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International Clinical Trials

Principled Progress


Aarti Pandey and Swaminath Ganesh at Wipro Technologies examine the seven key ethical considerations for organisations to tackle before embarking on clinical trials in developing countries

Collaborative clinical research between developed and developing countries has been equally commended and questioned. Clinical trials are conducted to collect the safety and efficacy data of a new or existing drug. The procedure involves testing the drug on both healthy subjects and patients to collect data for safety and efficacy respectively.

Developing countries attract many outsourced clinical trials due to their vast subject availability and significant cost saving offerings. For example, India has the largest pool of diabetic patients, making insulin-based drugs the most researched in the country. Moreover, India has advantages such as the highest number of qualified physicians as well as a large number of English speaking professionals, making it ideal for US- or Europe-based pharmaceutical companies to outsource their clinical trials to India.

The glitter of a vast patient pool, faster enrolment, relevant expertise and reduced costs has beclouded the ethics of trials and patients’ rights. The word ‘ethics’ is derived from the word ‘ethos’, which means character or manner. The dictionary defines ethics as ‘a set of principles of right conduct’. There is a growing realisation the world over that ethics is vital for any business today. This article looks into ethical aspects of clinical trials in developing countries.

STANDARD OF CARE

The issue concerns the ‘standard of care’ (that is, the nature of care and treatment provided) that should be given to subjects during research in developing countries. The rationale of this requirement is to safeguard research subjects from being harmed as a result of being deprived of proven medical treatment while participating in a study.

The standard of care provided to subjects in host countries varies from that provided in the country where the trial is being conducted, where the latter infrastructure tends to be inferior. Although developing countries may not support the infrastructure for providing a standard of care equivalent to developed countries, in these cases subjects should be offered the best treatment available in-country. The standard of care must be clearly defined after consultation with resident professionals and must be justified to the research ethics committee.

COMMITMENT TO TRIAL COMMUNITIES AFTER SUCCESSFUL TESTING

In more developed parts of the world, one would normally expect that a successful drug would become available to those who need it. In developing countries, this is often not the case. One example is the preventive malarone trials in African countries, resulting in licensing of this drug for the prevention of malaria in travellers and expatriates.

In Brazil, a resolution advises that “access to the medicine being tested must be assured by the sponsor or by the institution, researcher or promoter, if there is no sponsor, in the event its superiority to the conventional treatment is proven” (1). Researchers designing a trial for antiretroviral therapies (ARTs) to treat HIV/Aids patients initially were resistant to this requirement because of the high price of the medicines. However, after negotiation, all companies involved in sponsoring the trial agreed to comply. In one particular trial investigating the medicine Enfuvirtide (T-20), a pharmaceutical company provided supplies for more than two years after the trial was completed at no cost to the participants.

World Medical Association opinion on the availability of drugs post-trial is that “it is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as beneficial in the study or access to other appropriate care. Post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review” (2).

QUALITY OF INFORMED CONSENT

Informed consent is the core principle of the Declaration of Helsinki (3). Clinical trials should be carefully conducted and patients should be well-informed about the potential side effects and covered for all the treatments due to such side effects. With increased awareness about the risk and side effects of testing drugs under development, the number of volunteers in developed countries has decreased. Due to this, the drug industry is exponentially moving to underdeveloped and developing countries like India, where volunteers are readily available, lawsuits are unheard of, and compensation is minimal.

However, these volunteers can be uninformed and uneducated about the potential risks – it is therefore crucial to ensure proper conduct of trials. For example, investigators failed to get patients’ consent in the hepatitis trial conducted in 2006 in Kathmandu, Nepal (4). Due to illiteracy and cultural differences, subjects are unable to fully comprehend the risks mentioned in an informed consent form.

COMPENSATION TO RESEARCH PARTICIPANTS

The ICH-GCP mandates that the sponsor should address the compensation for, and side effects due to, trial participation. ICMR draft guidelines from 2006 explicitly mention compensation in terms of remedial action and after-care, including treatment during and after the research, and recommends both immediate and rehabilitative measures in the event of trial-related injury. This is extremely important in developing countries since, unlike developed countries, only a meagre number has medical insurance in developing countries. Ten companies (Wyeth, Merck, Quintiles, Lilly, Amgen, Bayer, Bristol Myers-Squibb, Sanofi, PPD and Pfizer) paid just over INR 50 lakh (£665,215) as compensation to the legal heir of 22 people who died because of adverse event of clinical trials conducted in India in 2010. Most of the families received between INR 1.5 lakh (£200,000) and INR 2.5 lakh (£332,500) as a one-off compensation, which is substantially less than the international standard (5).

ICMR guidelines on compensation do not specify how the amount of compensation should be decided; rather it suggests setting up an arbitration committee to decide these issues. The ICMR guidelines stipulate that the informed consent document (ICD) must state clearly that the research participant has the right to claim compensation in case of research-related injuries and whom to contact regarding their rights. Before conducting the trial, the consent form should also clearly state the compensation details in case of any adverse event due to the trial.

UNDER-REPORTING OF ADVERSE EVENTS OR SIDE EFFECTS

Safety of the drug depends on the accurate reporting of adverse events or side effects by all stakeholders – in other words, medical professionals, sponsors and consumers. Lack of awareness among the subjects in developing countries is one of the reasons that under-reporting from healthcare professionals occurs. For example, with the hepatitis E trial in Nepal, there were serious problems in record-keeping and delays, and underreporting of fatal and life-threatening problems. Fourteen deaths were not reported. Researchers acknowledged thousands of side effects and adverse reactions were not disclosed. Procedures for divulging serious adverse events (SAEs) were not followed (6).

THERAPEUTIC MISCONCEPTION

The concept of clinical trials is not fully understood in developing countries; it is usually associated with access to free drugs to ease a subject’s pain. Therapeutic misconception refers to the delusion that the purpose of a clinical trial is to benefi t the individual subjects rather than to gather data for the purpose of contributing to a larger audience. Subjects would probably receive good clinical care during the trial, but it is a misconception to believe that the purpose of clinical trials is to administer treatment rather than to conduct clinical research. Investigators should make clear to participants, in the initial consent process, which activities are elements of research and which are elements of clinical care.

CONFLICT OF INTERESTS

There are concerns that the financial confl icts of interest on the part of investigators conducting clinical trials may compromise the best interests of research subjects. These incentives may infl uence investigators to widen inclusion and exclusion criteria for subject enrolment. Such participation of disqualifi ed subjects has led to questioning of the validity of trial data. Apart from subject recruitment, fi nancial motives can infl uence the various decisions an investigator makes during the course of a trial. Prestige, grants, promotions and fi nancial incentive can influence the investigator’s estimation of the benefi ts of the trial or underestimation of the risks associated with the trial.

The financial disclosure regulations by the FDA mandate the applicant for the drug to submit a list of those investigating the trial and to certify and disclose their financial interests. Implementation of a mandate in developing countries has been drawn into question. Also, sponsors submit financial disclosure to the FDA along with their marketing application after the clinical trial ends. According to a study conducted, only one per cent of clinical investigators disclosed a financial interest. The study also mentions that the FDA cannot determine whether sponsors have submitted complete financial information for clinical investigators because it does not have a complete list of investigators (7).

The FDA should mandate a complete list of clinical investigators for all clinical trials. It should not approve the marketing application without the mandated fi nancial disclosure and the information should be submitted before conducting clinical trials, rather than submitting along with the marketing application.

CONCLUSION

Ethical methodology and implementation committees are facilitators rather than barriers to clinical research. Indeed, ethical behaviour plays a vital role in sustaining clinical research by upholding the public support for the process. The temptation to cut corners is always high because of the increasing cost of trials, expiring patents and tight regulations in developed countries. Drug makers are looking to accelerate the process by outsourcing safety and efficacy studies to developing countries. While many developing countries have established ethical standards for clinical trials, they are not always implemented either by the sponsor or the investigator, due to lack of resources and infrastructure. Harmonisation of guidelines should be adopted for conducting clinical trials uniformly in both developed and developing countries alike. “The greatest challenge in moving to mutual benefit is balancing the needs of biomedical research with the full protection of research participants and communities,” said Ames Dhai, director of the Steve Biko Centre for Bioethics at the University of Witwatersrand, South Africa.

 Adequate training should be provided to all to improve the standard of pharmacovigilance in developing countries. Participants should be recruited on the basis of requirements and not on the basis of probability of consent, thus reducing vulnerability.

The benefit-to-risk ratio of the subjects participating in trials should be improved; there should be clear guidelines on the compensation to subjects for participation and also in case of any adverse event. Clinical researchers should build training programmes to enhance local skills and build mutually beneficial partnerships.

References

1. Resolution 251 (251/97/IV.1.m), Brazilian National Health Council
2. Clinical research on Good Clinical Practice (GCP)
3. WMA Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects
4. SOMO briefing paper on ethics in clinical trials #1: Examples of unethical trials December 2006 (updated)
5. Times of India (Chennai edition), 11 August 2011, p13
6. Ethics concern over outsourcing clinical trial, http:// www.articlesbase.com/diseases-and-conditions-articles/ ethics-concern-over-outsourcing-clinical-trial-1739869.html
7. Offi ce of Inspector General, http://oig.hhs.gov/oei/reports/ oei-05-07-00730.pdf

Further Reading

1. Guardian development network, Ethics left behind as drug trials soar in developing countries, 4 July 2011
2. Research ethics in developing countries, Parliament Office of Science and Technology, April 2008 Number 304
3. WMA Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects
4. Killen J, Grady C, Folkers GK and Fauci AS, Ethics of Clinical Research in the Developing World, Macmillan Magazines Ltd, 2002
5. Brahmachari B and Bhatt A, Clinical research ethics in developing world: Challenges and way forward, Pharma Times 42(8), August 2010
6. Marshall PA, Ethical challenges in study design and informed consent for health research in resource – poor settings, TDR/ World Health Organization, TDR/SDR/SEB/ST/07.1

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Aarti Pandey currently works as an Associate Consultant in Healthcare and Life Sciences for Wipro Technologies, where she is responsible for researching current trends within the industry and identifying the technological gaps where Wipro’s expertise can help facilitate better practices in the industry. An engineering graduate from Indira Gandhi Institute of Technology, Delhi, Aarti fi rst worked as a developer in life sciences at HCL Technologies before then securing a place in the post-graduate programme in Management from the Great Lakes Institute of Management in Chennai. Email: shannon.tucker@wipro.com

Swaminath Ganesh heads up the pharmaceutical division for Wipro Technologies and has an international track record of information management, IT-enabled process change, and senior level business planning and program governance in the pharmaceutical industry. He has more than 18 years of experience working across the pharmaceutical, biotechnology and medical devices sectors for companies of all sizes. In his time, Swaminath has worked with pharmaceutical companies of all sizes throughout India and East Africa – from small to medium through to global leaders such as AZ, GSK, J&J, Merck, Novartis and Pfizer. Email: shannon.tucker@wipro.com
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