EATG's position paper on ethics of clinical trials in vulnerable populations

1 – Vulnerability
A vulnerable group can be part of the population of a high-income country, or of a middle or low-income country. The notion of vulnerability can also be applied to the entire population of a low or very low income country, or to a country where democracy is lacking and civil society under-represented. We define a group or a country as being vulnerable considering:

• The level of the proposed community’s economic power;
• The state of access to care, and treatment standards in that specific group / population, in comparison to other, less vulnerable groups
• The experience or understanding of scientific research in the group/country as a whole;
• Local infrastructure, human resources, and technical capacity for providing health care and treatment options;
• Experience and capacity in conducting ethical and scientific review;
• The ability of individuals in the community to provide informed, pressure-free consent.

Clinical research in vulnerable groups and /or populations conceivably involves particularly high risks to research subjects, represented by a range of reasons, including poverty, mal-nutrition, accompanying pathologies, logistic and economical difficulties, education levels, freedom of choice. All of the above might interfere with the person’s ability to freely and effectively decide upon participation in a trial, and on the probability of retention in the trial, and increase the risk and danger of adverse events.

In low income countries, in which access to treatment is lacking, clinical trials sponsored by pharmaceutical companies from high income countries may represent a valid source for early access to treatment. On the other hand, such trials are invariably complicated by the risk of lacking and insufficient healthcare infrastructure and personnel, by economical constraints, and by uncertain ethical standards. Most importantly, the individual consent for participation in drug development trials cannot be considered pressure-free, given that subjects in the study have no other alternative to access lifesaving treatments.

A particular source of concern is that research sponsors may be attracted to conduct studies in vulnerable populations due to the ease of enrolling large numbers of treatment naïve individuals, to the laxity of ethics standard and control, and to the ability to offer trial participants inadequate treatment and insurance standards with significant reductions in costs.

For this reason, trials conducted in vulnerable populations require an additional set of rules and regulations to defend the rights of individuals taking part in research, and to avoid exploitation of vulnerable groups as subjects to unethical studies based on substandard treatment and care.

In this setting, the role of ethics committees, and the quality of information given to the participants are also of particular importance.

As a general rule, phase II and III drug-development trials should be conducted simultaneously in the host community and the sponsoring country, and the aims and methods of the trials should be equal. This is an important control mechanism to ensure that collateral trials involving unnecessary risks to subjects are not conducted in vulnerable populations, and that competent ethics committees judge all trials applying uniform measures. A parallel conduction in the sponsoring country may be omitted only on condition that the drug is designed to treat or prevent a disease or other condition that rarely or never occurs in the sponsoring country. [1]

Trials may be conducted in a given country only when investigators have good reason for testing the intervention in that particular population and only when it is expected that the intervention will be accessible to that population.

2 - Before and during the trial
The two principal approaches to improving the protections of human participants in international clinical trials are:

Ethics committees

• The protocol must be submitted to an ethics committee in both the country where the trial is conducted, and the country of the sponsor. This procedure safeguards trial subjects in those settings where the existence and know how of ethics committees are incomplete but also offers input from local committees that may be aware of cultural barriers, economic constraints, health hazards and other factors that may elude members of international ethics boards.
• In cases where local committees are not formed, the sponsor must address a third party (i.e. the WHO, international aid organizations etc.) and provide funds to help to build this capacity in a way that will ensure the independence of the committee from the sponsor;
• The local ethics committee must be independent from the investigator and from the sponsor, and the roster of their members specifying professional skills and affiliations be made public;
• People living with HIV/AIDS must be represented in both ethics committees evaluating the trial;
• Research proposals submitted to ethics review committees should conform to the standard request from investigators in high income countries. Hence, all protocols should provide a clear explanation of study aims, methods, risks and benefits, and other treatment options. Presented protocols should also include an explanation of how the new interventions, that will be proven effective by the research conducted in the community will become available to some or all the host country population beyond the research participants themselves (cf below);

Involvement of organizations of people living with HIV/AIDS

In the setting of vulnerable communities the significant involvement of community representatives and advocates, allowing them to supply meaningful input, is an indispensable safeguard of research subjects.

By meaningful involvement it is intended that community representatives are individuals actively working for the HIV community, possessing basic scientific skills, and endorsed by the latter or by local NGOs, rather than being individuals selected by sponsors solely on the basis of HIV status, or of belonging to a known risk group.

Whenever such community representation is unavailable it is the responsibility of the sponsor to involve patient groups from high income countries providing them with resources to allow training and mentoring of their colleagues creating, whenever possible Community Advisory Boards (CABs) equipped by the knowledge necessary to express judgement on clinical trials in their countries. By meaningful input it is intended that such representatives be given access to research protocols in time to influence the design and ethics requirements, and in particular:

• The protocol must also be submitted to the local CABs that will work in parallel to the local ethics committees.
• The informed consent sheet must be written and/or revised in collaboration with these representatives;
• Regular information should be given to these representatives about enrolment, the march of the trial, any unexpected outcome or adverse events, trial conclusion, and so on.

Informed consent for participation in the study

Informed consent sheets should be realised with the aid of local community and healthcare professionals to guarantee their readability and understanding, or the ability to be administered to individuals unable to read. Each informed consent sheet should contain clear and truthful explanations of the following:

• The benefit/risk ratio for each trial participant, including the risk of adverse events, viral resistance, and limitations of future options.
• Eventual treatment options available to potential participants.
• Clear instructions regarding treatment management, adherence, and non medical factors able to interfere with treatment success, i.e. nutrition, life style factors etc.
• A clear commitment regarding continuation of treatment and care beyond study termination.
• A clear statement regarding the voluntary nature of the trial. This last is of particular importance when dealing with groups who have an impaired freedom of choice (i.e. prisoners, migrants, refugees etc.). When proposing a trial to such populations every effort must be made to dissuade local researchers from pressuring patients into participation.

Treatment during the trial

The Helsinki declaration recommends that participants in clinical trials should receive the best proven therapy. Neither the Helsinki declaration nor the CIOMS (Council for international Organizations of Medical Sciences) guidelines refer to restrictions in any circumstances. [2] Therefore, during the trial, the patients must receive nothing less the best proven therapy or the experimental drug / combination. Placebo is not acceptable where a treatment has proven been proven effective in the past, and hence new treatments must be compared to those already available. [3] lf a new treatment becomes available in the course of the study, the protocol must be revised and treatment arms adapted accordingly.

Expenses

The sponsor must pay for every expense related to participation in the study, including the provision of drugs to treat opportunistic infections, the best diagnostics. Sponsors must also ensure that patients receive the best possible environmental and nutritional conditions during the trial.

3 - After the trial
Life long treatment

All patients enrolled in a clinical trial should be provided the best proven therapy for a life long period. This means that, all patients who partake in the trials, including those in the control arms, are to be given free access to the combination proven effective by the trial, for a life time period. Similarly, patients must be given free access to every other drug in their treatment combination , even if this other drug is produced by another company. As treatment drugs and combination may change over time, past trial participants should automatically become eligible to new, improved medication as it becomes available. The same treatment options and rights must be extended also to patients forced to leave the trial prior to its completion, due to of tolerability / toxicity or other problems.

4 - Benefit for the whole population
As stated by the revised Helsinki Declaration (October 2000) ‘Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research».

THE CIOMS article 8 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: exceptions to this general requirement should be justified to by all concerned parties before the research bas begun“

Although the meaning of ”reasonably available“ is not clearly specified, the wording of the guidelines clearly implies that there is an obligation for the sponsor to ensure the availability of the product. Hence, the mechanism for ensuring such availability should be specifically set forth in an agreement before the study begins. The principle of justice requires that a vulnerable population should not be the focus of research unless the potential benefits of the research are extended to that group after the trial.

An agreement should be negotiated

Prior to the beginning of any research studies in vulnerable populations and/or countries, agreements should be negotiated between the relevant parties to make the effective intervention or other research benefits available to the host country after the study is completed.

In the particular case of a pharmaceutical company conducting trials on a new drug in developing countries, the company should commit to make this drug available at a locally affordable price after the completion of the drug development process.

The nature of any pre-research negotiations between sponsors, host country officials, patients’ advocates, and other appropriate parties should be included in the drug dossier evaluated by local ethics committees. In cases in which it is not foreseeable that successful interventions will become available in the host country, the ethics committees should be supplied with a detailed explanation of the reasons that render the research justifiable in the context of the single country and/or community, and a reasonable risk/benefit ratio presented.

5 - Benefit for the health care system
Several International guidelines recommend that, whenever proposing research in developing countries, the sponsor agency be required to build local and national capacity for designing and conducting trials and for the scientific and ethical review of research projects. Making resources available for improving the technical capacity to conduct and evaluate research, as well as the ability to carry out proper ethical review, is one way to promote this effort.

Other ways to ensure development of local capacities include:

• Execution of all laboratory testing locally, thus transferring technology to the host country;
• Appointing a local head researcher and local clinical staff, thus contributing to the education and skill level of healthcare professionals.

Conclusion
In the context of international research, ethics requirements dictate that that research risks are reasonable in relation to its potential benefits, but also that they respond to the health needs of the single AND the population studied.

Research in vulnerable populations is therefore only justifiable if the results will be extended to local patients and the health care system in general, and if the conduction methods and informed consent mechanisms take into account the particular social or biological vulnerability of trial participants.

References

1. International Ethical Guidelines for Biomedical Research involving Human Subject – Published in 1993 by CIOMS (Council for international Organizations of Medical Sciences) in collaboration WHO.
2. The provision of the declaration of Helsinki are applied in all biomedical research involving humans», article 14, CIOMS guidelines.
3. If there is already an approved and accepted drug for the condition that a candidate drug is designed to treat, placebo for controls cannot be justified no other interventions must be known to be superior to those being compared in the clinical trial», article 14, CIOMS guidelines.

EATN - European AIDS Treatment News, Volume 13, I – Spring 2005

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