Education Module
Clinical Research in the International Setting: Obligations to Participants During and After Trials
Introduction
Clinical research conducted in the international setting poses unique obstacles and entails many different obligations to participants, both during and after trials. This module reviews these obligations and ethical considerations in international clinical research.
International Collaborative Research
International collaborative research is defined as research involving two or more countries; a sponsor in one country and a host in another country (or multiple sites). There are distinctive ethical issues that arise when there are economic disparities between wealthier sponsors and poorer host communities. Potential research subjects and communities in developing countries are often in great need and vulnerable to exploitation. This is important to consider, since research participants must get a fair level of benefits from their research participation.
Obligations to Research Participants During Trials
Medical Care During Trials
Trial participation may provide care that is unavailable outside the trial. There is a need to distinguish between ancillary care (clinical care that is not part of the trial design) and care that is included in the trial design.
Ancillary care is medical care provided to participants in a trial that is not required for the trial's safety or scientific validity.
Three principles should be considered in providing ancillary care, including compensation for harm, duty of rescue, and the relationship between researchers and participants.
Compensation for Harm
Almost all medical research poses risks to clinical research participants. When research participants d not have other health care, not to treat research-related injuries would make research too risky.
Duty of Rescue
Duty of rescue means that researchers may be able to give life-saving treatments, and have an obligation to do so, especially when participants may not have other sources of treatment.
Researcher-Participant Relationship
During research, a relationship often develops between researchers and their participants. This is analogous to the doctor-patient relationship. Participants entrust aspects of their health to researchers.
Sources of Ancillary Care Obligations
There are several sources of ancillary care.
- Research-related injury: all harms caused by research should be compensated
- Rescue: urgent medical needs should be met, if low cost
- Relationship: care is provided proportional to the depth of the participant-researcher relationship, and is determined by the scope of entrustment
Case Study
A five-year observational study of malaria in children is taking place in a population where childhood malarial bouts are severe and often fatal, HIV prevalence is high, and there is no suitable treatment for HIV/AIDS.
In locations with poor health care facilities, researchers may be the only people who can help. Many researchers feel that they ought to provide some clinical care (ancillary care).
Any research-related injuries that occur during the study should be treated. HIV/AIDS treatment is urgent. Prophylatic treatment for opportunistic infections is affordable, but treatment for antiretrovirals (for HIV) is not affordable. Treatment for malaria is the focus of the study, and children's malaria treatment is entrusted to researchers.
Placebo-Controlled Trials
There are several scientific and economic reasons for the use of placebos. Some drugs are known to vary in effectiveness across different populations. Active control trials may not show that alternative treatments are better than a placebo – the active drug may just be ineffective in the population tested.
Sometimes an effective treatment is not available to a population for economic reasons. Researchers may want to develop a less expensive treatment that can be provided. Researchers may expect this treatment to be less effective than other treatments, but comparison to a placebo may be scientifically necessary.
Placebo controls are permissible when there is no known effective treatment, when there are scientifically compelling reasons plus no serious harm, and/or when there are scientifically compelling reasons plus social benefits to the host community plus no one is deprived of treatment.
Post-Trial Obligations to Research Participants
The Council for International Organizations of Medical Sciences states that, “although sponsors are, in general, not obliged to provide health care services beyond that which is necessary to conduct research, it is morally praiseworthy to do so.” The Declaration of Helsinki also discusses post-trial research obligations: “At the conclusion of the study, every patient entered into the study should be assured access to the best proven prophylatic, diagnostic, and therapeutic methods identified by the study.”
Researchers should identify sources or plans for post-trial access by study participants to prophylatic, diagnostic, and/or therapeutic procedures identified as beneficial in the study, or to other appropriate care.
There are limitations to the available guidance. Even if there is a provision for referral to a host country's system of treatment, the system may not be prepared for it. The host country may not be able to provide the same standard of care available in the trial or may be overwhelmed when large studies conclude and numerous people require care. If research is conducted only in places where post-trial care is available, this deprives the poorest countries of opportunities to host research.
Case Study
A trial of an expensive blood pressure medication is proposed to occur in India, but the company does not intend to market the drug anywhere except the United States. Is post-trial access for the participant community a necessary ethical requirement?
The Declaration of Helsinki states that, “medical research is only justified if there is a reasonable likelihood that the population in which the research is carried out stands to benefit from the results of the research.” The Council for International Organizations of Medical Science states that, “as a general rule, the sponsoring agency should ensure that, at the completion of successful testing, any product developed will be made reasonably available to the inhabitants of the underdeveloped community in which the research was carried out.”
Case Series
The remainder of this module is dedicated to a case series, comprised of five case studies that explore some of the practical and ethical issues related to conducting clinical research in the international setting. A number of questions have been posed for each case study in the series. While there may be no one specific correct answer to some of these questions, what is clearly wrong is not to consider these important practical and ethical issues.
A researcher wants to do a pilot study of rapid HIV testing. The researcher plans on offering HIV testing to mothers and their children in a family clinic where mothers bring their children for routine healthcare and vaccinations.
Several issues are encountered here. These include the following:
- Is consent required? If yes, from whom does the researcher obtain consent?
- Does the project have local buy-in?
- Are key stakeholders and community leaders involved?
- What will occur if someone is found to be HIV-positive?
- Who will be the director of the project?
Case 2
A young, ambitious researcher from the United States wishes to study a tropical disease. The exact disease mechanism is unknown, but it is known to be infectious. There is no effective treatment available. The disease leads to significant morbidity and is also sometimes lethal. The young researcher exposes the following subjects to infectious material, after getting informed consent: Indian servant, lab assistant, son, and a patient with a chronic illness, unrelated to the tropical disease. The researcher also exposes a patient who has just been treated for the same illness and survived, but consent is not obtained from this patient because the researcher fears the patient will not understand the consent process.
Ethical issues
- Informed consent is absolutely essential
- Independent review is essential, because self-regulation does not work
- Review of risks and benefits
- Informed consent procedures
- How do we balance encouragement of innovation and risk-taking among researchers with protection of research subjects?
- What is an acceptable level of risk to subjects in experiments that aim at gaining knowledge that might improve public health?
Case 3
Trachoma is the world's leading cause of infectious blindness, predominantly found in sub-Saharan Africa and Asia. It is caused by an eye infection with the bacteria Chlamydia trachomatis and is transmitted through direct contact of eye and nasal secretions, or by germs, parasites or flies. The disease manifests gradually and can be effectively treated with a single dose of azithromycin. There has been a trend of decreasing prevalence of the disease. A researcher wants to include a non-interventional group to control for whether the decrease in prevalence is because of the treatment, or because of a trend. Clinical trials of the new treatment randomize villages to a particular treatment.
Ethical issues
- Would it be ethical to give a placebo to a particular village?
- Could you test against the standard treatment instead?
- How would you obtain consent from people at the intervention village? The control village?
- What obligations does the researcher have to the control group afterwards?
- What obligations does the researcher have to the community?
- Would it be ethical to provide other benefits (i.e., money or food) instead of the treatment after the trial?
- What obligations does the researcher have for ensuring policy change and implementation of a successful intervention?
Case 4
A respiratory distress syndrome affects many premature babies and is caused by insufficient surfactant in the lungs. The syndrome is best treated with mechanical ventilation, IV, and surfactant replacement therapy. A new study, proposed by Discovery Labs, will use Surfaxin, a new synthetic surfactant. Discovery Labs proposes a placebo-controlled trial, which is unethical in the United States because alternative surfactants are available. The proposed trial includes 650 infants in Bolivia and three other Latin American countries. In the study, all premature infants will be given mechanical ventilation and IV. Half of the infants will be given Surfaxin, the other half will not be given a surfactant. Parents consent on behalf of their children.
Ethical Issues
- All the children are likely to do better than they would outside the trial, but this is a trial that would not be permitted in the US
- The primary market for Surfaxin will be the US and Europe (not Latin America)
- Is the trial unethical, even though everyone is better off?
- If you think the trial is unethical as it stands, could the design be changed to make the trial ethical? Could the researchers provide ancillary care to make it okay to use a placebo control?
Case 5
To text an experimental HIV vaccine, researchers find a high-risk population. A vaccine is proven effective when it prevents or reduces infection. Researchers hope to find a statistically significant difference in infections in the control arm compared to the intervention arm (receiving the vaccine). Researchers propose to study the vaccine in sex workers. The experimental vaccine will be tested against placebo injection.
Ethical Issues
- What is the standard of care that investigators should offer subjects to prevent HIV?
- Counseling, condoms, other?
- What if prevention options compromise the validity of the trial by decreasing the infection rate?
- What do the researchers owe subjects who seroconvert during the trial?
- Counseling?
- Treatment for opportunistic infections?
- Viral load monitoring?
- Antiretroviral therapy?
- Referral to nationwide program for antiretroviral therapy?
- What do researchers owe subjects who seroconvert if:
- Subjects thought they were protected by the experimental vaccine, and engaged in riskier behavior?
- The vaccine caused subjects to be more susceptible to infection?
Acknowledgements
This module was adapted from several power point presentations originally given as part of the National Institutes of Health/ Fogarty Scholars and Fellows Program, held in Washington, DC in July 2008.