Ethics in Research involving Human Subjects Dr. Walid S Ethics in Research involving Human Subjects Dr. Walid S. Abdelkader Head of Preventive Medicine and Primary Care Division IMC Feb. 2009 www.imceg.com www.imceg.com

Nazi Medical War Crimes (1939–1945) A well-known chapter in the history of research with human subjects opened on December 9, 1946, when an American military tribunal opened criminal proceedings against 23 leading German physicians and administrators for their willing participation in war crimes and crimes against humanity. Among the charges were that German physicians conducted medical experiments on thousands of concentration camp prisoners without their consent. Most of the subjects of these experiments died or were permanently crippled as a result. Prior to 1906, when the Pure Food and Drug Act was passed, there were no regulations regarding the ethical use of human subjects in research. There were no consumer regulations, no Food and Drug Administration (FDA), no Common Rule, and no Institutional Review Board (IRB). What follows is a brief discussion of why federal rules and regulations were established and why the IRB became a necessity. The Nazi War crimes have been one of the first large scale known violations against human subjects A photo for a burn induced in one of the prisoners , in a study for traetment of burns Medical Research involving human beings have created a lot of potential pitfalls that led to tragedies in the last century.

Tuskegee Syphilis Study - Alabama The study was stopped in 1973 by the U.S. Department of Health, Education, and Welfare only after its existence was publicized and it became a political embarrassment. In 1997, under mounting pressure, President Clinton apologized to the study subjects and their families. http://www.tuskegee.edu/Global/Story.asp?s=1207598 Tuskegee Syphilis Study (1932-1972). An equally well known chapter in history occurred during a research project conducted by the U.S. Public Health Service. Six hundred low-income African-American males, 400 of whom were infected with syphilis, were monitored for 40 years. Free medical examinations were given; however, subjects were not told about their disease. Even though a proven cure (penicillin) became available in the 1950s, the study continued until 1972 with participants being denied treatment. In some cases, when subjects were diagnosed as having syphilis by other physicians, researchers intervened to prevent treatment. Many subjects died of syphilis during the study.

Other Major Violations to Human Research Subjects 1963 -- Brooklyn - Jewish Chronic Diseases Hospital: Cancer cells were injected into debilitated elderly patients to see if they would immunologically reject the cells. 1972 - Willowbrook State Hospital in New York: Retarded children were deliberately infected with viral hepatitis to study its natural history.

It is clear that Various cultures such as ancient Egypt , Persia , Babylonia and Greece have attempted to regulate medicine and protect patient rights. One of the earliest written provisions in the field is that comes about 1750 BC is the Code of Hammurabi. . Polished Black Diorite Steel 1792 – 1750 BC WITH CODE OF Hammurabi inscribed and bas-relief at top of showing king receiving laws from Sun God

Voluntary informed consent Likelihood of some good resulting The Nuremberg Code Voluntary informed consent Likelihood of some good resulting Based on prior research (animal models) Avoidance of physical or psychological injury or harm Benefits should outweigh risks Proper experience of researcher Right to withdraw consent Research must stop if harm is resulting (no specific mention of children, unconscious people, or others who may not be competent to give consent) As a direct result of the trial, the Nuremberg Code was established in 1948, stating that "The voluntary consent of the human subject is absolutely essential," making it clear that subjects should give consent and that the benefits of research must outweigh the risks. Although it did not carry the force of law, the Nuremberg Code was the first international document which advocated voluntary participation and informed consent.

Respect for persons Beneficence Justice The National Research Act codified the requirement that human subjects in research must be protected and set the stage for the issuance of the Belmont Report. THE BELMONT REPORT Carrying out its charge, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research prepared the Belmont Report in 1979. The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations. The Report is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1974. Respect for persons Beneficence Justice

Helsinki Declaration The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. The first version was adopted in 1964 and has been amended six times since, most recently at the General Assembly in October 2008. The current (2008) version is the only official one. Declaration of Helsinki. In 1964, the World Medical Association established recommendations guiding medical doctors in biomedical research involving human subjects. The Declaration governs international research ethics and defines rules for "research combined with clinical care" and "non-therapeutic research." The Declaration of Helsinki was revised in 1975, 1983, 1989 and 1996 and is the basis for Good Clinical Practices used today. Issues addressed in the Declaration of Helsinki include: Research with humans should be based on the results from laboratory and animal experimentation Research protocols should be reviewed by an independent committee prior to initiation Informed consent from research participants is necessary Research should be conducted by medically/scientifically qualified individuals Risks should not exceed benefits

Other International Guidelines 1982 - International Ethical Guidelines for Biomedical Research Involving Human Subjects by World Health Organization (WHO) and Council for International Organizations of Medical Sciences (CIOMS) This 2002 text supersedes the 1993 Guidelines. It is the third in the series of biomedical-research ethical guidelines issued by CIOMS since 1982. Its core consists of 21 guidelines with commentaries. The Guidelines relate mainly to ethical justification and scientific validity of research; ethical review; informed consent; vulnerability ­ of individuals, groups, communities and populations; women as research subjects; equity regarding burdens and benefits; choice of control in clinical trials; confidentiality; compensation for injury; strengthening of national or local capacity for ethical review; and obligations of sponsors to provide health-care services.

The Four Principles of Ethics 1 - Autonomy (Respect for the person) 2 - Beneficence (Do Good) 3 - Non-malfeasance (Do No Harm) 4 - Justice The "four principles provide a simple, accessible, and culturally neutral approach to thinking about ethical issues in health care. The approach, developed in the United States, is based on four common, basic prima facie moral commitments - respect for autonomy, beneficence, non-maleficence, and justice - plus concern for their scope of application. It offers a common, basic moral analytical framework and a common, basic moral language. Although they do not provide ordered rules, these principles can help doctors and other health care workers to make decisions when reflecting on moral issues that arise at work.

Institutional Review Board (IRB) Also known as an Independent Ethics Committee (IEC) or Ethical Review Board (ERB) is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the research subjects . An institutional review board (IRB), also known as an independent ethics committee (IEC) or ethical review board (ERB) is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral l research involving humans with the aim to protect the rights and welfare of the research subjects . In the USA , the FDA and Department of Health and Human Services (specifically Office for Human Research Protections) regulations have empowered IRBs to approve, require modifications in (to secure approval), or disapprove research. An IRB performs critical oversight functions for research conducted on human subjects that are scientific, ethical, and regulatory. In the USA , the FDA and Department of Health and Human Services (specifically Office for Human Research Protections) regulations have empowered IRBs to approve, require modifications in (to secure approval), or disapprove research. An IRB performs critical oversight functions for research conducted on human subjects that are scientific, ethical, and regulatory.

The IRB must have at least five members. The members must have enough experience, expertise, and diversity If the IRB works with studies that include vulnerable populations, the IRB should have members who are familiar with these groups. The members must have enough experience, expertise, and diversity to make an informed decision on whether the research is ethical, informed consent is sufficient, and appropriate safeguards have been put in place. If the IRB works with studies that include vulnerable populations, the IRB should have members who are familiar with these groups. It is common for an IRB to include an advocate for prisoners when considering research that involves them.

The IRB should include both men and women. The members of the IRB must not be all of the same profession. The IRB must include at least one scientist and at least one non-scientist. These terms are not defined in the regulations. In order to actually vote on a proposal, more than half of the members of the board must be present and there must be a non-scientist present. There are exceptions for expedited review, where only the chair of the committee or a designee reviews research, but these are relatively narrow.

The IRB must include at least one person who is not affiliated with the institution or in the immediate family of a person affiliated with the institution. These are commonly called "Community Members.” IRB members may not vote on their own projects. The IRB may include consultants in their discussions to meet requirements for expertise or diversity, but only actual IRB members may vote.

Responsibilities of IRB Risks to study participants are minimized Risks are reasonable in relation to anticipated benefits Selection of study participants is equitable Informed consent is obtained and appropriately documented for each participant Adequate provisions for monitoring data collection to ensure safety of the study participants Participant privacy and confidentiality is protected The purpose of an IRB review is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in a research study. To accomplish this purpose, IRBs review research protocols and related materials (e.g., informed consent documents and investigator brochures) to ensure protection of the rights and welfare of human subjects of research. The chief objectives of every IRB protocol review are to assess the scientific merit of the research and its methods, to promote fully informed and voluntary participation by prospective subjects who are themselves capable of making such choices (or, if that is not possible, informed permission given by a suitable proxy) and to maximize the safety of subjects once they are enrolled in the project

The IRB/IEC should obtain the following documents Trial protocol(s)/amendment(s), Written informed consent form(s) Consent form updates that the investigator proposes for use in the trial subject recruitment procedures (e.g., advertisements), written information to be provided to subjects, Investigator's Brochure (IB), The IRB/IEC should obtain the following documents: trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures (e.g., advertisements), written information to be provided to subjects, Investigator's Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator's current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfill its responsibilities. The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for the following: approval/favourable opinion; modifications required prior to its approval/favourable opinion; disapproval/negative opinion; and termination/suspension of any prior approval/favourable opinion. According to ICH GCP the IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests. According to ICH GCP the IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year.

Available safety information, Information about payments and compensation available to subjects, the investigator's current curriculum vitae and/or other documentation evidencing qualifications, Any other documents that the IRB/IEC may need to fulfill its responsibilities. -

The Situation in Egypt Most medical research that have been conducted in Egypt were done without the knowledge or consent of whom the research was carried out. Culture is progressively changing towards this issue and many IRBS have been constructed in many Governmental and some NGO in Egypt

Egypt is an excellent pool for medical research due to : Large population size Diversity of population composition High prevalence of some chronic disorders such as chronic hepatitis C and DM Every health organization directly or indirectly involved in medical research should have an IRB Large population size provides wide pool for researches , diverse population composition is one of the important characteristics , Bedwens in Sinai with desert and Nubians in southern Egypt , famres with different epidemiology in Delta and typical stressed life in Urban areas in Large cities.

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