Human Research Training: A Historical Perspective

Human Research Training: A Historical Perspective

Introduction
For many years, medical research had gone on largely unregulated despite the fact that philosophers had been discussing the need to protect the safety and welfare of the human research subject volunteers. In ancient Egypt, the first century physician Celsius justified experiments on condemned criminals using words which became the classic defense for hazardous experimentation: "It is not cruel to inflict on a few criminals sufferings which may benefit multitudes of innocent people through all centuries."
Brady, Joseph V. and Jonsen, Albert R. "The Evolution of Regulatory Influences on Research with Human Subjects." A Handbook for Institutional Review Boards. Ed. Greenwald, Robert A. et. al. New York: Plenum Press, 1982. 3-18.
Today, people who are volunteering in research projects are safer than ever before. There are tremendous efforts by multiple groups to protect the safety and welfare of those who are good enough to stand up and decide to go first and try a new treatment. Especially, over the years, as tragedies have occurred, legislation to prevent their reoccurrence ensued. In the early 1900s in America, medicine and pharmacology was made up of folklore, charlatans, and alternative medicine. Numerous accounts of "snake oil salesmen" abounded.
In 1820, eleven physicians met in Washington, D.C., to establish the US Pharmacopeia, the first compendium of standard drugs for the United States.
In 1848, the Drug Importation Act passed by Congress requires US Customs Service inspection to stop entry of adulterated drugs from overseas.
In 1862, President Lincoln appoints a chemist, Charles M. Wetherill, to serve in the new Department of Agriculture. This was the beginning of the Bureau of Chemistry, the predecessor of the Food and Drug Administration.
The 1870s saw the rise of the Patent Medicine Industry. Because there were no restrictions on advertising, labeling or contents of any products, the patent medicine industry made up all sorts of concoctions, including the opiates, cocaine and other drugs, and sold them with the most extravagant advertising claims.
In 1880, Peter Collier, Chief Chemist, US Department of Agriculture, recommends passage of a national food and drug law, following his own food adulteration investigations. The bill was defeated, but during the next 25 years, more than 100 food and drug bills were introduced in Congress.
In 1883, Dr. Harvey W. Wiley becomes chief chemist, expanding the Bureau of Chemistry's food adulteration studies. Campainging for a federal law, Dr. Wiley is called the "Crusading Chemist" and "Father of the Pure Food and Drugs Act." He retired from government service in 1912 and died in 1930.
In 1897, the Tea Importation Act passed, providing for Customs inspection of all tea entering US ports, at the expense of the importers.
In 1898, the Association of Official Agricultural Chemists (now called AOAC International) establishes a Committee on Food Standards headed by Dr. Wiley. States begin incorporating these standards into their food statutes.
In 1902, the Biologics Control Act was passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans.
On June 30, 1906, the Pure Food and Drug Act was first enacted. It created the FDA in Washington. It said certain drugs could only be sold on prescription. And labeled habit-forming drugs. This was the beginning of the modern day FDA. This law came about as a result of an exposé written by Upton Sinclair entitled The Jungle. In it he exposed the horrible sanitary conditions that were part and parcel of the meat packing industry in that era. The result was the passage of the 1906 food and drug law that legislated that drugs must be proved and tested to be "pure" prior to their being available for sale to the public at large. Prior to this, there were ridiculous claims that these "patent medicines," as they were called because their secret ingredients were patented, could cure everything. In retrospect, the majority of these medicines only contained alcohol. Also that same day, the Meat Inspection Act was passed in reaction to shocking disclosures on unsanitary conditions in meat-packing plants in Chicago, as outlined in Upton Sinclair's exposé The Jungle.
1907 saw the first Certified Color Regulations that listed the seven colors found suitable for use in foods.
In 1911, US vs. Johnson was a Supreme Court ruling that the 1906 Food and Drugs Act does not prohibit false therapeutic claims, but only false and misleading statements about the ingredients or identity of a drug.
In 1912, Congress enacts the Sherley Amendment to overcome the ruling in US vs. Johnson. It prohibits labeling medicines with false therapeutic claims intended to defraud the purchaser, a standard difficult to prove.
In 1913, the required that food package contents be "plainly and conspicuously marked on the outside of the package in terms of weight, measure of numerical count."
In the 1914 case US vs. Lexington Mill and Elevator Company, the Supreme Court issued its first ruling on food additives. Also, the Harrison Narcotic Act passed, requiring prescriptions for products exceeding the allowable limit of narcotics and mandated increased record keeping for physicians and pharmacists who dispense narcotics.
In the 1924 case US vs. 95 Barrels Alleged Apple Cider Vinegar, the Supreme Court ruled that the Food and Drugs Act condemns every statement, design or device on a product's label that may mislead or deceive, even if technically true.
In 1930, the name of the Food, Drug and Insecticide Administration is shortened to the Food and Drug Administration (FDA) under an agricultural appropriations act.
In 1933, the FDA recommended a complete revision of the obsolete 1906 Food and Drugs Act. The first bill is introduced into the Senate, launching a five-year legislative battle.
In 1938, the Food, Drug and Cosmetic Act was passed. Its main tenet was that drugs now needed to be proven "safe!" That is, before 1938, the law only mandated that drugs were pure. There was no thinking that we should test them first to make sure that they were safe. In 1937, the Massengill Drug Company would have their name etched into the history of things gone wrong with drugs. At the time they were working on trying to formulate a liquid formulation of their popular antibiotic, sulfanilamide. It was thought that with the coming flu season if they could make an elixir of sulfanilamide that this would be a big seller to the pediatricians. Well, without any thought whether or not this new formulation was safe, Massengill released their new wonder drug to the children with flu in 1937. Unfortunately, they used ethylene glycol (antifreeze) to make the sufla water-soluble. At the time medical science didn't know that ethylene glycol was toxic to the kidneys. The children abruptly went to acute renal failure. Since hemodialysis was not invented as of yet, 107 of them died! It was in reaction to this horrific tragedy that the 1938 Food, Drug and Cosmetic Act ensuring that our drugs are safe was enacted.
Human Radiation Experiments
Between 1944 and 1974, the government sponsored several thousand human radiation experiments. They involved exposing people to radioactive tracers in doses likely to cause physical harm. During this time there was little attention paid to issues of fairness in the selection of the participants. Research was conducted without their awareness or consent and on participants not likely to derive any directly medical benefit. These research errors were finally exposed in 1993! And in 1994, President Clinton created the Advisory Committee on Human Radiation Experiments to identify ethical and scientific standards for evaluating these events, and to make recommendations to ensure that past wrongdoings cannot be repeated.
In 1951, the Durham-Humphrey Amendment defined prescription drugs as those that must be taken under a doctor's supervision.
In 1962, the Kefauver-Harris Amendments to the Food, Drug and Cosmetic Act were passed ensuring that our drugs were now required to be proven "effacious!" That is, finally, prior to a drug making it all the way to the marketplace, drug studies were required to be performed showing that this brand new treatment actually works! This amendment also came retrospectively as the result of a deficiency in our system to ensure only good new investigational treatments make it to our drug store shelves. In 1961, there was research on a investigational new drug to treat morning sickness and insomnia in pregnant women called thalidomide. At the time, doctors that were principal investigators in research studies were not required to keep the investigational study drug in a secure locked environment with limited access as we do today. In addition, nobody thought at the time that it was wrong to give out free samples of an investigational study drug to patients not enrolled in a formal research study. During the early 1960s, the world started to see children being born with a horrific birth defect called phocomelia. Over 300 infants were born with missing extremities. Some of them had both arms and legs missing! The United States government was shocked by this horrible tragedy that occured. In an attempt to make sure history didn't repeat itself again, the Kefauver-Harris Amendment was enacted, ensuring that all investigational study drugs now had to be strictly limited to sole use by participants who have agreed to become research volunteers in an investigational new drug study.
Alternative Medicines
Still no law guaranteeing the three basic qualities of a good drug: Pure, Safe, and Efficacious.
The Nuremberg Code
The international military tribunal in Nuremberg, Germany, in 1947, tried 26 German physicians for war crimes against humanity for recruiting unwilling prisoners for horrific, fatal medical experiments. The Nuremberg Code was a result of this. It attempts to make sure history doesn't repeat itself ever again. The Code outlines the fundamental ethical principles in human subject research and is regarded as the first internationally recognized set of guidelines to help promote safety. Its most important principle is: "The voluntary consent of the human research subject is absolutely essential." It also states that the risks to the volunteers should not outweigh the humanitarian importance of the problem. Other tenets include: only doing research if there is no other means of obtaining this information, and it will be to the good of society; we should do preliminary tests on animals; we should avoid all unnecessary physical and mental suffering and injury; no experiments where there is an a priori reason to believe that death or disabling injury will occur; physicians shouldn't enroll themselves as subjects like Dr. Jeckyl and Mr. Hyde; the degree of risk shouldn't supersede the potential benefit; proper preparations should be made to protect against even remote possibilities of injury; experiments should only be conducted by scientifically qualified persons; the subject has the right to leave the experiment at any time for any reason without prejudice; and the scientist should terminate the study should he become aware that a much better treatment has become available.
NIH Policy on the Protection of Human Research Subject Volunteers
Back in 1953, the NIH produced the first official US federal policy for the protection of human participants. This policy provided a mechanism for prospective review of research by individuals who had no direct involvement or intellectual investment in the research. This heralded the beginning of the first IRB.
The Wichita Jury Case
In 1953, University of Chicago researchers tape-recorded the deliberation of juries in six civil cases, with the consent of the judge and counsel for both sides, but without the jurors' knowledge. The researchers were investigating whether the comments of some lawyers might have inappropriately affected the deliberative process. When word of the research leaked out (one of the tapes was played at a Bar Association conference), public outrage led to Senate hearings chaired by James O. Eastland. Even though there was no evidence that the recording had influenced the actions of the jury, it was felt that the possibility of further recordings being made might affect jurors' statements or deliberations. A federal law was passed in 1956 banning all recording of jury proceedings.
Timothy Leary and Richard Alpert
In the 1960s, these two Harvard faculty (Leary was lecturer in Social Relations and Alpert was assistant professor at the Ed School) worked together at the Center for Research in Personality. Hallucinogenic drugs were not then illegal and they experimented with psilocybin and LSD obtained from Sandoz Pharmaceuticals, which were also dispensed to friends, associates and students. As time passed, the research became more and more freewheeling and, in the opinion of many departmental colleagues, rapidly lost any semblance of academic rigor. At this time the University Health Services was just formulating its policies regarding the use of human research subject volunteers. An agreement was reached with Alpert and Leary in the fall of 1961 that they would not include any undergraduates in their research. In early 1962, the two separated their activities from the Center for Research in Personality and formed their own private organization, the International Federation for Internal Freedom (IFIF). Eventually, both were fired from the university, Alpert for having given psilocybin to an undergraduate in 1962 in violation of the UHS agreement, and Leary for failing to teach his scheduled classes in the spring of 1963.
Research on Obedience to Authority
At Yale University in the early 1960s, Stanley Milgram was a social psychologist who devised a series of experiments to examine the circumstances under which naïve individuals would follow instructions whose consequence was the apparent injury of another person. Publication of the research, and a dramatic film of the study, generated much controversy among psychologists. Some argued that subjects had been harmed, if not through the stress of the experiment itself, then through the "inflicted insight" into their own personalities. Nevertheless, the relevance of the research to what was current events of the day, the trial of Adolph Eichman, who maintained that he was just following orders as he signed papers condemning concentration camp victims to death, made the findings all the more compelling.
The Jewish Chronic Disease Hospital Study
In 1963, studies were undertaken in Brooklyn, NY, at the Jewish Chronic Disease Hospital, which is now called Interfaith Hospital of Brooklyn. The doctors then did a terrible "study" on unwitting, unsuspecting, unconsenting patients on the body's ability to reject cancer cells. They injected live cancer cells intravenously into patients and watched to see if they developed any signs of neoplasia. They then proudly published their results for the world to read.
The Willowbrook Study
In the early 1960s, unethical research was conducted at the Willowbrook State School in Staten Island, NY, on vulnerable mentally retarded children to better understand the natural history of the hepatitis virus. Most of the kids "caught" the highly infectious virus after they came there. The doctors then decided to "coerce" the parents into enrolling their children in an experimental study whereby their children were deliberately infected with the live hepatitis virus. Only parents who agreed to the research were able to get their retarded children into Willowbrook! This controversial case raised important questions about the adequacy and freedom of consent, inadequate disclosure of the child's risk of later developing chronic liver disease, and the lack of information given to parents about access of doses of gamma-globulin.
The Declaration of Helsinki
First adopted by the World Medical Association in 1964 and subsequently modified every couple of years, it is a landmark international agreement on making additional safety recommendations to the Nuremberg Code. It said we should do preliminary experiments on animals prior to recruiting humans. It pointed out that we shouldn't enroll a human in a study unless the importance is in proportion to the risk. It also recommended formation of safety committees that later on became data safety monitoring boards (DSMB) and Institutional Review Boards (IRB).
The Public Health Service
In 1966, the Public Health Service was created. This led the way to providing research volunteers with informed consent with the use of informed consent forms (ICF) to make sure that they adequately understand the risks, benefits and alternative treatments of the proposed medical care they will receive in the research study and that they voluntarily agree with the proposed investigational treatment plan without any element of coercion. In addition, it led to the formation of Institutional Review Boards (IRB) whose function would be one of oversight of the research process with an eye on maintaining the protection, safety and welfare of the research subject volunteer.
Beecher Article
In 1966, Dr. Henry K. Beecher was an anesthesiologist who wrote an article in the NEJM describing 22 examples of unethical research conducted and published by "reputable" researchers of the time. He wrote, "medicine is sound, and most progress is soundly attained," however, if unethical research is not prohibited it will "do great harm to medicine." At that time it was assumed that the only unethical research was that which went on in the Nazis' prison camps.
Tea Room Study
In the 1960s, there was a study on the homosexual practices in public restrooms, then, to contact the men at a later time to conduct further investigation on their behavior. The researcher went undercover and gained the confidence of the gay men. He identified 100 active participants by tracing their car license numbers. A year after he completed the initial study, he distributed a "social health survey" throughout the communities where he knew the participants lived. The ethical problems were: use of a vulnerable population, reinforced the image that social scientists use deception casually in research, and lack of proper informed consent.
Humphreys, Laud. Tearoom Trade: Impersonal Sex in Public Places. Walter de Gruyter, Inc, February 1975.
The Belmont Report
Released in 1979 by the National Commission for the Protection of Human Subjects of Biomedical and Behavior Research, it provided more strenuous protection to human research subject volunteers. It was entitled Ethical Principles and Guidelines for Research Involving Human Subjects.
It was preceded by the National Research Act that legislated formation of IRBs in reaction to the Tuskegee Syphilis Study conducted by the United States Public Health Service back in 1932 involving poor blacks in rural Alabama who were enrolled in an observational study of the natural history of untreated syphilis. The men were recruited without informed consent and, in fact, were misinformed that some of the procedures in the interests of research (spinal taps were explained as back shots) were actually "special" free treatments. By 1936 it had already become apparent that many more infected men than controls had developed complications. In the 1940s penicillin was determined to be efficacious for syphilis. This study ended in 1972 when a reporter exposed the horrors of untreated tertiary lues. President Clinton issued a formal apology a few years ago to the families of the over 400 black men with syphilis and the 200 men without syphilis who served as health controls who were victims of the prolonged and knowing violations of the rights of a vulnerable group of research participants.
The Belmont Report pointed out the differences between "practicing medicine on patients" and "performing medical research on human research subject volunteers." It cautioned researchers to think about what hat they were wearing at any particular time. It identified three basic principles to guide researchers to provide safer medical research:

Respect for persons
Beneficence
Justice

Respect for persons is the principle involving recognition of the personal dignity and autonomy of individuals and the need for special protection to be afforded to those with diminished autonomy. That is, the person has to understand what they're getting into. Autonomy is protected by the consent process. Each prospective subject must be given ample time and information to decide whether to participate or not in a research study. There is need not only for initial consent, but also for an ongoing and continual informed consent process as the study progresses.

Obtain Informed Consent
Respect the privacy of research subjects
Does the consent process and protocol maximize autonomy?
Additional protections put in place to safeguard vulnerable populations
The study needs to maximally protect subject privacy
Need to adequately inform subjects of potential risks

Beneficence or the lack of malficence has to do with not doing harm and maximizing benefits. Explaining the risks, benefits and alternative treatment options available. This principle is the basis for the risk/benefit ratio assessment in which principal investigators, sponsors, CROs, IRBs and Independent Ethics Committees (IEC) and institutions all seek to ensure that any risks are minimized, and not taken unless there is likely to be a benefit to the individual research subject volunteer.

Use the best possible research design to maximize benefits and minimize harms
Make sure the researchers are able to perform the procedures and handle the risks
Research without a favorable risk/benefit analysis may not be conducted
Looking to see if adequate research designs can be improved further
Identifying and minimizing risks
Identifying and maximizing benefits

Justice has to do with how researchers distribute the burdens of research and who actually receives the benefits. For example, do you include only poor people in a study that would only have benefit to rich people? Therefore, the principle of distributive justice requires that both the burdens and the benefits of research be distributed equitably. Subject selection should be based on those who stand to bear the risks should also be the ones who will benefit from the research.

Select subjects equitable: recruitment targets the population that will benefit from the research
Avoid exploitation of a vulnerable population or a population of convenience
Does the recruitment unfairly target a population?
Are the inclusion/exclusion criteria fair?
Autonomy/respect to decide whether to participate or withdraw from a study

The Code of Federal Regulations
In 1980, the Food and Drug Administration established regulations on the protection of human subjects. These can be found in the Code of Federal Regulations (CFR), Title 21, Part 50, commonly abbreviated as 21CFR50. Institutional review board information can be found at 21CFR56.
CIOMS Guidelines
In 1982, the Council for the International Organization of Medical Sciences (CIOMS) published the International Ethics Guidelines for Biomedical Research Involving Human Subjects. These are designed to guide researchers from the more technologically advanced countries when conducting research in developing countries. It allows for cultural differences in ethical standards.
Office of Research Integrity
In March 1989, the Public Health Service (PHS) created the Office of Scientific Integrity (OSI) and the Office of Scientific Integrity Review (OSIR). These offices were to deal with scientific misconduct from the funding agencies. In May 1992, OSI and OSIR were consolidated into the Office of Research Integrity (ORI).
The Common Rule
The Common Rule was enacted in 1991. It is the Federal Policy for the Protection of Human Subjects. It covers research supported by the Departments of Agriculture, Energy, Commerce, HUD, Justice, Defense, Education, Veterans Affairs, Transportation, and HHS as well as NSF, NASA, EPA, AID, Social Security Adminstration, CIA, and the Consumer Product Safety Commission. The provisions are identical to the DHHS Regulations (45CFR46, Subpart A).
Death of a Normal Volunteer
On March 31, 1996, a 19-year-old female Asian-American student at the University of Rochester responded to an advertisement for study patients to undergo bronchoscopy for the harvest of alveolar macrophages. The patient died of an overdose of lidocaine. The protocol didn't limit the dose. The pulmonologist didn't record the amount of lidocaine administered.
Food and Drug Administration Modernization Act of 1997
Further improved regulation of drugs to ensure their purity, safety and efficacy.
Death on Gene Therapy Trial
In the fall of 1999, 18-year-old Jesse Gelsinger died as a result of his participation in a gene therapy trial. Jesse had a rare metabolic disorder, ornithine transcarbamylase deficiency syndrome (OTC), which was being controlled with diet and medication. Researchers were testing an innovative technique using adenovirus gene therapy. Shortly after treatment Jesse experienced multiple organ failure and subsequently died. This case catapulted research with human subjects into the national media. Serious concerns related to conflict of interest, data safety monitoring, and informed consent have made the Gelsinger case the most contemporary illustration of continued doubts about the ethical integrity of research with human subjects. This case has instigated deliberations on all these controversial topics at the national level. The outcome of such discussions have yet to be determined.
Veterans Administration
In April 1999, all research projects at the Veterans Administration West Los Angeles Medical Center were shut down after many allegations of medical research performed on patients who did not consent. An investigation showed that not only was research being done on patients without who had not given informed consent, but also that research was being done on patients who had expressly refused consent.
Duke University Medical Center
On May 12, 1999, the federal government ordered Duke Clinical Research Institute to stop its research due to problems with its IRB. The order was issued by the US Department of Health and Human Services' Office for Protection from Research Risks (OPRR).
The Office of Human Research Protections
The Office of Human Research Protections (OHRP) was established in 2000 with the US Department of Health and Human Services to increase the focus on protecting human research participants.
Death of a Healthy Research Subject Volunteer
Ellen Roche was a 24-year-old healthy research volunteer enrolled in an experimental drug study at Johns Hopkins Medical Center who died on June 2, 2001, following her participation in an asthma research study where she inhaled hexamethonium. The New York Times reported she died because of failure of scientists and administrators to recognize that the experiment was unsafe. All research there was halted until the following actions were taken to strengthen research oversight:

Increasing the number of IRBs
Intensifying training for all IRB members
Web-based instruction using IRB 101 by PRIMR
Academic review of protocols prior to IRB submission to evaluate study design, safety and validity
Working with OHRP
Establish a committee to review and revise policies for participation of students/employees in research
Taken steps to ensure timely, written documentation of IRB deliberations
Re-review consent forms: purpose, risk, benefits
Collaborate with a pharmacist and a librarian for literature searches on potential side effects
Query FDA to see if IND is necessary
Need to notify IRB if change in protocol or SAE
Pharmacist to be involved in the preparation of study drugs
Random quality control checks to insure safety and adherence to best practices