Ethics in Medical Research - Tuskegee for the Developing World?

(photo credit: The New Ruffian)

February is Black History month, as I hope you already know. For those of us who work in health, Black history month is, among other things, a reminder of one of the most terrible things that occurred in public health in America. The Tuskegee experiments. The United States Public Service knowing harmed human beings in the name of (bad) science.

We've got solid human subject protections now in place in the US, but minority and poor populations remain at risk in the developing world. When a drug company comes to a developing nation to do research, they may lack cultural awareness of the situation, and be genuinely unable to make ethical decisions. They just don't know enough. It is also very hard for well-off Americans to understand just how small a payment or incentive can be and still be coercive.

I just read an article in the New England Journal of Medicine addressing exactly this topic. It talks about trends in globalizing clinical research, ethical concerns, and recommends standards for this kind of research. It's an important article, and gated to subscribers, so I'll give you a fair-use summary, with a bit of commentary.

Trends in Globalization of Clinical Research

• Since 2002, the number of active Food and Drug Administration (FDA)-regulated investigators based outside the United States has grown by 15% annually, whereas the number of U.S.-based investigators has declined by 5.5%
• The number of countries serving as trial sites outside the United States more than doubled in 10 years, whereas the proportion of trials conducted in the United States and Western Europe decreased.
• One reason for this is cost - running a trial in India is 90% cheaper than running one in the US. Another reason is speed. Running an international trial lets you enroll more participants, more rapidly. The last, ugliest, reason, is to escape bureaucratic regulations. (Alanna: NEJM is more neutral on this then I am; they suggest that these regulations may not add anything to patient safety)

Ethical Questions

• We know little about the conduct and quality of research in countries that have relatively little clinical research experience.
• Participants in clinical trials may not understand that their treatment is experimental, or that they may get a placebo.
• In some places, financial compensation for research participation may exceed participants' annual wages.
• Participation in a clinical trial may provide the only access to care for persons with the condition under study.
• Standards of health care in developing countries may also allow ethically problematic study designs or trials that would not be allowed in wealthier countries.
• In one study, only 56% of the 670 researchers surveyed in developing countries reported that their research had been reviewed by a local institutional review board or health ministry.³⁹ In another study, 90% of published clinical trials conducted in China in 2004 did not report ethical review of the protocol and only 18% adequately discussed informed consent. I am especially bothered by the informed consent number; it indicates we're enrolling people in studies who have no real idea what they've agreed to.
• Many of the drugs being tested in developing nations will have no real benefit to the people in those countries if approved. Examples include medications for overactive bladder and allergic rhinitis (runny nose). The Declaration of Helsinki expresses an expectation that every patient enrolled in a clinical trial should, at the end of the trial, be assured access to the best proven therapy identified in the study. That's unlikely when you're testing an expensive new allergy drug in rural India.

Scientific Concerns

• Investigators in developing countries are generally less experienced and less familiar with international guidelines on access to data and control over publication, and are therefore less likely to have access to trial data or to publish results.
• Hospitals and health care systems may be so different in the developing world that trial results are cannot be generalized to wealthy nations, rendering trail data irrelevant. Detailed information about standards of care is rarely included in study reporting, so there is now ay to allow for these differences.
• People in the developing world have often never been treated before for a given illness or ailment, which is very different from people in wealthy nations who have often tried several things already. This is likely to lead to different degrees of effectiveness in medications when they are tested. (Alanna: if you've never had access to painkillers, then Aleve will be a miracle drug for your arthritis. Aspirin is much cheaper and may have been just as good, but nobody will know that since you've never tried aspirin.)
• Geographically separated populations actually have different genetic makeups, and that can affect how effective drugs are. For example, we already know that African-Americans have different responses to cardiac drugs that Caucasians.

What do we do about this?

I think these recommendations are kind of weak, but it's hard to blame the article for that. It's a tough problem that's going to take a lot of work to solve.

• Greater use of centralized institutional review boards, standard terms for research contracts, and the development of streamlined best practices to reduce unnecessary work for investigators and medical institutions are needed.
• Different types of trials require different monitoring procedures. A rigid set of rules will not suffice and may even impair the quality of the research; instead, a vast improvement in the quality of clinical research is needed, so that trial procedures match the research goals and societal needs.
• Key strategies for clinical trials should be outlined in formal plans, publicly vetted, and submitted to regulatory agencies. The plans would outline the anticipated study design, the choice and justification of trial sites, and mechanisms for ensuring the quality of the clinical trial, including independent oversight and site evaluation and monitoring. Sponsors of multinational research should also be required to document that study sites are determined on the basis of anticipated product availability after approval. (Alanna: I think this last point will be near impossible.)
• Improved international collaboration among academic investigators would increase the quality of multinational trials. Investigators in developing countries would benefit from rigorous training in the design, conduct, and ethical oversight of trials, which would allow them to engage more fully in multinational clinical research at a leadership level. (Alanna: I like this one a lot - it builds capacity so that developing countries gain from hosting clinical trails.)
• An international mechanism for tracking investigators who are trained through such programs or, conversely, who have been prohibited from conducting clinical studies is needed.
• Accordingly, provisions for the publication of all clinical trial data and protection of publication rights for investigators should be preserved, independent of sponsorship.

Lastly, check out this case of unethical research in Malawi. A guy who's not a doctor was testing random meds on terminally ill patients. Sixc people died. While he wasn't sponsored by a major pharmaceutical company, he and his institution belong on some kind of black list, I think.