| Abstract|| |
Malaria remains a major problem with the significant public health dimension affecting hundreds of millions of people annually, mainly in sub-Saharan Africa. The effectiveness of the measures currently used to control the disease is now drastically reduced because of the development of parasite resistance to the anti-malarial drugs and vector adaptation to the insecticides. On account of this development, efforts are ongoing to develop a malaria vaccine to help in the prevention of the disease as well as in reducing the severity in patients. Drug research and development have always raised a lot of ethical issues, especially in the context of developing countries like those of sub-Saharan Africa. This article discusses some of these ethical dilemmas using a template based on the four principles of biomedical ethics.
Keywords: Biomedical ethics, clinical trials, ethical issues, Malaria vaccine, principles
|How to cite this article:|
Fadare JO, Ademowo OG. Ethical issues in malaria vaccine clinical trials: A principle-based approach. Ann Trop Med Public Health 2010;3:35-8
|How to cite this URL:|
Fadare JO, Ademowo OG. Ethical issues in malaria vaccine clinical trials: A principle-based approach. Ann Trop Med Public Health [serial online] 2010 [cited 2019 Sep 18];3:35-8. Available from: http://www.atmph.org/text.asp?2010/3/1/35/76185
| Introduction|| |
Malaria remains a major problem with the significant public health dimension affecting hundreds of millions of people annually, mainly in sub-Saharan Africa.  The disease is especially devastating among children and pregnant women, leading to high rates of infant and child mortality and obstetric and peri-natal complications.  It also promotes the cycle of poverty among the population of the affected region.  The current control measures include environmental sanitation, use of long-lasting insecticide treated nets, indoor residual spraying of insecticide, intermittent preventive treatment in pregnant women, and the artemisinin-based combination therapy.  The effectiveness of these measures is now drastically reduced because of the development of parasite resistance to the anti-malarial drugs and vector adaptation to the insecticides. On account of this development, efforts are ongoing, to develop a malaria vaccine to help in the prevention of the disease as well as to reduce the severity of its manifestation in patients. Various vaccine candidates, based on different parasite antigens, are currently being developed and some are already undergoing clinical trials.  Indeed one of the candidate vaccines is already at Phase III, while several others are either in the Phase I or II stages. , There are accepted ethical standards for the conduct of clinical trials worldwide, as outlined in the World Medical Association Declaration of Helsinki,  the Council for International Organizations of Medical Sciences (CIOMS),  and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guidelines on Good Clinical Practice (ICH-GCP).  However, there are peculiarities when discussing clinical trials for the anti-malarial vaccine. This is because the disease affects mainly infants, children, and pregnant women in resource-poor countries, where the autonomy of the subjects is somehow diminished. The aim of this article is to explore the ethical issues that are relevant to malaria vaccine trials in countries of sub-Saharan Africa.
| Methods|| |
A review of the relevant literature (both online and print) for this article was done by using PubMed and Google Scholar search. The article was developed using a theoretical framework of the four principles of biomedical ethics,  namely respect for autonomy, beneficence, non-maleficence, and justice. Although the authors are aware of other theories and frameworks of reasoning in bioethics, it was agreed that approaching this particular issue through the prism of the four principles of biomedical ethics gave room for a richer discussion.
| Ethical Issues|| |
Respect for Autonomy
In healthcare generally, respect for autonomy means allowing a patient who is competent to take a decision relating to his health without any form of coercion. This is the basis for the concept of informed consent that is obtained from patients in clinical practice and research subjects taking part in all forms of human subject research. Obtaining informed consent from research subjects is now an established rule before research on human beings can commence. The main question when discussing informed consent in the African setting is whether it can be totally voluntary and informed. This is because of the high level of illiteracy, which makes understanding of the informed consent document difficult; poverty and lack of affordable healthcare are factors that might unduly influence the decision of the people to participate.  One of the main issues when discussing informed consent is the adequacy of information given to the patient before they are enrolled into a clinical trial. Especially in the setting of a developing country in sub-Saharan Africa the question is, how much information should be given so as not to discourage people from participating in clinical trials? In literature, information given to patients is divided into three different categories: reasonable physician standard, reasonable patient standard, and subjective standard.  The latter is the most preferred, but it is also the most challenging in the African setting, as the information would have to be tailored to individual research subjects. Also there is the belief in these settings that the physician who is also the researcher in a lot of cases knows all and has their interest at heart. Because of this, patients and indeed research participants do not pose any question to the researchers regarding the possible risks and benefits of the research in question. The communitarian way of life among people in this part of the world means that sometimes decisions are taken collectively by members of the family. This is at variance with the western countries where autonomy of the individual reigns supreme. Recent research ethics guidelines from developing countries like South Africa, Kenya,  and Nigeria  have advocated the need for some form of community engagement by the research sponsors, which if properly carried out, could promote a better understanding between both parties. This acknowledgment of the role of the community is also noted in the international research ethics guidelines, but the consensus is that individual consent is non-negotiable. Another interesting point to note is that malaria vaccine trials would recruit mainly infants and children who are legally incompetent to consent; the question here is, whether we are sure that the interest of the children is really being looked after and whether they are not just enrolled because of the benefits that would go to their guardians, who normally give consent on their behalf? To prevent or reduce this kind of abuse, most research ethics guidelines, in their most recent update, have introduced the concept of 'assent' of the child, in addition to the parent / guardian's consent  (Article 15). However, it is not very clear how this will play out in the typical African setting, where the child has little if any say in decisions concerning him or her.
The problem of comprehension of the informed consent process by the participants has been discussed widely, and while it is not only a problem of the developing countries alone, the tendency toward non-comprehension is more in these countries because of the multi-lingual and multi-cultural setting and differences in their understanding of health and diseases.  The consensus is that the information should be given in a simplified manner, in the local language, preferably by a member of the research team, who is a native. This definitely does not solve all the problems, but it can significantly improve the level of understanding of the research participants. Another ethical issue worth mentioning is the relationship between the researcher / physician and the research participant, keeping in mind that in most settings in sub-Saharan Africa, the former role is still played by just one person. How then can we be sure that there is no conflict of interest or how can it be reduced to the barest minimum?
| Beneficence / Non-Maleficence|| |
This bioethical principle states that the express intention and act of the health care personnel is to be of benefit to his patients or research subjects, while that of non-maleficence stands against all forms of harm. The development of an effective and safe malaria vaccine to prevent or mitigate the manifestation of the dreaded disease will indeed be beneficial to mankind and in particular to people living in the malaria endemic regions of the world. The possible benefits of an effective malaria vaccine would include: a reduction in the transmission of the parasite and a reduction in the number and severity of malaria attacks, leading to an overall reduction in the morbidity and mortality associated with the disease.  However, it is also important to discuss the possible adverse outcomes in malaria vaccine trials and these include: the question of efficacy and duration of protection offered by these vaccines, the short- and long-term adverse effects of the trial vaccine on the health of the tested population, and the possibility of changing the transmission pattern of malaria. There is a risk, especially in the latter scenario, of changing from a stable to an unstable pattern of transmission, which would expose the population, both vaccinated and unvaccinated, to a more severe and unpredictable manifestation of the disease.  Issues relating to the provision of medical care outside those specific for the conduct of the clinical trial should be discussed and an agreement reached, before commencement of the trial. There are divergent opinions whether providing extra medical care would be a sort of inducement to residents of the trial site to participate, especially as there is a lack of access to basic health care in these communities.  Although there might be some truth in the above-mentioned statement, it is believed that the sponsors have a moral duty to take care of the 'reasonable' medical needs of the research participants. By reasonable medical needs, we mean acute medical conditions that are prevalent in those settings like respiratory tract infections, diarrheal diseases, and so on. No one would expect the sponsors to continue to treat chronic diseases like diabetes mellitus or chronic liver disease unless the clinical trials are carried out for the said conditions. Another important ethical issue is the use of placebo controls in these trials, which has generated heated debates in the research community in recent years,  but in the case of malaria vaccine trials it is accepted that placebo could be used, because of the fact that there is presently no existing vaccine (standard treatment) and the placebo control group are not exposed to any significant risks. The only disadvantage of the placebo control group is that if the vaccine is found to be effective, they would have missed out on the protective effects of the vaccine. Recent malaria vaccine trials now use vaccines that are already approved for other conditions such as Hepatitis B and Rabies, as comparator vaccines. , The risks here will be those that are already established for the mentioned vaccines in immunization practice, however, the potential overall benefit to the community is an important factor in permitting the use of placebo or comparator vaccines in these trials. The possibility of reducing the burden of malaria in these societies and its potential socioeconomic benefits has tilted the scale in favor of the malaria vaccine trial in general and placebo use in particular. It is important when giving information to the research participants, however, to state categorically the possibility of them being assigned to a placebo group.
| Justice|| |
The issue of justice, as it relates to malaria vaccine trials, can be seen from the equitable distribution of the burden and benefits, the selection of research subjects, and the availability of post-trial benefits. It has been agreed that trials in developing countries must reflect the health needs of those populations,  and that carrying out a clinical trial for a medication that will be used only in developed countries will be unethical. A clinical trial for malaria vaccines readily satisfies the above-mentioned conditions, and hence, it is ethical for it to be carried out in developing countries. Justice in the selection of research subjects indicates that they are not chosen just because it is convenient for the researchers, but efforts must be made to involve people from different strata of society. The question of recruiting pregnant women into malaria vaccine trials is also a challenging one. Historically, there was a blanket ban worldwide regarding the inclusion of pregnant women and those with childbearing potential in clinical trials, especially Phases I and II, because of the potential teratogenicity of the investigational product. However, there has been a paradigm shift in this regard in recent years, because this group of patients also stands to benefit scientifically for conditions that are prevalent during this phase of life.  Clinical trials that have been done mainly on pregnant women include those of antiretroviral drugs, for the prevention of mother-to-child transmission, and those of aspirin for the prevention of pre-eclampsia, among others. , Therefore, we argue that it would be ethical to include pregnant women in malaria vaccine trials in developing countries for the following reasons; the heavy burden of the disease among them, the overwhelming potential benefits to them, and the inadequacy of using only the result of post-marketing surveillance as a guide to introduce the vaccines later. The latter method, which could last several years, would deny many pregnant women the timely benefit of the intervention. Post trial availability of products of clinical trials (in this case malaria vaccines) is another point that has aroused a lot of controversies in recent times.  Most guidelines and policy statements on research ethics now advocate for some form of post-trial availability of the investigational product for the host community at the completion of the trial. ,, An underlying ethical dilemma in this case is whether to make it available only for those that participated in the trials or for the whole population of the country where the clinical trial took place, and for how long this must last. In this case of malaria vaccines, we believe that making it available only for the clinical trial population will ultimately defeat the purpose of the intervention, as the majority of the population will still be left uncovered, thus the transmission of the disease will continue unabated. Another reason for advocating a full coverage of the population is that the majority of these trials are carried out in resource-poor settings, where there is no centralized health insurance and only the well-off will be able to afford these drugs when eventually licensed. This of course is a form of inequality, which is not compatible with the principle of distributive justice. This can be done through a form of public-private partnerships between government agencies and non-governmental organizations, in the sponsor and trial countries, as it presently exists for the treatment of HIV / AIDS, Tuberculosis, and Malaria. 
Under the topic of justice, the issue of capacity building of researchers in the countries where these clinical trials are carried out is very important. Literature has shown that most developing countries lack the capacity in the area of research ethics, especially as it relates to the availability, funding, and training of local research ethics committees, who ideally should act as gatekeepers for their communities. , It would be unethical to bring in researchers from the sponsor countries to get the necessary scientific data without building up the capacity among the local scientific community. To ensure this, the national and local ethics review committees or IRBs should make it compulsory for capacity building initiatives to be included in the research protocol approved by them.
| Conclusion|| |
Although the development of malaria vaccines is a welcome addition to the anti-malarial arsenal, there is a need for all stakeholders to be conscious of the ethical issues discussed earlier in the article, in order to chart a way forward to resolving them. Although various international and national research ethics guidelines provide some guidance on these issues, a lot still needs to be done in practice. A combined effort by the international non-governmental organization sponsors of research and local regulatory authorities in the host countries, such as, the ministries of health, research ethics committees, and institutional review boards must ensure that ethical malaria vaccine clinical trials are carried out in their communities.
| References|| |
|1.||World Malaria Report 2008. World Health Organization, Geneva 2008. |
|2.||Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 2007; 7:93-104. |
|3.||Chima RI, Goodman CA, Mills A. The economic impact of malaria in Africa: a critical review of the evidence. Health Policy 2003; 63:17-36. |
|4.||Lisingu JP, Von Seidlein L. Challenges in malaria control in sub-saharan Africa: the vaccine perspective. Tanzania J Health Res 2008; 10:253-66. |
|5.||Kilama WL. Malaria vaccines for Africa. Acta Trop 2003; 88:153-9. |
|6.||Lusingu JP, Gesase S, Msham S, Francis F, Lemnge M, Seth M, et al. Satisfactory safety and immunogenicity of MSP3 malaria vaccine candidate in Tanzanian children aged 12-24 months. Malar J 2009; 8:163. |
|7.||Sagara I, Dicko A, Ellis RD, Fay MP, Diawara SI, Assadou MH, et al. A randomized controlled phase 2 trial of the blood stage AMA1-C1/Alhydrogel malaria vaccine in children in Mali. Vaccine 2009; 27:3090-8. |
|8.||Council for International Organizations of Medical Sciences. International Ethical Guidelines for Biomedical Research involving Human Subjects. Geneva: CIOMS; 2002. Available from: http://www.cioms.ch/guidelines_nov_2002_blurb.htm [last accessed on 2009 Sep 24]. |
|9.||World Medical Association. Declaration of Helsinki, 2008. Available from: http://www.wma.net/e/policy/b3.htm [last accessed on 2009 Sep 24]. |
|10.||International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). E6 (R1). Good Clinical Practice consolidated guideline. Available from: http://www.fda.gov/cder/guidance [last accessed on 2009 Sep 26]. |
|11.||Beauchamp TL, Childress JF, editors. Principles of biomedical ethics. 5th ed. Oxford: Oxford University Press; 2001. |
|12.||Bhutta ZA. Beyond Informed Consent. Bulletin of the World Health Organization 2004; 82:771-7. |
|13.||Childers R, Lipsett PA, Pawlik TM. Informed consent and the surgeon. J Am Coll Surg 2009; 208:627-34. |
|14.||Langlois A. The UNESCO Universal Declaration on Bioethics and Human Rights: Perspectives from Kenya and South Africa. Health Care Anal 2008; 16:39-51. |
|15.||National Code for Health Research Ethics of the Federal Republic of Nigeria. Available from: http://www.nhrec.net. [last cited in 2007]. |
|16.||Council of Europe′s Convention on Human Rights and Biomedicine, Additional Protocol Concerning Biomedical Research. Available from http://www.conventions.coe.int/Treaty [last cited in 2005]. |
|17.||Barry M, Molyneux M. Ethical dilemmas in malaria drug and vaccine trials: a bioethical perspective. J Med Ethics 1992; 18:189-92. |
|18.||Alonso PL. Malaria: deploying a candidate vaccine (RTS,S/AS02A) for an old scourge of humankind. Int Microbiol 2006; 9:83-93. |
|19.||Carter R. Epidemiological considerations for malaria reduction by transmission blocking vaccination. Parassitologia 1999; 41:415-20. |
|20.||Bhutta ZA. Ethics in International Health Research: a perspective from the developing world. Bulletin of the World Health Organization 2002; 80:114-20. |
|21.||Lie RK, Emanuel E, Grady C, Wendler D. The standard of care debate: the Declaration of Helsinki versus the international consensus opinion. J Med Ethics 2004; 30:190-3. |
|22.||Ogutu BR, Apollo OJ, McKinney D, Okoth W, Siangla J, Dubovsky F, et al. MSP-1 Malaria Vaccine Working Group. Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya. PLoS One 2009; 4:e4708. |
|23.||Benatar SR, Singer PA. A new look at international research ethics. BMJ 2000; 321:824-6. |
|24.||Merkatz RB. Inclusion of women in clinical trials: a historical overview of scientific, ethical, and legal issues. J Obstet Gynecol Neonatal Nurs 1998; 27:78-84. |
|25.||Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314:253-7. |
|26.||Bajunirwe F, Massaquoi I, Asiimwe S, Kamya MR, Arts EJ, Whalen CC. Effectiveness of nevirapine and zidovudine in a pilot program for the prevention of mother-to-child transmission of HIV-1 in Uganda. Afr Health Sci 2004;4:146-54. |
|27.||Kottow MH. Who is my brother′s keeper? J Med Ethics 2002; 28:24-7. |
|28.||McMillan JR, Conlon C. The ethics of research related to healthcare in developing countries. J Med Ethics 2004; 30:204-6. |
|29.||Kilama WL. The 10/90 gap in sub-Saharan Africa: Resolving inequities in health research. Acta Trop 2009; 112:S8-15. |
|30.||Kirigia JM, Wambebe C, Baba-Moussa A. Status of national research bioethics committees in the WHO African Region. BMC Medical Ethics 2005; 6:10. |
|31.||Nyika A, Kilama W, Chilengi R, Tangwa G, Tindana P, Ndebele P, et al. Composition, training needs and independence of ethics review committee across Africa: are the gate-keepers rising to the emerging challenges? J Med Ethics 2009; 35:189-93. |
Joseph O Fadare
Department of Medicine, Kogi State Specialist Hospital, Lokoja
Source of Support: None, Conflict of Interest: None