There are three “trigger” words that evoke images of unethical clinical research—Tuskegee, Nuremberg and most recently Guatemala.1-3 These represent some of the most egregious, but not the only, violations of medical ethics.  Tuskegee involved performing historical observations of untreated syphilis in black African Americans; Nuremberg consisted of forced sterilizations, extermination of individuals with mental illness and medical experiments that resulted in an estimated 200,000 deaths; Guatemala, only recently discovered, involve the deliberate exposure of prisoners and prostitutes to gonorrhea to determine the effectiveness of treatment.  All three have in common experiments conducted by academic physicians and scientists, utilization of vulnerable minority populations, experiments which were rationalized as benefiting either the state (Nuremberg) or mankind (Tuskegee and Guatemala) and gradual erosion and an eventual violation of fundamental principles of medical ethics.

In August 2012 Lancet published an article, “Apologizing for Nazi medicine: a constructive starting point.”4-,5  The article presented a written apology by the German Medical Assembly and makes for sobering reading. It is a cautionary warning about how medical science can be seduced into abrogating its role from a patient oriented approach and an ethically driven philosophy to an authoritarian approach with justification of clinical research for the benefit of the “state.” An Editorial in the American medical Association Journal Agreed.6

It may seem strange that an apology should be offered some 80 years after the atrocities began but it is clear that the German Medical Assembly has wrestled for decades with trying to understand how those events could have occurred.  Their apology is an important analysis of the events and an evaluation of those who were responsible.  Their conclusion is certainly a warning of how violations of human ethics can occur, do occur, and are likely to continue if fundamental ethical principles are perverted to benefit the state rather than individuals.

The 115th German Medical Assembly apology begins with, “This is the city ( Nuremberg) where, 65 years ago, 20 physicians were tried for their roles as leading representatives of the state medical authorities of the Nazi regime in committing medical crimes against humanity. Research conducted over the past decades has documented that the extent of human rights violations was vastly greater than documented during the trial. Today, we know considerably more about the goals and practices of various involuntary human experiments, which often ended in death, and the killing of over 200,000 psychologically ill and disabled people, as well as the forced sterilization of over 360,000 individuals classified with hereditary illness.”

It seems clear from their apology and discussion that they arrived at a very difficult conclusion for the medical profession and one that those engaged in research on humans everywhere should take seriously.

The apology continues. “In contrast to still widely accepted views, the initiative for the most serious human rights violations did not originate from the political authorities, but rather from physicians themselves. The crimes were simply not the acts of individual doctors, but rather took place with the substantial involvement of leading representatives of the medical association and medical specialisms as institutional bodies, as well as with the considerable participation of eminent representatives of university medicine and renowned biomedical research facilities. These human rights violations perpetrated in the name of medicine under the Nazi regime continue to have repercussions to this day and raise questions concerning the way in which physicians perceive themselves, their professional behavior, and medical ethics. We acknowledge the substantial responsibility of doctors for the medical crimes committed under the Nazi regime and regard these events as a warning for the present and the future.”

It would be appropriate to ask whether the trend in current medical research and resource poor and even resource rich countries has already tilted toward the interests of the state (economic) rather than the individual. Offering inferior treatment as a comparative study arm, especially to vulnerable subjects, based on economic interests of the “state” is an example.7.8  A perceptible shift in the ethical interpretation of what is standard of care in poor countries is another example and has made it possible to perform clinical research studies that could not be performed in a resource rich country. The impact of such studies are significant as they have been used by international organizations such as WHO to base their standard or care recommendation on false economic rationales providing justification for countries to neglect the health of their subjects.9  It has not gone unnoticed that there are increasing numbers of studies that compare established treatment regimens to shortened treatment regimens to determine if equal efficacy can be attained at a reduced cost but in the process, placing research subjects at risk, conducting research that has little or no direct benefit to individual research subjects and studies that do not properly inform participants of risks.10-13

As the World Medical Association is in the process of revising their international ethical guidelines for research in humans, and as there are increasing questions as to how carefully ethical principles are considered in clinical research studies sponsored by the National Institutes of Health, it is perhaps time to closely examine the process of approval of clinical research studies performed both in the US and in resource poor countries to determine if they comply with established scientific and ethical principles.

References

  1. Remembering Tuskegee. http://www.npr.org/programs/morning/features/2002/jul/tuskegee/
  2. Famous World Trials. Nuremberg Trials. 1945 – 1949 http://law2.umkc.edu/faculty/project Famous World Trials Nuremberg Trials. 1945 – 1949s . http://law2.umkc.edu/faculty/projects/ftrials/nuremberg/nuremberg.htm
  3. NY Times. U.S. Apologizes for Syphilis Tests in Guatemala. http://www.nytimes.com/2010/10/02/health/research/02infect.html?_r=0
  4. Kolb S, Weindling P, Roelcke V, Seithe H. Apologizing for Nazi medicine: a constructive starting point. Lancet 2012; 380: 722–23. http://www.ncbi.nlm.nih.gov/pubmed?term=380[volume]+AND+722[page]+AND+kolb[author]&cmd=detailssearch
  5. Supplement to: Kolb S, Weindling P, Roelcke V, Seithe H. Apologising for Nazi medicine: a constructive starting point. http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673612613968.pdf
  6. Physicians’ Actions, Warning for Future  JAMA 2012. 308: 657. http://www.ncbi.nlm.nih.gov/pubmed?term=308[volume]+AND+657[page]+AND+future&TransSchema=title&cmd=detailssearch
  7. Who Will Protect Vulnerable Populations from Research Exploitation? http://ethicsinhealth.org/?p=221
  8. Molyneux E, Nizami SQ, Saha S, Huu KT, Azam M, Bhutta ZA, Zaki R, Weber MW, Qazi SA; CSF 5 Study Group.5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double-blind randomised equivalence study. Lancet. 2011 May 28;377(9780):1837-45. http://www.ncbi.nlm.nih.gov/pubmed?term=377[volume]+AND+1837[page]+AND++meningitis&TransSchema=title&cmd=detailssearch
  9. An open letter to the World Health Organization. http://ethicsinhealth.org/?p=430
  10. Multiple steps must be taken before ethical pediatric anthrax vaccine trials can be considered http://blog.bioethics.gov/2013/03/19/multiple-steps-must-be-taken-before-ethical-pediatric-anthrax-vaccine-trials-can-be-considered/
  11. An Ethical Breakdown. http://www.nytimes.com/2013/04/16/opinion/an-ethical-breakdown-in-medical-research.html?_r=0
  12. Impact, ethics of surgery slammed http://www.sacbee.com/735/
  13. Vaccine Enterprise Meeting report. Prevention Trials in the Population of Infants Born to HIV-Infected Mothers. http://www.vaccineenterprise.org/content/prevention-trials-infants