Exam Room at Buchenwald Pathology Barracks

The phrase "human subject research" conjures a gamut of images from nobility to infamy.

In the former category we find Peruvian medical student Daniel Carrión. The twenty-six-year-old died in 1885 after self-experimentation that contributed mightily to understanding a fatal blood disease. Among the infamous we recognize Josef Mengele, whose human experiments during World War II constituted war crimes. Extreme examples vividly illustrate basic principles. They may also, however, obscure reflection about conduct occurring in the greater middle ground of "everyday" ethics.

Dr. Henry Beecher made this point in a seminal article of 1966. Emphasizing that "American medicine is sound, and most progress in it soundly attained," he nonetheless concluded that in America's leading medical schools, hospitals, and government institutions, "unethical or questionably ethical procedures are not uncommon." Although most of the identified breaches resulted from "thoughtlessness and carelessness" rather than "willful disregard," Beecher implicitly linked American researchers' attitudes and actions to infringement of ethical principles a generation earlier.

Emerging out of the prosecution of war criminals, the 1947 Nuremberg Code declared voluntary consent to be "absolutely essential" in human subject research. In 1954 the World Medical Association issued "Principles for Those in Research and Experimentation" and a decade later its "Declaration of Helsinki." Although intended for the entire international research community, these ethical statements were not widely discussed in this country. Nazi atrocities seemed unrelated to scientific experiments in the States. However, after abuses within our own borders were brought to light, Americans were more willing to embrace the notion that within scientific research there exists an inherent tension between generalizable knowledge and individual welfare.

Among the violations Beecher identified were withholding known effective treatments from patients with rheumatic fever and typhoid, injecting non-therapeutic agents into the spleens of healthy and seriously ill subjects, and infecting mentally handicapped children with hepatitis.

These disclosures coincided with professional and governmental action and numerous investigative reports in the popular press describing unethical research practices. That same year the New England Journal of Medicine published Beecher's findings, the American Medical Association released its "Ethical Guidelines for Clinical Investigation," and the National Institutes of Health (NIH) published rules applicable to all federally funded human subject research. The NIH guidelines established institutional review boards (IRBs)—local peer review committees charged with ensuring that ethical standards are maintained. Researchers must not enroll subjects in any study without IRB approval.

In 1972 the Associated Press reported on the U.S. Public Health Service's Tuskegee syphilis study. Since the 1930s researchers had studied syphilis in 399 black men, withholding treatment and not informing them that they had a sexually transmitted disease. By the time the story ran, forty wives and nineteen children of participants had contracted the disease, and 128 of the men had died from syphilis or its complications.

In addition to increased press coverage of scientific misconduct, during the 1960s and 70s theologians and philosophers were encouraging greater public involvement in contemporary issues previously considered the domain of experts. Princeton University's Paul Ramsey, having written about civil disobedience and warfare as a Christian ethicist, turned his attention to medical science. Ramsey maintained that without public scrutiny and meaningful informed consent medical research would become dominated by a radical utilitarianism in which individual welfare is subjugated to a search for knowledge in service of the greater good. He did not believe that exercise of individual integrity alone would adequately protect human subjects. In The Patient as Person he wrote, "No man is good enough to experiment upon another without his consent."

The post-war years were also characterized by a tremendous escalation in research funding. At the NIH alone, Beecher noted a 624% increase between 1945 and 1965. While this created unprecedented opportunity for the scientific community, it also intensified pressure on investigators vying for tenure at prestigious institutions, thus contributing to an atmosphere in which protecting individual subjects was more easily overlooked.

Just as social, economic, and other forces changed the research milieu after World War II, similar trends have altered the context of scientific inquiry since Beecher's article. Last year, eighteen-year-old Jesse Gelsinger died during a gene therapy trial in Philadelphia. Following widespread news coverage of this calamity, researchers notified federal authorities about more than 600 adverse events that had occurred in other gene-transfer studies, but had not been reported as required by law. Secretary of Health and Human Services Donna Shalala has thus called for improvement in monitoring the actual conduct of studies once protocols are approved, in order to ensure that standards of clinical care remain high, informed consent is properly obtained, and reports of research progress and problems are filed on time.

Shalala's recent remarks in the New England Journal of Medicine, like Beecher's thirty-four years ago, were not motivated by evidence that the entire scientific community lacks moral integrity, but by the need to re-examine our ethical assumptions and commitments in light of changes in the research environment. Reduction of federal funding during the 1980s stepped up the competition for grants and professional advancement described in 1966. Unforeseen by Beecher was the extent to which medical research has become an entrepreneurial and proprietary enterprise.

Individual scientists and their institutions may receive millions of dollars if their studies lead to effective therapies. At a minimum, failure to disclose stock options, patent ownership, and other benefits creates the appearance of dual allegiance. More importantly, such conflicts of interest may bias scientific judgment in favor of initiating or continuing studies that endanger individual subjects without their knowledge. Federal authorities who monitor research have recently reported that investigators and IRB members lack adequate knowledge of research ethics, and that universities, hospitals, and other research facilities often do not adequately staff or fund their IRBs.

Publication of Beecher's article and other events around 1966 signify a post-war re-evaluation of ethical conduct in research. Likewise, the death of Jesse Gelsinger, Secretary Shalala's recommendations, and other incidents during the past year signal a new era of vigilance in that arena. Scientific research is a collaborative enterprise of individual investigators, their sponsors, research participants, regulatory bodies, and the public. Our tax and consumer dollars fund most medical studies, and we benefit whenever we receive treatments developed through human experimentation. Moreover, during every research study fundamental principles of human dignity and justice are upheld or abrogated. The stakes are high, and maintaining the ethical integrity of research requires personal and collective accountability.

Web Resources

National Institutes of Health

NIH's Office of Human Subjects Research

NIH's ClinicalTrials.gov

National Cancer Institute's Cancer Clinical Trials System

Office for Human Research Protections of the Department of Health and Human Services