III. IRB Procedures – 18. The FDA regulations exempt an emergency use of a test article from prospective IRB review, however, “. any subsequent use of the test article at the institution is subject to IRB review.” What does the phrase “subsequent use” mean? FDA regulations allow for one emergency use of a test article in an institution without prospective IRB review, provided that such emergency use is reported to the IRB within five working days after such use.
- An emergency use is defined as a single use (or single course of treatment, e.g., multiple doses of antibiotic) with one subject.
- Subsequent use” would be a second use with that subject or the use with another subject.
- In its review of the emergency use, if it is anticipated that the test article may be used again, the IRB should request a protocol and consent document(s) be developed so that an approved protocol would be in place when the next need arises.
In spite of the best efforts of the clinical investigator and the IRB, a situation may occur where a second emergency use needs to be considered. FDA believes it is inappropriate to deny emergency treatment to an individual when the only obstacle is lack of time for the IRB to convene, review the use and give approval.19.
Are there any regulations that require clinical investigators to report to the IRB when a study has been completed? IRBs are required to function under written procedures. One of these procedural requirements requires ensuring “prompt reporting to the IRB of changes in a research activity.” The completion of the study is a change in activity and should be reported to the IRB.
Although subjects will no longer be “at risk” under the study, a final report/notice to the IRB allows it to close its files as well as providing information that may be used by the IRB in the evaluation and approval of related studies.20. What is expedited review? Expedited review is a procedure through which certain kinds of research may be reviewed and approved without convening a meeting of the IRB.
The Agency’s IRB regulations permit, but do not require, an IRB to review certain categories of research through an expedited procedure if the research involves no more than minimal risk. A list of categories was last published in the Federal Register on January 27, 1981, The IRB may also use the expedited review procedure to review minor changes in previously approved research during the period covered by the original approval.
Under an expedited review procedure, review of research may be carried out by the IRB chairperson or by one or more experienced members of the IRB designated by the chairperson. The reviewer(s) may exercise all the authorities of the IRB, except disapproval.
- Research may only be disapproved following review by the full committee.
- The IRB is required to adopt a method of keeping all members advised of research studies that have been approved by expedited review.21.
- The number of studies we review has increased, and the size of the package of review materials we send to IRB members is becoming formidable.
Must we send the full package to all IRB members? The IRB system was designed to foster open discussion and debate at convened meetings of the full IRB membership. While it is preferable for every IRB member to have personal copies of all study materials, each member must be provided with sufficient information to be able to actively and constructively participate.
- Some institutions have developed a “primary reviewer” system to promote a thorough review.
- Under this system, studies are assigned to one or more IRB members for a full review of all materials.
- Then, at the convened IRB meeting the study is presented by the primary reviewer(s) and, after discussion by IRB members, a vote for an action is taken.
The “primary reviewer” procedure is acceptable to the FDA if each member receives, at a minimum; a copy of consent documents and a summary of the protocol in sufficient detail to determine the appropriateness of the study-specific statements in the consent documents.
In addition, the complete documentation should be available to all members for their review, both before and at the meeting. The materials for review should be received by the membership sufficiently in advance of the meeting to allow for adequate review of the materials. Some IRBs are also exploring the use of electronic submissions and computer access for IRB members.
Whatever system the IRB develops and uses, it must ensure that each study receives an adequate review and that the rights and welfare of the subjects are protected.22. Are sponsors allowed access to IRB written procedures, minutes and membership rosters? The FDA regulations do not require public or sponsor access to IRB records.
However, FDA does not prohibit the sponsor from requesting IRB records. The IRB and the institution may establish a policy on whether minutes or a pertinent portion of the minutes are provided to sponsors. Because of variability, each IRB also needs to be aware of State and local laws regarding access to IRB records.23.
Must an investigator’s brochure be included in the documentation when an IRB reviews an investigational drug study? For studies conducted under an investigational new drug application, an investigator’s brochure is usually required by FDA, Even though 21 CFR part 56 does not mention the investigator’s brochure by name, much of the information contained in such brochures is clearly required to be reviewed by the IRB.
The regulations do outline the criteria for IRB approval of research.21 CFR 56.111(a)(1) requires the IRB to assure that risks to the subjects are minimized.21 CFR 56.111(a)(2) requires the IRB to assure that the risks to subjects are reasonable in relation to the anticipated benefits. The risks cannot be adequately evaluated without review of the results of previous animal and human studies, which are summarized in the investigator’s brochure.
There is no specific regulatory requirement that the Investigator’s Brochure be submitted to the IRB. There are regulatory requirements for submission of information which normally is included in the Investigator’s Brochure. It is common that the Investigator’s Brochure is submitted to the IRB, and the IRB may establish written procedures which require its submission.
Investigator’s Brochures may be part of the investigational plan that the IRB reviews when reviewing medical device studies.24. To what extent is the IRB expected to actively audit and monitor the performance of the investigator with respect to human subject protection issues? FDA does not expect IRBs to routinely observe consent interviews, observe the conduct of the study or review study records.
However, 21 CFR 56.109(f) gives the IRB the authority to observe, or have a third party observe, the consent process and the research. When and if the IRB is concerned about the conduct of the study or the process for obtaining consent, the IRB may consider whether, as part of providing adequate oversight of the study, an active audit is warranted.25.
- How can a sponsor know whether an IRB has been inspected by FDA, and the results of the inspection? The Division of Scientific Investigations, Center for Drug Evaluation and Research, maintains an inventory of the IRBs that have been inspected, including dates of inspection and classification.
- The Division recently began including the results of inspections assigned by the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health.
This information is available through Freedom of Information Act (FOIA) procedures. Once an investigational file has been closed, the correspondence between FDA and the IRB and the narrative inspectional report are also available under FOI.26. If an IRB disapproves a study submitted to it, and it is subsequently sent to another IRB for review, should the second IRB be told of the disapproval? Yes.
- When an IRB disapproves a study, it must provide a written statement of the reasons for its decision to the investigator and the institution,
- If the study is submitted to a second IRB, a copy of this written statement should be included with the study documentation so that it can make an informed decision about the study.21 CFR 56.109(a) requires an IRB to “.
review, all research activities,” The FDA regulations do not prohibit submission of a study to another IRB following disapproval. However, all pertinent information about the study should be provided to the second IRB.27. May an independent IRB review a study to be conducted in an institution with an IRB? Generally, no.
Most institutional IRB have jurisdiction over all studies conducted within that institution. An independent IRB may become the IRB of record for such studies only upon written agreement with the administration of the institution or the in-house IRB.28. Could an IRB lose its quorum when members with a conflict of interest leave the room for deliberation and voting on a study? Yes.
“The quorum is the count of the number of members present. If the number present falls below a majority, the quorum fails. The regulations only require that a member who is conflicted not participate in the deliberations and voting on a study on which he or she is conflicted.
The IRB may decide whether an individual should remain in the room.” 29. Does FDA expect the IRB chair to sign the approval letters? FDA does not specify the procedure that IRBs must use regarding signature of the IRB approval letter. The written operating procedures for the IRB should outline the procedure that is followed.30.
Does FDA prohibit direct communication between sponsors and IRBs? It is important that a formal line of communication be established between the clinical investigator and the IRB. Clinical investigators should report adverse events directly to the responsible IRB, and should send progress reports directly to that IRB.
However, FDA does not prohibit direct communication between the sponsor and the IRB, and recognizes that doing so could result in more efficient resolution of some problems. FDA does require direct communication between the sponsors and the IRBs for certain studies of medical devices and when the 21 CFR 50.24 informed consent waiver has been invoked.
Sponsors and IRBs are required to communicate directly for medical device studies under 21 CFR 812.2, 812.66 and 812.150(b). For informed consent waiver studies, direct communication between sponsors and IRBs is required under 21 CFR 50.24(e), 56.109(e), 56.109(g), 312.54(b), 312.130(d), 812.38(b)(4) and 812.47(b).
Which of the following is a role of the Institutional Review Board IRB?
Institutional Review Board (IRB) – The primary purpose of the IRB is to protect the rights and welfare of human subjects involved in research activities being conducted under its authority. In so doing, the IRB shall ensure adherence to the criteria for IRB approval as listed in 45 CFR 46.111 and 21 CFR 56.111 i.e., that:
The risks to human research subjects are minimized by using procedures that are consistent with sound research design and that do not unnecessarily expose the research participants to risk, and whenever appropriate, by using procedures already being performed on subjects for diagnosis or treatment purposes.
- The risks to human research subjects are reasonable in relation to the anticipated benefits (if any) to the individual, and the importance of the knowledge that may be expected to result.
- For the purpose of IRB consideration, “benefit” is defined as a valued or desired outcome; an advantage.
- For the purpose of IRB consideration, “risk” is defined as the probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study.
- In evaluating risk, the IRB is to consider the conditions that make the situation dangerous, per se (i.e., as opposed to those chances that specific individuals are willing to undertake for some desired goals). In evaluating risks and benefits, the IRB considers only those risks and benefits that may result from the research (i.e., as distinguished from risks and benefits of treatments or procedures that the patient would undergo if not participating in the research).
- In evaluating risks and benefits, the IRB does not consider possible long-range effects of applying knowledge gained in the research (e.g., the possible effects of research on public policy).
- The selection of human subjects for research participation is equitable.
- Human research subjects are adequately informed of the risks and benefits of research participation and the procedures that will be involved in the research; and that informed consent is obtained from each prospective human research subject, or his/her legally authorized representative, in accordance with, and to the extent required by federal regulations and IRB policies.
- Informed consent of human research subjects is obtained in advance of research participation and appropriately documented in accordance with, and to the extent required by federal regulations and IRB policies.
- The research plan, when appropriate, makes adequate provisions for monitoring the data collected to ensure the safety of human research subjects.
- There are adequate provisions to protect the privacy of human research subjects and to maintain the confidentiality of research data.
- Appropriate additional safeguards have been included in the study to protect the rights and welfare of human research subjects who are likely to be vulnerable to coercion or undue influence (e.g., children, prisoners, pregnant women, decisionally impaired persons, or economically or educationally disadvantaged persons).
The criteria at 45 CFR 46.111(8) will not be utilized as broad consent will not be implemented. As a secondary purpose, the IRB must seek to ensure that the University, affiliate institutions, and the investigators that it serves are compliant with the ethical standards and regulations governing human subject research.
Which of the following describes the role of the Institutional Review Board?
Primary goal of IRB: Protect the right and safety of human subjects who participate in clinical trial.
Which of the following is a role of the IRB?
What is the Institutional Review Board (IRB)? – The Institutional Review Board (IRB) is an administrative body established to protect the rights and welfare of human research subjects recruited to participate in research activities conducted under the auspices of the institution with which it is affiliated.
- The IRB is charged with the responsibility of reviewing, prior to its initiation, all research (whether funded or not) involving human participants.
- The IRB is concerned with protecting the welfare, rights, and privacy of human subjects.
- The IRB has the authority to approve, exempt, disapprove, monitor, and require modifications in all research activities that fall within its jurisdiction as specified by both the federal regulations and institutional policy.
The IRB shall have at least five members of varying backgrounds in order to provide complete and adequate review of human research and its institutional, legal, scientific, and social implications. The Board will also include at least one member who is not affiliated with the institution and one member who is not a scientist.
Which of the following describes the role of the Institutional Review Board IRB quizlet?
The purpose of the IRB is to ensure that all human subject research be conducted in accordance with all federal, institutional, and ethical guidelines.
What are two main roles of the institutional review boards?
Abstract – Institutional review boards (IRBs) or research ethics committees provide a core protection for human research participants through advance and periodic independent review of the ethical acceptability of proposals for human research. IRBs were codified in US regulation just over three decades ago and are widely required by law or regulation in jurisdictions globally. Since the inception of IRBs, the research landscape has grown and evolved, as has the system of IRB review and oversight. Evidence of inconsistencies in IRB review and in application of federal regulations has fueled dissatisfaction with the IRB system. Some complain that IRB review is time-consuming and burdensome without clear evidence of effectiveness at protecting human subjects. Multiple proposals have been offered to reform or update the current IRB system, and many alternative models are currently being tried. Current focus on centralizing and sharing reviews requires more attention and evidence. Proposed changes to the US federal regulations may bring more changes. Data and resourcefulness are needed to further develop and test review and oversight models that provide adequate and respectful protections of participant rights and welfare and that are appropriate, efficient, and adaptable for current and future research. Institutional review boards (IRBs) or equivalent bodies provide a core protection for human participants in biomedical and behavioral research in the United States and > 80 other countries around the world.1 IRBs are charged with providing an independent evaluation that proposed research is ethically acceptable, checking clinical investigators’ potential biases, and evaluating compliance with regulations and laws designed to protect human subjects. Independent review of clinical research by an IRB is required for US studies funded by the Department of Health and Human Services (DHHS) and other US federal agencies, as well as for research testing interventions—such as drugs, biologics, and devices—that are under the jurisdiction of the US Food and Drug Administration (FDA) ( Table 1 2, 3 ). US research institutions can and often do extend federal regulatory requirements to all of their human subjects research. Research conducted outside of the United States but funded by the US government is subject to the same US federal regulations and so requires IRB review or equivalent protections.4 Research conducted outside of the United States, not under an investigational new drug that submits data to the FDA for a new drug or biologic license application, must comply with Good Clinical Practice guidelines, which include review and approval by an independent review committee and informed consent.5 Regulations and laws in many other jurisdictions around the world also require review by an independent research ethics committee or IRB.6 Regulatory bodies in the European Union, Japan, United States, Canada, Australia, and Nordic countries, among others, follow Good Clinical Practice guidelines such as those delineated by the International Conference on Harmonisation, which require approval by an independent ethics committee or IRB.7 IRBs or research ethics committees, composed of a group of people independent of the specific research, review proposed research plans and related documents before a study can begin and then periodically (usually annually) for the study duration. The goal of IRB review is to assure that the rights and welfare of participating research subjects will be adequately protected in the pursuit of the proposed research study. To be ethically acceptable and comply with regulatory requirements, the IRB determines that risks to subjects are minimized and reasonable in relation to the importance of the knowledge the study is expected to produce, that the process and outcomes of subject selection are fair (including delineated inclusion and exclusion criteria), and that there are adequate plans for obtaining informed consent.
What are the roles of review board?
Role of the Institutional Review Board at Saint Xavier The Institutional Review Board (IRB) at Saint Xavier University is established in compliance with Title 45, Part 46 of the Code of Federal Regulations (Rev. June 18, 1991). The role of the IRB is to review all proposals for research involving human subjects prior to commencement of such research, and to monitor the progress of projects which have received IRB approval.
The purpose of IRB review is not to place obstacles in the path of legitimate research, but rather to ensure that the rights of human research subjects are fully protected. The Code of Federal regulations defines research as “systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge” ().
In effect, human subjects research is any activity involving the collection of data about living individuals for the purpose of generalization, including pre-tests and pilot studies (). It not only includes faculty research, but also student research involving human subjects (for example master’s theses and class projects involving surveys or human subjects experiments).
Examples of human subjects research include, but are not limited to, psychological experiments, comparative studies of teaching outcomes, ethnographic research or anthropological field work, sociological surveys and interviews, biological experiments, medical clinical trials, classroom surveys, evaluation research, market surveys, telephone and mail surveys and focus groups.
The mandate of the IRB is:
to monitor and review all research conducted by Saint Xavier University faculty, students and staff that compiles and analyzes data gathered from or about human subjects, and to monitor and review all human subjects research conducted at Saint Xavier by parties not affiliated with the University which uses Saint Xavier students, faculty or staff as research subjects.
Only two categories of human-data collection are excluded from institutional review:
administrative record-keeping and information processing activities, such as maintaining transcripts, registration records, or billing files; and service activities which do not have a research component, such as educational tests, diagnostic evaluations, counseling files, or student advising files.
However, the subsequent aggregation of administrative records or service/clinical files for the purpose of generalization is accordingly viewed as human subjects research and must apply for IRB review. Persons who are not sure if they are required to apply for IRB review should contact the IRB Chair or Co-Chairs for further information.
at least 5 members, with varying backgrounds to promote complete review of research activities; a diversity of race, gender, and cultural backgrounds; a balance of qualified persons on both sexes; at least one member whose primary concerns are in scientific areas and at least one member whose primary concerns are in nonscientific areas; and at least one member who is not otherwise affiliated with the institution.
Saint Xavier University endorses and complies with these regulations. Saint Xavier’s IRB includes at least three full- time faculty members from a variety of scientific disciplines, at least one member who is not affiliated with the University, and at least one member whose primary concerns are in nonscientific areas.
The membership reflects a balance of gender, race, and areas of specialization. The IRB meets as needed during both the academic year and the summer, but must convene at least once each academic year. Telepresence is an acceptable form of attendance for IRB members, and such attendance counts towards quorum.
In accordance with Section, no member of the IRB may participate in the initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB. Accordingly, any department chair serving on the IRB will recuse him- or herself from the review of any proposed research project involving one or more faculty members from the chair’s department, aside from the provision of information requested by the IRB.
What are the principles of the IRB?
When reviewing research IRBs are guided by three ethical principles that are fundamental to human subject protection – respect for persons, beneficence, and justice. Respect for persons : Addresses the personal dignity and autonomy of individuals, and the importance of proper informed consent for individuals participating in research.
- Beneficence : Addresses the obligation to protect human subjects from harm by assessing the risks and benefits of the research and assuring that the anticipated benefits are greater than the anticipated risks.
- Justice : Requires that research subjects are fairly selected with regard to the purpose and expected outcome of the research, including consideration of the subject as an individual and as a member of society.
The population of research subjects should be similar to those who may benefit from the outcome of the research. These ethical principles, are discussed in the Belmont Report, and form the basis for the regulatory standards for human subject protection in the United States.
What are the functions of the review board?
Function of the Institutional Review Board | Akron Children’s Hospital Akron Children’s IRB functions under a federal-wide assurance based on common rule (45 CFR 46) and FDA policies (21 CFR 56).
- The IRB shall have the responsibility to review and the authority to approve, require modification in, or disapprove all activities and all proposed changes in previously approved activities. In rare circumstances, emergency approval of a research study can be approved for one time use by the Chair prior to full IRB review as discussed below. In the event of disapproval, the investigator shall have the opportunity to appeal the decision to the IRB. IRB approval does not mean the institution must support the study. No one other than the IRB has the authority to approve human subject research at Children’s Hospital.
- The IRB shall initially review and approve human subject research as described in procedures below, consistent with federal regulation.
- The IRB will provide continuing review of all approved human subject research as described in procedures below, consistent with federal regulation.
- The IRB will review and approve any changes to research protocols and informed consents or assents as described in the procedures below, consistent with federal regulation.
- The IRB will receive, review and act upon, if necessary, reports of serious adverse events as described in the procedures below, consistent with federal regulation.
- In accordance with regulation, all IRB reviews (except exempt, expedited and emergency reviews as defined below must be conducted at a convened meeting at which a majority of voting members (or voting and appropriate alternated members) are present, including at least one member whose primary concerns are in a non-scientific area (a quorum). Approval of research is by a majority vote of the quorum. Should the quorum fail during the meeting, the IRB may not take further votes or actions until the quorum is restored.
- The IRB shall prepare and maintain adequate documentation of its activities including:
- Written procedures, a membership list and copies of OHRP certificates of designated individuals.
- Minutes of meetings in sufficient detail to show voting members and others present, actions taken, and the vote on these actions, including the number of members voting for, against and abstaining. If a member in attendance has a conflicting interest regarding any project, minutes shall document that the member did not participate in the review except to provide information, and did not vote.
- Copies of all research protocols and investigator brochures, when available, reviewed.
- Certificates of researcher training for investigators as required by regulation. Completed applications, copies of primary protocol review and consent review forms, and copies of informed consents and assents approved.
- Records of all continuing review documents and review forms and actions, including amendments to protocols, consents and assents, and reportable adverse reactions. A database will be maintained to document all events that were acted on and adverse reactions.
- Copies of all correspondence of the IRB.
- Copies of significant new findings provided to subjects.
- Copies of any recruitment or advertising materials provided to potential subjects.
- Written notification to investigators and the Institutional Official of its decision to approve or disapprove the proposed research.
- All records shall be maintained in an area accessible to review for 3 years following the termination of the last IRB approval. All records will be maintained for 6 years.
- The IRB shall meet at least quarterly and publish its list of scheduled meetings on a yearly basis.
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– Phone color – Coat pocket – Stethoscope earpiece color – Stethoscope bell dot – Clipboard paper color Need help finding a doctor, choosing a location or getting a general question about Akron Children’s answered? Call us or fill out the form and we’ll help in any way we can. We offer many ways to get pediatric care all over Northeast Ohio. Use this page to find the right kind of care and the most convenient location for you. : Function of the Institutional Review Board | Akron Children’s Hospital
What is the IRB role in ethical concerns?
Institution – The Institution has the responsibility to comply with the laws and guidelines regarding oversight of all human research activities, especially when the research involves vulnerable people, It also has the responsibility of educating investigators on ethical issues, scientific truthfulness, preventing misconduct and conflicts of interest.
- The institutions are required to have 1) ethical (IRB) review of protocol and informed consent, 2) administrative review of proposals, contract and grants, 3) scientific peer review,
- Ethical review: By compliance with the law and guidelines, the institution can guard the rights, safety and welfare of research participants.
The IRB must review the following requirements in order to give approval to research: 1) the risks are rational and minimized in relation to the anticipated benefits to the subjects based on a risk/benefit analysis; 2) the choice of subjects is equitable; 3) informed consent is obtained from each potential subject or a legally responsible representative unless waived in harmony with the law and guidelines.
This should be documented on the consent form; 4) when subjects are likely to be vulnerable to coercion or undue influence, additional safeguards are needed; 5) appropriate monitoring and observation with continuing review should be scheduled when collecting data to ensure the safety of the subjects, protect the privacy of participants and to maintain the confidentiality of data.
The purpose of the IRB is to ensure that the investigator complies with the protocol and to demonstrate that the trial is necessary and that the risk-benefit ratio is acceptable by reviewing key trial documents to ensure that the subjects’ rights and well-being are protected.
- Administrative review: the research institution generally ensures that proposals and allied budgets are in compliance with the law and institutional policy including IRB review where suitable.
- If the researcher has a conflict of interest, the institution should make a decision as to whether the conflict can be managed.
The research institution has usually established a Conflict of Interest (COI) committee to avoid and/or to minimize potential conflicts under the instruction of institutional policy. Scientific peer review: scientific review should examine the soundness and worth of the hypothesis, the procedure to prove the hypothesis and the appropriateness of the methods to be used.
- It is unethical to expose subjects to unnecessary risks and sample size justifications must be back up based on the expected results and statistical significance.
- When the IRB plays the dual role of conducting the scientific review, scientifically qualified experts must be added to the IRB, or the IRB should establish a subcommittee for supporting scientific review.
ICH-GCPs provide protection for human volunteers and ensure the accuracy and reliability of data generated in the course of clinical trials. Compliance with these standards is a public pledge that the rights, safety and well-being of clinical trial participants will be protected.
What is one of the key responsibilities of an IRB IEC?
The International Council on Harmonisation (ICH) defines an institutional review board (IRB) as a group formally designated to protect the rights, safety and well-being of humans involved in a clinical trial by reviewing all aspects of the trial and approving its startup.
What is the role of IRB in protecting privacy?
Updated July 13, 2021 To approve research, federal regulations require the IRB to determine, when appropriate, that there are adequate provisions to protect the privacy of participants and to maintain the confidentiality of data (see 45 CFR 46.111(a)(7) and 21 CFR 56.111(a)(7)).
Research-related concerns about privacy pertain primarily to the methods used to identify and contact prospective participants and obtain information about them. When researchers obtain information that participants have disclosed for public use or information for which participants have given consent for the researchers’ use, there is little concern about privacy.
Concerns about privacy arise when information is obtained for research purposes without the consent of the individual. Researchers must include a plan to protect participants’ privacy and confidentiality. The IRB reviews the researcher’s plan to protect participants’ privacy and maintain confidentiality of data, utilizing regulatory, institutional and internal policies, procedures, and guidance.
What is the role of the Institutional Review Board for research Studies quizlet Nursing?
IRB responsibility IRBs are responsible for confirming that research protocols are devel- oped in accordance with federal regulations based on Protection of Human Subjects (Common Rule) guidelines. Respect for individuals, beneficence, and justice are the reg- ulation’s guiding ethical principles.
What is an IRB in psychology quizlet?
Institutional Review Board (IRB) A committee at each institution where research is conducted to review every experiment for ethics and methodology.
What are IRB members responsible for quizlet?
The IRB administrator is responsible for ensuring the development and maintenance of policies or standard operating procedures that provide consistency and structure to the human research protection program.
Which of the following characteristics must an Institutional Review Board have?
Who Serves on an IRB? – An IRB consists of at least five members of varying backgrounds. IRB members should have the professional experience to provide appropriate scientific and ethical review. An IRB must have at least one scientist member and at least one member whose primary concerns are nonscientific.
What is the role of institutional review boards ethics committees in monitoring ethics in research?
From Wikipedia, the free encyclopedia This article is about research ethical oversight in the United States. For a worldwide perspective, see Ethics committee, An institutional review board ( IRB ), also known as an independent ethics committee ( IEC ), ethical review board ( ERB ), or research ethics board ( REB ), is a committee that applies research ethics by reviewing the methods proposed for research to ensure that they are ethical,
- Such boards are formally designated to approve (or reject), monitor, and review biomedical and behavioral research involving humans,
- They often conduct some form of risk-benefit analysis in an attempt to determine whether or not research should be conducted.
- The purpose of the IRB is to assure that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in a research study.
Along with developed countries, many developing countries have established national, regional or local Institutional Review Boards in order to safeguard ethical conduct of research concerning both national and international norms, regulations or codes.
A key goal of IRBs is to protect human subjects from physical or psychological harm, which they attempt to do by reviewing research protocols and related materials. The protocol review assesses the ethics of the research and its methods, promotes fully informed and voluntary participation by prospective subjects capable of making such choices (or, if that is not possible, informed permission given by a suitable proxy), and seeks to maximize the safety of subjects.
While its composition varies, it often includes a balance of academia and non-academia members. This serves to provide a greater scope of understanding which helps ensure ethics in research. IRBs are most commonly used for studies in the fields of health and the social sciences, including anthropology, sociology, and psychology,
Which of the following is true regarding the Institutional Review Board IRB?
Which of the following is true of Institutional Review Boards (IRBs)? They are liable for the research they approve.
Who is responsible for IRB approval?
The HHS regulations at 45 CFR part 46 use the term “investigator” to refer to an individual performing various tasks related to the conduct of human subjects research activities, such as obtaining informed consent from subjects, interacting with subjects, and communicating with the IRB.
obtaining information about living individuals by intervening or interacting with them for research purposes;obtaining identifiable private information about living individuals for research purposes;obtaining the voluntary informed consent of individuals to be subjects in research; andstudying, interpreting, or analyzing identifiable private information or data for research purposes.
Investigators can include physicians, scientists, nurses, administrative staff, teachers, and students, among others. Some research studies are conducted by more than one investigator, and usually one investigator is designated the “principal investigator” with overall responsibilities for the study.
- In every human subjects research study, investigators have certain responsibilities regarding the ethical treatment of human subjects.
- Yes, investigators are responsible for obtaining IRB approval before beginning any nonexempt human subjects research ( 45 CFR 46.109(a) and (d) ).
- Investigators are responsible for providing the IRB with sufficient information and related materials about the research (e.g., grant applications, research protocols, sample consent documents) so that the IRB can fulfill its regulatory obligations, including making the required determinations under 45 CFR 46.111 and, if applicable, subparts B, C and D,
Investigators should follow institutional policies and procedures for IRB review that are required by HHS regulations at 45 CFR 46.103(b)(4), Investigators play a crucial role in protecting the rights and welfare of human subjects and are responsible for carrying out sound ethical research consistent with research plans approved by an IRB.
obtaining and documenting informed consent of subjects or subjects’ legally authorized representatives prior to the subjects’ participation in the research, unless these requirements have been waived by the IRB ( 45 CFR 46.116 ; 45 CFR 46.117 ); obtaining prior approval from the IRB for any modifications of the previously approved research, including modifications to the informed consent process and document, except those necessary to eliminate apparent immediate hazards to subjects ( 45 CFR 46.103(b)(4) ); and ensuring that progress reports and requests for continuing review and approval are submitted to the IRB in accordance with the policies, procedures, and actions of the IRB as referenced in the institution’s OHRP-approved Federalwide assurance ( 45 CFR 46.103(b)(4), 45 CFR 46.109(e), 45 CFR 46.115(a)(1)), In certain circumstances, investigators also would be responsible for meeting the following additional regulatory requirements: providing to the IRB prompt reports of any unanticipated problems involving risks to subjects or others 45 CFR 46.103(b)(5) ; providing to the IRB prompt reports of serious or continuing noncompliance with the regulations or the requirements or determinations of the IRB ( 45 CFR 46.103(b)(5) ); and keeping certain records as required by the HHS regulations for at least three years after completion of the study ( 45 CFR 46.115(b) ).
Yes, investigators are responsible for obtaining and documenting the informed consent of research subjects or their legally authorized representatives, unless the IRB approves a waiver of informed consent, or a waiver of documentation of informed consent, respectively ( 45 CFR 46.116, 45 CFR 46.117 ).
Investigators must give a copy of the informed consent document to each research subject (or the subject’s legally authorized representative), and keep the signed original or a copy of it for their records ( 45 CFR 46.117(a) ; 45 CFR 46.115(b) ). When the documentation requirement is waived, the IRB may require investigators to provide subjects with a written statement regarding the research ( 45 CFR 46.117(c) ).
(For information about parental permission and assent, see the FAQs related to subpart D of 45 CFR part 46,) If investigators wish to modify an ongoing IRB-approved research study, they must submit a request to the IRB and receive IRB approval before implementing the proposed modification, unless the change is designed to eliminate an apparent immediate hazard to subjects ( 45 CFR 46.103(b)(4) ).
If the investigators change the research in order to eliminate apparent immediate hazards to subjects without prior IRB approval, they should report those changes promptly to the IRB. The HHS protection of human subjects regulations allow for expedited review and approval of requests for minor changes in previously approved studies ( 45 CFR 46.110(b)(2) ).
Investigators should consult with the appropriate institutional authority whenever questions arise about whether planned changes to an exempt study might make that study nonexempt human subjects research. OHRP recommends that institutions have policies in place that designate the individual or entity authorized to determine whether human subjects research qualifies for exemption under HHS regulations at 45 CFR 46.101(b),
OHRP recommends that investigators not be given the authority to make an independent determination that human subjects research is exempt. The person(s) authorized to make the determination should be knowledgeable about the human subject protection regulations. In addition, the institution should ensure the appropriate communication of such a policy to all investigators.
Yes, investigators are responsible for fulfilling requirements associated with continuing review in time for the IRB to carry out review prior to the expiration date of the current IRB approval. Continuing review of research and approval of research studies is required so long as the research study is ongoing, that is, until research-related interactions and interventions with human subjects or the obtaining and analysis of identifiable private information described in the IRB-approved research plan have been completed.
Investigators are responsible for submitting sufficient materials and information for the IRB to meet its regulatory obligations, and should follow the institutional policies and procedures for continuing IRB review of research that are required by HHS regulations at 45 CFR 46.103(b)(4) and referenced in the institution’s OHRP-approved Federalwide assurance.
OHRP guidance regarding continuing review is available at http://www.hhs.gov/ohrp/regulations-and-policy/guidance/guidance-on-continuing-review-2010/index.html, If IRB approval of a specific study expires before continuing review and approval occur, investigators must stop all research activities involving human subjects related to that study ( 45 CFR 46.103(b) ), except where they judge that it is in the best interests of already enrolled subjects to continue to participate.
When investigators make this judgment, they must promptly notify the IRB ( 45 CFR 46.103(b)(5) ). When the IRB reviews the investigator’s decision, it may decide whether it is in the best interests of already enrolled subjects to continue to participate in the research by considering the best interests of subjects either one at a time or as a group.
If an IRB determines that it is not in the best interests of already enrolled subjects to continue to participate, investigators must stop all human subjects research activities, including intervening or interacting with subjects, or obtaining or analyzing identifiable private information about human subjects ( 45 CFR 46.103(b) ).
Investigators may resume the human subjects research activity once continuing review and approval by the IRB has occurred. If all research-related interventions or interactions with human subjects have been completed, and all data collection and analysis of identifiable private information described in the IRB-approved research plan have been finished, then the human subjects research study has been completed.
When a human subjects research study has been completed, the investigators no longer are required to obtain continuing review and approval of that study by the IRB. The investigators should follow any applicable institutional policies and procedures for notifying the IRB of the study’s completion.
- Once a study has been completed, investigators may keep the data they collected, including identifiable private data, if consistent with the IRB-approved research plan.
- Investigators should continue to honor any confidentiality protections of the data.
- Investigators also should honor any other commitments that were agreed to as part of the approved research, for example, providing information about the study results to research subjects, or honoring commitments for compensation to research subjects for research participation.
The HHS protection of human subjects regulations require institutions to retain records of IRB activities and certain other records frequently held by investigators for at least three years after completion of the research (45 CFR 46.115(b)). In addition, other regulations may apply and require retention of these records for a longer period of time.
Documentation of the informed consent of the subjects – either the signed informed consent form or the short form and the written research summary – are records related to conducted research that are typically held by investigators and must be retained for at least three years after completion of the research, unless the IRB waived the requirement for informed consent or the requirement for documentation of informed consent (45 CFR 46.117).
If investigators have been designated to retain certain records (e.g., informed consent documents signed by subjects) on behalf of the institution as required by the HHS regulations at 45 CFR 46.115(b), they must retain the records in some form. Such records may be preserved in hardcopy, electronic or other media form and must be accessible for inspection and copying by authorized representatives of HHS at reasonable times and in a reasonable manner ( 45 CFR 46.115(b) ).
Retention of multiple copies of each record is not required. Investigators should follow the institution’s policies and procedures for retaining records. If investigators who have been designated to retain records on behalf of the institution leave that institution, the investigators and the institution should identify the successor responsible for maintaining those institutional records, either at the original institution or wherever the records are relocated, for the period of time required under HHS regulations at 45 CFR 46.115(b).
Other regulations or policies may apply to the retention of records, including study data. The HHS regulations for the protection of human subjects ( 45 CFR part 46 ) do not require investigators to obtain training in the protection of human subjects in research.
However, an institution holding an OHRP-approved Federalwide Assurance (FWA) is responsible for ensuring that its investigators conducting HHS-conducted or -supported human subjects research understand and act in accordance with the requirements of the HHS regulations for the protection of human subjects.
Therefore, as stated in the Terms of the FWA, OHRP strongly recommends that institutions and their designated IRBs establish training and oversight mechanisms (appropriate to the nature and volume of their research) to ensure that investigators maintain continuing knowledge of, and comply with, the following:
relevant ethical principles; relevant federal regulations; written IRB procedures; OHRP guidance; other applicable guidance; state and local laws; and institutional policies for the protection of human subjects.
Furthermore, OHRP recommends that investigators complete appropriate institutional educational training before conducting human subjects research. In some cases, other federal requirements regarding training for investigators must be met, such as the National Institute of Health’s (NIH) requirement for the training of key personnel in NIH-sponsored or -conducted human subjects research.
Which of the following should be included in an IRB proposal?
IRB Proposal Creation Guidelines Guidelines detailing obligatory and optional documentation to be included in proposals submitted to Colgate’s Institutional Review Board, as well as example proposals. All proposals submitted for either expedited or full review must contain four primary sections:
Purpose of investigation and procedures Anticipated risk and potential benefits to participants Steps taken to protect the participants Manner of obtaining participants
Details regarding what should be included in each of the four sections are shared below. Additional documents may also be required in an appendix, depending on the nature of the proposal. Any researcher who intends to work with human participants should seek legally effective informed consent from each prospective participant, or the participant’s legally authorized representative.
Under federal regulations, this is a mandate, not an optional matter, because informed consent is one of the primary ethical requirements underpinning research with human subjects, reflecting the principle of respect for persons. It is therefore critical that a certificate of informed consent accompany the proposal as a part of the appendix.
Researchers are asked to use the provided consent form template, and modify it to fit their particular circumstances. It is important that researchers retain a copy for their records and provide a copy to every participant for their records. It is therefore necessary to provide a place for both the experimenter and the potential participant to sign the Certificate of Informed Consent.
- If this form represents the only record of a participant’s identity, then the IRB may, at its discretion, waive some or all of the sections listed on the template provided.
- The Certificate of Informed Consent should be written in clear, simple language at the 5th grade level.
- It should be written in the second person (e.g., “you,” “your”) and not the first person (e.g., “I”).
In accordance with federal regulations, the CIC should address specific concerns, outlined as follows: A debriefing form is typically read aloud to the participant once he or she has completed the study. The form itself should explain to the participant the full aim of the study he or she has just completed.
If the proposed study involves some degree of deception, or manipulation of behavior that could lead to moderate (or greater) levels of physical and/or psychological distress, a debriefing form (signed by both the participant and the experimenter) must accompany the proposal as a part of the appendix.
If a proposed study does not contain either of the above, a debriefing form is not required, but may be included at the researcher’s discretion (but does not need to be signed by the participant). Below are several links to example proposals. Please keep in mind that these are to be used for reference only, and not meant to be followed explicitly.
The informed consent needs to inform participants that there will be such recordings. After the study is complete, participants must be given an audio/video release form to be signed by participants indicating whether or not they provide permission for the recordings to be used by a) researchers working on the study and/or b) future participants, depending on the intentions of the researchers. Samples of such audio/video release forms appear below.
: IRB Proposal Creation Guidelines
What are the 4 important ethical issues IRB guidelines address?
Introduction The Institutional Review Boards (IRB), or Institutional Ethics Committees (IEC), represent American configurations designed to evaluate the ethical aspects of research involving human subjects. Other countries have similar organizations, termed Research Ethic Committees or Ethical Review Boards.
- The following description will detail the history behind the legislation establishing IRBs followed by a discussion of the role of the IRB in human research protection, the composition of IRBs, and the oversight of research involving human subjects.
- Brief History of Research Ethics and Regulation In the last half century, the level of oversight for research using human subjects has exploded from almost none to what is now an exhaustive system of protections.
At the end of World War II, the Nuremberg trials were conducted to bring justice to Nazi leaders for crimes against humanity. A significant portion of the trials undertook the case of Nazi physicians who forced prisoners to undergo appalling, and often inhumane, procedures in the name of clinical research.
At that time, there were no laws, regulations, codes or formal documents describing the ethical standards for conducting research in human subjects. The Nuremberg proceedings resulted in the development of a document articulating the basic requirements for conducting research in a manner that respects the fundamental rights of research subjects, called the Nuremberg Code (available at http://www.hhs.gov/ohrp/references/nurcode.htm ).
The three basic elements of the Code, namely the requirement for voluntary and informed consent, a favorable benefit to risk analysis, and the right of the participant to withdraw voluntarily without repercussions have become the foundation for subsequent ethical codes and federal research regulations.
Thus, every person involved in conducting human subjects research should read and familiarize themselves with this Code. Despite the creation of the Nuremberg code, the United States federal government still had only a very minor role in regulating research conduct as recently as 1950. At that time, federal regulations requiring Institutional Review Board (IRB) approval were lacking for most research settings.
Between 1950 and 1974, however, numerous controversies in human research became highly publicized, especially involving perceived abuses in the rights of vulnerable human populations. In 1955, unbeknownst to jurors, researchers audiotaped jury deliberations of criminal trials in Wichita, Kansas in an attempt to better understand the decision making process undertaken by such groups.
Post-publication discussions focused on the unethical nature of deceiving people in a setting where privacy and confidentiality were important for research purposes. Shortly thereafter, Congress marked the beginning of legislation regulating human subject research by passing a federal law prohibiting the recording of jury deliberations.
In 1962, the use of Thalidomide, an investigational drug, prompted the first instance of a federal agency establishing and enforcing specific ethical standards for the conduct of research in human subjects. Prior to this, it was not standard practice to inform patients of the investigational nature of pharmaceuticals still being tested.
Once it became clear that this drug led to birth deformities, public outrage led to an amendment in the Food, Drug and Cosmetic Act that required investigators to obtain informed consent from subjects before administering investigational medications. During the 1960’s, three events heralded a change in the ethical oversight of human subject research.
In 1964, James Shannon, Director of the National Institutes of Health, established a policy that required an ethics committee review of all research funded by the Public Health Service. That same year, the World Medical Association met in Helsinki, Finland to draft a document describing the standards of ethical research involving human subjects.
In addition to the three central ethical principles outlined in the Nuremberg Code, the Declaration of Helsinki (available at http://www.fda.gov/oc/health/helsinki89.html ) added two novel elements: 1) the interests of the subject should always be placed above the interests of society; and 2) every person in clinical research should get the best known treatment,
In 1966, researchers began using these guidelines to police their own conduct in human research and focus attention on the need to improve the ethical standards for conducting such research. Dr. Henry Beecher, a senior member of the anesthesiology faculty at Harvard Medical School, published an article entitled “Ethics of Clinical Research.” In this New England Journal of Medicine publication, Dr.
- Beecher detailed unethical practices in twenty-two studies conducted by respected investigators and published in prestigious medical journals,
- Although none individually resulted in new federal regulation, the conduct of four infamous studies during this time period received unheralded national media attention and resulted in public outrage.
In the 1950s, studies investigating issues in the transmission of the hepatitis virus were performed in the Willowbrook State School, an extended care facility for mentally-challenged children in New York State. These studies generated intense debate in professional journals and the national media over their design, which involved intentionally infecting children with hepatitis by feeding them a solution made from the feces of those with active hepatitis.
- The Jewish Chronic Disease Hospital study generated similar debate in the 1960s.
- In this study, live cancer cells were injected into the bloodstream of chronically ill, mostly demented, elderly patients residing in this New York City hospital to determine the influence of a weakened immune system on the spread of cancer.
In the early 1970s, a contraception clinic serving mostly indigent patients in San Antonio, Texas, evaluated the efficacy of different types of oral contraceptive pills using a randomized, blinded, placebo-controlled design. Unfortunately, none of the participants were informed that they were participating in this type of research or that they might be receiving inactive medication.
Not unexpectedly, many of those receiving placebo had unplanned pregnancies. The most infamous study also occurred during this time period. The details of the Tuskegee Syphilis Study are well known to most investigators. The purpose of this study, funded by the U.S. Public Health Service, was to investigate the natural history of untreated syphilis in humans.
To accomplish this, participants with known syphilis, were observed without treatment and subjected to tests and procedures, including spinal taps, to follow the course of their illness. When this study was developed in 1932, it was considered ethically sound because effective treatment for syphilis did not exist.
- However, the subjects continued to be followed for several years without treatment so as to not interrupt the study, even after the antibiotic penicillin, known to be highly effective in the treatment of syphilis, became widely available.
- The study was finally halted in 1972 after national media attention generated public outrage over the exploitation of this vulnerable population of indigent, uneducated, African-American sharecroppers from Tuskegee, Alabama who believed they were receiving beneficial medical care for their disease.
The National Research Act of 1974 and The National Commission All of this national debate culminated in Congressional hearings about research in human subjects, directed by Senator Edward Kennedy, in 1973. From these hearings, a consensus was reached that federal oversight was required to protect the rights and welfare of research subjects.
- This consensus led to the development and passage of the National Research Act in 1974, which initiated the process of developing ethical standards and oversight for the conduct of human research.
- Although Congress did set forth some early regulations in this legislation, the highly contested debate and hearings forced many to realize that establishing ethical standards for the conduct of research in human subjects was riddled with complexity.
Consequently, the legislation also called for the establishment of the National Commission for Protection of Human Subjects of Biomedical and Behavioral Research, commonly known simply as the National Commission. This commission, composed of experts in ethics, religion, law, industry, and medicine, met numerous times over the next few years and issued recommendations on the conduct of research in human subjects.
The National Commission published numerous population-specific reports for classes of subjects they considered vulnerable, including children, pregnant women, prisoners, and cognitively-impaired persons. The Belmont Report In 1978, the National Commission detailed the fundamental ethical principles that should guide the conduct of research involving human subjects,
This Belmont Report (available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm ), named for the Belmont Conference Center at the Smithsonian Institution where the meetings took place, is an eight-page document describing the three fundamental principles for conducting research involving human subjects.
- These principles, namely respect for persons, beneficence, and justice are now accepted as the requirement for the ethical conduct of such research.
- The principle of respect for persons incorporates two components related to individual autonomy, namely that each individual has the right to self-determination and persons with diminished autonomy, who thus lack the capability of self-determination, are entitled to additional protection to prevent exploitation.
The term “vulnerable” has been used in describing those populations with diminished autonomy. Four requirements for ethical conduct of research follow directly from this principle of respect for persons: 1) Participants must voluntarily consent to participate in research; 2) The voluntary consent obtained from participants must be informed consent; 3) Protection of privacy and confidentiality must be incorporated into the research; and 4) Participants must maintain the right to withdraw from research participation without penalty or repercussions.
- The principle of beneficence requires that research be designed to maximize benefit and minimize harm.
- In other words, the risks of research must be justified by the potential benefits to the individual and/or society.
- The founders of the Belmont Report acknowledged that comparing the risk of research to an individual with the benefit derived by society will often be difficult and recommended determinations be made on a case-by-case basis.
The third principle is that of justice. The concept of justice relates to the distribution of risk across society. The Belmont Report directs that members of society who are likely to benefit from the research bear the potential risks of such research equally.
In other words, the research should not systematically select specific classes of individuals simply because they are readily available where research is conducted, or because they are “easy to manipulate as a result of their illness or socioeconomic condition.” Instead, enrollment should focus on individuals for reasons directly related to the research.
Recent years has seen debate over whether the principle for justice also extends to protect persons from systematic exclusion from research that may apply to them. The implication of such is that research should not systematically exclude a specific type of person (i.e.
children or pregnant women) who is likely to benefit from participation or in whom the results of the research are likely to be applied. The Institutional Review Board (IRB) In addition to establishing the National Commission, legislation in the National Research Act of 1974 also paved the way for the modern IRB system for regulating human subject research.
Federal regulations in the act required IRB approval for most research involving human subjects, defined the policies and procedures that the IRB must follow when reviewing such research, and established criteria to be utilized by the IRBs to approve the research.
- After the National Commission disbanded, responsibility for implementing its recommendations was delegated to The Office of Human Research Protections (OHRP), a division of the Department of Health and Human Services (DHHS).
- IRBs function under the power of the OHRP, whose job is to develop regulations for the protection of human subjects and oversee compliance with these regulations.
In 1981, the Secretary of the DHHS signed a revised Code of Federal Regulations for the Protection of Human Subjects, as put forth by the OHRP in Title 45, Part 46 of the Code of Federal Regulations (45 CFR 46) ( http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm ).
In 1991, these regulations were adopted by the 16 federal agencies that conduct, support, or otherwise regulate human subjects research, including the National Institutes of Health. This has resulted in the regulations becoming better known as the “Common Rule,” which despite modification over time, still serves as the guideline for IRB decisions and approvals, today.
Of note, the Food and Drug Administration also adopted certain provisions of the Common Rule, but has its own set of regulations for the protection of human subjects, codified at Title 21 Parts 50 and 56 of the Code of Federal Regulations. Membership of an Institutional Review Board Although many IRBs have more, federal law mandates each IRB must have at least five members, with varying backgrounds and expertise to promote complete and adequate review of research activities commonly conducted by their institution.
The members should represent a diversity of backgrounds to promote respect for its advice and counsel in protecting the rights and welfare of human research subjects. This diversity should include considerations of their sensitivity to community attitudes, in addition to racial and cultural heritage.
An IRB may chose to invite individuals with competence in certain areas to review issues which require expertise beyond that available to the IRB, but these expert ad hoc reviewers may not vote at the committee meeting. At least one member of each IRB must possess primary concerns in a non-scientific area, and at least one other member must possess primary concerns in a scientific area.
Investigators can be members of the IRB, but as such, cannot participate in the review and approval process for any project in which he or she has a present or potential conflict of interest. In addition, at least one member must not be affiliated with the institution nor be part of the immediate family of a person who is affiliated with the institution.
This non-affiliated member of the IRB, often called the community member, should be drawn from the community-at-large. This member should possess extensive knowledge about the type of community from which the institution will draw its research subjects and be willing to evaluate and discuss the research proposals from that unique perspective.
- Ministers, attorneys, teachers, business persons, or homemakers make ideal community members.
- If an IRB regularly reviews research involving vulnerable populations, (such as children, pregnant women, cognitively impaired persons, or prisoners), at least one member should be knowledgeable about and experienced in working with these subjects.
Furthermore, when the IRB reviews research which proposes targeted inclusion of either handicapped children or mentally disabled persons, the roster must include at least one person primarily concerned with the welfare of these vulnerable subjects. What is the Purpose of an Institutional Review Board? Institutional Review Boards are charged with protecting the rights and welfare of human subjects recruited to participate in research activities conducted under the auspices of the institution to which the IRB is affiliated.
- The IRB reviews proposed research activities and has the authority, granted by the federal regulations and local institutional policy, to approve, disapprove, or require modifications to all research activities involving human subjects.
- In this role, the IRB assumes numerous duties and often must collaborate closely with other institutional bodies, including scientific review committees, human subject radiation committees, biosafety experts, conflict of interest committees, and requested ad hoc expert reviewers.
To accomplish this, IRBs must first determine whether the proposed activity involves research and if so, whether the research involves human subjects. Research is defined as “a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.” The regulations define human subjects as “living individuals about whom an investigator (whether professional or student) conducting research obtains 1) data through intervention or interaction with the individual, or 2) identifiable private information.” Determining whether an activity qualifies as human subjects research represents only the beginning.
What follows is an extensive review process by the IRB, assessing the risk to benefit ratio. In protecting human subjects, the IRB is commissioned with the task of evaluating whether the risks to participants are minimized for accomplishing the research objectives. This requires a detailed analysis of the study design, level of expertise of the investigators, and characteristics of the research participants.
In addition, IRBs must rigorously assess the proposed process of informed consent, including any written forms, to ensure that participants are able to voluntarily provide informed consent without coercion. IRBs also bear the responsibility of reviewing ongoing research at least annually in order to re-evaluate the risk to benefit assessment and ensure that the research continues to be conducted according to the regulations.
In order to abide by the regulations governing the conduct of human subject research, investigators and other research personnel require education and training. This education and training also rests within the domain of the IRB. Conclusion In conclusion, Institutional Review Boards were established as part of federal legislation in response to growing concerns over the ethical conduct of research involving human subjects.
The main role of the IRB is to protect the rights and welfare of human research subjects. The complexity of providing such protection has rendered the make-up and functioning of these configurations equally as complex. The ultimate goal of the IRB, however parallels that of the researcher; both are charged with ensuring that research on human subjects is conducted ethically, with sound scientific rationale, maximized benefits, and minimized risks.
|1.||World Medical Association Declaration of Helsinki: Recommendations guiding physicians in biomedical research involving human subjects. JAMA.1997;277:925-6.|
|2.||Beecher HK. Ethics of clinical research. N Engl J Med.1966;274:1354-60.|
|3.||National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission). Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, DC: Federal Register Document 79-12065; April 18, 1978.|
What does the IRB do to protect a research participant from harm?
Why Human Subjects Research Protection Is Important Background: Institutional review boards (IRBs), duly constituted under the Office of Human Research Protection, have the federally mandated responsibility of reviewing research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in any study.
The road leading to the current regulations and ethical considerations has been long and checkered. Methods: This paper reviews the history of human subjects participating in research, including examples of egregious events, and the ethical analyses that precipitated the evolution of the mandated protections afforded participants in research under current federal regulations.
Results: Key documents—from the Nuremberg Code in 1947 to the Belmont Report in 1978 to Moral Science: Protecting Participants in Human Subjects Research in 2011—that have informed the ethics debate regarding human subjects protection in research activities are presented in light of their historic significance, highlighting the complexity of the issues surrounding protection of human subjects in research.
- Conclusion: The examples from history and the scarcity of contemporary examples demonstrate that the regulations for the protection of humans participating in research have evolved in a way that minimizes the probability that subjects will be harmed when they choose to participate in research.
- The examples also reinforce the importance of individual responsibility.
Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol. Understanding how we arrived at the current approach and some of the failures that directed this course can support efforts to continually reevaluate and improve the safety of subjects who are willing to participate in research activities.
- Eywords: Ethics committees–research, ethics–research, research subjects Participation of human subjects in research presents a challenging ethical dilemma.
- A research subject may be asked to participate in a study of no benefit and no substantial risk or in a study with the potential for significant benefit but also significant risk.
In placebo-controlled studies, subjects may be exposed to significant risk for no benefit to the individual. These variants are confounded by treatment protocols—most commonly encountered in oncology trials—that compare the effect of an investigational arm to the standard of care, further blurring the distinction between research and medical treatment.
Institutional review boards (IRBs) have the federally mandated responsibility to review research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in the study. The road leading to the current regulations and ethical considerations has been long and checkered.
The system that has evolved minimizes the risks for unethical behavior and serious adverse events but is not infallible. Understanding how we have arrived at the current approach and analyzing some of the ethical lapses that directed this course support efforts to continually reevaluate the regulations in order to improve the safety of subjects who are willing to participate in research activities.
Our current approach to human subjects protection has evolved with efforts to understand questionable ethical behavior in research over the course of several hundred years. One might suggest that the jester conscripted to sample the king’s food to ensure that it was safe to eat presaged the use of vulnerable populations as subjects for research, but the evolution of the management of smallpox is perhaps a more applicable early perspective on research in humans.
Three centuries ago, reports of good outcomes following variolation—inhalation of the scabs from persons infected with smallpox—were circulating in Asia. In 1717, Lady Mary Wortley Montagu, the wife of the British ambassador to Turkey, became an advocate of variolation after learning about it in Constantinople.
- In 1721, after she returned to England, Lady Montagu and the Princess of Wales urged variolation of “several prisoners and abandoned children” by having smallpox scabs inserted under their skin.
- Several months later, the children and prisoners were deliberately exposed to smallpox.
- When none contracted the disease, the procedure was deemed safe, and members of the royal family were treated according to this new protocol.
Later that same century, Edward Jenner developed inoculation with a vaccine. Many of his contemporaries had noted that milkmaids who had contracted cowpox seemed immune to the much more lethal smallpox. In May 1796, Jenner isolated material from the cowpox lesions on the milkmaid Sarah Nelms and inoculated 8-year-old James Phipps who developed fever and malaise about 9 days after the inoculation.
Some accounts report that Phipps was the son of Jenner’s gardener. A few months later, Jenner deliberately inoculated Phipps with material from fresh smallpox lesions, and the child remained healthy. The adoption of this process was not immediate but slowly spread and is widely cited as the first scientific approach proving vaccination.
This early use of children and prisoners portends a long history of selecting what are now considered vulnerable populations to be the subjects of research. Participation was commonly without consent, with no knowledge of their participation, and with no explanation of the research.
Information was withheld from those selected to participate in research activities perceived as dangerous to more acceptable members of society, and the therapies developed were generalized only if they were proven relatively safe and effective in what are now recognized as vulnerable populations. Numerous instances of research experiments in subsequent years exposed vulnerable subjects to risk, including a pivotal research disaster in Germany just before World War II that led to regulations for human subjects participation in research projects.
As reported by Sir Graham Wilson in the book The Hazards of Immunization, “Between 10 December 1929 and 30 April 1930, 251 of 412 infants born in the old Hanseatic town of Lubeck received three doses of BCG vaccine by the mouth during the first ten days of life.
- Of these 251, 72 died of tuberculosis, most of them in two to five months and all but one before the end of the first year.
- In addition, 135 suffered from clinical tuberculosis but eventually recovered; and 44 became tuberculin-positive but remained well.” Bonah and Menut describe how Albert Calmette was able to establish the BCG vaccine as a nonexperimental “prophylactic treatment” against tuberculosis.
By definition, a medical experiment, as opposed to any other medical action, has definite ethical implications and consequences. Even though the BCG vaccine was in experimental stages, Calmette convinced a court that the vaccine was a “post-experimental, routine medical treatment.” By avoiding the definition of an experiment, Calmette did not have to inform the children’s parents about the risks of the vaccine.
As a result of this tragedy, Dr Julius Moses, a critic of unethical human experimentation who referred to “experimental mania,” drafted guidelines for human experimentation. After debate in parliament and the press, the guidelines were published and became official in 1931. The guidelines applied to everyone in Germany.
, These rules for research in human subjects were issued as the Reich Circular of 1931 (). The document is quite informative for its contrast with later events in Germany and worth reviewing for correlation with ethical concepts now well accepted in ethical thinking.
- It is worth noting that these guidelines emphasize special responsibilities for utilization of “innovative therapy,” suggesting a similar level of responsibility for these procedures as for research.
- The Reich Circular, 1931 6 Despite the ethical ideals espoused in the Reich Circular, the travesty of the Holocaust followed shortly afterward, leading to war criminal trials after the surrender of Germany ended World War II in Europe.
The Nuremberg trials that began in 1945 and concluded in 1947 were held in response to the atrocities Germany committed during the war. The so-called Doctors’ Trial represents a major turning point in human research protection. Twenty-three physicians were indicted, accused of crimes against humanity by conducting criminal scientific and medical experiments on concentration camp prisoners.
Sixteen defendants were found guilty. Several German doctors had argued that no international law or informal statement differentiated between legal and illegal human experimentation, despite the aforementioned Reich Circular. Two US doctors who worked with the prosecution during the trial, Andrew Ivy and Leo Alexander, objected to this argument.
On April 17, 1947, Dr Alexander submitted a memorandum to the United States Counsel for War Crimes outlining 6 points defining legitimate medical research. The trial verdict reiterated almost all of these points in a section entitled Permissible Medical Experiments and expanded the original 6 points into 10.
- These 10 points became known as the Nuremberg Code ().
- The Nuremberg Code, 1947 10 Similar atrocities were carried out on Chinese citizens in Japanese camps; of particular note are the biological warfare experiments at Unit 731 in the Pacific theater that were obscured by agreements made during the surrender of Japan and with the complicity of the United States.
The details of these atrocities remained classified until they were acknowledged by Congress in the Japanese Imperial Government Disclosure Act of 2000 (Pub L No.106-567, Title VIII of the Intelligence Authorization Act of 2000) that called for declassification and release of records related to Japanese war crimes during World War II.
The tenets of the Nuremberg Code, while guiding the future for human research protection, represent a military code of conduct with no standing in civil international or US law. By absolutely requiring the voluntary consent of the individual, the Nuremberg Code notably does not address the needs of children or other special populations unable to provide consent.
The Nuremberg Code inspired the World Medical Association (WMA)—an international association currently comprised of 114 national medical associations, including the American Medical Association—to propose a similar code of conduct for participating members by publishing the Declaration of Helsinki in 1964.
- This document reiterates the provisions of the Nuremberg Code and expands the provisions to allow for the participation of children and other potentially compromised subjects in research.
- The Declaration of Helsinki serves as a guideline for ethical research and has been amended 7 times, most recently at the WMA General Assembly in October 2013, to reflect contemporary ethical issues as they have evolved since the initial statement in 1964.
Meanwhile, research continued in the United States with particular concerns attached to research involving vulnerable populations, exemplified by numerous studies involving institutionalized children and studies that breached ethically sound research practices.
Henry Beecher, a well-recognized physician at Massachusetts General Hospital, surveyed the contemporary literature to identify ethical concerns and organized lectures around his observations. These lectures eventually culminated in a special article published in the New England Journal of Medicine in 1966.
In “Ethics and Clinical Research,” Beecher reported that he had reviewed 100 consecutive articles published in 1964 “in an excellent journal,” and after culling his list to address the editor’s request, selected 12 articles that demonstrated serious ethical concerns.
- The purpose of Beecher’s article was to demonstrate the widespread lapse in ethical issues in medical research and to encourage reform in the ethical approach to human subjects research that inspired Congress to reconsider legislative reforms for human subjects protection.
- An article by Jean Heller that appeared in the Washington Star on July 25, 1972 placed an exclamation point in the history of human research ethics.
Heller reported on a long-term study sponsored by the US Public Health Service on the effect of syphilis if left untreated in poor rural African American subjects. Officially known as the “Tuskegee Study of Untreated Syphilis in the Negro Male,” the study enrolled 399 subjects with syphilis and 201 uninfected controls from the African American community surrounding Tuskegee, AL for “treatment of bad blood.” In exchange for taking part in the study, the men received free medical examinations, free meals, and burial insurance but were not given the benefit of providing informed consent.
No treatment was provided; the research plan was to follow the subjects to establish a natural history for the disease if left untreated. Although originally projected to last 6 months, the study continued for 40 years. Treatments available at the onset of the trial in 1932, even if provided, were not very effective and would have been heavy metals, involving at least 30 months of treatment, a 30% cure rate, and significant toxicity.
By 1945, penicillin had been proven to be an effective therapy for syphilis with few side effects. Once penicillin was established as effective, the US Public Health Service set up centers for treatment but determined that the data from the Tuskegee experiments were too important to abandon and decided that the study should be continued with no treatment provided to the participants.
Similar determinations were made in subsequent years, with the last review occurring as recently as 1969. While medical research such as the Tuskegee study garnered most of the attention for ethical lapses, other areas of research involving human subjects also raised concerns. The Milgram experiments carried out in the early 1960s at Yale University are a lightning rod for discussion of ethical issues in human subjects research in social sciences.
Intrigued by the Nuremberg trials defendants’ argument that they were simply following orders, Stanley Milgram set out to determine if the German defendants were particularly obedient to authority figures compared to other members of society. Milgram recruited subjects for an experiment in learning via newspaper ads.
- The male research subjects were assigned to act as a teacher asking questions of a learner (a confederate of Milgram) who was attached to electrodes.
- The teachers were instructed to increase the severity of electrical shocks if the learner answered the questions incorrectly.
- Shocks were labeled from 15v to 450v, with 15v indicated as mild, 300v as severe, and 450v as XXX.
Many of the teacher subjects eventually shocked the learner at 450v and exhibited increasing signs of distress as the shocks they delivered increased in perceived severity. These experiments evoked significant concern among those in social sciences in regard to the questionable ethics of the deception used, as well as the potential for long-term psychological harm that might be incurred by unwitting participants.
The public outcry over the Tuskegee study, other reports of ethical lapses in both medical and social research, and the alarm in the medical community raised by Dr Beecher’s article in the New England Journal of Medicine led Congress to action. On May 30, 1974, the US Department of Health, Education, and Welfare (DHEW), responsible for oversight of the National Institutes of Health, replaced previous policies with comprehensive regulations governing the protection of human subjects (45 CFR §46).
One month later in July 1974, Congress passed the National Research Service Award Act of 1974 (Pub L No.93-348). Title II of the act, Protection of Human Subjects of Biomedical and Behavioral Research, created the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research.
- Along with being assigned several other tasks, the National Commission was directed to make recommendations to the DHEW secretary about the ethical principles that should underlie human subjects research.
- The National Commission issued several reports in response to the directives.
- The most notable among a collection of important documents is the Belmont Report, named after the Smithsonian conference center where the group convened, that was issued in 1978.
This document, widely regarded as the landmark analysis of ethics in human subjects research, serves as the foundation for discussion of ethical concerns in research ethics involving human subjects, as well as the source of federal regulations for research established by the Office for Human Research Protections (OHRP).
The Belmont Report is divided into three sections. The first section briefly states the National Commission’s recognition that even as the report was being written, the distinction between medical practice and research was blurred. The report defines medical practice as “interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation for success.
Research, on the other hand, is defined as “an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships).” This section further expounds on the conflation between the use of the terms experimental and research.
When used in reference to a procedure or treatment that significantly deviates from typical (ie, a treatment that is “new, different or untested”), the report notes that an “experimental” treatment is not necessarily research. Although they excluded “experimental” treatment from research and the applicable anticipated regulations, the National Commission strongly recommended that such treatments should eventually be incorporated into formal research protocols “to determine if they are safe and effective.” The first section of the Belmont Report concludes with the recognition that practice and research may go hand in hand: “the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects.” This language is reminiscent of the Reich Circular recommendation regarding “innovative therapy.” The second section is the heart of the report and defines three principles that should guide the discourse surrounding any ethical concerns related to research in human subjects: respect for persons, beneficence, and justice.
The principle of nonmaleficence, now commonly accepted as one of the four principles of biomedical ethics, was notably absent.
- Respect for persons : The principle of respect for persons requires that “individuals should be treated as autonomous agents,” and those with “diminished autonomy are entitled to protection.” These concepts inform “two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.” The National Commission defines the elements that would be necessary to qualify as an autonomous individual and explores circumstances that would define those who should be considered to be of diminished autonomy and thus deserving of protection.
- Beneficence : The principle of beneficence as defined by the National Commission encompasses the concept of do no harm included in the Hippocratic Oath and notes that the term is commonly thought “to cover acts of kindness or charity that go beyond strict obligation.” The National Commission proposes two general rules that inform beneficence as an obligation: “(1) do not harm and (2) maximize possible benefits and minimize possible harms.” The implications of these duties within the context of both individual investigators and society at large are examined.
- Justice : The principle of justice is posed as the following question: “Who ought to receive the benefits of research and bear its burdens?” This principle is broad in potential implications and can be summarized as evaluating the appropriate distribution of the risks and burdens of research among individuals, groups, or even situations in which inherent inequalities may need to be considered to reach an ethically informed decision. The National Commission proposes the following framework for beginning these discussions: “(1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.” The discussion of justice continues with the historic context for including the principle of justice and how lapses in justice (ie, the Tuskegee study) were the primary impetus for the formation of the National Commission.
The final section of the Belmont Report addresses the application of these principles and the implications of their requirements when considering three important elements of research involving human subjects: informed consent, assessment of risks and benefits, and selection of subjects for research.
Informed consent. The consent process has three components: information, comprehension, and voluntariness. Reaching agreement on an appropriate standard for evaluating the quality of information that should be provided to potential participants about a proposed research project is difficult and eventually ends with the suggestion that the standard of “the reasonable volunteer” might best fulfill the requirements of respect for persons, beneficence, and justice.
A caveat is provided, citing the problem posed by research where “informing subjects of some pertinent aspect of the research is likely to impair the validity of the research,” a key area of ethical concern (lack of disclosure) raised by the Milgram study discussed previously.
The National Commission proposes that such studies may only be appropriate if “(1) incomplete disclosure is truly necessary to accomplish the goals of the research, (2) there are no undisclosed risks to subjects that are more than minimal, and (3) there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them,” further noting that “Care should be taken to distinguish cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply inconvenience the investigator.” Regarding the component of comprehension, the Belmont Report states, “The manner and context in which information is conveyed is as important as the information itself.” The level of comprehension is also important within the context of the individual’s ability to understand the information, with emphasis that the obligation for ensuring subject understanding increases in importance relative to the level of risk posed by participation in the study.
The National Commission suggests that some level of questioning the subject to ensure comprehension is appropriate and even suggests that written responses to questions may be appropriate if risks are exceptionally high. If participation of subjects with compromised abilities is anticipated, researchers must be particularly diligent in evaluating the level of comprehension by the subject’s proxy and ensure that the proxy is indeed capable of representing the best interests of the subject.
- The report even suggests that the proxy might need to be present or available during the research interventions to withdraw the subject from the study if the proxy perceives that withdrawal may be in the subject’s best interest.
- Voluntariness is a concept consistently emphasized in the Reich Circular, the Nuremberg Code, the Declaration of Helsinki, and the Belmont Report.
Although voluntariness may appear to be self-evident, it may be the most difficult concept to address. The Belmont Report emphasizes that the subject must be “free of coercion and undue influence.” Coercion is specifically defined as “an overt threat of harm” and in most circumstances is relatively easy to evaluate.
- However, arguments can be made about what defines “undue influence.” Discussions about appropriate levels of compensation for participation are common, particularly when studies involve financial or other considerations made to possibly financially compromised subjects.
- The Belmont Report specifically notes, “inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable.” Other concerns related to undue influence involve social standing, employment, or other circumstances that may be difficult to assess but are worthy of consideration for individual subjects.
Assessment of risks and benefits. The National Commission notes that a favorable risk/benefit assessment is associated with the principle of beneficence. This definition is particularly appropriate in that the National Commission’s interpretation of beneficence includes the duty of nonmaleficence.
The Belmont Report examines the meaning of risk and benefit in the setting of potential types of harm that may be experienced by individual subjects, the families of the individual subjects, society at large, or special groups of subjects in society. Benefits are also discussed in relation to the individual and society at large.
In summarizing the risks and benefits of research, the Belmont Report states assessment of the justifiability of research should reflect at least the following considerations: Brutal or inhumane treatment of human subjects is never morally justified.
- Risks should be reduced to those necessary to achieve the research objective.
- It should be determined whether it is in fact necessary to use human subjects at all.
- Risk can perhaps never be entirely eliminated, but it can often be reduced by careful attention to alternative procedures.
- When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk (looking usually to the likelihood of benefit to the subject—or, in some rare cases, to the manifest voluntariness of the participation).
When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. A number of variables go into such judgments, including the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits.
Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process. Selection of subjects for research. The third element, selection of subjects for research, finds its primary guidance in the principle of justice where the moral requirements demand that the procedures and outcomes for the selection of subjects are fair to the individual and within the social context.
Participation in potentially beneficial research should be fairly distributed to all who wish to participate, and risky research should not be offered only to less desirable subjects. In the context of society, risks should be distributed after careful consideration of the burdens and the ability of individuals in identifiable groups to bear those burdens.
As a generalization, adults should be considered before children, and participation by institutionalized individuals should invoke very careful consideration. Even with these safeguards, the National Commission believed that the selection of subjects may continue to reflect injustice arising from social, racial, sexual, and cultural biases institutionalized in society.
Harking back to the ethical concerns that prompted the National Commission, the Belmont Report concludes with the following: “One special instance of injustice results from the involvement of vulnerable subjects. Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted.
Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.” Although not included in the body of the report, a footnote specifically addresses the difficulty in extrapolating these tenets to human subjects research in the social sciences: “Because the problems related to social experimentation may differ substantially from those of biomedical and behavioral research, the Commission specifically declines to make any policy determination regarding such research at this time.
Rather, the Commission believes that the problem ought to be addressed by one of its successor bodies.” An appropriate ethical approach for some areas of social and psychological studies remains elusive. Matthew Salganik, professor of sociology at Princeton University, discusses the issues surrounding the difficulty in applying the Belmont Report recommendations at his blog.
- The Belmont Report was submitted to Congress on April 18, 1979.
- Although the Belmont Report is the centerpiece for the analysis of research in human subjects, the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research provided significant additional guidance for Congress to consider as the legislators moved forward to formulate regulations for the governance of human subjects in research.
During the 4 years of the National Commission’s appointment, other publications provided analysis of concerns related to specific questions (Table), and many of the recommendations were incorporated into the subsequent regulations for human subjects protection.
|Research on the Fetus||July 25, 1975|
|Research Involving Prisoners||October 1, 1976|
|Psychosurgery||March 14, 1977|
|Disclosure of Research Information Under FOIA||April 8, 1977|
|Research Involving Children||September 6, 1977|
|Research Involving Those Institutionalized as Mentally Infirm||February 2, 1978|
|Institutional Review Boards||September 1, 1978|
|The Belmont Report||September 30, 1978|
|Delivery of Health Services||September 30, 1978|
|Special Study on Implications of Advances in Biomedical and Behavioral Research||September 30, 1978|
Another landmark publication from 1979 deserves attention for its sustained influence on the field of biomedical ethics and its deviation from the three ethical principles put forth by the Belmont Report. In Principles of Biomedical Ethics, Tom Beauchamp and James Childress argue for inclusion of nonmaleficence as an independent principle to formulate the now-familiar four principles that inform contemporary bioethical discourse.
- As previously noted, nonmaleficence is considered a duty under the umbrella of the principle of beneficence in the Belmont Report.
- Beauchamp and Childress maintained that the tradition to do no harm central to the tenets of the Hippocratic Oath incorporates the concept of nonmaleficence at its core and is essential to any discussion of the ethics of medical practice.
As such, they argued, this concept should be considered as separate from and not subsidiary to beneficence: “First, to confuse them is to obscure distinctions that we make in ordinary moral discourse. Second, ordinary moral discourse expresses the defensible conviction that we have certain duties not to injure others that are not only distinct from but also more stringent than our duties to benefit others.” The authors make the distinction that the negative duty to cause no harm should be encompassed by nonmaleficence, and the positive but not so strongly established moral duty to benefit others should constitute the core of beneficence.
The authors acknowledged that other eminent scholars disagreed with the separation of nonmaleficence and beneficence, but they constructed an argument that has been upheld by the historic inclusion of nonmaleficence in most bioethics discussions following their book’s original publication (the book is now its seventh edition).
The book has had a significant influence on the still-evolving field of bioethics contemporary to its publication and the Belmont Report. Both authors regularly served as staff members for the Kennedy Institute Intensive Bioethics Course, and Beauchamp served as staff philosopher for the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research that produced the Belmont Report.
The authors acknowledged the influence of several other members of the commission and other colleagues who contributed significantly to their deliberations as their work progressed. DHEW officially became the Department of Health and Human Services (HHS) in 1980, and in response to the Belmont Report, the HHS and the US Food and Drug Administration (FDA) significantly revised their protection of human subjects regulations in 1981 (45 CFR §46 and 21 CFR §50).
, These regulations specifically address concerns related to vulnerable populations in Subparts B, C, and D, incorporating the recommendations from the National Commission. The Research on the Fetus report informed Subpart B (additional protections for pregnant women, human fetuses, and neonates), Subpart C (additional protections for prisoners) reflected the recommendations in Research Involving Prisoners, and Subpart D (additional protections for children) was informed by the Research Involving Children report.
To this point, this review has focused on some of the historic events and documents precipitating evaluation of the ethical requirements for human subjects research in the United States and a review of the regulations that evolved from that history. The question not yet addressed is how these regulations should be enforced.
As with the discussion of research ethics, the approach to enforcement of regulations also lies within the National Research Service Award Act of 1974 (Pub L No.93-348). In addition to establishing the National Commission responsible for the Belmont Report, the National Research Act elected to perpetuate the regulatory mechanism for research extant within many departments of DHEW that evolved from the US Public Health Service requirements initiated by the Surgeon General in 1966.
The background of this development is described in William Curran’s article, “Government Regulation of the Use of Human Subjects in Medical Research: The Approach of Two Federal Agencies.” This system for review of human subjects research within DHEW as described in The Institutional Guide to DHEW Policy on Protection of Human Subjects became the model for institutional review boards (IRBs) that the National Research Act would require of grantees and contractees for review of research involving human subjects.
The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research was specifically charged with reviewing the function of IRBs and making recommendations for integrating the role of the IRB into the regulatory process to provide oversight of the application of ethical principles and of the regulations.
On September 1, 1978, the National Commission completed the less spectacular but equally important report, Institutional Review Boards, before submitting the Belmont Report on September 30 that same year. Institutional Review Boards outlines the National Commission’s concept of the ideal environment for the application of the federal regulations.
In the introduction to the report, the National Commission provides this understated assessment of the role of the IRB: “This review of proposed research by IRBs is the primary mechanism for assuring that the rights of human subjects are protected.” The document outlines the ideal responsibilities of the IRB in the oversight of research to ensure that human subjects receive appropriate protections and ethical treatment for their willingness to participate in research, sometimes at no benefit to themselves.
The National Commission summarized their objective as follows: In the recommendations that follow, the Commission expresses its judgment about the ways in which those elements ought to be brought to bear on research practices, so that a reasonable and ethical balance of society’s interests may be attained.
The Commission’s deliberations begin with the premise that investigators should not have sole responsibility for determining whether research involving human subjects fulfills ethical standards. Others, who are independent of the research, must share this responsibility, because investigators are always in positions of potential conflict by virtue of their concern with the pursuit of knowledge as well as the welfare of the human subjects of their research.
The Commission believes that the rights of subjects should be protected by local review committees operating pursuant to federal regulations and located in institutions where research involving human subjects is conducted. The document continues this proposal and is seemingly all-inclusive in its conception of the IRB.
Highlights include a list of the requirements that must be met to approve research and details for reviewing and approving the consent process, including the essential elements to be included and the safeguards that should be in place to ensure that the process is respected.
Specific recommendations also address the constitution of the IRB; how it should be funded; and legal protections for the board, the process, and its members. Most of the recommendations from the Institutional Review Boards report were incorporated into the HHS regulations—HHS being the responsible federal agency—as part of the rules revision in 1981 in response to the Belmont Report and several other publications of the National Commission.
Acting independently from HHS, the FDA also adopted IRBs as a regulatory mechanism, with regulations first issued in 1981 as part of the agency’s response to provisions of the National Research Act., One particularly relevant recommendation of the National Commission from Institutional Review Boards remained outstanding after the changes in 1981: “Recommendation (1) (A) Federal law should be enacted or amended to authorize the Secretary of Health, Education, and Welfare to promulgate regulations governing ethical review of all research involving human subjects that is subject to federal regulation.” The report notes significant “variations arising out of differences in wording, imposition of additional requirements, introduction of minor changes, etc.” among the different agencies apart from DHEW involved in research involving human subjects and expresses concern that this variability places an unnecessary burden on the individual IRBs for interpreting and properly enforcing the regulations.
- The National Commission’s recommendation was to establish “DHEW as the sole authority” for regulations, expressing the belief that such a rule “would reduce the burden on IRBs to interpret and apply the regulations to which they are subject.
- Moreover, uniformity would assure a minimum level of protection to human subjects of research, no matter which federal agency is supporting the research or which entity is conducting it.” Having inherited the mantle of responsibility from the now-extinct DHEW and recognizing the reality of this assessment, the newly designated HHS explored implementation of this recommendation, particularly as it related to the function of IRBs.
As with most changes affecting multiple branches of government, the process became complex. In December 1981, the President’s Commission for the Study of Ethical Problems in Medicine and in Biomedical and Behavioral Research, a new commission appointed by Congress in 1978, entered the fray and recommended that all federal departments and agencies adopt the HHS regulations (45 CFR §46).
In addition, an ad hoc Committee for the Protection of Human Subjects—composed of representatives and ex officio members from departments and agencies that conducted, supported, or regulated research involving human subjects—was appointed in May 1982 by the president’s science advisor to respond to the recommendations of this new commission.
After much consideration and negotiation, these efforts were finally addressed by adoption of the Federal Policy for the Protection of Human Subjects, known as the Common Rule, in 1991 and codified in the individual regulations by 15 federal departments and agencies.
- Each of these agencies includes in its chapter of the Code of Federal Regulations (CFR) section numbers and language that are identical to those of the HHS codification at 45 CFR §46, Subpart A for the regulation of human subjects participation in research.
- The HHS regulations also include Subparts B, C, and D as additional regulations pertaining to vulnerable subjects.
, In addition to harmonizing the regulations across agencies of the federal government, the Common Rule requires institutions that receive funds for research involving human subjects from federal agencies that are signatories to the Common Rule to certify that the research has been reviewed and approved by an IRB that meets the specific requirements for composition, for functioning, and for the criteria followed to approve research.
By mandate of the Common Rule, IRBs are empowered to approve, require modifications of, or disapprove research activities and are required to conduct continuing review of ongoing research at least annually. The FDA concurs with the Common Rule but claims special privilege in not signing on to it. In the Federal Register of November 10, 1988 (53 FR 45678), the agency proposed to amend its regulations in 21 CFR §50 and §56 so that they conformed to the Federal Policy for the Protection of Human Subjects to the extent permitted but noted that the FDA is a regulatory agency that rarely supports or conducts research under its regulations.
With the adoption of the Common Rule, regulations for human subjects research conducted within the United States became well established, but research has never been confined by the borders of the United States. Even though a project funded by federal monetary support may have some leverage to require adherence to US regulations, significant numbers of human research subjects participate in studies well beyond the influence of the US regulations.
The international norms for participation of human subjects in research evolved along a course that frequently cross-pollinated with the concepts culminating in the Common Rule. The Declaration of Helsinki was an early statement of basic tenets that should apply to all research involving human subjects, and it has continued to evolve, with updates reflecting new issues as they become relevant.
While addressing the ethical concepts, the Declaration of Helsinki does not provide an organizational or regulatory framework for human subjects protection. Providing this framework on an international basis presented a challenge well beyond the challenge of harmonizing regulations across different federal agencies as was accomplished by the Common Rule.
- The difficulties encountered in implementing the Common Rule represent only a microcosm of the enormous task of harmonizing regulatory and organizational concepts across the borders of different cultures and political systems.
- However, this task was particularly relevant because of the evolution of research into an international enterprise with multicenter drug trials and the expansion of vaccine trials in children.
Many of these studies are conducted by multinational contract research organizations that have access to populations of subjects with exposure to diseases that may not be widely encountered in the United States. An argument can be made that the process for oversight of human subjects in research at the international level started in 1948 before the Declaration of Helsinki when the United Nations Educational, Scientific and Cultural Organization (UNESCO) joined with the World Health Organization (WHO) to establish a permanent Council for Coordination of International Medical Congresses, formally constituted in Brussels in 1949 as a nongovernmental organization with the purpose of facilitating “the exchange of views and scientific information in the medical sciences by securing continuity and coordination between international organizations of medical sciences, by making their work known, and by providing them with material aid where necessary.” The scope of activities gradually expanded to include collaborative efforts among international medical activities in addition to the coordination of participating congresses.
- In 1992, the name of the council was changed to the Council for International Organizations of Medical Sciences (CIOMS), and its statutes were revised to reflect the expanded role.
- The original council ventured into medical research by organizing a 1959 meeting in Vienna under the auspices of UNESCO and the WHO “to discuss the principles, organization and scope of ‘controlled clinical trials,’ which must be carried out if new methods or preparations used for the treatment of disease are to be accurately assessed clinically.” The executive secretary summarized the meeting: “The conference was in itself an experiment.” Following this meeting, the council became much more involved in considerations regarding research and particularly the participation of human subjects in research trials, eventually publishing Proposed International Guidelines for Biomedical Research Involving Human Subjects in 1982.
The purpose of the guidelines was “to indicate how the ethical principles that should guide the conduct of biomedical research involving human subjects, as set forth in the Declaration of Helsinki, could be applied, particularly in developing countries, given their socioeconomic circumstances, laws and regulations, and executive and administrative arrangements.” This quote is from the background notes for International Ethical Guidelines for Biomedical Research Involving Human Subjects published in 1993 after discussion and reconsideration of the comments received in response to the proposed guidelines.
The publication of the guidelines in 1993, soon after the name change to CIOMS, represented a landmark for international research ethics. The steering committee included an international staff of 24 members and an even larger list of advisors and consultants. The committee was co-chaired by Robert Levine from Yale University, who was listed as a “Special Consultant” on the Belmont Report and authored the first four articles for discussion in the appendix to the Belmont Report, and John H.
Bryant, an American physician with a distinguished career in international medical practice. In addition to the Declaration of Helsinki, the International Ethical Guidelines for Biomedical Research Involving Human Subjects was strongly influenced by the Belmont Report as demonstrated by the inclusion of the following text under the heading General Ethical Principles: All research involving human subjects should be conducted in accordance with three basic ethical principles, namely respect for persons, beneficence and justice.
- It is generally agreed that these principles, which in the abstract have equal moral force, guide the conscientious preparation of proposals for scientific studies.
- The guidelines acknowledge the evolution of the principles following the publication of the Belmont Report with the statement, “Beneficence further proscribes the deliberate infliction of harm on persons; this aspect of beneficence is sometimes expressed as a separate principle, non-maleficence (do no harm).” The table of contents of the 1993 International Ethical Guidelines for Biomedical Research Involving Human Subjects, provided in, outlines the subjects the steering committee felt to be the most pertinent issues for research conducted in an international setting.
In addition to the obvious influence of the Declaration of Helsinki, this document reinterprets many of the issues presented in the Belmont Report, in reports from the presidential commissions, and in 45 CFR §46, Subparts A, B, C, and D to provide an adaptable set of guidelines suitable for application across a broad spectrum of cultural and political environments.
The notable exception to the similarities with the US regulations is the inclusion of a guideline titled “Compensation of Research Subjects for Accidental Injury” that provides for the following: “Research subjects who suffer physical injury as a result of their participation are entitled to such financial or other assistance as would compensate them equitably for any temporary or permanent impairment or disability.
In the case of death, their dependents are entitled to material compensation. The right to compensation may not be waived.” To date, no uniform program for compensation of human subjects injured in research is addressed in the US regulations. The International Ethical Guidelines for Biomedical Research Involving Human Subjects was updated in 2002, and CIOMS continues its efforts to revise the guidelines as dictated by changes in research requiring human subjects.
All the efforts described to this point promoted regulations and procedures based on an ethically sound approach to protecting human subjects who, by consent or proxy, will be participating in research. The ethics of the research environment seems to have improved as a result of these efforts both in the United States and internationally.
Institutional Review Board (IRB) – Institutional Review Board, Ethics Committee
Notable instances of particularly egregious studies have come to light since the publication of the Belmont Report, but most of these studies originated before that document was issued. One study in particular raised eyebrows for its similarity to the transgressions committed in the Tuskegee study and, after investigation, was found to have ties to the Tuskegee study.
In October 2010, the United States disclosed that the US Public Health Service sponsored studies of sexually transmitted diseases in Guatemala beginning in 1946. This exposé began with the discovery of documents among papers donated by Dr John Cutler to the library at the University of Pittsburgh. Before retiring, Cutler was on the faculty at the university’s School of Public Health following a long career in the US Public Health Service where he had been one of the staff members involved with the Tuskegee study.
Hoping to gain insight into the Tuskegee study, Dr Susan Reverby from Wellesley was reviewing Cutler’s papers when she came across previously unknown information about experiments investigating sexually transmitted diseases in Guatemala that Cutler and his associates conducted.
An account in the American Journal of Public Health reports that ” more than 5000 uninformed and unconsenting Guatemalan people were intentionally infected with bacteria that cause sexually transmitted diseases” and many were never treated. When the details of these experiments came to light, they precipitated an apology from President Barack Obama and specific directives to the Presidential Commission for the Study of Bioethical Issues, a commission appointed by Obama, to “convene a panel to conduct, beginning in January 2011, a thorough review of human subjects protection to determine if Federal regulations and international standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government.
I also request that the Commission oversee a thorough fact-finding investigation into the specifics of the U.S. Public Health Service Sexually Transmitted Diseases Inoculation Study” (). The Presidential Commission’s first report, ” Ethically Impossible” STD Research in Guatemala from 1946 to 1948, provides a detailed account of the history surrounding the Guatemala studies and all of the supporting evidence.
In the preface, the Presidential Commission reports, “With dual responsibilities to give a full and fair accounting of events largely hidden from history for nearly 65 years and also provide an assessment of the current system, the Commission decided to publish two reports. This is the first report, a historical account and ethical assessment of the Guatemala experiments.” The specific political circumstances in which the experiments were conceived and carried out is critical to gaining some understanding of how ethically questionable research, however ill-conceived, was carried out by people who most probably had good intentions.
The significance of the deleterious effects of sexually transmitted diseases among troops in World War II and how those effects precipitated the experiments are difficult to understand in today’s world of effective antibiotics. In the 1940s wartime environment, however, understanding all aspects of sexually transmitted diseases was perceived as a crucial aspect of the military’s ability to field an effective fighting force for the war in Europe.
- The experiments must be viewed in this historic context to understand the powerful motivation behind the studies.
- The ” Ethically Impossible ” report includes an excerpt from a 1943 letter from Dr Joseph Earle Moore, Chair of the Subcommittee on Venereal Diseases under the National Research Council, to A.N.
Richards, Chair of the Medical Research Committee of the Office of Scientific Research and Development, in which Moore wrote that he expected “approximately 350,000 fresh infections with gonorrhea, will account for 7,000,000 lost man days per year, the equivalent of putting out of action for a full year the entire strength of two full armored divisions or of ten aircraft carriers.” Moore estimated that the cost of treating the anticipated infections would be $34 million, equivalent to approximately $440 million today, adjusted for inflation.
Within this context, serious planning to meet the challenge of understanding and treating sexually transmitted diseases appears to have coalesced at the national level in 1942. Planning for these studies continued through the following year, with one of the principals suggesting “the possibility of using federal prisoners, Army prisoners, or conscientious objectors as an alternative” for research subjects.
In 1943, experiments began at the US Penitentiary in Terre Haute, IN, that continued for 2 years. The focus of the experiments was on efforts to infect prisoners with Neisseria gonorrhoeae to test various methods for prophylaxis and treatment. Isolates of bacteria were applied directly to the penises of subjects in an effort to reliably infect the “volunteers.” However, the failure to reliably infect subjects in this fashion clearly indicated that studies of prophylactic techniques would not be possible with this approach, leading to consideration of other options.
The studies were performed under the direction of Dr John F. Mahoney, then head of the US Public Health Service/Venereal Disease Research Laboratory (VDRL) set up within the US Marine Hospital in Staten Island, NY. Mahoney directed the Terra Haute prison studies from his Staten Island laboratory, while 28-year-old Dr Cutler ran the studies at the prison.
Following the end of World War II in 1945, the military support for the studies was less enthusiastic, but the Public Health Service remained committed to supporting the research with plans to move the research to Guatemala. A 1947 article Mahoney published in the Journal of Venereal Disease Information provides some insight into why the studies were moved: “It has been considered impractical to work out, under postwar conditions in the United States, the solution of certain phases concerned with the prevention and treatment of syphilis.
- These problems are largely concerned with the development of an effective prophylactic agent for both gonorrhea and syphilis and the prolonged observation of patients treated with penicillin for early syphilis.
- Because of the relatively fixed character of the population and because of the highly cooperative attitude of the officials, both civil and military, an experimental laboratory in Guatemala City has been established.” As fate would have it, a Guatemalan physician named Funes, who had served a fellowship at the VDRL and returned to Guatemala, was essential to the transition of the studies to his country.
In August 1946, Cutler transitioned from Terra Haute to Guatemala at Funes’s urging. Cutler staffed a clinic that provided the regular health inspections required for registered sex workers and suggested that the facility provide an environment of “normal exposure” through which sexually transmitted diseases could be more predictably transmitted.
The studies in Guatemala evaluated possible prophylactic intervention “in cooperation with the Guatemalan Venereal Disease Control Department” that Funes directed and the local penitentiary “where exposure of volunteers to infected prostitutes would provide the testing opportunities.” Enrolling prisoners, a contained and restricted population, after they had had sexual intercourse with commercial sex workers known to be infected with sexually transmitted diseases, promised to establish, according to Cutler, a “rapid and unequivocal answer as to the value of various prophylactic techniques” through the preferred technique of “normal exposure.” After beginning with studies of “normal exposure” in prisoners, Cutler expanded the population of research subjects to include patients in a psychiatric hospital and again tried artificial means of infection, including scarification—mechanically damaging the skin and mucous membranes of the penis—to enhance the likelihood of infecting the subject.
An even more aggressive study included at least 7 women in a psychiatric institution who were infected by the injection of syphilis specimens directly into the subarachnoid space surrounding the brain. Only 5 of them later received medical therapy. In addition, studies to follow the serology of children in a large orphanage were undertaken to better understand the specificity of tests for sexually transmitted diseases, an additional goal of the Guatemalan studies.
Studies in which subjects were intentionally infected were completed in the later months of 1948, and Cutler left Guatemala in December 1948 to join a WHO Disease Demonstration Team in India. From April 1949 to July 1950, this team worked to establish a venereal disease control demonstration in various parts of India and teach advanced methods of control for sexually transmitted diseases.
Meanwhile, the US Public Health Service hired Funes and another Guatemalan physician, Dr Salvado, to continue “the observation of certain of the patient groups” after Cutler left Guatemala. Funes’s staff collected data on residents of the orphanage, inmates of the penitentiary, individuals from the psychiatric hospital, schoolchildren, and the members of “various Indian tribes in the vicinity of Guatemala” who had participated in the experiments.
Funes was hired to “advise concerning the clinical examinations of treated patients, their re-treatment as may be required, the collection of blood specimens for serologic examinations at periodic intervals, the preparation and shipment of all blood specimens collected for serologic examination” to the United States, and “the submission of such reports as may be necessary for the completion of the study of this patient group.” Based on the one report available in the Cutler Documents, Funes and his staff followed approximately 248 people from the mental institution, completing 243 blood draws and 170 lumbar punctures.
Several of those subjects tested positive for syphilis during the follow-up experiments. The subjects from the psychiatric hospital were followed until at least 1953. The published work resulting from the Guatemala experiments also indicates that Funes continued to do serological testing on the children at the orphanage until at least 1949.
The experiments in Terra Haute were conducted and supported by many of the same people involved in the Guatemala experiments with the same goal of finding suitable prophylaxes for sexually transmitted diseases. However, throughout their discussion of the background leading to the experiments in the United States and the subsequent Guatemalan experiments, the Presidential Commission provides details of concerns voiced among those planning the studies.
These details construct a compelling argument that all along the way there was an undercurrent of concern that the studies proposed were at the least controversial, most probably unethical, and in some instances arguably illegal. The Presidential Commission reached the conclusion that “Conducting the experiments in Guatemala provided an opportunity to work with reduced concern for some of the key obstacles associated with the Terre Haute experiments: fear of adverse legal consequences and bad publicity.” In a footnote to the report, the authors point out that “These concerns followed the researchers to Guatemala, however, as evidenced by some of their efforts to limit and restrict access to information about the work.” The Presidential Commission summarized their findings as follows: “In the Commission’s view, the Guatemala experiments involved unconscionable violations of ethics, even as judged against the researchers’ own understanding of the practices and requirements of medical ethics of the day.” The report concludes Although some individuals are more blameworthy than others, the blame for this episode cannot be said to fall solely on the shoulders of one or two individuals.
- The unconscionable events that unfolded in Guatemala in the years 1946 to 1948 also represented an institutional failure of the sort that modern requirements of transparency and accountability are designed to prevent.
- In the final analysis, institutions are comprised of individuals who, however flawed, are expected to exercise sound judgment in the pursuit of their institutional mission.
This is all the more true and important when those individuals hold privileged and powerful roles as professionals and public officials. One lesson of the Guatemala experiments, never to take ethics for granted, let alone confuse ethical principles with burdensome obstacles to be overcome or evaded, is a sobering one for our own and all subsequent generations.
- We should be ever vigilant to ensure that such reprehensible exploitation of our fellow human beings is never repeated.
- The second charge from President Obama to the Presidential Commission was to provide a “thorough review of human subjects protection to determine if Federal regulations and international standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government.” The Presidential Commission addressed this directive in their report Moral Science: Protecting Participants in Human Subjects Research that was completed in December 2011.
Regarding whether the regulations would prevent abuses similar to the studies in Guatemala, the Commission noted, “Existing evidence suggests both that the rules governing federal research today adequately guard against abuses analogous to those perpetrated in Guatemala in the 1940s and that current regulations generally appear to protect people from avoidable harm or unethical treatment, insofar as is feasible given limited resources, no matter where U.S.-supported research occurs.” The report summary continued as follows: The current U.S.
System provides substantial protections for the health, rights, and welfare of research subjects and, in general, serves to “protect people from harm or unethical treatment” when they volunteer to participate as subjects in scientific studies supported by the federal government. However, because of the currently limited ability of some governmental agencies to identify basic information about all of their human subjects research, the Commission cannot say that all federally funded research provides optimal protections against avoidable harms and unethical treatment.
The Commission finds significant room for improvement in several areas where, for example, immediate changes can be made to increase accountability and thereby reduce the likelihood of harm or unethical treatment. The report outlines the Presidential Commission’s observations and recommendations based on a thorough review of federally funded research, including studies that may involve human subjects in other countries.
- One issue the Commission raised was the general lack of accessibility to data: “there is no ready source that comprehensively describes its basic characteristics, such as level of funding, or number of studies, subjects, or geographic locations.
- Instead, what exists are isolated pockets of information and some descriptive summaries.” This difficulty in acquiring information prompted the Presidential Commission’s first recommendation to improve accountability through public access: “accountability can and should be refined through improving access to basic information about the scope and volume of human subjects research funded by the government.” The commission cites precedent for this recommendation from the Institute of Medicine–issued Responsible Research: A Systems Approach to Protecting Research Participants, with its recommendation to extend the oversight system to all research, regardless of funding source or research setting.
Treatment and compensation for research-related injuries were also identified as an issue of concern, a subject that has been scrutinized regularly in past discussions as human research protection has evolved. Obama’s Commission noted that this issue still required attention at the time of their review, pointing out that most other developed countries require sponsors, investigators, or others engaged in research to provide treatment or reimbursement free of charge to the subject for research-related injury or illness.
- As discussed earlier, one of the deviations from the general agreement between CIOMS and US regulations is the recommendation for subject compensation in the CIOMS guidelines.
- The Presidential Commission “draws a bright line affirming the view of most bioethicists and others, including the majority of nations supporting human subjects research around the globe, that human subjects should not individually bear the costs of care required to treat harms resulting directly from that research.” Recognizing that previous bioethics commissions and other advisory bodies had opined in favor of compensation or treatment for research-related injuries with relative silence by the government, the Commission advocated a response as to reasons for changing or maintaining the status quo.
This issue remains open with no progress as this article is being written. The Commission also asked that the OHRP examine, recognize, and define when protections delineated in foreign laws and regulations are accepted as equivalent to US regulations and exercise its longstanding authority to recognize these protections when available.
Protections offered by international partners have been a source of confusion, as the federal regulations state that equivalent protections from international studies should be accommodated but do not provide guidance for how they should be defined. This directive has been reevaluated several times since its inception, including a specific request from the United Kingdom in 2007 to provide a determination of equivalence for human research protections afforded by UK regulations.
As of the Commission’s report in 2011, the OHRP had not formally recognized any country’s protections as equivalent. The Commission also noted that the FDA, while not signatory to the Common Rule, does adhere to the regulations at 45 CFR §46, Subpart A whenever possible and accepts data from foreign studies that comply with certain international standards for human subjects protection, such as studies that abide by good clinical practice, the Declaration of Helsinki, or certain host country regulations.
- This practice should provide a model to develop a system for recognizing equivalent protections as currently regulated by provisions in the Common Rule.
- In its final recommendation, Promoting Current Federal Reform Efforts, the Presidential Commission called for broad reform of federal research rules and procedures beyond simply addressing equivalent protections.
The Commission supports the federal government’s proposed reforms to: a) Restructure research oversight to appropriately calibrate the level and intensity of the review activities with the level of risk to human subjects; b) Eliminate continuing review for certain lower-risk studies and regularly update the list of research categories that may undergo expedited review; c) Reduce unnecessary, duplicative, or redundant institutional review board review in multi-site studies.
- Regardless of the process used to review and approve studies, institutions should retain responsibility for ensuring that human subjects are protected at their location as protection of human subjects includes much more than institutional review board review.
- The use of a single institutional review board of record should be made the regulatory default unless institutions or investigators have sufficient justification to act otherwise; d) Make available standardized consent form templates with clear language understandable to subjects; e) Harmonize the Common Rule and existing regulations of the Food and Drug Administration, and require that all federal agencies conducting human subjects research adopt human subjects regulations that are consistent with the ethical requirements of the Common Rule; and f) Work toward developing an interoperable or compatible data collection system for adverse event reporting across the federal government.
Most of these provisions were included in the revisions to the Common Rule that updated the original provisions from 1991 and were effective January 21, 2019, with the exception of staged implementation of single IRB review for multisite studies. Twenty federal agencies follow the Common Rule, with the notable exception of the FDA.
So far, no official indication of the FDA’s intent has been provided, although the expectation is that some effort will be made to harmonize the regulations—at least in a similar fashion as previous agreements. This exposition of how we have arrived at the current rules and regulations for protecting human subjects who participate in research is lengthy but is at best an outline.
Even this abbreviated history should elicit an appreciation of the complexity of the ethics surrounding protection of human subjects in research. A fair question is whether these provisions have significantly altered the landscape since Dr Beecher published his concerns in the New England Journal of Medicine in 1966.
- A cursory review turns up a few exceptions to the relative safety afforded by the current protections, with three that are particularly instructive.
- Jesse Gelsinger had just turned 18, the legal age for consent, when he volunteered in 1999 for a phase 1 gene therapy study designed for treatment of ornithine transcarbamylase (OTC) deficiency.
Phase 1 studies are designed primarily to determine the appropriate dose of a drug. Gelsinger was born with a mild form of OTC that was well controlled by diet and drug therapy; he had minimal risk of serious complications from the disease as long as he followed his treatment protocol.
- He did not stand to benefit significantly from his participation in the phase 1 study but felt that he should volunteer because of the knowledge that might benefit others.
- Gelsinger died 4 days after receiving an experimental therapy consisting of a gene attached to an adenovirus that would theoretically serve as a delivery system to insert the new gene into the DNA of his liver cells.
The death was unexpected in a relatively healthy 18-year-old, and the outcome precipitated a long and contentious investigation into how the protections that should have prevented Gelsinger from participating in the study were circumvented or ignored.
The investigation uncovered questions regarding (1) information that should have been included in the consent form, (2) the actual risk posed by the study based on complications from similar studies that were not disclosed in reports to regulatory bodies, (3) why Gelsinger was enrolled in the study in violation of the protocol’s inclusion/exclusion criteria, (4) the potential risk/benefit analysis based on the mild nature of his disease that would argue against his participation, and (5) an undisclosed conflict of interest for the director of the gene studies program that may have clouded decisions at critical points during conduct of the study.
– Examination of this study demonstrates that the protections afforded to subjects are well established but still depend on the assumption that the individuals responsible for every step of the evaluation and approval of studies and those who actually conduct the research all perform reliably in their roles.
- Another notable case revolves around the issues of appropriate consent, appropriate risks for children (or any vulnerable population), and disclosure of results obtained in research studies.
- The Kennedy Krieger Institute (KKI), an affiliate of Johns Hopkins Children’s Center, conducted a study evaluating the effectiveness of lead abatement programs in low-income housing in Baltimore, MD during the 1990s.
The study recruited families to live in houses either untouched or treated with different abatement techniques to determine which processes were most effective in protecting children from the significant neurologic effects of elevated lead levels that were endemic among children living in low-income housing in Baltimore.
The goal was “to find a relatively inexpensive and effective method for reducing—though not eliminating—the amount of lead in children’s homes and thereby reducing the devastating effect of lead exposure on children’s brains.” A total of 108 families with young children were recruited to live in houses with lead levels ranging from none to levels just below the existing legal limit, and the children’s serum lead levels were monitored.
In two homes, the lead levels in the children crossed into toxic levels, but the families were not informed or advised to move out of the toxic environment. Eventually, a lawsuit was filed on behalf of the two children, and it raised significant ethical questions surrounding informed consent, appropriate risks, and disclosure of results that are reviewed at length in the article “With the Best Intentions: Lead Research and the Challenge to Public Health.” The Maryland Court of Appeals opinion equated the multiyear lead study with the Tuskegee study in its egregious disregard for research ethics in a vulnerable population.
- Ellen Roche was a healthy 24-year-old laboratory technician at the Johns Hopkins Asthma and Allergy Center.
- She volunteered to take part in a 2001 lung function physiology experiment in which normal pulmonary function in healthy volunteers would be manipulated by inhalation of hexamethonium, a compound that interferes with normal nervous system interaction with the lungs to mimic a mild asthma attack.
Although it had been used in the 1950s to treat hypertension, hexamethonium fell into disuse as more effective drugs became available, and the FDA withdrew approval in 1972. Of note, hexamethonium was never approved as an inhaled medication. Roche was the fourth patient to receive hexamethonium in the trial.
- The literature search relied on PubMed and one contemporary textbook of pulmonary medicine to explore the potential use of hexamethonium for the purpose proposed in the research plan. Neither source revealed any indication of concerns, although other databases and older textbooks warned of significant pulmonary complications associated with hexamethonium.
- No request was made to determine if the FDA required an investigational new drug application, even though the medication was no longer approved and had never been approved as an inhalational drug.
- The consent form referred to hexamethonium as a medication but failed to mention that FDA approval had been withdrawn.
- A few subjects included in previous studies used inhaled hexamethonium with no mention of problems in the subsequent publications, but two subjects did have significant difficulties that were not reported as the investigator did not consider them related to the drug.
- The hexamethonium used in the study was of chemical grade and was not prepared as a pharmaceutical agent.,
This list is not complete and raises many concerns, but the focus of the investigation became the lack of adequate research to confirm that the compound used to induce asthma symptoms was safe. The responsibility for this failure primarily attached to the investigator, with additional concern focusing on a review process that failed to follow proper procedures for approval of the protocol.
During the follow-up, several articles from the 1950s reporting that hexamethonium could cause fatal lung inflammation similar to the pulmonary complications leading to the demise of Ellen Roche were identified. PubMed’s coverage of the literature starts in the mid-1960s. In addition, review of the FDA records related to the withdrawal of hexamethonium in 1972 cited the drug’s “substantial potential toxicity” as one element leading to the decision.
The examples of ethical issues from history and the scarcity of contemporary examples demonstrate that regulations for the protection of humans participating in research have evolved in a way that minimizes the probability of harm to subjects choosing to participate in research.
These examples also reinforce the importance of individual responsibility to faithfully execute the requirements of their assigned roles. Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol.
Furthermore, these examples support the argument that no amount of regulation or oversight can completely remove the variable of individual failures to adhere to the rules or accept the responsibility associated with their role in research that may precipitate serious unexpected consequences.
- The rules and expectations for those charged with the review, administration, and performance of research requiring human subjects can only minimize the probability that these instances will occur.
- The point at which the primary responsibility of protecting human subjects from preventable harm deviates to focus on some other aspect of the research that leads to harm is rarely predictable.
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Why was the IRB made?
Purpose of IRB Review – The purpose of IRB review is to ensure that ethical standards for the care and protection of human subjects have been established and that research activities are in compliance with all pertinent regulations (federal, state and local) and with Fred Hutch policy. The term “human subjects” may include the following:
Inpatients and outpatients Donors of organs, tissues and services Informants and normal volunteers, including students who are placed at risk during training
In addition, the term “human subject” is not limited to activities involving the intact human, but extends to activities involving the use of human embryos, fetuses, abortuses, organs, tissues, body fluids, or graphic written or recorded information.