Institutional Review Boards: What Clinician Researchers Need to Know

CONCISE REVIEW FOR CLINICIANS

Institutional Review Boards: What Clinician Researchers Need to Know Maria I. Lapid, MD; Bart L. Clarke, MD; and R. Scott Wright, MD CME Activity Target Audience: The target audience for Mayo Clinic Proceedings is primarily internal medicine physicians and other clinicians who wish to advance their current knowledge of clinical medicine and who wish to stay abreast of advances in medical research. Statement of Need: General internists and primary care physicians must maintain an extensive knowledge base on a wide variety of topics covering all body systems as well as common and uncommon disorders. Mayo Clinic Proceedings aims to leverage the expertise of its authors to help physicians understand best practices in diagnosis and management of conditions encountered in the clinical setting. Accreditation Statement: In support of improving patient care, Mayo Clinic College of Medicine and Science is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. Credit Statements: AMA: Mayo Clinic College of Medicine and Science designates this journalbased CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. MOC Credit Statement: Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 MOC point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Learning Objectives: On completion of this article, you should be able to (1) describe the general role of institutional review boards in protecting human research participants, (2) discuss the elements of legally effective informed consent, and (3) name 3 populations of research participants given special protection in human subjects research. Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine and Science (Mayo School of Continuous Professional

Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation. In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Jenna M. Pederson, have control of the content of this program but have no relevant financial relationship(s) with industry. Dr Clarke is a member of the GlaxoSmithKline Data Monitoring Board and has served as a consultant for and received a grant from Shire, Inc (all funds paid to his institution). Dr Wright has received consulting fees, travel support, and fees for participation in review activities from The Medicines Company, Sanofi, and Boehringer Ingelheim GmbH and fees for provision of writing assistance, medicines, equipment, or administrative support from Sanofi. Method of Participation: In order to claim credit, participants must complete the following: 1. Read the activity. 2. Complete the online CME Test and Evaluation. Participants must achieve a score of 80% on the CME Test. One retake is allowed. Visit www.mayoclinicproceedings.org, select CME, and then select CME articles to locate this article online to access the online process. On successful completion of the online test and evaluation, you can instantly download and print your certificate of credit. Estimated Time: The estimated time to complete each article is approximately 1 hour. Hardware/Software: PC or MAC with Internet access. Date of Release: 3/1/2019 Expiration Date: 2/28/2021 (Credit can no longer be offered after it has passed the expiration date.) Privacy Policy: http://www.mayoclinic.org/global/privacy.html Questions? Contact [email protected].

From the Department of Psychiatry and Psychology (M.I.L.), Department of Medicine, Division of Endocrinology (B.L.C.), Department of Cardiovascular Medicine (R.S.W.), and Mayo Clinic Institutional Review Board (M.I.L., B.L.C., R.S.W.), Mayo Clinic, Rochester, MN.

Abstract The institutional review board (IRB) is a group federally mandated to review and monitor research involving humans to ensure protection of their rights and welfare as research participants. Clinicians engaged in research require IRB approval for all research involving human participants, whether living individuals, data, or specimens. The process for obtaining IRB approval may seem like a daunting task. However, it is critical for clinical researchers to conduct research in a manner that protects human participants, and it is the mission of the IRB to help researchers accomplish this task. The purpose of this article is to review the role and purpose of the IRB, highlight federal and regulatory standards in human research participants protection, and help clinical researchers have a broader understanding of IRB functions that will help them conduct high-quality research with human participants. ª 2019 Mayo Foundation for Medical Education and Research

Mayo Clin Proc. n March 2019;94(3):515-525 n https://doi.org/10.1016/j.mayocp.2019.01.020 www.mayoclinicproceedings.org n ª 2019 Mayo Foundation for Medical Education and Research

n

Mayo Clin Proc. 2019;94(3):515-525

515

MAYO CLINIC PROCEEDINGS

I

nstitutional review boards (IRBs) are pivotal for the safe, ethical, and standardized conduct of human participant research. Human participant research is more complex now than a decade ago, yet remains critically important for the development of safe, effective, and comprehensive medical treatments and the discovery of knowledge about health conditions. Clinicians and scientists who conduct human participant research face ever more complex rules and regulations and ever changing societal expectations with regard to consent and transparency and find themselves at times confused or frustrated about the growing regulatory burden of research conduct.1,2 Current research regulation issues highlight the importance of understanding the IRB’s role regarding approval of human participant research and the issues that IRBs must consider regarding research approval.

ROLE AND PURPOSE OF IRBs An IRB is an appropriately constituted group formally designated in federal regulations to review and monitor biomedical research involving human participants. In accordance with US Food and Drug Administration (FDA) regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. The IRB review serves an important role in protecting the rights and welfare of human research participants.3 The federal mandate for the IRB to regulate research in humans comes from the FDA and the Office for Human Research Protections and is detailed in the Code of Federal Regulations Title 21 Part 56.3 Historically, the infamous Tuskegee syphilis study conducted by the federal government in the 1930s recruited vulnerable African American men who were misled into thinking they were receiving medical care for syphilis but instead were merely followed up throughout the course of their illness even when penicillin became available.4 The outrage over this study resulted in the passage of the National Research Act of 1974 to establish Department of Health and Human Services policy for protection 516

Mayo Clin Proc.

n

of human research participants and led to required IRB review and approval of all human participants research in the United States. Institutional review boards are locally administered, although multisite research studies can rely on a single central IRB for partial or complete review of a study. Because protection of human research participants cannot be done by the IRB alone, IRBs typically reside under a larger human research protection program within an institution or organization. Human research protection programs exist to coordinate the work of many entities involved in protecting human participants in research including but not limited to IRBs and other functional units (Figure). Diversity within IRB membership is required, including consideration of race, sex, cultural backgrounds, and sensitivity to such issues as community attitudes.5 The diversity of representative capacities and disciplines is intended to bring a wide range of experience and expertise beyond the specific research that allows for a comprehensive review of the research, not just for its scientific merit but also for acceptability from a social, legal, and institutional perspective. The composition of an IRB is specified within 21CFR56.107 and includes scientific reviewers with biomedical or behavioral expertise, nonscientific reviewers with little or no medical experience, community members to bring a layperson perspective, and IRB staff trained to conduct IRB activities.6 In addition, the decisions of an IRB are final and independent of review/reversal by the institution where it is convened. Institutional review board reviews must include evaluation of the research for compliance with ethical principles laid out in federal regulations in the United States, as well as from the International Council for Harmonisation guidance for Good Clinical Practice for international research. Institutional review boards may choose to be accredited through the Association for the Accreditation of Human Research Protection Programs, but is not mandatory. The US Department of Defense also establishes

March 2019;94(3):515-525

n

https://doi.org/10.1016/j.mayocp.2019.01.020 www.mayoclinicproceedings.org

IRB FOR CLINICIANS

IRB

Conflict of interest board

Pharmacy services

Investigators and research staff

Office of research regulatory support

Office of research public affairs

Office of research quality management services

Office of research biospecimens

Office of sponsored projects administration

Office of research communication

Clinical trials office

Office of compliance

Centers and institutes

Departmental scientific and resource review

Bioethics program and research participant advocacy program

Research administrative services

Legal services and legal contract administration

Clinical research resources and education

FIGURE. Human research protection program. IRB ¼ institutional review board.

accreditation requirements for its own IRBs and affiliated IRBs. DEFINITION OF RESEARCH AND LEVELS OF IRB REVIEW Research is defined as a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge.7 Activities that are deemed not to be research include reports of single cases, public health surveillance activities that are necessary during public health crises, collection and analysis of data solely for criminal justice or investigative purposes, or agencyauthorized operational activities in support of intelligence, homeland security, defense, or other national security missions.8 Quality improvement activities that do not satisfy the definition of “research” do not require IRB review, and the intent to publish the results does not necessarily mean it is research. On the other hand, quality improvement Mayo Clin Proc. n March 2019;94(3):515-525 www.mayoclinicproceedings.org

n

projects that involve human participant research require IRB review.9 A human subject is defined as a living individual about whom an investigator conducting research obtains data through intervention or interaction with the individual or identifiable private information.7 Human subject research is a systematic investigation of human participants, whether living individuals, data, or specimens.7 Institutional review boards have the authority to determine whether an activity is considered human participant research. There are 3 levels of IRB review depending on the level of potential risk to, and the vulnerability of, the human participants: (1) exempt review, (2) expedited review, and (3) full board review (Table). Exempt review means the research meets requirements for exempt research under federal regulations 45CFR46.101, which includes categories that involve no risk or only less than minimal risk to human participants.10 Studies deemed exempt by IRB do

https://doi.org/10.1016/j.mayocp.2019.01.020

517

518

TABLE. Levels of Institutional Review Board (IRB) Review Level of IRB review Variable

Expedited review

Full board review

Definition

Exempt review means the research involves no risk or less than minimal risk to human participants The research meets standards for exempt research categories as defined by federal regulations. IRB determination is required for exempt research status This review type is conducted by the IRB chair or experienced IRB reviewers designated by the chair or other institution-specific process for exemption determination (see review process below) Research not eligible for exempt review may be eligible for an expedited review

Expedited review means the research involves no more than minimal risk to human participants The research falls under the categories eligible for expedited review procedures defined by federal regulations This review type is conducted by the IRB chair or experienced IRB reviewers designated by the chair Research not eligible for expedited review is referred to full board for review

Full board review means the research involves greater than minimal risk to participants or sensitive topics or protected or vulnerable populations such as children, prisoners, those with disabilities, or terminally ill individuals This review type involves a fully convened board with voting members, presence of quorum, and formal review procedures as required by federal regulations Research is not eligible for exempt or expedited review

Review process

1. IRB document submission 2. Review by IRB chair or designee or other process* 3. Exemption determination *Some institutions have processes in place such as checklists or Web-based forms that allow investigators to determine whether a study is exempt research or not10

1. IRB document submission 2. Review by IRB chair or designee 3. IRB decisiondapproval or referral* to a fully convened board for review *Research cannot be disapproved under expedited review procedures. Referral to a fully convened board occurs when there are questions or concerns regarding the research that require a full board discussion and nonexpedited review

1. IRB document submission 2. Review by fully convened IRB, with primary, secondary, and if needed tertiary reviewer 3. IRB decisiondapproval, deferral, or disapproval

Type of application

1. Initial* application Note: IRB approval of continuing review or modifications will be required for any change in risk to participants or significant study procedure changes *Initial ¼ new application

1. Initial application 2. Continuing reviewdfor research previously approved by full board review, if enrollment is permanently closed, participants have completed all research-related interventions, and research remains active only for long-term follow-up of participants or data analysis 3. Modificationsdfor minor changes that do not change the risk to participants

1. 2. 3. 4.

Federal regulations

Exempt research7 1. Research in educational settings that involve normal educational practices that are not likely to adversely impact students’ opportunity to learn or assessment of educators 2. Research that only includes interactions involving educational tests (cognitive, diagnostic, aptitude,

Expedited review categories11 Content created by the Office for Human Research Protections: 1. Clinical studies of drugs and medical devices when an investigational new drug or investigational device exemption application is not required 2. Collection of blood samples by finger stick, heel

Criteria for IRB approval of research8 1. Risks to participants are minimized 2. Risks to participants are reasonable in relation to anticipated benefits, if any, to participants, and the importance of the knowledge that may reasonably be expected to result. 3. Selection of participants is equitable

Mayo Clin Proc.

Exempt review

n

March 2019;94(3):515-525

Initial application Continuing review Modifications Reportable events

n

MAYO CLINIC PROCEEDINGS

https://doi.org/10.1016/j.mayocp.2019.01.020 www.mayoclinicproceedings.org

Continued on next page

Level of IRB review Variable

Exempt review

3.

n

https://doi.org/10.1016/j.mayocp.2019.01.020

4.

5.

6.

achievement), survey procedures, interview procedures, or observation of public behavior (including visual or auditory recording) without directly identifying a participant Research involving benign behavioral interventions that collect verbal or written responses or audiovisual recording with permission for the participant; are benign, brief, harmless, painless, not physically invasive, and not likely to have a significant adverse lasting impact on the participants (examples: online game, puzzles under various noise conditions, decide how to allocate a nominal amount of received cash between themselves and someone else); or if involving deception, the participant authorizes the deception through a prospective agreement to participate in research in circumstances in which the participant is informed that he or she will be unaware of or misled regarding the nature or purposes of the research Secondary research for which consent is not required: Secondary research uses of identifiable private information or identifiable biospecimens, if publicly available, or without the ability to directly identify a participant, or for the purposes of “health care operations” or “research” for “public health activities and purposes,” or research conducted by the federal government maintained on information technology according to federal regulations Research and demonstration projects that are conducted or supported by a federal department or agency for public benefit or service programs Taste and food quality evaluation and consumer acceptance studies

519

Expedited review

Full board review

stick, ear stick, or venipuncture are not more than 2 times per week and do not exceed 550 mL in an 8-week period from healthy, nonpregnant adults who weigh at least 110 lb (49.5 kg); or 50 mL or 3 mL per kg in an 8-week period from other adults and children 3. Prospective collection of biological specimens for research purposes by noninvasive means 4. Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves 5. Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for nonresearch purposes (such as medical treatment or diagnosis) 6. Collection of data from voice, video, digital, or image recordings made for research purposes 7. Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies 8. Continuing review of research previously approved by the convened IRB when the research is permanently closed or remaining research activities are limited to data analysis 9. Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified

4. Informed consent will be sought from each prospective participant or the participant’s legally authorized representative 5. Informed consent will be appropriately documented or appropriately waived 6. When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of participants 7. When appropriate, there are adequate provisions to protect the privacy of participants and to maintain the confidentiality of data

IRB FOR CLINICIANS

Mayo Clin Proc. n March 2019;94(3):515-525 www.mayoclinicproceedings.org

TABLE. Continued

MAYO CLINIC PROCEEDINGS

not require continuing review submission unless the risk to participants changes due to any change in research procedures. Institutions and IRBs are required to have policies that clearly describe a method for how exempt determinations are made for any research involving humans.10 Expedited review means the research involves no more than minimal risk to humans and is eligible for IRB review through expedited review procedures. Expedited review may also be used when minor changes are being proposed to a previously approved research that does not change the level of risk to participants. There is no federal definition of "minor change" in research, although a study of 184 institutional IRB policies found that definitions of minor change are based on lack of significant changes in risks or discomforts; research methods, aims, or procedures; risk/benefit ratio; research team; research facilities; study population size or composition; and consent process or willingness to participate.12 The expedited review procedures may be conducted by the IRB chairperson or another experienced reviewer designated by the IRB chairperson, using the same standards applied to studies being reviewed by a full board. Each institution should have clear policies and procedures in place for expedited review procedures, including who has the authority to make the determinations. The intent of exempt and expedited review is to streamline IRB procedures without any diminution in the protection for human participants. Full board review means the research involves greater than minimal risk to participants or involves protected or vulnerable populations and is not eligible for exempt or expedited review.7 The research is reviewed and discussed at a fully convened IRB meeting. The differences between minimal risk and greater than minimal risk are not always clear to investigators. Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of 520

Mayo Clin Proc.

n

routine physical or psychological examinations or tests.7 Research studies that do not meet this definition, and any studies that involve vulnerable or protected populations, are considered greater than minimal risk and require a full board review. The terms minimal risk and expedited do not imply that any less rigor is applied for review of the research. Likewise, “minimal-risk” studies do not justify minimal efforts regarding protocol preparation and human participant protection. INFORMED CONSENT AND CONSENT CAPACITY Informed consent is central to human participant protection in research. Ensuring that an individual is truly informed about research participation reflects the basic ethical principles of autonomy and respect for persons as described in the Belmont Report.13 For informed consent to be valid, there are 3 required elements: that an individual (1) is fully informed, (2) is competent to make a decision, and (3) voluntarily chooses to participate.14 Fully informed means that a potential participant receives sufficient and relevant information regarding the proposed research to facilitate adequate understanding of the risks, benefits, and alternatives, including the option of not participating at all, and reasoning through these different options. Competence means that a person must have adequate decisional capacity to consent to or refuse participation in the proposed research. Voluntary means that a decision must be made freely in a noncoercive environment. It is important to determine whether a potential participant has consent capacity because individuals who have adequate capacity have the right to make choices regarding research and those who lack adequate capacity should be protected from potential harm of their decisions. The informed consent form is a nonelegally binding document that should reflect the consent process. All consent form sections are critical to human participant protection and compliance with federal regulations

March 2019;94(3):515-525

n

https://doi.org/10.1016/j.mayocp.2019.01.020 www.mayoclinicproceedings.org

IRB FOR CLINICIANS

and therefore heavily scrutinized during the IRB review process. The term consent capacity is recommended by the Secretary’s Advisory Committee on Human Research Protections to refer to a research participant’s abilities to consent to research.15 When adult participants have impaired consent capacity, federal regulations governing research allow proxy consent from a legally authorized representative as determined by local or state laws.16 A wide range of conditions may affect consent capacity temporarily (eg, psychiatric or neurologic disorders, metabolic impairments, head trauma, substance use, psychoactive medications, psychosocial environment) or permanently (eg, developmental disorders, intellectual disabilities, neurodegenerative disorders). For research involving children or minors, assent is obtained to confirm the willingness to participate in research, and permission is required from parent(s) or guardian, unless a waiver is appropriate.17 VULNERABLE POPULATIONS Vulnerable research participants are those who have compromised autonomy or are vulnerable to coercion or undue influence when making decisions to participate in research.18 Protected populations who require additional safeguards to prevent their abuse and exploitation include pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates (US Department of Health and Human Services regulation 45CFR46, Subpart B), prisoners (45CFR46, Subpart C), and children (45CFR46, Subpart D). Vulnerable populations include individuals who are involuntarily committed to a medical facility; employees or subordinates such as students, trainees, and coworkers; economically or educationally disadvantaged persons; those with a language barrier; those with a cognitive disability; and those with an illness for which all standard treatment options have been exhausted.18 Mentally disabled persons are also vulnerable participants in research for whom IRBs may need to undertake increased responsibilities.19 Patients in life-threatening medical situations who might benefit from Mayo Clin Proc. n March 2019;94(3):515-525 www.mayoclinicproceedings.org

n

investigational products in emergency research but who are unable to provide informed consent are also vulnerable, although Title 21, Code of Federal Regulations, Section 50.24 (21CFR50.24) provides exception from the informed consent requirements in these emergency settings.20 The need to protect vulnerable individuals must be balanced with the need to conduct research to advance science. Investigators should justify the inclusion of vulnerable participants who may not be capable of protecting their own interests and put in place additional safeguards to protect their rights and welfare. However, excluding vulnerable persons from research is not necessarily the correct safeguard and may even deny a person the right to self-determination. Examples of measures to protect vulnerable participants include appropriate use of surrogate decision makers or research participant advocates or provisions to ensure a participant’s understanding and appreciation of relevant research information. PROSPECTIVE SUICIDE ASSESSMENT IN CLINICAL TRIALS Prospective assessments of treatmentemergent suicidal ideation and behavior should be carried out in clinical trials of investigational new drugs and biologic products being developed for any psychiatric indication, antiepileptic drugs, or any drug with central nervous system activity. Possible suicidality risks have already been identified for certain drugs such as isotretinoin and other tretinoins, b-blockers, reserpine, drugs for smoking cessation, and drugs for weight loss. The FDA offers guidance for prospective assessments in both inpatient and outpatient settings and multiple-dose phase 1 trials involving healthy volunteers.21 The main goals are to identify patients at risk for suicide and manage that risk to ensure participant safety. The IRB requires an investigator safety plan to manage suicidality with the ability to capture responses immediately and respond to positive responses promptly. Certain populations do not have to be assessed for suicidality if they have conditions that make

https://doi.org/10.1016/j.mayocp.2019.01.020

521

MAYO CLINIC PROCEEDINGS

assessment difficult, such as individuals with substantial cognitive impairment that interferes with understanding the concept of suicide, critically ill patients, or young children who have no concept of death.21 A survey of clinical trial sites conducting investigations covered under the FDA guidance indicates that the prospective assessment of suicidality is viewed positively by investigators.22 The suicidality assessment is used across many indications and is believed to contribute to the safety of participants by identifying those who are at risk, although there are some implementation challenges. FDA-REGULATED DRUGS OR DEVICES Any clinical research testing new or noneFDA-approved drugs or biologics must be reviewed and approved by the FDA, which is done by filing an Investigational New Drug (IND) application.23 Not all studies require an IND application, and some clinical investigations may be exempt from the IND application requirements.24 The 3 types of IND are Investigator IND (submitted by a physician), Emergency Use IND (use of an investigational drug on an emergency basis without enough time to file a full IND), and Treatment IND (use of experimental drugs clinically). An investigator makes a commitment to comply with FDA regulations when signing a Statement of Investigator Form FDA 1572, and noncompliance can have serious consequences for the investigator and their institution.25 A medical device is defined by the FDA as n

n

n

522

an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part or accessory which is: recognized in the official National Formulary, or the US Pharmacopoeia, or any supplement to them, intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other Mayo Clin Proc.

n

animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.26 Significant risk devices present potential serious risk to participants as proposed for use in the study, and their investigational use requires an Investigational Device Exemption approval by the FDA before the initiation of any research activity. If a device poses nonsignificant risk, no Investigational Device Exemption is required, but IRB approval is required for nonsignificant risk determination. A Humanitarian Use Device is a medical device to benefit patients with rare conditions, ie, not more than 8000 individuals in the United States per year. Manufacturers are required to request a Humanitarian Device Exemption from the FDA that allows a device to be marketed as a Humanitarian Use Device.27 An IRB reviews clinical progress reports yearly. COMPLIANCE Compliance with research protocols is critical for both maintaining participant safety and answering the investigative questions being asked. The investigational plan should be followed, and any deviation from the protocol, or any event considered reportable, should be reported promptly to the IRB. The report should include an investigator’s assessment of any change in risk for participants, need for consent form revisions, reconsenting requirements, and corrective or future prevention plan. Research noncompliance is intentional or unintentional failure to follow the approved research plan, IRB requirements or determinations, or federal regulations, state laws, local regulations, or institutional policies relevant to human participant research. Research noncompliance can be serious or nonserious and may involve protocol violations or deviations. Serious noncompliance results in potential or actual harm to participants, negative impact on study data integrity and validity,

March 2019;94(3):515-525

n

https://doi.org/10.1016/j.mayocp.2019.01.020 www.mayoclinicproceedings.org

IRB FOR CLINICIANS

or compromise of the institutional human research protection program. Continuing noncompliance is a pattern of multiple instances of noncompliance. Protocol violation/deviation is any change, divergence, or departure from the study design or research procedures that has not been approved by the IRB. Unanticipated problems are events that are unexpected, related or possibly related to participation in the research, and place participants or others at a greater risk of physical, psychological, economic, or social harm than was not previously known or recognized.28 Unanticipated problems must be reported promptly and generally require substantive protocol or consent form changes or corrective actions to ensure the safety, welfare, or rights of participants or others. Delays in reporting may constitute research noncompliance. The most significant concern is with research noncompliance that rises to a level regarded as serious and continuing. Institutional review boards are required to report this level of noncompliance to the FDA and/ or Office for Human Research Protections, depending on whether a study is FDAregulated or not.29 The process of determining noncompliance may vary across institutions or organizations. Institutional review boards are required to have written operational procedures that include definitions of serious or continuing noncompliance, detailed description of the review process, identification of the responsible person or group who makes the noncompliance determination, and reporting requirements to the appropriate institutional officials, heads of department or agency, Office for Human Research Protections, and FDA.30 An analysis of 6511 incident reports received by the Office for Human Research Protections between January 1, 2008, and December 31, 2014, from 780 institutions showed that the most common type of incident was serious noncompliance. The top 2 categories of serious and continuing noncompliance are related to changes in research protocol without IRB review and approval (required study interventions not performed, participants compensated more than permitted in Mayo Clin Proc. n March 2019;94(3):515-525 www.mayoclinicproceedings.org

n

the protocol, failure to adhere to inclusion or exclusion criteria) and informed consent issues (informed consent not obtained prior to research, informed consent document lacking risks of the research, and informed consent document not signed before participation in research).31 NEW ISSUESdSINGLE IRB AND REVISED COMMON RULE The new National Institutes of Health policy requires the use of a single IRB (sIRB) review process for National Institutes of Healthefunded multisite studies in which each site will conduct the same protocol in order to enhance and streamline the IRB review process and reduce problems with multiple IRB reviews and determinations without compromising human participant protections.32 Exceptions to the policy include career development, research training, or fellowship awards.32 The Common Rule is a federal policy regarding human participant protection with main elements that include requirements for (1) research institutions to assure compliance, (2) researchers to obtain and document informed consent, and (3) IRB structure and function.33 The US Department of Health and Human Services and 15 federal agencies and offices issued final revisions to the Common Rule in December 2017 to update and strengthen regulations to better protect human participants in research while reducing administrative burdens, especially in low-risk research. The effective date of the revised Common Rule was January 21, 2019. Important elements of the final rule include the requirement for consent forms at the beginning of the document to include a concise presentation of key information to assist prospective subjects in deciding whether to participate in the research; requirements for multi-institutional research studies to use sIRB; obtaining broad consent for future research on stored identifiable data or identifiable biospecimens; establishment of new exempt research categories based on the level of risk; removal of continuing review for certain research studies; and requirement for certain federally funded clinical trial

https://doi.org/10.1016/j.mayocp.2019.01.020

523

MAYO CLINIC PROCEEDINGS

consent forms to be available publicly.34 Whether the sIRB policy and revised Common Rule will enhance human participant protection and reduce burden on investigators remains to be seen. NONNESEARCH/CLINICAL FUNCTION OF IRBs Institutional review boards have been tasked by the FDA to review applications to use noneFDA-approved drugs or devices in special circumstances that could benefit a patient. The IRB focus remains on protection of vulnerable patients against exploitation. Expanded access or “compassionate use” programs allow patients with serious diseases or conditions access to investigational drugs, biologics, and medical devices for purposes of treatment and not research. Under IND regulations, the 3 distinct categories of expanded access are based on the number of patients participating, including individual patient (emergency and nonemergency), intermediate-size patient population, and expanded access (widespread use).35 Expanded access is possible only if a sponsor provides the investigational product; expanded access programs must report serious or unexpected adverse events and submit a written summary report at the conclusion of treatment. The Right to Try Act is a new federal law to create a pathway for certain patients with life-threatening diseases or conditions to access investigational drugs outside a clinical trial. It applies only to single-patient treatment use and to investigational drugs that have passed phase 1 trials.36 It is too early to tell how this new access will work, as it circumvents FDA processes, and IRB review is not required. It is not clear whether this federal law will overrule state right-to-try laws. Institutions and drug manufacturers need to identify a process to review requests by patients and physicians under the Right to Try Act and develop criteria for deciding on this new pathway vs continuing to provide expanded access under the existing FDA program. CONCLUSION This review has highlighted the role of an IRB in protecting human research participants 524

Mayo Clin Proc.

n

from harm during clinical investigation. Clinicians engaged in research must be aware of the policies and regulations affecting the conduct of human research. These policies and regulations may change, and investigators need to be aware of the changes as they occur. The IRB is an excellent resource for up-to-date knowledge of current policies and regulations. It is critical for investigators to conduct human participant research safely, scientifically, and ethically in a manner that complies with current local, state, and federal regulations. ACKNOWLEDGMENTS We thank Tamyra L. Armbrust, CIP, CCRP, for creating the Figure depicting a human research protection program. Abbreviations and Acronyms: FDA = Food and Drug Administration; IND = Investigational New Drug; IRB = Institutional Review Board; sIRB = single IRB

Potential Competing Interests: Dr Clarke is a member of the GlaxoSmithKline Data Monitoring Board and has served as a consultant for and received a grant from Shire, Inc/ Takeda (all funds paid to his institution). Dr Wright has received consulting fees, travel support, and fees for participation in review activities from The Medicines Company, Sanofi, and Boehringer Ingelheim GmbH and fees for provision of writing assistance, medicines, equipment, or administrative support from Sanofi. Correspondence: Address to Maria I. Lapid, MD, Department of Psychiatry and Psychology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).

REFERENCES 1. Steneck NH. ORI Introduction to the Responsible Conduct of Research. Revised edition. Office of Research Integrity website, https://ori.hhs.gov/sites/default/files/rcrintro.pdf. Published August 2007. Accessed December 3, 2018. 2. Stark L, Greene JA. Clinical trials, healthy controls, and the birth of the IRB. N Engl J Med. 2016;375(11):1013-1015. 3. US Food and Drug Administration. CFR - Code of Federal Regulations Title 21, Chapter 1, Subchapter A; Part 56, Institutional Review Boards. https://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/cfcfr/CFRSearch.cfm?CFRPart¼56. Updated September 4, 2018. Accessed December 3, 2018. 4. Centers for Disease Control and Prevention. U.S. Public Health Service Syphilis Study at Tuskegee. https://www.cdc.gov/ tuskegee/timeline.htm. Published 2015. Accessed December 3, 2018. 5. US Food and Drug Administration. Institutional review boards frequently asked questions - information sheet. https://www.fda. gov/RegulatoryInformation/Guidances/ucm126420.htm#IRB Member. Updated July 12, 2018. Accessed December 3, 2018. 6. US Food and Drug Administration. CFR - Code of Federal Regulations Title 21, Chapter 1, Subchapter A; Part 56, Institutional Review

March 2019;94(3):515-525

n

https://doi.org/10.1016/j.mayocp.2019.01.020 www.mayoclinicproceedings.org

IRB FOR CLINICIANS

7.

8.

9.

10.

11.

12. 13.

14. 15.

16.

17.

18.

19.

20.

21.

Boards; Subpart B, Organization and Personnel, Sec. 56.107. https:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm?fr¼56.107. Updated September 4, 2018. Accessed December 3, 2018. Electronic Code of Federal Regulations (e-CFR). Title 45, Subtitle A, Subchapter A; Part 46, Protection of Human Subjects, x46.104. https://www.ecfr.gov/cgi-bin/retrieveECFR?gp¼&SID¼ 83cd09e1c0f5c6937cd9d7513160fc3f&pitd¼20180719&n¼pt 45.1.46&r¼PART&ty¼HTML#se45.1.46_1104. Updated July 18, 2018. Accessed December 3, 2018. Electronic Code of Federal Regulations (e-CFR). Title 45, Subtitle A, Subchapter A; Part 46, Protection of Human Subjects, x46.101. https://www.ecfr.gov/cgi-bin/retrieveECFR?gp¼&SID¼ 83cd09e1c0f5c6937cd9d7513160fc3f&pitd¼20180719&n¼pt 45.1.46&r¼PART&ty¼HTML#sp45.1.46.a. Updated July 19, 2018. Accessed December 3, 2018. US Department of Health and Human Services. Quality improvement activities FAQs. https://www.hhs.gov/ohrp/ regulations-and-policy/guidance/faq/quality-improvement-activi ties/index.html. Accessed December 3, 2018. US Department of Health and Human Services. Exempt Research Determination FAQs. https://www.hhs.gov/ohrp/ regulations-and-policy/guidance/faq/exempt-research-determi nation/index.html. Accessed December 3, 2018. US Department of Health and Human Services. OHRP expedited review categories (1998). https://www.hhs.gov/ohrp/regulationsand-policy/guidance/categories-of-research-expedited-reviewprocedure-1998/index.html. Updated March 21, 2016. Accessed December 3, 2018. Resnik DB, Babson G, Dinse GE. Minor changes to previously approved research: a study of IRB policies. IRB. 2012;34(4):9-14. Department of Health, Education, and Welfare. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Reserach. Rockville, MD: Office for Human Research Protections; 1979. Meisel A, Roth LH, Lidz CW. Toward a model of the legal doctrine of informed consent. Am J Psychiatry. 1977;134(3):285-289. US Department of Health and Human Services. Attachment: Recommendations regarding research involving individuals with Impaired Decision-Making. https://www.hhs.gov/ohrp/ sachrp-committee/recommendations/2009-july-15-letter-attach ment/index.html. Updated July 15, 2009. Accessed December 3, 2018. US Department of Health and Human Services. Informed consent FAQs. https://www.hhs.gov/ohrp/regulations-and-policy/ guidance/faq/informed-consent/index.html. Accessed December 3, 2018. US Department of Health and Human Services. Research with children FAQs. https://www.hhs.gov/ohrp/regulations-and-policy/ guidance/faq/children-research/index.html. Accessed December 3, 2018. US Department of Health and Human Services. Vulnerable populations. https://www.hhs.gov/ohrp/regulations-and-policy/ guidance/vulnerable-populations/index.html. Accessed December 3, 2018. US Food and Drug Administration. CFR - Code of Federal Regulations Title 21, Chapter 1, Subchapter A; Part 56, Institutional Review Boards; Subpart C, IRB Functions and Operations. https:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? fr¼56.111. Updated September 4, 2018. Accessed December 3, 2018. US Food and Drug Administration. Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research. https://www.fda.gov/downloads/RegulatoryInforma tion/Guidances/UCM249673.pdf. Published March 2011. Updated April 2013. Accessed December 3, 2018. US Food and Drug Administration. Guidance for Industry: Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials. https://www.fda.gov/Drugs/GuidanceCompliance

Mayo Clin Proc. n March 2019;94(3):515-525 www.mayoclinicproceedings.org

n

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

RegulatoryInformation/Guidances/ucm315156.htm. Updated March 22, 2018. Accessed December 3, 2018. Stewart M, Butler A, Alphs L, et al. Study site experiences and attitudes toward prospective assessments of suicidal ideation and behavior in clinical trials: results of an Internet-based survey. Innov Clin Neurosci. 2013;10(5-6, suppl A):20S-28S. US Food and Drug Administration. Investigational new drug (IND) application. https://www.fda.gov/Drugs/Development ApprovalProcess/HowDrugsareDevelopedandApproved/App rovalApplications/InvestigationalNewDrugINDApplication/ucm 2007026.htm. Updated October 5, 2017. Accessed December 3, 2018. US Food and Drug Administration. IND application procedures: exemptions from IND requirements. https://www.fda. gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDev elopedandApproved/ApprovalApplications/InvestigationalNew DrugINDApplication/ucm362743.htm. Updated October 9, 2015. Accessed December 3, 2018. US Food and Drug Administration. Information sheet guidance for sponsors, clinical investigators, and IRBs. https://www.fda. gov/downloads/RegulatoryInformation/Guidances/UCM214282. pdf. Published May 2010. Accessed December 3, 2018. US Food and Drug Administration. Medical device overview. https://www.fda.gov/ForIndustry/ImportProgram/ImportBasics/ RegulatedProducts/ucm510630.htm. Updated September 14, 2018. Accessed December 3, 2018. US Food and Drug Administration. Designating humanitarian use device (HUD). https://www.fda.gov/ForIndustry/Develop ingProductsforRareDiseasesConditions/DesignatingHumanitari anUseDevicesHUDS/default.htm. Updated October 24, 2017. Accessed December 3, 2018. US Department of Health and Human Services. Unanticipated problems involving risks & adverse events guidance (2007). https://www.hhs.gov/ohrp/regulations-and-policy/guidance/ reviewing-unanticipated-problems/index.html#Q1. Published January 15, 2007. Accessed December 3, 2018. US Department of Health and Human Services. Guidance on reporting incidents to OHRP (2011). https://www.hhs.gov/ohrp/ compliance-and-reporting/guidance-on-reporting-incident/index. html. Published June 20, 2011. Updated March 19, 2016. Accessed December 3, 2018. US Department of Health and Human Services. Institutional review board (IRB) written procedures: guidance for institutions and IRBs. https://www.hhs.gov/ohrp/regulations-and-policy/ requests-for-comments/guidance-for-institutions-and-irbs/index .html. Updated August 2, 2016. Accessed December 3, 2018. Ramnath K, Cheaves S, Buchanan L, Borror K, Banks-Shields M. Incident reports and corrective actions received by OHRP. IRB. 2016;38(6):10-15. US Department of Health and Human Services. Single IRB policy for multi-site research. National Institutes of Health website. https://grants.nih.gov/policy/clinical-trials/single-irbpolicy-multi-site-research.htm. Updated January 14, 2019. Accessed December 3, 2018. US Department of Health and Human Services. Federal policy for the protection of human subjects (’Common Rule’). https:// www.hhs.gov/ohrp/regulations-and-policy/regulations/comm on-rule/index.html. Updated March 18, 2016. Accessed December 3, 2018. US Department of Health and Human Services. Revised Common Rule. https://www.hhs.gov/ohrp/regulations-and-policy/ regulations/finalized-revisions-common-rule/index.html. Updated January 19, 2017. Accessed December 3, 2018. Jarow JP, Lurie P, Ikenberry SC, Lemery S. Overview of FDA’s expanded access program for investigational drugs. Ther Innov Regul Sci. 2017;51(2):177-179. Wendler T, Mongiello F, McLinn J, Bellina M. Right to Try Act of 2017. https://www.congress.gov/bill/115th-congress/senate-bill/ 204/text. Accessed December 3, 2018.

https://doi.org/10.1016/j.mayocp.2019.01.020

525