1. Chairperson Ethical Review Board
Research ethics in practice: the experience of the MSF Ethical Review Board
Doris Schopper, MD, DrPH
Chairperson Ethical Review Board
MSF UK Scientific Day
1 June 2006

2. The MSF Ethical Review Board (ERB) in a nutshell
Instituted in 2001 according to international standards
Currently six members  gender balance, 4 continents, various disciplines (bioethics, public health, medicine, anthropology, law)
Independent from MSF
Reviews coordinated by internet + meetings in person ~ every 18 months
Approval of national ERB is “precondition”
MSF decided in 1999 to organise its own ethical review board (ERB) to endorse with confidence any research proposed to take place under its responsibility. Currently the ERB is composed of six permanent members in line with international recommendations, ensuring geographic (Africa, Asia, Europe, North America) as well as professional (medicine, public health, law, anthropology, bioethics) variety. To ensure independence, members should not have a working relationship with MSF during the time of their appointment. Reviews are carried out in a decentralised manner.

3. Research proposals reviewed 2002-2005
29 approved (1-3 rounds)
3 not carried out
Main areas
Malaria (10)
HIV (5 + 3 abandoned) + STI (2)
Trypanosomiasis (3); visceral leishmaniasis (3)
Nutrition (2), tuberculosis (1+ 2 linked to HIV)
Variable research activity
4 (2002)  14 (2003)  8 (2004)  6 (2005)… 5 in 2006
Remarks: In 2003 main research activity were malaria treatment efficacy studies. Has now subsided as ACT is accepted as the way to go. In 2006 we have witnessed emergence of new research theme: antiretroviral treatment resistance patterns in HIV-infected persons. Trypano and leishmaniasis = orphan diseases
Stark decrease in number of proposals submitted to ERB in 2005 (3 were cancelled or not implemented in 2005): decrease in activity?

4. MSF is asking ethical advice on…
Type of research
14 / 32 efficacy or clinical equivalence studies
4 / 32 effectiveness – feasibility studies
3 / 32 evaluation of test method
Geographical areas
Mainly in Africa (25 / 32)
Asia (4), Latin-America (1), Europe (2)
Some MSF sections ask more than others…
Holland (17), Belgium (13), Spain (1), Switzerland (1)
All studies needed ethical review. 4 could be done by expedited review (3 reviewers instead of 6) as minimal harm to participants.
Main research activity in Sub-saharan Africa, which also corresponds to MSF’s focus of intervention. Some sections seem to have a much more intense research agenda than others. MSF-France conspicuously absent…

5. MSF is asking ethical advice on…
Type of research
14 / 32 efficacy or clinical equivalence studies
4 / 32 effectiveness – feasibility studies
3 / 32 evaluation of test method
Geographical areas
Mainly in Africa (25 / 32)
Asia (4), Latin-America (1), Europe (2)
Some MSF sections ask more than others…
Holland (17), Belgium (13), Spain (1), Switzerland (1)
All studies needed ethical review. 4 could be done by expedited review (3 reviewers instead of 6) as minimal harm to participants.
Main research activity in Sub-saharan Africa, which also corresponds to MSF’s focus of intervention. Some sections seem to have a much more intense research agenda than others. MSF-France conspicuously absent…

6. What should be submitted to the ERB
Clinical research
Production of new generalisable knowledge (testing research hypothesis) within usual monitoring and evaluation
Need for ER based on risk analysis  potential harm and risk of wronging research participants
Routine monitoring and evaluation  ER useful if new public health knowledge generated
Emergency research exempted
One should clearly distinguish between routine monitoring and evaluation (no need for ethical review), the production of new generalisable knowledge within usual monitoring and evaluation, and clinical research. The last two need ethical review. The main difficulty is to define what “producing generalisable knowledge” means. If a research hypothesis is to be tested (as compared to a purely descriptive study), new knowledge is being generated. However, even in purely descriptive studies, prior ethical review may be useful, if it generates new public health knowledge. Nowadays publication of any data in a peer-reviewed journal usually requires previous ethical review.
During last years meeting it was proposed that the need for ethical review should be established based on a risk analysis for research participants. This approach is useful, but should not only examine potential harm, but also the risk of wronging research participants (see example of tissue samples above).
In conclusion
The following categorization was proposed:
Full review: clinical trials and operational research projects with hypothesis testing must go for full ERB review.
No review: monitoring and evaluation as part of normal implementation of projects does not need ethical review.
Gray area: Descriptive studies, involving monitoring and evaluation as a means to test a new approach (“Innovative practice”) with the intention of publication should consider ethical review. There are two possibilities: (1) expedited review of a fully developed research proposal; (2) submission of a letter of intent to the ERB to ask if ethical review is deemed necessary; ERB chair quickly indicates if no review, expedited review or full review is necessary.
Comments:
–       Emergency research is exempted from review.

7. A consistent framework for ethical review
Since June 2003 ERB uses adapted version of “Emmanuel Framework”
Intends to provide “unified and consistent ethical guidance”, derived from ethical theory and international guidelines
Tailored for developing world context
Employs principles and explicit benchmarks
Initially the ERB used a framework derived from general guidelines on research ethics (Helsinki, Belmont, CIOMS). In June 2003 it was decided to test an ethical framework for health research drafted by some members of the U.S. National Institutes of Health. The experience with a slightly revised version of this framework is positive. It does not add ethical requirements but makes them explicit and systematic; the benchmarks provide more specific, practical guidance for planning and evaluating research; and, it narrows the scope of disagreement.
Benefits of standardization
Consistent framework and format for reviewers to work with
Consistent format for chair to summarize review board deliberations
Consistent format delivered to the field
Field knows what review board is evaluating

8. Recurrent ethical issues in MSF research proposals
Informed consent procedure
Community involvement
Benefits to research participants and community in medium term
Export of tissue samples
Quality of research proposals has been variable, but one can say that generally there has been much improvement over the past years. Three issues have been problematic, virtually in all proposals: consent procedure, community involvement, how to ensure benefits in medium term. In addition, one issue that needs special attention: export of tissue samples.
Ensuring benefits to research participants and the community are a major issue because MSF usually has only a relatively short time commitment (2-3 years). MSF thus can only commit to making benefits of the research available during the period immediately after the research. Usually some commitment for advocacy and lobbying with local authorities and MoH. But no guarantee of success. Big issue e.g. in malaria efficacy trials, and now in HIV resistance studies.

9. How to ensure informed consent
Main shortcomings
Consent form insufficient, too complicated, biased
No pretesting (also of translation)
Overestimation of the benefit for participants and community
No educational process foreseen
What should be done
Explain procedure to obtain informed consent in detail in research protocols
More emphasis on information process than formal consent form
Ensure community involvement
main shortcomings
insufficient information, or incomplete information given to the participants about objectives, risks or adverse effects, house visit, etc
sometimes too much information, too many details or too complicated language
lack of pretesting of the informed consent form
formulation of the text biaised to induce a positive answer
overestimation of the benefit for participants and community
problem of addressing the good person e.g. parent for children
community consent instead of individual consent
lack of alternatives for presentation of the research (video, etc)
translation in local language not addressed (at least one back and forth translation needed)
any information given during the informed consent process must be pretested with people of a similar cultural and educational background as potential study participants;
the information provided on the consent form must be in simple language, avoiding technical terms;
the consent form must be translated into the local language and then back-translated into the “international” language used to get a sense of the accuracy of the translation and correct mistakes;
if needed, the person should get time to discuss the information received with members of the community or family before deciding on consent;
in addition, community information or “schooling” on the research to be done and on the purpose and process of seeking informed consent will raise pre-enrolment awareness and thus help people to decide if they want to participate in the study.

10. Community Partnerships
Articulated in Emanuel framework as necessary for research in developing world to be ethical
Often neglected in MSF proposals
What to do:
Ideally “functional” community body to follow research from start to end
At minimum, community consultation before – during – after (feedback of research results)
Be careful in defining “community”
Ideally a “functional” community body should be available in each research project, by either using an existing body or creating one for the specific purpose. Its tasks are as follows.
Before research starts, it should check the design, the research set-up, the informed consent procedure etc.
During research, it will feed back intermediate results to the community and provide advice on problems (i.e. high patient drop-out).
After research, it will be the main channel to inform the community about the results.
If it is not possible to have a well functioning community body throughout the research process, at a minimum the community must be consulted during the planning stage of the research, should be consulted on an ad-hoc basis while the research is being done, and should be informed in a structured manner at the end of the research about the results. It is not enough to do this dialogue by consulting local staff, as they may not really represent the community. One option would be to add a few current or past patients (e.g. former kala azar patients, former or current TB patients) to the group planning the study to make sure the objectives, approach, etc. are adequate and adapted to the local context.

11. Tissue samples
Tissue samples exported from point of origin with uses, storage and destruction unclear
How will MSF weigh interests of research subjects and research partners (also: ensure benefit sharing)?
MSF needs to address 3 distinct situations
Tissue samples taken outside the country: tuberculosis resistance, HIV resistance
A posteriori analysis of samples: lymph node aspirates leishmaniasis
No direct benefit: HIV viral clades
In weighing harm and benefit to research participants, it is important to not only examine potential harms, but also wrongs. For example, if blood is taken from HIV patients for ARV therapy monitoring or viral clade analysis that is of no direct benefit to them, they will not be harmed, but may be wronged. In addition, the research may lead to commercial benefits without their knowledge. Of course, legal action by research participants that have been wronged will probably be difficult, if not impossible, in most countries where MSF works, as there is no legal infrastructure to deal with this type of infraction. But this does not imply that MSF would want to wrong people.
The highest standard will be to involve people in whose interest the research takes place in the decision making (dialogue, deliberation with potential research participants and with the community).
Tissue samples will be taken outside the country for analysis during a study that is otherwise ethically accepted. The issues are: are patients clearly informed about the fact that samples are taken outside the country? Will the samples be destroyed after analysis for the study purpose? If not, how can consent for future use be obtained? Will refusal for future use mean exclusion of the study? How will it be ensured that the laboratory that receives the samples will destroy them after analysis?
A posteriori analysis of tissue samples that were stored at the study site or during usual medical practice. The recent example of 3000 lymph nodes aspirate from Malakal, Sudan to be used in Antwerp to develop new diagnostic test was discussed. In principle, these samples can be used even if it is impossible to get a posteriori consent, if there is a strong public health interest, no potential commercial gain and no prejudice to the donors. However, the decision should be made with and supported by the government of Sudan, and the partner institution that would use the samples should be carefully chosen and a clear MoU developed.
Using samples for research of no direct benefit to study participants. MSF should only exceptionally engage in this type of research.

12. Conclusions Interaction between ERB and MSF very constructive
“Educational” value of ERB recognized
Ethical framework very useful
Big improvement in research quality since inception of ERB
Is all research in MSF “ethical”? We don’t know…

13. Issues that need greater attention in future
Should ERB have role in checking what happens after approval?
Developing local (research) capacity
Assessing benefits of research in medium and longer term