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The Journal of Bone and Joint Surgery (American). 2007;89:418-426. doi:10.2106/JBJS.F.00362 © 2007 The Journal of Bone and Joint Surgery, Inc.
Institutional Review Board Approval: Why It Matters
1 Rothman Institute of Orthopedics at Thomas Jefferson University Hospital, 925
Chestnut Street, Philadelphia, PA 19107. E-mail address for J. Parvizi:
parvj{at}aol.com
Investigation performed at Thomas Jefferson University, Philadelphia,
Pennsylvania
The modern institutional review boards originated in the 1970s. They exist to protect human subjects participating in research from potential harm. The Belmont Report provided the ethical principles (respect for persons, beneficence, and justice) that should be observed while conducting research on human subjects. Compliance with the ethical principles of the Belmont Report is a first step in successful submissions to an institutional review board. Regulations regarding conflict of interest represent an attempt to ensure that research is not biased by financial or other interest and to maintain public trust.
The history of protection of human research subjects in the modern era started in earnest after the Nazi doctors' trials illuminated the horrendous "experiments" performed on concentration camp internees during World War II. The Nuremberg War Crime Trials resulted in the formulation of the Nuremberg Code1, a set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp internees. Several key episodes of human experimentation led to the formulation and implementation of rules and regulations that currently govern research on human subjects. First adopted in 1964, the World Medical Association Declaration of Helsinki2 further outlined principles that had international relevance for medical research involving human subjects. Since its inception, the Declaration of Helsinki has been amended five times. The most recent revision, the addition of paragraphs 29 and 30, has been the source of continued controversy stemming from stances related to post-study access to treatment in populations that otherwise would not have access to such treatment3 and the role of placebo controls when treatment for investigated pathological conditions exists4. The United States of America was also the venue for notable unethical research, which led to policy and legislation reform to protect human participants. The United States Public Health Service study of untreated syphilis in African-American males was conducted for forty years at the Tuskegee Institute without review and denied participants the effective and available treatment for syphilis. At the Willowbrook State School, parents were coerced into enrolling their mentally retarded children in studies on the natural history of hepatitis that had no potential benefit for participants. In both examples, the investigators deemed the designs "studies in nature" and received scorn from ethicists5. These experiments and others, often individually but certainly collectively, violated nearly every ethical consideration that should have governed investigators performing research on humans and precipitated an intense federal government investigation that culminated in the Belmont Report6, released in 1979. The Belmont Report provided the ethical principles (respect for persons, beneficence [defined as the act of doing or producing good; performing acts of kindness and charity], and justice) that should be observed while conducting research on human subjects. The rules and regulations as set forth by the United States Health and Human Services Code of Federal Regulations Title 45 CFR 46 provide laws that ensure that these ethical principles are followed7. Are they necessary? The answer is a resounding yes. Despite the best efforts of those in governmental agencies, institutional review boards, and research teams to educate people involved in research on human subjects, infractions that have very serious consequences, including the death of subjects, continue. Compliance with the ethical principles of the Belmont Report is a first step in successful submissions to institutional review boards.
The modern concept of the institutional review board originated in the 1970s. Duties promulgated to institutional review boards include ethics consultation, education, peer review, monitoring of clinical trials, and protection of the safety and welfare of research subjects8. Additional roles include initial protocol review, ongoing review, and monitoring of adverse events. Furthermore, institutional review boards maintain the authority to sanction and enforce rules regarding noncompliant investigators by rejecting a proposal or terminating an investigation. Institutional review boards consist of scientists, lay community members, physicians, and lawyers. Interestingly, few investigators have examined the structural makeup of institutional review boards. One published study of surveys completed by chairs of institutional review boards revealed that 447 of 488 United States hospitals had an institutional review board9. The committee size of the institutional review board varied but averaged fourteen members with representation from twenty-seven medical specialties. Orthopaedics had the least representation on institutional review boards (10% of the committee members were in the field of orthopaedics), followed by emergency medicine (12%) and ophthalmology (15%).
At present, an institutional review board can be a local (institutional or private), central, or contractual agency. Local investigators must have a thorough understanding of the trial and its objectives and be able to assess the potential risks and benefits for subjects involved in the research10. The institutional review board is ultimately not responsible for the results of human subject research; that responsibility remains with the well-informed investigator. A high-quality institutional review board review, although necessary, cannot guarantee the full protection of research subjects, unless the research investigators abide by the rules11. Improving the protection of human subjects is the unifying goal of each institutional review board. In 2002, a pilot program developed by the National Cancer Institute established a central institutional review board that reviewed protocols for multicenter phase-3 clinical trials12. The central institutional review board now provides protocol and consent-form reviews to local institutional review boards by means of an institutional review board authorization agreement. Changes to protocols are not allowed, but local sites can make consent forms site-specific (such as with contact numbers for the principal investigator and page headers). Local institutional review boards are then able to review studies more expeditiously, on the basis of the review and recommendations of the central institutional review board. This approach reduces redundancy and capitalizes on the strengths of both central and local institutional review boards working together to protect human subjects involved in clinical research. Other recent initiatives such as commercial institutional review boards that work under contract and systems of accreditation were designed to ensure protection of human subjects. These systems arose from a common aim to relieve the burden resulting from increasingly complex protocols and increasing volumes of research conducted in the modern day. While efficiency in the review process is important, one criticism of commercial institutional review boards is the inherent conflict of interest that exists when a committee is performing reviews for entities that pay their salaries.
Review boards strive to remain free of research bias while retaining perspective on linguistic, cultural, and socioeconomic characteristics of research subjects13. Local institutional review boards enable investigating sites to protect human research subjects at both macro and micro levels, but they introduce variability into the review process. This variability may have an impact on the sometimes tenuous relationship between the institutional review board and the investigators. Some studies have shown the institutional review board review process to be cumbersome and nonstandardized, with a great variety in the results14. Authors of other studies have called for a centralized review of multicenter investigations and of practice-based research when the principal investigators are not affiliated with an institution15 and particularly to accelerate genetic research discoveries16. They have called on professional societies to facilitate education while fostering the practice-based research clinician's ability to perform research. There is a large variation among institutional review boards with regard to the number of forms required for submission, the number of days from submission to approval, and the process of approval17. Others have suggested that, although variability exists, institutional review boards adhere to similar procedures for governing research9. A new shift in the funding of clinical research from a once primarily federal source at a primary research site to a split between government and private industry has placed new strain on the modern institutional review board8. Clinical research is on the rise10,18-20, and the present abundance of such research has increased the workload and time constraints for those who safeguard human subjects21. A federal inquiry concluded that, as a result of the increased number of submissions, the average time devoted to discussion during the initial review of a protocol was twenty-one minutes for a low-volume institutional review board and three minutes for a high-volume institutional review board22. In response to these demands, some have recommended expanding the committee membership while others have suggested that adding more committee members to an institutional review board will likely have a limited impact on performance23.
The federal regulations of Title 45 CFR, Part 46 provide researchers and institutional review boards with a definition of research on human subjects: "[A] systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge" [45 CFR 46.102(d)]. Although this definition provides clear guidance for the majority of human research that is conducted, there is a contingent of activities that seems to adhere to this definition but ultimately does not require institutional review board oversight. This subset of research comprises certain quality improvement and quality assurance initiatives as well as certain case reports and case reviews. Quality improvement assessments that involve structured data collection and analysis but have the fundamental goal of improving specific processes and systems within specific organizations may not be considered research and thus may not require institutional review board approval prior to inception24. There are two general criteria that indicate that a quality improvement and quality assurance initiative constitutes human research according to Food and Drug Administration (FDA) definition: (1) the investigators will seek publication of the data in a national journal or presentation at a national meeting and/or (2) the results of the initiative will have application beyond the confines of the investigators' local institution or practice. If either of these criteria is met, then the investigators are considered to be collecting "generalizable" knowledge and the study therefore constitutes human subjects research and requires institutional review board approval. When an investigator is in doubt, the local institutional review board should be contacted to discuss the situation. It is a bit more challenging for institutional review board administrators to determine whether case reports and case reviews constitute research on human subjects and thus require institutional review board review. Unfortunately, there is no regulatory guidance regarding this issue, and there continues to be national debate among institutional review board professionals about whether case reports and reviews constitute "generalizable" knowledge or simply unique information about rare conditions that deserves greater exposure through presentation or publication. Because this is largely a philosophical issue, the policies of institutional review boards vary from institution to institution. It is advisable to consult one's local institutional review board to determine the definitions of a case report requiring approval. Review boards may review individually or refer the protocol to a privacy officer or privacy board at each institution that is charged with overseeing compliance with the HIPAA (Health Insurance Portability and Accountability Act) regulations. There is another level of screening to which investigators can look for guidance. As the national attention on human subject research has intensified, journal editors and conference planners are more likely to screen for institutional review board approval before accepting articles for publication and posters for presentation. When an investigator does not require institutional review board approval to conduct a project that will generate data that he or she intends to publish or present, the investigator should provide a statement with the article or presentation explaining that the institutional review board and the investigating site or institution did not require that the particular project be approved. One of the main reasons for assessing the need for institutional review board approval is that the consequences of violating research regulations can be severe. In one example, the development of a medical curriculum was being evaluated with a survey of students. During the initial phase of the survey, no identifier was used and hence the survey was exempt from institutional review board approval25. During the second and third years of the study, and in order to collect demographic information from the participants, the students' badge numbers were recorded. The faculty and staff conducting that survey faced possible suspension and other disciplinary action because they did not obtain institutional review board approval.
Submission Process The submission process can be an arduous task and may contribute to the sometimes strained relationship between institutional review boards and investigators. It is not uncommon for studies to be approved (or disapproved) after requests for a number of modifications of the protocol and consent form. Common reasons for modifications to be requested include improperly designed consent forms, poor study design, unacceptable risk to human subjects, and questions regarding ethical or scientific merit9. Although there is a lack of reported data on the rate of revisions of research submissions, Kent concluded that only 24% of research submissions were approved without modifications26. There are no metrics with which to assess the success and effectiveness of an institutional review board, as its ultimate success depends on its ability to protect human subjects. However, an efficient institutional review board infrastructure that allows easy submissions and faster turnaround is to be commended.
Levels of Review
Studies requiring full review are those that pose "greater than minimal" risk to research subjects; these include most clinical studies involving investigational drugs, devices, or procedures and many studies involving vulnerable populations. Full reviews require evaluation by the convened institutional review board committee (Table I). An exempt study is one that meets the narrow federal criteria allowing a study to be exempted from the purview of the human subjects regulations and therefore from the review of an institutional review board. Examples include retrospective reviews of de-identified data or collection of de-identified tissue samples. However, the exemption designation must be made by the institutional review board. Once a study is exempted from institutional review board review, no further notification of the institutional review board is required except if there are revisions in the protocol. In certain instances, revisions may alter the protocol to the degree that the study can no longer be exempted and will require a new review designation. In any case, we recommend consulting one's local institutional review board when in doubt about the level of review that an individual study requires and what paperwork must be completed prior to submission.
Training Programs
Impact of HIPAA Regulations on Modern Research
Conflicts of Interest Regulations regarding conflict of interest represent attempts to ensure that research is not biased by financial or other interest and to maintain public trust in the integrity of the researcher, the research, and the institution. Management of conflict of interest generally requires the individual and/or institution to do any or all of the following: disclose significant financial interests, allow independent reviews, modify protocols to remove or distance the individual with the conflict from research, divest oneself of significant financial interests, sever relationships that create actual or potential conflicts, and/or disqualify investigators from participation in relevant sponsored research. In collaborative research involving investigation of a drug or a device produced by a company with which an individual has a relationship that creates a conflict of interest, the conflict also needs to be disclosed to the other research co-investigators. Annual conflict-of-interest disclosures are typically required by institutions, and any conflicts should be revealed in the informed consent form. The usual thresholds for reporting conflicts, based on the recommendation of a task force assembled by the Association of American Medical Colleges (www.aamc.org/research/coi/2003coiresults2003.pdf), are >5% equity ownership interest in a company and >$10,000 of investment or other financial interest. Acceptance of gifts, gratuities, or entertainment that reach the $10,000 threshold should also be reported, as should being a manager, a scientific advisor, or a board member of the entity for which one is performing research. Conflict of commitment varies, but generally more than three to four days per month away from a primary job should be reported to institutional officials. The trend now is for zero tolerance for investigators who have a significant interest in a publicly traded company or any interest whatsoever in a non-publicly traded one. Zero tolerance in this context means that the investigator will not be allowed any involvement with the study in question.
The Protocol Protocols also need to address the nature of the drug or device and whether it has FDA approval for the intended use in the research study or is being used under an investigational new drug (IND) or an investigational device exemption (IDE) number. The risks associated with the test article must be clearly presented, ideally in a format indicating the expected incidence of these events (e.g., >10%, 2% to 9%, or <2%). If an FDA-approved device is being used in a research study for an off-label indication, a separate IDE application to the FDA for that research use may be required. The FDA-approved uses explicitly stated in the device labeling should be consulted to determine the need for additional applications. Inquiries can be made by contacting the Office of Device Evaluation (ODE) at the FDA (telephone number: 301-594-1190).
Monitoring of Research
Involvement of Vulnerable Populations The National Institutes of Health (NIH) (http://grants2.nih.gov/grants/guide/notice-files/not98-024.html) provides specific explicit criteria for exclusion of children from a research study, and these can be used as general guidelines when one is considering whether a non-NIH-funded study should include children. These exclusion criteria are as follows:
While children should be included in research, institutional review boards must ensure that risks are acceptable in relation to the anticipated benefits. As children are a vulnerable population because they are (1) not autonomous and (2) do not yet have adult cognitive ability, the parameters of allowable risk are much narrower than those for an autonomous adult. Subpart D of Title 45 CFR 46 stipulates that the institutional review board can approve research involving children if it poses minimal risk, greater than minimal risk with the prospect of direct benefit to the child subjects, and a "minor increase over minimal risk" when there is no prospect of direct benefit to the subjects but the research is likely to yield generalized knowledge about the subjects' disorder or condition. The same stipulation for inclusion, however, does not apply to cognitively impaired populations. Also, no specific exclusion criteria for this population are provided by federal guidelines or regulations. There is a general consensus among institutional review board professionals that cognitively impaired persons should not be involved in research that can be adequately conducted with non-impaired subjects, unless the research poses the possibility of direct benefit to the impaired subjects. Furthermore, no impaired persons should be involved in research involving greater than minimal risk when there is no potential for benefit to the subjects35. As there are no current federal regulations addressing inclusion of cognitively impaired subjects in research, special care should be taken when considering these issues and deciding whether it is ethical to enroll them in a particular research study. The institutional review board can provide guidance on this issue and will make the final decision regarding whether this population can be included. Ethical practices are of paramount concern for vulnerable populations in developing countries, especially when industrialized countries sponsor clinical trials in these regions36,37. International clinical trials often span various jurisdictions; however, research must be founded on ethical principles and should not exploit human subjects38. Some have suggested that the ethical standards espoused by the United States and other countries, such as prior review and review board approval (including informed consent), should be adopted in developing nations in conjunction with local customs and culture to ensure protection of human subjects36. An important point worth mentioning relates to the potential abuse of patients by subjecting them to multiple simultaneous research projects that may place an undue burden on their time, energy, and attention. In addition, the inability to comprehend the consent form, due to linguistic barriers and so on, could also result in potential abuse of subjects. It is the responsibility of the investigator to ensure that the potential for subject abuse is avoided at all times.
The Consent Form Prior to submission to the institutional review board, proofreading and spell-checking documents will result in fewer required modifications. Providing a lay-language title for the research and avoiding lengthy descriptions of the background supporting the research are useful suggestions, particularly for the informed consent forms. Additionally, avoiding irrelevant details about drug or device development is recommended for this form. Federal guidelines suggest that consent forms be written between a sixth and eighth-grade reading level. While challenging, practical solutions may include a review of the form by a non-medical colleague, especially to indicate medical terminology that may need to be changed. Software packages that analyze and modify the reading level are also available to the investigator. In most cases, medical terms should be replaced with lay terminology. Also, distinction between the standard of care and the research drug, device, or treatment needs to be made in the appropriate sections of the consent form (Introduction, Procedures, and Costs). The subject's alternatives—namely, the ability not to participate in research and yet receive the standard of care—should be clearly explained. These elements are vital to the participant's understanding of the research. If he or she is not able to distinguish the investigational procedure, drug, or device from the standard application, then he or she cannot truly give informed consent to participate. The investigator needs to adhere as closely as possible to local institutional review board guidance, instructions, and recommendations for formatting on the consent form. On signing a protocol and informed consent form as the principal investigator, one assumes full responsibility. Description of study procedures should include the number of visits, the duration of visits, the estimated time required for filling out questionnaires, and whether a pregnancy test, blood drawing (including how much, in teaspoon equivalents), and additional procedures such as radiographic and imaging studies will be required. Subjects should have costs clearly defined, including research costs incurred by the sponsor and costs billed to insurance providers or individuals. The consent form must include disclosure of conflicts of interest as well as guidelines for indemnification. If the study involves long-term follow-up of patients—e.g., to determine the success or failure of a device or patient survival—provisions for contacting subjects should be included in the consent form. Such provisions could include the subject providing the name and contact information of a relative or friend who would always know the current address of the subject or whether the subject was alive or dead. In addition, HIPAA regulations require that patients' consent for long-term follow-up be sought.
Consent Process The informed consent document is important because it serves as the initial contract between the researcher and the participant as well as a detailed reference document for the participant. However, informed consent is a principle that should underlie all interactions between the participant and the research team. A participant's questions at any time during the study should be addressed immediately and thoroughly by research personnel. The participant should be able to contact the principal investigator (hence the need to provide a telephone number) at any time that he or she has new concerns about the study. The participant should also be able to contact the institutional review board at any time if he or she has concerns about the research and would like to consult with advocates independent of the research. New risks should be communicated to the institutional review board in a timely fashion, and the subjects should be notified accordingly if necessary. The consent form may also be revised, reflecting the new risk, and submitted to the institutional review board for reapproval. Revised informed consent should be obtained from new and all active participants. If a subject decides not to continue participating once he or she has been informed of new risk data, it must be clear that he or she is free to do so without risk of retribution or of not being able to receive additional care at the institution. Common sense dictates that an ethical study is one in which the lines of communication between the research staff and participants are always open.
One should be aware of the inherent conflict between the dual roles of the clinical investigator: i.e., the role of the physician versus the role of the researcher. The former wants to treat or cure the patient, whereas the latter is obligated to collect data by following the protocol without adjusting treatment to obtain the best clinical outcome. One should be prepared to remove a subject from a study if he or she is in medical jeopardy. Institutional review boards operate under strict regulations handed down by the federal government, and a "cut and paste" strategy from sponsor protocols or investigator brochures should be avoided when constructing a protocol synopsis. Sponsor-generated consent forms must also be closely scrutinized for errors and the potential to underemphasize the associated risks. The sponsor-generated consent forms can benefit from a streamlined institutional review board audit prior to full submission to detect errors and shortcomings, thereby reducing the burden on both the investigators and the institutional review board staff without sacrificing the protection of human subjects.
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