Protecting research participants

In 18th century Britain, smallpox claimed the lives of one in three affected people. Then came Edward Jenner, an English country doctor, whose experiments with cowpox resulted ultimately in the eradication of the disease. However, perhaps more noble than the work of Jenner was the selfless heroism and dedication to social betterment of James Phipps.

Wait a minute. You have never heard of James Phipps? Surely, with an introduction like that, there must be a Phipps Institute, a Phipps Wing in every hospital, or at the very least a Phipps’s syndrome? Not so. James Phipps was the 8 year old boy whom Jenner injected with the pus from blisters of a milkmaid thought to have cowpox, a disease similar to smallpox.

Jenner, not satisfied by this act of child experimentation, went on to inject Phipps with the deadly smallpox virus itself just to make sure he really was immune. Then, just to rub it in perhaps, Jenner forgot the all important tenet of patient privacy when later publishing Phipp’s name with his results. Luckily for all of us, Phipps was healthy after the experiments and rather too young to know what a lawsuit was.

You might argue that given the vaccine’s unequivocal success, Jenner can be forgiven for his crude methodology. But vaccination and germ theory were just guesses on Jenner’s part, but that didn’t stop him from essentially exploiting the poverty around him (Jenner paid Phipps and others to ensure participation) and exposing his patients to grave risk to prove his ideas. Medical ethics has travelled a long and painful road since that day, but unfortunately the journey is far from complete.

Development of ethical guidelines

The ethical guidelines in the past have tended to be reactive rather than proactive. Nazi atrocities led to the Nuremburg Code (box 1); continued offences, such as the Wichita jury trials, led to the Declaration of Helsinki; and the infamous Tuskegee syphilis study led to the Belmont report (see box 2).^w1 Today, such violations are far less common, but by no means absent. The US Office for Protection from Research Risks reported abuses in the past decade in more than 60 facilities, including prestigious institutions such as Johns Hopkins and Yale universities.

For example, in 1990, researchers at Johns Hopkins gave “mostly minority” children in Los Angeles high titres of the experimental Edmonston Zagreb measles vaccine, a drug associated with several deaths during clinical trials in Senegal and Haiti.^w2 The parents were not informed that the vaccine was experimental. In 2004 a class action lawsuit claimed that the drug company GlaxoSmithKline suppressed data that indicated that its blockbuster antidepressant, paroxetine, was associated with an increased risk of suicide in 18-35 year olds.^w3 GlaxoSmithKline settled out of court and still denies the charges.

The guidelines that such events have triggered are complex,^w4 mostly because any set of rules must walk the line between protecting the vast majority of legitimate research against less common, but potentially damaging, transgressors. A simplified approach is highlighted in the Belmont report. The report states the governing principles of human subject research are beneficence, non-malfeasance, justice, and respect for people. Beneficence and non-malfeasance are straightforward concepts—help and don’t harm. Justice considers the concepts of fair selection and equal burden of risk among trial participants. Therefore, an “ethical” trial may compare a new treatment against the existing best treatment, rather than placebo. In addition, a randomised trial has the extra benefit of dividing participants among treatments without any bias on the part of the researcher or participant. Finally, respect for people is an overarching term that incorporates ideas of patients’ autonomy, confidentiality, and human rights. Although simple, taken together, these principles are a powerful tool for ethical analysis and study design.

New dilemmas have arisen

The existing ethical guidelines mean that violations in developed countries are rare But what of research that involves human participants in the developing world? Concerns have been raised in recent years over medical imperialism—essentially transferring risks from the developed to the developing world.^w5

No one denies that the costs of developing a new drug is huge—upwards of £500m (€670m; $980m) a drug, few of which ever reach the market. After they get there, they can only be sold at a higher price for a limited time before their patent expires, and recovering the costs of research and development is difficult. Clearly, drug companies have a tough job, and for every company that succeeds, many others fail.

One solution for reducing cost is simply to outsource clinical trials to the developing world. Smaller compensation payments for trial participation, cheaper infrastructure, and lower cost of operations could mean cheaper drugs for all.

The reality is of course more complex—and a number of questions arise. If you test, for example, an HIV drug on 100 people in Rwanda, what happens when the trial is over? Should they be continued on the drug cocktail that saved their lives or simply be discarded now they have no further use? If they are to continue taking the drug then who pays for it?

Is it ethical to test a drug on a population that has essentially no chance of benefiting from it because of its prohibitive cost? After all, the annual cost of a “cheap” HIV drug cocktail can be as much as most Rwandans earn in a year. A new drug, tipranavir, clocks in at an impressive $12 000 a year, and that’s just one drug in the cocktail.

Finally, is it fair to test drugs in an environment in which high quality medical care is not always available? TeGenero’s phase I test of monoclonal antibody TGN1412 at Northwick Park hospital led to the rapid ill health of six previously well male volunteers. Without the benefit of developed world intensive care, these men may well have died.

Slippery slope to exploitation

Other, more sinister, outcomes are also possible. Countries with few ethical restrictions, and populations desperate for drugs and money, represent a worryingly fertile ground for exploitation. Dystopian scenarios in which developing nations act as guinea pigs for medicine for the developed world are not outside the realms of possibility.

Should these concerns preclude industry from testing ideas in the developing world? Probably not, but the motives for testing in the developing world rather than the developed world should be justified. Is the goal to speed research and reduce cost, or to circumvent the stringent guidelines of the West? If it’s the latter, and morally acceptable answers to the above questions are not available, then human trials should be restricted.

Clearly, research ethics have come a long way in recent decades. However, the old problems of exploitation of patients still exist, compounded by newer problems, such as suppression of unfavourable research data and medical imperialism. An awareness of such problems is important not only because many doctors work on research trials, but also because the medical community more broadly has a responsibility to protect the rights of patients, irrespective of where in the world they may be.

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

1. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. National Institute for Health; 1979. Available from http://ohsr.od.nih.gov/guidelines/belmont.html
2. Bennett et al., Edmonston-Zagreb measles vaccine: A good vaccine with an image problem. Pediatrics. 1999 Nov;104(5 Pt 1):1123-4
3. Dyer, O. GlaxoSmithKline faces US lawsuit over concealment of trial results. BMJ, Jun 2004; 328: 1395
4. Medical Research Council’s Position Statement on Research Regulation and Ethics. London, UK: MRC; [updated 2005 May]. Available from http://www.mrc.ac.uk/pdf-mrc_statement_regulations_ethics_may_2005.pdf
5. Wilmshurst, P. Scientific imperialism. BMJ, Mar 1997; 314: 840
6. Annas GJ, Testing poor pregnant patients for cocaine: physicians as police investigators. N Engl J Med. 2001 May 31;344(22):1729-32
7. Kovac, Nigerians to sue US drug company over meningitis treatment. BMJ. 2001 September 15; 323(7313): 592

       

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