E-DRUG: Hepatitis E vaccine trial in Nepal
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Dear friends and colleagues:
As highlighted in today's Financial Times [see below], several of us have been concerned about the hepatitis E vaccine trial conducted in Nepal by GlaxoSmithKline and the US Army. The trial involved several lapses in ethics, forcing the researchers to move it out of a civilian population; the trial was subsequently conducted on Nepalese army soldiers, posing more ethical problems.
Now that the vaccine has demonstrated effectiveness against hepatitis E, we are advocating for its accessibility to the Nepalese population that took on the burden of being tested under questionable circumstances. It is notable that the study researchers told the medical journal The Lancet, "the US army is interested in this vaccine because it has military implications for American soldiers [and] SmithKline Beecham [now GlaxoSmithKline] has the rather different motivation of wanting to come up with a profitable travellers vaccine." [Stevenson, P. Lancet. 355, 1623 (2000)].
If your organization would like to be included on the letter of concern to GlaxoSmithKline, pasted below, please email the organization's name and address to sanjay.basu@yale.edu by March 10th.
regards
Sanjay Basu
sanjay.basu@yale.edu
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For further information about this issue, see:
Sarkar, S. Nepal questions US Army vaccine experiments. ISN Security Watch.
http://www.isn.ethz.ch/news/sw/details.cfm?id=14309
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Today's Financial Times:
http://omega.med.yale.edu/~sb493/FT.pdf
Andrews, J.R. 2005. U.S. Military Vaccine Trials and La Resistance in Nepal. Am J Bioeth. 5(3):W1-3.
http://omega.med.yale.edu/~sb493/AJOB.pdf
Andrews, J.R. 2006. Research in the Ranks: Vulnerable Subjects, Coercible Collaboration, and the Hepatitis E Vaccine Trial in Nepal. Perspectives in Biology and Medicine 49(1):35-51.
http://omega.med.yale.edu/~sb493/PBM.pdf
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Letter to Glaxo:
We are writing to express our concern over a clinical trial conducted in Nepal on a recombinant vaccine for hepatitis E, licensed by GSK. As recently reported in the lay press and medical journals,[1-3] GSK and its collaborators (primarily the US Armed Forces Research Institute of Medical Sciences, or AFRIMS) appear to have committed several ethical lapses in the course of conducting trials on the vaccine, placing vulnerable populations at risk and compromised the integrity of their research.
In spite of this, the results of the Nepalese trial are unmistakably positive in scientific terms, with an on-treatment efficacy of 87% for 2 doses and 96% for 3 doses of the vaccine.[4] This high efficacy leads us to ask whether GSK will choose to pursue a course that follows the ethical principle of distributive justice and ensures that the vaccine is made available at no or low cost to Nepalese communities affected by the trial.
While we acknowledge that GSK acted in collaboration with several other research institutions in conducting the trial and was not alone in its ethical errors, GSK--as the holder of the vaccine license--is now the actor most responsible for distribution of the vaccine.
As signatories to this open letter to GSK, we aim to ensure that the post-trial development of the vaccine is undertaken with basic ethical principles in mind.
Should GSK choose to undergo further testing on the vaccine, we also believe that it is imperative that GSK sign prior agreements with the communities impacted by such research, ensuring that post-trial access to a successful vaccine is available to the communities in which the vaccine is tested.
Much has been written about the conduct of the vaccine trials, and we summarize the major points here. Originally, the trial had been piloted among subjects recruited in communities in Lalitpur, one of the three municipalities in Kathmandu, Nepal. Lalitpur, however, would ultimately not be the site of the full trial, given popular opposition to the study, which prompted community leaders to take issue with whether trial participants were being adequately informed about the risks of the study, why the urban poor seemed to be disproportionately recruited, and why researchers were conducting a vaccine trial rather than improving sanitation as a strategy to reduce hepatitis E prevalence.
Subsequent to the failure to assure the civilian population of the safety and utility of the vaccine trial, the researchers moved the study to the Royal Nepalese Army (RNA). Soldiers of the RNA, however, qualify as a vulnerable population for multiple reasons: they are subject to coercion from their superior officers, they are some of the poorest members of a least-developed country, and they are involved in an active conflict during which human rights and civil liberties have been repeatedly violated.[5-7] In accordance with international research ethics guidelines and U.S. federal regulations, two key ethical requirements would need to be met to justify the use of these soldiers as study subjects: (1) that the research could not be carried out equally well with less vulnerable subjects, and (2) that the research would lead to improved health interventions characteristic of, or unique to, the vulnerable population.[8-9] Given both the earlier recruitment of a non-soldiered population and the epidemiology of hepatitis E, neither of these requirements could be fulfilled.
Will the Nepalese public ultimately benefit from the results of this vaccine trial? The scientific community has a responsibility to follow the principle of distributive justicethat the risks of a study not be born by one population while the benefits enjoyed by another. International research ethics codes and Nepals national research ethics guidelines stipulate that researchers should plan, in advance of the start of a trial, to make effective products developed through their research available to the host population after completion of the study.[8,10] Unfortunately, the distributive justice principle is often not heeded by those undertaking clinical research on vulnerable populations. Two other vaccines developed through research carried out in collaboration with AFRIMSfor hepatitis A and for Salmonella Typhiare not publicly distributed in the countries in which they were tested.[11]
We hope that GSK will not consign the Hepatitis E vaccine to a similar fate. The vaccine was initially advertised to the local population and Nepali government as a potentially powerful public health technology for fighting endemic hepatitis E. Indeed, it appears that the vaccine may be highly effective and useful in Nepal.
We specifically call for the following actions to be taken by GSK:
1. The vaccine is made available for free to the Royal Nepalese Army and the Lalitpur community at no cost to the beneficiaries for the duration of GSK's license to exclusively manufacture the vaccine. These were the communities directly affected; as such, they should be those to most benefit from the manufacture of the vaccine.
2. The vaccine is to be offered to the Nepali Ministry of Health at no-profit prices for the duration of GSK's license to exclusively manufacture the vaccine. Much of the arguments surrounding the need for the vaccine centered around the epidemic in Nepal as a whole; as such, Nepal as a whole should benefit.
3. If any further trials are conducted on the vaccine, a prior agreement should be signed ensuring that affected communities gain post-trial access to a successful vaccine.[12]
As GSK goes through the business of approval and manufacture of this great public health tool and begins to profit from it, we hope that it is simultaneously able to comply with these requests, which appear to be of small cost in comparison to the profits made in wealthier locales. This will of course directly benefit those who donated their time and bodies to the study. Just as importantly, it will help restore some of the lost faith among the citizens of countries like Nepal, who are caught between the dire need for new public health tools and the very real dangers of participating in clinical trials that may not benefit them or their communities.
References
1. Andrews, J.R. 2005. U.S. Military Vaccine Trials and La Resistance in Nepal. Am J Bioeth. 5(3):W1-3.
2. Andrews, J.R. 2006. Research in the Ranks: Vulnerable Subjects, Coercible Collaboration, and the Hepatitis E Vaccine Trial in Nepal. Perspectives in Biology and Medicine 49(1):35-51.
3. ISN Security Watch. Nepal questions US Army vaccine experiments. January 12, 2006.
4. Shrestha MP, Scott, RN. Protection against hepatitis E by a recombinant vaccine. Presentation at the American Society for Tropical Medicine and Hygiene (ASTMH) 54th Annual Meeting 2005, Washington, DC.
5. Amnesty International. Nepal: A Deepening Human Rights Crisis: Time for International Action. 2002. Available at:
http://web.amnesty.org/library/eng-npl/reports&start=1.
6. United Nations Commission on Human Rights (UNHCR). Question of enforced or involuntary disappearances: Report of the Working Group on Enforced or Involuntary Disappearances (Executive Summary). Fifty-ninth Session. January 21, 2003. Available at:
http://ods-dds-ny.un.org/doc/UNDOC/GEN/G03/113/18/PDF/G0311318.pdf.
7. United States Department of State (State Department), Bureau of Democracy, Human Rights, and Labour. Country Reports on Human Rights Practices: 2003.
Available at: http://www.state.gov/g/drl/rls/hrrpt/2003/.
8. Council for the International Organizations of Medical Sciences (CIOMS). International Ethical Guidelines for Biomedical Research Involving Human Subjects. Guideline 10. Geneva: CIOMS, 1993; updated, 2002 (Guideline 13).
9. Department of Health and Human Services (DHHS). (45 CFR Part 46). Federal policy for the protection of human subjects, Final Rule. Fed Register 56 (June 18): 28003-18. 1991.
10. Nepal Health Research Council. National Ethical Guidelines for Health Research in Nepal. Kathmandu, 2001.
11. Department of Health and Human Services (DHHS). (45 CFR Part 46). Federal policy for the protection of human subjects, Final Rule. Fed Register 56 (June 18): 28003-18. 1991.
12. Page, A. 2002. Prior Agreements in International Clinical Trials: Ensuring the Benefits of Research to Developing Countries. Yale J Health Policy, Law & Ethics (3):1.