EEB 180: Genetic Engineering in Developing Countries
Issues with IRB review in developing countries
- Informed consent is the first safeguard for protection of human subjects in research.
- IRB committees are the second safeguard for protection.
- IRBs must find a balance between:
- Ensuring the ethical protection of human subjects; and
- Encouraging research to benefit people.
- US IRBs require IRB review in foreign countries if:
- Research is conducted there;
- Foreign collaborators collect data there.
- What issues of IRB review are unique to developing countries?
IRB principles at UCLA:
- Based on the Belmont Report (1979).
- Respect for people:
- Protection of people with diminished autonomy.
- Effort to secure well-being, kindness, charity.
- Do no harm (non-maleficence).
- Maximize benefits, minimize risks.
- Distribute benefits justly.
- On the basis of need, effort, social contribution, merit, equality.
- Informed consent:
- Requires capable subjects and comprehension.
- Risk/benefit analysis:
- Provide an array of data.
- Provide the best methods of treatment available.
- Selection of subjects
- Non-discrimination based on gender/ethnicity.
- Need to explain selection of vulnerable people/children.
IRB issues specific to developing countries:
- How do judgments about risks, benefits and informed consent differ between the US and host country?
- What options for care are avilable in the country where the research is being carried out?
- What are the risks to participants in the host country compared to in the US?
- e.g. stigma associated with the disease being studied.
- How will these risks be minimized?
- What barriers are there to free informed consent compared to in the US?
- e.g. low literacy rate, non-Western beliefs about illness, different attitudes to contracts and signatures, the role of third parties in decision-making (e.g. husbands or village chiefs).
- How can these barriers be minimized?
- If there is compensation paid to the participant?
- How much is this relative to the average living wage?
- Imagine a clinical trial administering INH preventative therapy to HIV+ children in Kenya.
- The clinical trial must be submitted for IRB approval, first in the US.
- What questions might the IRB panel ask of the trial?
- Possible questions:
- What treatment options are currently available to Kenyan children?
- Has INH therapy already been trialed in the US?
- If so, what were the side-effects?
- Could there potentially be additional side-effects among Kenyan children?
- If there are side-effects, will infrastructure be available to treat the Kenyan children?
- Is there more stigma around AIDS in Kenya than in the US?
- If children are not allowed to assent to participate in the study, are there any barriers to a parent or guardian assenting?
- Are teenagers treated differently from children?
- Will children who are orphans but have no legal guardian be eligible for the study?
- Are there discrepancies between Kenyan and US standards of citizenship?
- Is there a possibility that family members will share INH pills?
- Would this adversely affect their health?
- Is the wording of the consent document appropriate for a Kenyan population?
- Is there compensation paid to participants in the survey?
- If so, how much is this relative to the average living wage?
Potential failures of the system:
- Researcher provides the IRB committee with insufficient information.
- Researcher fails to submit a proposal.
Problems with collaborative research at Harvard School of Public Health:
- 12 studies were carried out in a rural provence of China beginning in the mid-1990's.
- Included poor and relatively-uneducated subjects.
- Sought to evaluate genetic and environmental causes of ailments ranging from obesity to respiratory diseases.
- Examples of studies:
- Genetic susceptibility to the effects of aromatic solvents on reproductive health.
- Effect of rotating shift work on reproductive outcomes.
- Studies involved:
- Blood samples from participants,
- Lung-function tests,
- Allegation of unethical research led to research by the Office for Human Research Protection (OHRP).
- Numberous vioations discovered by the OHRP:
- Some studies were not submitted to the HSPH IRB.
- Some studies commenced prior to IRB approval.
- Some approved work was altered without seeking IRB approcal:
- e.g. In one case the amoung of blood drawn was increased without approval.
- The informed consent documents were found to be inadequate.
- Consent forms were written in a language that was too complex for the participants to understand.
- Consent forms did not thoroughly explain the research.
- No information was provided about the degree of confidentiality.
- On the issue of consent, the IRB noted these facts, but approved the project anyway.
- The IRB did not thoroughly review the ongoing projects once they were approved.
- Subjects were not physically harmed as a result of study defects; but this shows fundamental problems with the ability of the IRB process to protect research subjects.
Problems with collaborative research at UCLA:
- UCLA professor of microbiology failed to seek IRB approval to analyze blood samples obtained by a former student and now collaborating researcher in China.
- The research in China involved injecting malaria-infected blood ingo Chinese AIDS patients (malariotherapy).
- This practise was already discredited by the medical community.
- Lack of benifit and presence of risk meant that this would be unlikely to pass an IRB committee in the US.
- Another example of the failure of researchers to abide by IRB principles even at highly-respected and well-resourced institutions.
- Why do you think there is a breakdown in adherence to IRB principles, even at well-resourced institutions?
- How can better adherence be encouarged?
Problems with collaborative research in developing countries:
- Developing countries are still in the process of establishing IRB committees and regulations.
- US IRBs rarely try to communicate with host country IRBs.
- US IRBs don't usually even ascertain whether an IRB exists in the developing country of interest.
- How should disagreements between US and developing country IRBs be resolved?
- Developed country IRBs should ensure that a viable local IRB exists and will review the protocol.
- Better communication between sponsor IRB and local IRB committees.
- Complementary knowledge and skills should be acknowledged, and the 2 IRBs could work together rather than alone.
- How much responsibility do you think there is of developed countries to ensure that developing countries have functioning IRBs?
Gilman and Garcia (2004) argue that "overly-legalistic" IRBs are reducing the amoung of research done in developing countries:
- 18 years of collaborative research experience in Peru.
- They have found the IRB procedure to be "duplicated unecessarily and frequently based in... invalid concerns."
- They cite an example of a village survey study over a 5 year period that required 40 separate IRB approvals.
- They complain about:
- Bureaucratic delays.
- Contradictory demands of different IRB committees.
- Interruption of multi-year projects due to conflicting demands.
Suggest a balance between:
- Ensuring the ethical protection of human subjects in developing countries.
- Encouraging research to benefit people in developing countries.
Complaint that IRB members in developed countries have little understanding of the local issues in developing coutries:
- Lack of knowledge of the local culture.
- Lack of trust in the local IRB committee and investigators.
- This can lead to the developed country recommending procedures that are not culturally suitable, and hence difficult for researchers to apply.
- This can lead to consent forms that are difficult for local people to understand.
Complaint that time delays due to the slow IRB process can prevent beneficial research being conducted in developing countries:
- IRBs in developed countries don't want to ruin their institution's public image.
- They can therefore be very cautious.
- Gilman and Garcia (2004) cite an example of a proposed project to study drug-resistance to tuberculosis in a prison population in Peru.
- They argue that the risks of their study were low and that many people could have been treated for tuberculosis in a prison where multidrug-resistant tuberculosis is common.
- They complain that, due to bureaucratic delays and a concern that they were taking advantage of a vulnerable population, the project was no longer viable.
- By the time of acceptance, one of the collaborators had relocated and the research could no longer proceed.
- A less repetitive system with the same high standard of protection.
- 2 IRB committees - the sponsor country and developing country.
- The sponsor country IRB committee should include people who have worked in a developing country.
- The consent document should be the one approved by the local IRB, not the developed country IRB.
- Accreditation and acknowledgement of competent IRB committees in developing countries:
- IRBs in developed countries are "almost always paternalistic" and tend to have a "low regard" for IRBs in developing countries.
- But some IRB committees in developing nations are competent and also have local knowledge of their community.
- There should be a move towards improving the competency of IRB committees in developing countries.
- The advice of competent IRB committees in developing countries should be respected.
- Do you think there is any legitimacy to the complaints of Gilman and Garcia (2004) about the US IRB process?
- What do you think about Gilman and Garcia's (2004) recommendations for improing the efficiency of the IRB process?
- Specifically, what do you think of the recommendation that the developing country should have primary responsibility for the consent document?
- Are the recommendations of Gilman and Garcia (2004) reconcilable with the concern that the IRB process does not provide adequate protection of human subjects?
- Selecting members and operating procedures appropriately:
- Need local members who can assess local risks within their own local context.
- Also need local people who understand research ethics and protocols.
- Obtaining resources for administration and training:
- Resources in developing countries are already stretched by educational and medical infrastructure.
- In the absence of something like the Tuskeegee Syphilis Study, IRBs are not seen as a budget priority.
- Gaining official support for researchers to abide by IRB decisions:
- Difficult in countries where the democratic method is not highly valued.
- Satisfying both:
- International ethical guidelines; and
- Local cultural and socioeconomic factors.
- e.g. Heightened stigma was scene in participants for an HIV vaccine in the Carribean.
IRBs are often funded externally:
- The Council for International Organizations of Medical Sciences (CIOMS).
- Externally sponsored clinical and vaccine trial.
IRB bureaucracy needs to be efficient and inexpensive:
- IRB review can be seen as burdensome in developing countries.
- Reviews can be late and decisions can surpass deadlines.
- If the IRB is not expected to respond to an application in a timely manner, phsyicians may get frustrated and not bother with research, focusing on patient care.
- Costs should should match available funds in developing countries.
- Consent forms:
- Should be limited to one page.
- Written in language that non-academics can understand
IRBs in the Carribean:
- Jamaica, Trinidad, Barbados.
- Increased foreign research collaboration; hence a need for IRBs.
- However, there are very few Carribean IRBs.
- Very few adhere to international standards:
- Diversity and number of members;
- Frequency and documentation of meetings.
- Establish a regional, online network about research ethics (but no resources to do this).
- The Carribean Health Research Council (CHRC) has begun to teach research ethics in its workshops.
- Some funding provided by St George's University to provide research ethics training in Grenada, employ an IRB administrator and register in the US.
IRBs in India:
- Research of an NGO on the prevention and management of HIV in India in collaboration with Britain, Japan and the US.
- 1994-1999: Relied entirely on external IRBs.
- 1999: Developed own local IRB.
- Incentives need to be culturally appropriate and not coercive.
- Cultural and situational problems with obtaining informed consent must be understood and overcome.
IRBs in Latin America:
- Last year (2008), a Canadian contract research organization, Ethica, partnered with an Argentinan company to provide IRBs for clinical trials in Latin America.
- Run through a Canadian non-profit independent IRB.
- First Latin American IRBs to be accredited by the Association for the Accreditation of Human Research Protection (AAHRPP).
- Ethica had previously conducted clinical trials in Brazil and India.
- What do you think is the single major challenge for a developing country looking to set up an IRB panel?
- Do you think there are sometimes conflicts of interest when companies set up IRBs?
- If IRBs in developing countries are to be accredited, what organization should carry out this accreditation?
- Only IRB approval from the developing country is necessary.
- Only IRB approval from the US is necessary.
- Both US and developing country IRB approval is necessary.
- International guidelines should be followed.
- Claim of "ethical imperialism."
- Survey by National Bioethics Advisory Commission:
- 77% of US researchers recommended international guidelines for joint projects instead of US regulations.
- 85% of developing country researchers recommended intational guidlines.
- Interesting case when non-US institutions seek to register for research with the US government in order to be authorized for US-funded research:
- Foreign researchers must indicate which statement of ethical principles its institution abides by:
- Either chose the Declaration of Helsinki;
- Or select "other" and supply these principles with the application.
- Accepted regulations include:
- National regulations of Canada (1998)
- Indian Council of Medical Research Ethical Guidlines (2000)
- Macklin (2004) argues that it is easier to comply with a set of ethical principles that US regulations because ethical principles are general and can be weighed against each other arbitrarily.
- Do you think that the current system of requesting a US and host country IRB is appropriate?
- Is the application of international principles appealing?
- What problems do you think this approach would entail?
- Ghersi, D., 2004 The future of institutional review boards. The Lancet Oncology 5: 325-329.
- Gilman, R. H., and H. H. Garcia, 2004 Ethics review procedures for research in developing countries: A basic presumption of guilt. CMAJ 171: doi:10.1503/cmaj.1031121.
- Kabeer, P., A. K. Ganesh, S. Solomon, Y. R. D'Souza, S. P. Thyagarajan et al., 2002 Building an Institutional Review Board in an NGO in India. Int Conf AIDS 14: abstract no. MoPeG4320.
- Lo, B., 2009 Ethical issues of research in developing countries. CTSpedia.
- Macklin, R., 2004 Double Standards in Medical Research in Developing Countries.Cambridge University Press, Cambridge.
- Watanabe, M. E., 2002 Local IRBs fail to assess remote human studies. Nature Medicine 8: 543.