Category Archives: IRE

International Research Ethics

Reasons to Support a Binding Treaty on Health R&D for Developing Countries

The 65th World Health Assembly of the WHO is currently considering a treaty that will fund and coordinate research for diseases affecting developing countries. The proposal was put forward by the Consultative Expert Working Group on Research and Development: Financing and Coordination (CEWG), a body created in 2010 to develop the efforts of previous committees established to consider health R&D. In a report last month, the CEWG concluded that “a binding instrument on R&D is necessary to secure appropriate funding and coordination to promote R&D needed to address the diseases that disproportionately affect developing countries and which constitute a common global responsibility” (p. 120).

Economic and moral justifications for the treaty

The economic justification provided by the CEWG frames the treaty as a response to a market failure resulting from the inability of intellectual property (IP) rights to incentivize companies to invest in drug development for diseases affecting the developing world. The treaty’s funding mechanism is designed to address this economic barrier to research investment.

The moral justification contains two arguments. The first is based on the problem of access: the international community has medical resources and the capacity to distribute them, and yet a multitude still suffers and dies from lack of medicines. The CEWG deems this preventable gap between means and needs as morally unacceptable. The CEWG urges that the moral argument for equitable access to existing medicines be extended to drugs not yet developed, a goal reflected in the proposed R&D treaty. Of particular interest is the second moral argument, which is based on health-related human rights responsibilities that governments have assumed toward their citizens as a matter of international law. A multilateral treaty requiring governments to spend money in their health sectors would mark a departure from the practice of the last sixty years.

A return to post-WWII international ethical principles

Although the treaty would mark a change in practice, it would represent a return to ethical principles agreed to by the international community after World War II. The Universal Declaration of Human Rights (UDHR), a nonbinding legal document, was adopted by the United Nations in 1948. It embodied an ethical vision based on the principle that “[a]ll human beings are born free and equal in dignity and rights.” Moreover, it sketched a blueprint for realizing that vision in a legally binding document. The UDHR described rights and obligations for governments to respect and assume so that the freedom, dignity and equality of all people could be ensured.

However, competing visions of human rights tussled during the drafting of the UDHR, and intensified further during the Cold War. When it came time for a binding legal instrument, the single vision and framework was split into two treaties: the International Covenant on Civil and Political Rights (ICCPR, 1966) and the International Covenant on Economic, Social and Cultural Rights (ICESCR, 1966). The ICCPR was spearheaded by the US-led Western, capitalist bloc and focused on negative rights, i.e. rights fulfilled by governments refraining from actions that interfered with citizens’ rights (e.g. freedoms of expression, religion, movement, etc.). The ICESCR was championed by the USSR-led Communist bloc and focused on positive rights, i.e. rights realized by government action (e.g. rights to education, health, housing, etc.).
Over time, rights in the ICCPR were prioritized over those in the ICESCR. This was partly because the latter were harder to enforce in law courts, but also because they were much costlier (a point relevant to the proposed treaty). This imbalance resulted in reduced health spending among governments, particularly among developing countries. However, as the Cold War waned, the tension between the treaties subsided and the international community reaffirmed in the Vienna Declaration and Program of Action (1993) the indivisibility, interrelatedness and interdependence of human rights. This has allowed for greater international cooperation in the area of health, perhaps most visibly with the HIV/AIDS epidemic. Governments, private organizations and philanthropists have since combined efforts to address various health challenges from malaria to tuberculosis. These laudable efforts notwithstanding, there has not been a broad-based legally binding health-related treaty containing an explicit funding obligation.

Three reasons to support a binding treaty for health R&D

First, it ensures a source of sustainable funding for health R&D in the developing world. Global health today involves many actors, including governments, nongovernmental organizations, corporations and philanthropists, all able to act alone or in partnerships. Of these actors, however, governments are able to make funding commitments least susceptible to market trends, waning voluntary donations, or shifting public interests. A binding treaty would keep R&D funding from slipping off the global health agenda.

Second, a binding treaty ensures, not just funding, but public accountability for health R&D. Of the global health actors listed above, governments are accountable to the broadest constituencies. Particularly if they are democratic, governments can provide a means for diverse sectors of society – beyond stockholders and donors – to inform, criticize and influence funding decisions.

Third, a binding treaty recognizes that the commoditization of health is an inadequate approach for addressing health needs in developing countries. As the CEWG Report noted, a health R&D market failure has created, among other things, the need for public action through the concerted legal commitments of governments. The CEWG’s proposal recognizes the critical role governments will need to play in global health.

Funding sustainability, policy accountability and public engagement constitute three grounds for a health R&D treaty. By involving governments in funding health R&D, such a treaty would begin to restore the split vision of the UDHR. Of greater importance, it will encourage research addressing needs of those with the least access to health.

— Ibrahim Garba

Advertisements

Attend the Third Annual Teaching Skills in International Research Ethics Workshop

TaSkR IIIThe IU Center for Bioethics and the IU-Moi University Academic Research Ethics Partnership will host its annual Teaching Skills in International Research Ethics (TaSkR) workshop April 12-14 in the Health Information and Translational Sciences (HITS) Building, room 1110.

This workshop will focus primarily on the ethics of research involving human subjects—both behavioral and biomedical—conducted in an international forum, as well as developing stronger pedagogical skills.

The workshop will be attended by over 40 participants plus faculty facilitators.  Participants include faculty who teach within the broad domain of international research ethics, whether this is in the classroom, through lectures, or mentoring students, fellows, and post-docs.  Attendees include faculty who teach in medicine, public health, behavioral science, and a number of liberal arts subjects.  Our guest speakers include: Henk ten Have (University of Duquesne) Peter Schwartz (Indiana University), Margaret Gaffney (Indiana University), Edwin Were (Moi University), Kenneth Goodman (University of Miami), Martin Were (Indiana University), Charles Rotimi (National Institutes of Health), and David Ayuku (Moi University).  We will be joined by Joseph Ali (Johns Hopkins University), Ross Upshur (University of Toronto), Henry Silverman (University of Maryland), and Solomon Benatar (University of Toronto, University of Cape Town). TaSkR will also include an African Fogarty Director’s Roundtable discussion.  We hope this discussion will lead to mutual problem solving strategies and enhance collaboration between the African Fogarty Directors.

There is no cost to attend.  For more information or to register, contact Kalli D. McBride, JD, at kdmcbrid@iupui.edu.

International Clinical Trials and the Challenges of FDA Oversight

The Department of Health and Human Services Office of Inspector General (OIG) recently released a report [PDF 1.8 MB] raising doubts about the FDA’s capacity to monitor the safety of clinical trials conducted in foreign countries. According to the report, the FDA needs to:

1. Improve electronic reporting: many international trials reported safety and human subjects data in database-unfriendly formats;
2. Increase the monitoring of foreign clinical trials: the FDA is 16 times less likely to inspect foreign research sites than domestic sites;
3. Look for new ways to expand FDA oversight of foreign clinical trials, including: building new agreements with national regulatory agencies and creating new oversight programs.

While the FDA agreed with all three OIG recommendations, the agency may not have the money and staff to do the job. Inspecting research sites in other countries is logistically difficult and expensive. (According to one FDA source, inspections cost “about $40,000 each”.) With a growing number of multisite trials (with subjects enrolled in different cities, countries and regions), the cost of ensuring the safety of international medical research is indeed a high one. On the other hand, the benefits of conducting trials at non-U.S. sites are enticing. In addition to easier recruitment, diverse populations, and lower financial overhead, the Association of Clinical Research Organizations (ACRO) press release insists: “globalized trials can reduce development time by more than half”. With these and other incentives, the percent of international clinical trials has doubled in the last decade. As would be expected, while the number of FDA regulated investigators in non-U.S. countries has increased by 15% each year since 2002, the number of non-U.S. subjects enrolled in international clinical trials has also grown. In the year 2008, 78% of all human subjects participating in FDA regulated clinical trials were enrolled in foreign sites.

The impact of the OIG’s report may lead to new or increased scrutiny of how these clinical trials are conducted and regulated. While some of this increased scrutiny may come from the FDA, other government agencies, including the Department of Justice (DOJ) may get involved. An advisory [PDF 532 KB] written by Kirk Ogrosky (the former Deputy Chief for Health Care Fraud in the DOJ) and attorneys at the firm of Arnold & Porter, encourages researchers to: prepare for heightened FDA inspections; strengthen internal oversight of CROs; and ensure that research-related payments “pass muster” under anticorruption laws, including the FCPA. According to Arnold & Porter, the DOJ will be interested in payments that “may have been used as an incentive to inappropriately increase subject enrollment” and will examine “differences in payments among investigators in varying locations, and between sites overseen by … local CROs”.

For its part, ACRO stands behind a July 2009 report it commissioned on the ethics and safety of international clinical trials. In addition to restating its findings, ACRO responds to the OIG report by calling for: fully funded FDA oversight, improved research infrastructure, and universal protection of human subjects, including by the standards of the International Conference on Harmonisation’s Guideline for Good Clinical Practice [E6(R1) – PDF 380 KB].

In an editorial published in The Washington Examiner, two ethicists expressed similar confidence in the safety of international research, but worried that the public might miss the fact that a disproportionately large portion of clinical research is currently conducted in the U.S. In their assessment, to effectively and fairly address global health disparities, the number of international clinical trials should (by necessity) increase in the coming years.

In the absence, however, a simultaneous and proportional increase in FDA and other oversight, the risk that foreign clinical trials may be conducted in an unsafe or unscrupulous manner will remain unknown. At the very least (rightly or wrongly), without transparent oversight, public perception may increasingly reflect the sentiments of Adil E. Shamoo in The New York Times. Shamoo, on thinking about the “potential problems” of accountability in international research and the allure for CROs, noted: “There is less liability, patient recruitment is far easier, the concept of informed consent is not well established, and it’s cheaper.”

References:

ACRO responds to HHS report on FDA inspection of foreign clinical trials. Association of Clinical Research Organizations. 2010 Jun 22. Available from: http://www.acrohealth.org/acro-responds-to-hhs-report-on-fda-inspection-of-foreign-clinical-trials.html

Clark, Todd D. The case for globalization: ethical and business considerations in clinical research. Value of Insight Consulting [Commissioned by Association of Clinical Research Organizations]. 2009 July 21. Available from: http://www.acrohealth.org/globalization-white-paper.html

Harris, Gardener. Concern over foreign trials for drugs sold in U.S. The New York Times. 2010 Jun 21. Available from: http://www.nytimes.com/2010/06/22/health/research/22trial.html

ICH. Guideline for good clinical practice. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 1996 Jun 10. E6(R1). Available from: http://www.ich.org/LOB/media/MEDIA482.pdf

Malani, Anup and Tomas J. Philipson. Push for more trials may hurt patients. The Washington Examiner. 2010 Jul 21. Available from: http://www.washingtonexaminer.com/opinion/columns/Push-for-more-clinical-trials-may-hurt-patients-1002114-98875969.html

Office of the Inspector General, HHS. Challenges to FDA’s ability to monitor and inspect foreign clinical trials. Department of Health and Human Services (US); 2010 Jun. 50 p. Report No.: OEI-01-08-00510. Available from: http://oig.hhs.gov/oei/reports/oei-01-08-00510.pdf

Ogrosky, Kirk and Arnold & Porter. Heightened scrutiny of foreign clinical trials. Arnold & Porter, LLP. 2010 Jul 12. Available from: http://www.arnoldporter.com/resources/documents/Advisory-Heightened_Scrutiny_of_Foreign_Clinical_Trials_071210.pdf

Other Research Ethics News

Jonathan D. Moreno. One Small Step for Embryonic Stem Cells: FDA approves first clinical trial for stem cell treatment. Science Progress. August 4, 2010.

Janet Moore. U is closer to a campuswide policy on business conflicts of interest. Star Tribune [Minneapolis-St. Paul, Minnesota]. August 4, 2010.

Elizabeth Cooney. Industry-funded drug trials more likely to report positive results, study finds. White Coat Notes. [The Boston Globe]. August 2, 2010.

Yojana Sharma. Conference agrees global science ethics code. SciDevNet. July 28, 2010.

Columbia Professor accused of research misconduct/fraud. GhanaWeb. July 21, 2010.

Benedict Carey. Studies halted at brain lab over impure injections. The New York Times. July 16, 2010.

Kathy D. Miller. Is mandatory biopsy in clinical trials justifiable? Medscape Today. July 13, 2010.

Gardiner Harris. Diabetes drug maker hid test data, files indicate. The New York Times. July 12, 2010.

David Glenn. Inside the Risky World of Drug-Trial ‘Guinea Pigs’. The Chronicle of Higher Education. July 11, 2010.

Meredith Wadman. Institute of Medicine weighs in on the ethics of post-market drug trials (Subtext: Avandia). The Great Beyond. July 9, 2010.

Peer-Driven Recruitment: Research Ethics in the Academic Literature

In peer-driven recruitment (PDR) research subjects recruit new subjects. These subjects, in turn, may recruit additional subjects. In some cases, the process may repeat for successive waves. Often, subjects are paid or given other incentives to recruit their peers. As an approach to recruitment, PDR can be a very effective tool—some difficult to reach populations (examples might include: sex workers, immigrants, abuse victims, and others) are more likely to participate in a research study when engaged by a “peer.” However, when subjects are recruited by their peers, researchers should be aware of potential ethical problems. For example, if peers are “driven” by money to recruit new subjects from their social networks, they may be tempted to take shortcuts when acquiring consent and conducting other responsible research practices. At the same time, one’s peers (perhaps, particularly when from a tight social network) are not always the best people to entrust with confidential information. Privacy prefers anonymity.

In their recent paper, “Community members as recruiters of human subjects: ethical considerations,” Simon and Mosavel explore these issues and provide an account of a variant version of PDR (Am J Bioeth. 2010 Mar;10(3):3-11. PubMed PMID: 20229402). The authors identify four ethical concerns worth consideration prior to employing peers in subject recruitment: 1) PDR without comprehensive community engagement in the research project can devalue the role of community participation; 2) as “insiders,” peer recruiters may inadvertently bias the sample; 3) maintaining privacy and confidentiality in intimate communities; and 4) “the potential for exploitation of peer recruiters and/or their social networks, particularly in cases where peer recruiters are compensated on a per-capita basis.”

Simon and Mosavel offer what they consider to be a variant version of PDR which (although not without its challenges) is less susceptible to ethical difficulties. In a “resource-poor community” near Cape Town, South Africa, the authors conducted a study of the health knowledge and attitudes of women regarding cervical cancer. With a pre-existing, intensive community engagement program in place, the project hired “community members” to work as research staff. Seven, bilingual women were hired from the neighborhood and received training which included sessions addressing the ethical conduct of research. These new research staff members helped to troubleshoot the study design, revised and translated the informed consent forms, consented subjects, and conducted the research interviews in the subjects’ homes.
Some staff members were emotionally distressed following interviews with women living with illness or in unhealthy environments. To develop stress-related coping strategies, the team met with a trained psychologist, kept diaries, and (when appropriate) distributed a list of local support services to interviewees. Over the three year lifecycle of the research, only one staff member left. When the project was complete, some staff members received help from the PIs in finding new employment opportunities.

Although Simon and Mosavel’s account of a community engaged research project in Cape Town, South Africa is certainly a memorable and instructive narrative, and although their review of the ethical issues inherent in PDR is informative, the article struggles to bring these topics together. The research team hired in Cape Town may have been from the “community,” but they were not “peers”—as staff they were not subjects, nor were they “driven” by incentives to recruit new subjects. This variant of PDR is not “peer,” not “driven” and not really “recruitment.” Nevertheless, Simon and Mosavel’s recommendations are worth considering for future PDR projects and other forms of community-based research employment: ethical training, ongoing support, and the anticipation challenges related to researcher/subject proximity.

Reference:

Simon C, Mosavel M. Community members as recruiters of human subjects: ethical considerations. Am J Bioeth. 2010 Mar;10(3):3-11. PubMed PMID: 20229402.

Open Peer Review Commentaries on Simon and Mosavel:

Landy DC, Sharp RR. Examining the potential for exploitation by local intermediaries. Am J Bioeth. 2010 Mar;10(3):12-3. PubMed PMID: 20229405.
Phillips T. Protecting the subject: PDR and the potential for compromised consent. Am J Bioeth. 2010 Mar;10(3):14-5. PubMed PMID: 20229406.
Fry CL. Ethical implications of peer-driven recruitment: guidelines from public health research. Am J Bioeth. 2010 Mar;10(3):16-7. PubMed PMID: 20229407.
Bean S, Silva DS. Betwixt & between: peer recruiter proximity in community-based research. Am J Bioeth. 2010 Mar;10(3):18-9. PubMed PMID:20229408.
Anderson EE. The role of community-based organizations in the recruitment of human subjects: ethical considerations. Am J Bioeth. 2010 Mar;10(3):20-1. PubMed PMID: 20229409.
Constantine M. Disentangling methodologies: the ethics of traditional sampling methodologies, community-based participatory research, and respondent-driven sampling. Am J Bioeth. 2010 Mar;10(3):22-4. PubMed PMID: 20229410.
Molyneux S, Kamuya D, Marsh V. Community members employed on research projects face crucial, often under-recognized, ethical dilemmas. Am J Bioeth. 2010 Mar;10(3):24-6. PubMed PMID: 20229411.
Simon C, Mosavel M. Response to open peer commentaries on “community members as recruiters of human subjects: ethical considerations”. Am J Bioeth. 2010 Mar;10(3):W1-3. PubMed PMID: 20229401.

Related Links and Literature:

Respondent Driven Sampling [Cornell]
DeJong J, Mahfoud Z, Khoury D, et al. Ethical considerations in HIV/AIDS biobehavioral surveys that use respondent-driven sampling: illustrations from Lebanon. Am J Public Health. 2009 Sep;99(9):1562-7. PubMed PMID: 19608961.
Semaan S, Santibanez S, Garfein RS, et al. Ethical and regulatory considerations in HIV prevention studies employing respondent-driven sampling. Int J Drug Policy. 2009 Jan;20(1):14-27. PubMed PMID: 18243679.
Scott G. “They got their program, and I got mine”: a cautionary tale concerning the ethical implications of using respondent-driven sampling to study injection drug users. Int J Drug Policy. 2008 Feb;19(1):42-51. PubMed PMID: 18226516.
Tiffany JS. Respondent-driven sampling in participatory research contexts: participant-driven recruitment. J Urban Health. 2006 Nov;83(6 Suppl):i113-24. PubMed PMID: 16933100.
Brace-Govan J. Issues in snowball sampling: the lawyer, the model and ethics. Qualitative Research Journal. 2004;4(1):52-60. informit.com.au

Other Recent Research Ethics Articles

– J.O.

Are Clinical Trials in the Developing World Safe and Ethical? Research Ethics in the News

The Association of Clinical Research Organizations (ACRO) recently released a report asserting “Clinical trials conducted in the developing world meet the same safety, ethical and quality standards as those conducted in the developed world.” ACRO represents “companies whose focus is clinical research. The association provides an active voice for the global CRO industry, which provides specialized services that are integral to the development of drugs, biologics and medical devices”.

If the ethical issues are properly addressed, ACRO sees many benefits to encouraging globalized clinical trials. These include: the increased speed of drug development, improving local economies, and finding new markets for products. To avoid incidents like the 1996 Trovan debacle, ACRO recommends increasing the FDA’s resources, encouraging local government measures to protect research subjects while facilitating globalization, and ensuring equity in ethics:

“All participants in clinical research — no matter where they live or the environment in which research takes place — be protected by the same level of safety and ethical considerations, and that they be afforded the same standard of care, including adherence to the GCP principles promulgated by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)”.

Reference:

Clinical Research Safety and Ethical Standards in Developing World Up to U.S. Levels, Report Says. Association of Clinical Research Organizations (ACRO), PRNewswire-USNewswire. July 21, 2009.

Related:

“Enormous” improvement in emerging-country trials, claims ACRO. Peter Mansell, PharmaTimes. July 22, 2009.

The International Conference on Harmonisation  – http://www.ich.org/

Glickman SW, McHutchison JG, Peterson ED, Cairns CB, Harrington RA, Califf RM, Schulman KA. Ethical and scientific implications of the globalization of clinical research. N Engl J Med. 2009 Feb 19;360(8):816-23. PMID: 19228627.

ACRO Comments on NEJM Article on Globalization of Clinical Research. Association of Clinical Research Organizations, Reuters. February 20, 2009.

Other News

NHLBI Stops Study of Treatment for Pulmonary Hypertension in Patients with Sickle Cell Disease Due to Safety Concerns. National Heart, Lung, and Blood Institute (NHLBI), NIH News. July 28, 2009.

Are clinical trials risky or dangerous? ABC Action News. July 27, 2009.

Chinese Research Teams Build Mice from Reprogrammed Cells, Raising New Bioethical Questions. Michael Rugnetta, Science Progress. July 27, 2009.

A Peek Inside NIH Peer Review. Vivian Cheng, Science Progress. July 27, 2009.

Manimal Planet: Anti-Mermaid Legislation Rises from the Deep. Jonathan D. Moreno, Science Progress. July 24, 2009.

Financial Conflicts of Interest 101: How Money Shapes Research and How Policy Can Protect Patients. Vivian Cheng, Science Progress. July 20, 2009.

Context counts when assessing the social value of research. Nancy Walton, The Research Ethics Blog. July 19, 2009.

Data Bank: Public Support for Stem Cell Research On the Rise. Vivian Cheng, Science Progress. July 16, 2009.

Obama’s Guidelines on Human Stem Cell Research: Expanding Funding, Improving Oversight. Robert Streiffer, Bioethics Forum. July 16, 2009.

Merck and Schering-Plough settle investigation. Marley Seaman (AP), The Washington Post. July 15, 2009.

Obama and the President’s Council on Bioethics: An Insider’s View. Ryan M. Antiel, Bioethics Forum. July 13, 2009.

Public Praises Science; Scientists Fault Public, Media. The Pew Research Center for the People & the Press, Survey Reports. July 9, 2009.

Jesus Goes to Bethesda: Just how religious is Obama’s nominee for director of the NIH? Chris Wilson, Slate. July 9, 2009.

‘Synthetic sperm’ from stem cells raises hope for male infertility. Mark Henderson, The Times. July 8, 2009.

Related: Transforming Stem Cells into Sperm Cells Yields Unexpected Bioethical Questions. Andrew Plemmons Pratt, Science Progress. July 13, 2009.

— J.O.

Helsinki Discords

If you’re interested in the ethical issues of international research, be sure to read Helsinki discords: FDA, ethics, and international drug trials. This is a recent commentary co-authored by IUCB’s Eric M. Meslin. The full text is free (with registration) and a brief excerpt has been posted that this CiteULike account.

Full citation:

Kimmelman J, Weijer C, Meslin EM. Helsinki discords: FDA, ethics, and international drug trials. Lancet. 2009 Jan 3;373(9657):13-4. PMID: 19121708

Otmar Kloiber, M.D. – Ethical Perspectives in Medicine, Health and Science

Join us at the Center for Bioethics this Tuesday at 3:00 p.m. for this event. Dr. Kloiber Otmar Kloiber, M.D.will address a number of critical ethical and policy issues in international health and health research, including: global efforts in TB resistance, health and human rights, and the next revisions to the Declaration of Helsinki.