Past Abuses and the Evolution of Patient Proection

Despite the strong ethical underpinnings of modern clinical research, there have been cases over history where human research has been abused. The most extreme example of unethical human research occurred in the 1940s when German physicians performed horrific experiments on Jewish prisoners in Nazi concentration camps.  The torturous records of these crimes were examined during the Nuremberg Trials and resulted in the prosecution of physicians found guilty of crimes against humanity.  Thereafter, the Nuremberg Code (http://ohsr.od.nih.gov/nuremberg.html3) was established in 1945 to outline basic ethical principles for all human research.  The major tenants stated that the participant must be competent and participation must be voluntary.   

In the U. S. there have been many cases of unethical abuses in research.  In 1956-63, institutionalized children at Willowbrook State School in Staten Island, N.Y., were offered better living conditions in exchange for parental approval to participate in a “research trial” which infected the children with Hepatitis A.   Also, in 1963, debilitated elderly at the Jewish Chronic Disease Hospital in Brooklyn, N.Y., were injected with live cancer cells.  These atrocities led to another global attempt to define ethical human research with the Declaration of Helsinki, adopted by the Word Medical Association in 1964.   A recently updated version can be found at http://www.wma.net/e/policy/b3.htm.    This provided the most significant ethical adaptation of human rights and safety while balancing the progress of science and the conduct of clinical trials for public good. It turned the focus of research from the investigator towards the patient’s perspective, by requiring informed consent.  Thus, patient volunteers finally had written detailed explanations of the trial protocol, including the risks, potential side effects, and medical alternatives to the trial.  

Despite these protections, unethical research continued.  During the 1960’s in Tuskegee, Alabama, a large group of African American men with syphilis were enrolled in a research trial where they were withheld from lifesaving penicillin in order to study the natural history and complications from untreated syphilis infections.  When a physician finally objected to the trial in 1972, the principle investigators rationalized the trial by weighing the public benefit of scientific advancement over the injustices to the Tuskegee men.  According to the Nuremberg Code and Declaration of Helsinki, the trial design was clearly unethical.  Public benefit and scientific advancement should never be weighed against the ethical principle of justice.  As an ethical principle, human research should never be performed as an injustice to others. 

In 1971, women in San Antonio, TX, voluntarily entered a research trial to evaluate the efficacy of a new oral contraceptive pill.  They were not told about the 50% chance of receiving a placebo (sugar pill), which resulted in more women becoming pregnant than anticipated.  It was unethical not to fully disclose the possible randomization to a placebo arm, violating the Declaration of Helsinki’s covenant of Informed Consent. 

Between 1961 and 1972, during the cold war, the Department of Defense sponsored a variety of radiation experiments on adults, many without consent.  Initially advertised as “cancer irradiation” trials for patients with incurable cancer, these trials involved predominately black patients with average 4th grade intelligence level.  Later, patients without terminal cancer were enrolled to receive escalating doses of total and partial body irradiation.  According to congressional transcript, among the 82 patients treated with “sublethal” irradiation and plutonium injections, all suffered from acute radiation toxicity and 20 patients died from the experiments.  In 1994, a Presidential Advisory Commission released a full report of the injustices, commenting that the “physical harm from the radiation is probably less than the damage to the individuals, community, and government caused by the initial secrecy… and failures to deal honestly with the public thereafter.”  President Clinton released the full investigation to the public, compensated the families, and vowed to prevent these wrongdoings from happening again.

In 1974, as a response to human research violations, the U.S. Congress passed the National Research Act, which created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.  The Commission established important boundaries and guidelines for research and how informed consent applied in various research settings.  It enacted Federal law requiring human research trials and their informed consent process to be approved by an Institutional Review Board (IRB) if the trial was federally funded or subjected to FDA regulation.  Ethical guidelines established by this commission were published in 1979, known as the Belmont Report that guided IRB to protect the rights of trial participants (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm).   IRB members are selected based on their sensitivity to community issues, and their ability to review and approve only the highest quality research in light of ethical principles.  Federal guidelines for IRBs require at least 20% non-medical members (such as clergy, social workers or attorneys) and 20% who are not affiliated with the institution (http://ohrp.osophs.dhhs.gov/irb/irb_guidebook.htm).

In 1981, the Department of Health and Human Services (DHHS) and the FDA developed the Federal Policy for the Protection of Human Subjects that further refined the clinical trial process.  This also created the Office for Human Research Protections (OHRP) (http://ohrp.osophs.dhhs.gov) whose oversight includes registering IRBs, providing guidelines for financial conflicts of interest, and assuring compliance with regulations of clinical research.  These federal regulations were further developed in 1991, in what is often referred to as the “Common Rule” (http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm).  These guidelines by the sixteen federal agencies that conduct, support, or otherwise regulate human subjects research make uniform the human subjects protection system in all relevant federal agencies and departments.

The common rule policies set forth the specific documentation and requirements of both the informed consent and IRB approval process.  The informed consent, written for a 6th grade reading level, became the focus for whether the IRB would determine if full disclosure of the trial existed and if its risks and ethical criteria were met. Informed consent must include the diagnosis, purpose of the study, treatment options and alternatives, expected outcomes, benefits and risks, and a description of procedures.  Additionally, it must explain methods to maintain confidentiality and contacts for persons responsible for the study.  The informed consent must also explain if treatment or compensation will be provided if the participant is injured during the trial. 

In extraordinary circumstances, the ethical principles of human research have been exempted by an act of the U.S. Congress for the protection of our military or national security.  For example, in 1990, Congress approved a Department of Defense Exemption during the Persian Gulf War that mandated an experimental anthrax vaccine to be administered to 1 million soldiers.  The vaccine had not been FDA approved, so it was still considered an investigational agent of which efficacy and safety were not fully known.  Medical experts calculated that the potential risk of a catastrophic anthrax attack vrs the benefit of vaccination and potential lives saved outweighed the ethical principle of autonomy.   This Congressional act serves as a precedent for future ethical human research exemptions.  Recently, mandatory anthrax vaccination was banned by a federal judge because it “inoculated service members without their consent.”    The pentagon reacted immediately by changing to voluntary anthrax vaccination with consent.  The FDA has since stated the vaccine is “safe” but it has not been FDA market approved as of yet. The federal courts ban on mandatory military vaccination may be over-ruled by the President if deemed necessary for national security.   If SARS becomes widespread or if small pox is released, experimental vaccinations may become congressional agenda again because public health and/or national security may outweigh individual autonomy.