DEPARTMENT: Clinical Services Group – Research
/ POLICY DESCRIPTION: IRB Guidance PolicyPAGE: 1 of 19 / REPLACES POLICY DATED: 1/1/03, 4/14/03, 3/1/04
EFFECTIVE DATE: March 1, 2008 / REFERENCE NUMBER: CSG.RES.001 (formerly QM.RES.001 )
APPROVED BY: Ethics and Compliance Policy Committee
SCOPE: All Company-affiliated facilities engaged in human subject research, especially research overseen by a facility-affiliated Institutional Review Board (IRB).
PURPOSE: To provide general guidance for IRB activities and development of local Standard Operating Procedures (SOP) and to serve as the introductory policy regarding protection of human subjects involved in research trials.
This is the first in a series of policies, CSG.RES.001 through CSG.RES.013, designed to ensure compliance with the U.S. Department of Health and Human Services (DHHS) regulations, 45 CFR 46 (known as the Common Rule); the Health Insurance Portability and Accountability Act (HIPAA) Standards for Privacy of Individually Identifiable Health Information (Privacy Standards), 45 CFR Parts 160 and 164; and the Food and Drug Administration (FDA) regulations, 21 CFR 50, 54, 56, 312.6, 812.6 and 814.124. Such regulations underlie each policy in the series, and individuals affected by the policies are encouraged to consult those regulations and related resources for further information and guidance regarding human subject research.
POLICY: All Company-affiliated facilities engaged in human subject research must either have a facility IRB or an IRB Authorization Agreement with one or more external IRB(s). Each facility must develop policies that outline the facility’s research program. These governing policies must support compliance with applicable federal and state regulations.
The ethical conduct of research is a shared responsibility. It requires cooperation, collaboration, and trust among the institution; investigators and their research staff; the research sponsor; the human subjects; and the IRB members and staff. A clear delineation of the responsibilities of each of these parties in the local institution’s IRB SOP can help assure protection of human subjects who volunteer to participate in research programs.
The series of IRB policies reflects requirements incorporated from the DHHS and FDA regulations and the HIPAA Privacy Standards. It is expected that all Company-affiliated facilities engaged in human subject research will observe all the requirements set forth in the series of policies as well as the relevant regulations. As the regulations do differ in some areas, the facilities must review and apply the correct set of regulations to the type of protocol submitted for review, whether it is FDA or federally-funded DHHS research. Additionally, if a facility elects in its Federal Wide Assurance (FWA) to have the Common Rule apply to all research, then Common Rule will apply in addition to (as opposed to instead of) those of the FDA.
The Belmont Report, issued by the Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1978, provides direction regarding human subject research and must be reviewed by IRB staff and facility personnel engaged in research or overseeing the facility’s clinical research efforts. It can be obtained at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm.
Individuals involved in IRBs and/or research projects will adhere to principle of ethical IRB performance contained in the Belmont Report, particularly the following three basic ethical principles:
1. Respect for persons (evidenced by obtaining informed consent, considering the subject’s privacy, protecting confidentiality of information, and extending additional protections for vulnerable populations);
2. Beneficence (evidenced by weighing risks and benefits); and
3. Justice (evidenced by the equitable and appropriate selection of subjects).
Individuals involved in IRBs and/or research projects that have any potential conflicts of interest shall either eliminate the potential conflict of interest or follow appropriate guidance to eliminate any potentially negative influence it may have on human subject protection.
All IRBs with which Company-affiliated facilities are affiliated must conduct self-audits on an annual basis. It is suggested the IRBs follow audit guidance issued by the Office for Human Research Protections (OHRP) and/ or the FDA or be accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP). The OHRP guidance can be accessed at: http://www.hhs.gov/ohrp/humansubjects/qip/qasatool.rtf. The FDA IRB checklist can be accessed at: http://www.fda.gov/oc/ohrt/irbs/irbchecklist.html. The AAHRPP standards and list of accredited programs can be located at www.AAHRPP.org.
DEFINITIONS:
The following definitions apply to this policy and the remainder of the series of policies regarding IRBs, CSG.RES.002 through CSG.RES.013.
Admitting Physician: A physician who admits a patient to a facility for inpatient or outpatient care that is medically necessary or emergent but not indicated as a routine part of the research trial.
Assent: A child's affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent.
Adverse Event (AE): Any untoward occurrence in a patient or clinical investigation subject which does not necessarily have to have a causal relationship with their participation in the study. Adverse Drug Experiences and Adverse Drug Reactions may be Adverse Events (AEs) as do abnormal lab findings, symptoms or disease concurring with the research. Adverse events may also be non-medical in nature such as economic or social harms.
Central IRB: Use of a centralized IRB review process is consistent with the existing IRB regulations. Section 56.114 (21 CFR 56.114 Cooperative Research) provides, “institutions involved in multi-institutional studies may use joint review, reliance upon the review of another qualified IRB, or similar arrangements aimed at avoidance of duplication of effort.” When this rule was proposed, the preamble to the proposed rule indicated that the purpose of this section is “to explicitly reduce duplicative review of multi-institutional studies.” The preamble to the final rule also stated that “the purpose of this section is to assure IRBs that FDA will accept reasonable methods of joint review.” Physical proximity of an IRB to a research site is not necessarily of significance, provided that the IRB is competent to understand the local context of the research. As stated in 21 CFR 56.107(a), this would require sensitivity to community attitudes, familiarity with the standards of professional conduct and practice where the research takes place, and knowledge about local laws and regulations applicable to the study. Source: http://www.fda.gov/cber/gdlns/irbclintrial.htm.
Children: Persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. By regulatory definition, children are persons who have not attained the legal age for consent to treatments or procedures involved in the research, under applicable law of the jurisdiction in which the research will be conducted. Generally the law considers any person under 18 years old to be a child.
Clinical Investigator: Any listed or identified investigator or sub-investigator who is directly involved in the treatment or evaluation of research subjects. The term also includes the spouse and each dependent child of the investigator.
Conflict of Interest: A conflict of interest exists when the designated official(s) or IRB reasonably determines that a non-research interest (i.e., a significant financial interest or personal relationship) could directly and significantly affect the design, conduct, or reporting of research activity, consequently, such conflicts may bear directly on issues of human subject protection. Conflicts of interests can be actual, potential or perceived.
Covered clinical study: Any study of a drug, biological product or device in humans submitted in a marketing application or reclassification petition that the applicant or FDA relies on to establish that the product is effective (including studies that show equivalence to an effective product) or any study in which a single investigator makes a significant contribution to the demonstration of safety. This would, in general, not include phase 1 tolerance studies or pharmacokinetic studies, most clinical pharmacology studies (unless they are critical to an efficacy determination), large open safety studies conducted at multiple sites, treatment protocols and parallel track protocols. The Sponsor of the Clinical Study or the IRB may consult with FDA as to which clinical studies constitute "covered clinical studies" for purposes of complying with financial disclosure requirements.
Disqualification of a Clinical Investigator: If the FDA has information that a Clinical Investigator or Sponsor Investigator has repeatedly or deliberately provided false information, the FDA, after review of submitted documents and defense, may disqualify the Investigator from participating in research or receiving investigational drugs, http://www.fda.gov/OHRMS/DOCKETS/98fr/09059701.txt.
Emergency Use: The use of a test article on a human subject in a life-threatening situation in which no standard of acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval.
Engaged (Participating) in Research: Department of Health and Human Services (HHS) regulations at 45 CFR 46.103(a) require that each institution "engaged" in human subjects research provide OHRP with a satisfactory Assurance to comply with the regulations, unless the research is exempt under 45 CFR 46.101(b). An institution becomes "engaged" in human subjects research when its employees or agents (i) intervene or interact with living individuals for research purposes; or (ii)obtain individually identifiable private information for research purposes [45 CFR 46.102(d),(f)]. An institution is automatically considered to be "engaged" in human subjects research whenever it receives a direct HHS award to support such research. In such cases, the awardee institution bears ultimate responsibility for protecting human subjects under the award.
Expedited Review: Both the FDA and OHRP have established and published in the Federal Register a list of categories of research that may be reviewed by the IRB through an expedited review procedure. Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research.
Federal Wide Assurance (FWA): A formal written, binding commitment that is submitted to OHRP in which an institution promises to comply with DHHS regulations governing the protection of human subjects in research. An FWA is only required for an institution that is engaged in the review and approval process for federally- funded human research. Terms of Assurance can be accessed at: http://www.hhs.gov/ohrp/humansubjects/assurance/filasurt.htm.
Fetus: The product of conception from implantation until deliveryGuardian: An individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.
Human Subject: An individual who is the object of study in a research project. A living individual about whom an investigator conducting research obtains: (1) data through intervention or interaction with the individual; or (2) identifiable private information. [45 CFR 46.102(f)(1),(2)].
An individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient.
Humanitarian Device Exemption: A humanitarian device exemption (HDE) is submitted for FDA review and approval by a manufacturing company/company/sponsor. The purpose of the HDE is, to the extent consistent with the protection of the public health and safety and with ethical standards, to encourage the discovery and use of devices intended to benefit patients in the treatment or diagnosis of diseases or conditions that affect fewer than 4,000 individuals in the United States. Although a device may have HDE approval, it still falls under the category of an HUD.
Humanitarian Device Exemption Final Rule Summary: An HUD is approved for marketing through an HDE application filed in accordance with the requirements of this final rule. An HDE application is a PMA application that is not required to contain clinical data demonstrating "effectiveness'' (defined under Sec. 860.7(e)(1) (21 CFR 860.(e)(1)) as "reasonable assurance…based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results''). An HDE application will contain all other information ordinarily required in a PMA. In addition, an HDE application will require certain special information to satisfy the statutory requirements established by section 520(m) of the act, http://www.fda.gov/orphan/humuse.htm.
Humanitarian Device Exemption Holder: The company providing the device. The company providing the device is responsible for ensuring that the HUD is only used in facilities having an IRB or Central IRB agreement constituted and acting in accordance with 45 CFR Part 56; is required to maintain records of the names, addresses of the facilities to which the HUD has been shipped, is required to maintain copies of correspondence with reviewing IRBs as well as any other information required by the reviewing IRB or FDA.
Humanitarian Use Device: An HUD is a device that is (1) intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year; (2) the device would not be available to a person with such a disease or condition unless the exemption is granted; (3) no comparable device (other than a device that has been granted such an exemption) is available to treat or diagnose the disease or condition; and (4) the device will not expose patients to an unreasonable or significant risk of illness or injury, and the probable benefit to health from using the device outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.
Humanitarian Use Device IRB Approval: Section 520(m)(4) of the act states that an HUD may only be used in facilities that have established, in accordance with FDA regulations, "a local institutional review committee [commonly known as an institutional review board or IRB] to supervise clinical testing of devices in the facilities.'' The statute also requires an IRB to approve the use of the HUD before the device is administered to humans. In accordance with this statutory requirement, FDA has specified in subpart H of part 814 that the HDE holder must ensure that the HUD is administered only to patients at health care facilities having an IRB. IRBs which oversee the use of an HUD should be constituted and act in accordance with the agency's regulations governing IRBs (21 CFR part 56), including responsibility for continuing review of use of the device. FDA has codified this requirement in Sec. 814.124. The agency does not believe the statute intends to require IRB review and approval for each individual use of the HUD. FDA has interpreted the statute to permit the IRB to approve the use of the device in general, use of the device for groups of patients meeting certain criteria, or use of the device under a treatment protocol. If it so wishes, an IRB may specify limitations on the use of the device based upon one or more measures of disease progression, prior use and failure of any alternative treatment modalities, reporting requirements to the IRB or IRB chair, appropriate follow-up precautions and evaluations, or any other criteria it determines to be appropriate. It should be emphasized that under the final rule (Sec. 814.124), it is the HDE holder who is responsible for ensuring that the HUD is not administered to or implanted in a patient prior to obtaining IRB approval at the health care facility. An HDE holder may wish to enforce this requirement by not shipping the HUD to the health care facility until it has received confirmation of IRB approval. In order to provide flexibility to the approval requirement, FDA has included a provision that permits an IRB located at a treatment facility to defer (in writing) to another similarly constituted IRB that has agreed to assume responsibility for initial and continuing review of the use of the device, http://www.fda.gov/orphan/humuse.htm.