Human subjects research:global issues.

Phil 133 – Ethics in ScienceSan José State University

Belmont Report’s basic ethical principles:

• Respect for personsinformed consent, extra protection for those with diminished autonomy

• Beneficenceminimizing risks, maximizing benefits

• Justicesubjects don’t carry unfair burden, benefits distributed fairly, access to participation in research

Also of concern:

DOING GOOD SCIENCE(falls under beneficence)

Not ethical to subject human subjects to risk without benefit of producing reliable scientific knowledge!

(Might be an argument for prioritizing study of problems whose solutions would be of benefit to lots of people – esp. research subjects)

Lots of medical studies with human subjects done in developing world.

WHY?• Lots of diseases in the developing world for

which effective and/or economical treatments have not been found.

• May be easier to identify large groups of potential participants in the developing world than in the U.S. or other developed countries.(Maybe we should ask why.)

Best way to test new AIDS therapies in the developing world?

• Randomized double-blind trials with placebo controls. (Neither subjects nor researchers know who gets treatment and who gets placebo while data are being collected.)

• Experimental treatment vs. best established treatment

AIDS Clinical Trials Group protocol 076

• Research conducted in sub-Saharan Africa in 1990s on effect of AZT on maternal transmission of HIV

• Experimental group got AZT• Control group got a placebo

Was this trial ethical?

Pair of papers in New England Journal of Medicine consider ethics of trial.

Marcia Angell, "The Ethics of Clinical Research in the Third World," New England Journal of Medicine September 1997: Vol. 337. pp. 847 - 849.

Harold Varmus and David Satcher, "Ethical Complexities of Conducting Research in Developing Countries," New England Journal of Medicine October 1997: Vol. 337. pp. 1003 - 1005.

Angell argues against placebo-controlled trials:

“An essential ethical condition for a randomized clinical trial comparing two treatments for a disease is that there be no good reason for thinking one is better than the other.”

Angell argues against placebo-controlled trials:

“Usually, investigators hope and even expect that the new treatment will be better, but there should not be solid evidence one way or the other. If there is, not only would the trial be scientifically redundant, but the investigators would be guilty of knowingly giving inferior treatment to some participants in the trial.” (p. 578)

Ethical concern about placebo-controlled trials:

• Investigators are responsible for welfare of all participants in the trial (including those in control group).

• Goals of research are secondary to well-being of subjects.

Ethical concern about placebo-controlled trials:

• Investigators are responsible for welfare of all participants in the trial (including those in control group).

• Goals of research are secondary to well-being of subjects.

Objection: Getting an unambiguous result quickly can help improve the care of future patients.

Angell on protocol 076:

“Although I believe an argument can be made that a placebo-controlled trial was ethically justifiable because it was still uncertain whether prophylaxis would work, it should not be argued that it was ethical because no prophylaxis is the ‘local standard of care’ in sub-Saharan Africa.” (p. 580)

Angell on protocol 076:

“[T]he Declaration of Helsinki requires control groups to receive the ‘best’ current treatment, not the local one. The shift in wording between ‘best’ and ‘local’ may be slight, but the implications are profound.” (pp. 580-581)

Angell on protocol 076:

“Acceptance of this ethical relativism could result in widespread exploitation of vulnerable Third World populations for research programs that could not be carried out in the sponsoring country.” (p. 581)

Larger implications for human subjects research:

“The retreat from ethical principles may … be explained by some of the exigencies of doing clinical research in an increasingly regulated and competitive environment. Research in the Third World looks relatively attractive as it becomes better funded and regulations at home become more restrictive.”

Larger implications for human subjects research:

“Despite the existence of codes requiring that human subjects receive at least the same protection abroad as at home, they are still honored partly in the breach. The fact remains that many studies are done in the Third World that simply could not be done in the countries sponsoring the work.”

Larger implications for human subjects research:

“Clinical trials have become a big business, with many of the same imperatives. To survive, it is necessary to get the work done as quickly as possible, with a minimum of obstacles.” (p. 582)

Varmus and Satcher defend protocol 076

“Trials that make use of impoverished populations to test drugs solely for use in developed countries violate our most basic understanding of ethical behavior.” (p. 584)

Justice requires (?) investigating interventions that are not out of the reach of the citizens of the country in which clinical trials are conducted.

Considering 076 regimen as proven therapy in future research.

Should control group get zidovudine (AZT) or placebo?

• AZT therapy requires HIV testing early in pregnancy, fairly rigorous oral and IV drug regimen, no breastfeeding, 6 weeks of oral AZT for newborn, careful monitoring throughout.

• Also, AZT is expensive.

Considering 076 regimen.

Should control group get zidovudine (AZT) or placebo?

• Biggest mother-to-child HIV transmission in countries where women don’t get early prenatal care or HIV testing, deliver infants outside modern medical settings, rely on breastfeeding to protect babies from other diseases.

Considering 076 regimen.

Should control group get zidovudine (AZT) or placebo?

• Safety of AZT in populations with high incidence of malnutrition, anemia, and other diseases is unknown.

Is this a standard of care that works in this environment?

Defending placebo control:

“The most compelling reason to use a placebo-controlled study is that it provides definitive answers to questions about the safety and value of an intervention in the setting in which the study is performed, and these answers are the point of the research.”

Defending placebo control:

“Without clear and firm answers to whether and, if so, how well an intervention works, it is impossible for a country to make a sound judgment about the appropriateness and financial feasibility of providing the intervention.” (p. 587)

Placebo control:

INTERVENTION 1vs.

PLACEBO

Discover if intervention is better than nothing(but leave control group essential untreated)

Alternative to placebo control:

INTERVENTION 1vs.

INTERVENTION 2

Discover which intervention is more effective(but the two may differ in cost or toxicity)

Varmus and Satcher:

“If the affordable intervention is less effective than the 076 regimen — not an unlikely outcome — this information will be of little use in a country where the more effective regimen is unavailable. Equally important, it will still be unclear whether the affordable intervention is better than nothing and worth the investment of scarce health care dollars.” (p. 587)

Tension between beneficence and justice:

If you expose subjects to unknown risks, you have a duty to do it in such a way that you are likely to produce results that are useful to them and others in their population.

Dealing with this tension:

“[I]t is permissible to offer research participants in developing countries less-effective interventions than those used in developed countries if doing so (i) is scientifically necessary to answer an important question; (ii) does not deny anyone treatment they would otherwise receive; and (iii) is intended to develop interventions that will benefit the developing country.”

Joseph Millum and Ezekiel J. Emanuel, "The Ethics of International Research with Abandoned Children," Science 21 December 2007: Vol. 318. no. 5858, pp. 1874 - 1875.

Dealing with this tension:

Desire for clean data is not enough to warrant choosing local standard of care (that would not be permitted elsewhere) for your control group.

What about informed consent?

• There may be cultural factors that affect good transmission of information.

(Cf. Anne Fadiman, The Spirit Catches You and You Fall Down)

What about informed consent?

• There may be cultural factors that affect whether consent can be freely given.

e.g., permission from village elders or national governments.

Whose interests are they protecting?How important in the potential subject’s

autonomy in this cultural context?

What about informed consent?

Is there an element of coercion if participation affords a standard of care (to the subjects or the community) otherwise unavailable?

HOW TO HANDLE THESE ETHICAL CHALLENGES?