronizing and unfair." He maintains that if a study is ethically sound, higher compensation does not compromise its integrity, and suggests compensation should reflect the time and effort invested rather than the inherent risks.
Jill Fisher, a bioethicist at the University of North Carolina at Chapel Hill, has highlighted concerns about participant exploitation if compensation is insufficient. Her research over two decades indicates that U.S. clinical trial participants are predominantly Black or African American in the Northeast and Midwest, and Hispanic or Latino in the Southwest and Southeast. These individuals often lack alternative reliable income sources or affordable healthcare. Observations from the trial indicated mixed motivations among participants, with some joining for scientific contribution and others for financial necessity, while many expressed gratitude for the income opportunity, they may also feel exploited. Repeat participation in clinical trials is common, with some individuals relying on them as a significant, though rarely primary, form of income. Motivations for participation are often a blend of altruism and financial consideration.
Participant Perspectives
The participant in this dengue trial stated a motivation to understand the business and ethical frameworks governing human medical experimentation. Others involved in similar challenge trials have shared their motivations:
- Jacob Hopkins, the first participant in a UK COVID-19 challenge trial in 2020, cited altruism as a primary motivation, which subsequently developed into an interest in clinical trials and advocacy.
- Roopesh Chavda, who participated in two COVID-19 challenge trials, viewed his involvement as contributing to the greater good, while also emphasizing compensation for risks as a necessary factor.
The employment statuses of these participants varied, with some being unemployed, others working remotely, and some having employer approval for their participation. Researchers and ethicists involved in clinical trials continue efforts to enhance the participant experience.