The DDIR, on behalf of the NIH Director, is responsible, through the NIH MPA, for NIH compliance with 45 CFR 46. However, protecting the rights and welfare of human research subjects is a responsibility that is shared by the PI's, the Branch Chiefs, NIH Institutes and Centers, and other governmental components.
The OHRP is an administrative unit of DHHS. Although located on the NIH campus, it maintains national responsibility for overseeing the regulations that guide the conduct of human-subjects research, provides guidance on and interpretations of 45 CFR 46, and conducts educational activities for all domestic and foreign institutions that receive DHHS funds.
The OHSR is part of the Office of the DDIR. The OHSR was established in 1992 to help NIH investigators understand and comply with ethical guidelines and regulatory requirements for human-subjects research. OHSR activities include planning, organizing, and conducting educational activities for NIH personnel about the protection of human subjects; working closely with IRB's to promote their mandate to protect the rights and welfare of human subjects; interpreting 45 CFR 46; and working with other NIH groups as appropriate to formulate and develop NIH policies and procedures consistent with regulations.
The OHSR developed a computer-based training course that is mandatory for all intramural investigators and extramural staff involved in planning, conducting, and overseeing research involving human subjects. The course can be found at http://ohsr.od.nih.gov/cbt. The OHSR also maintains a data base of all NIH collaborative protocols conducted off-site, that is, not at the CC.
In its role as the NIH intramural research program's liaison with OHRP, OHSR assists, at the request of the DDIR, in conducting inquiries and investigations of noncompliance with 45 CFR 46 or noncompliance with NIH policies and procedures that pertain to human-subjects research.
Each Institute enhances its own scientific credibility by assuming responsibility for the quality of the scientific ideas and the care with which the ideas are tested. To do this, each Institute has a clinical research infrastructure that supports and assists investigators in their research activities. The ideal infrastructure helps investigators develop, organize, implement, and analyze protocols. It should offer centralized data management, statistical consultation, internal peer review and quality assurance, and help with obtaining approvals from sponsoring agencies.
Each Institute is responsible for ensuring rigorous scientific review of its protocols before review by the IRB. Mechanisms of review vary, but generally they are performed by a committee that includes the Institute's Scientific and Clinical Directors, and a staff member from the Institute's extramural program. The committee considers the protocol's quality, originality, and importance to science or clinical practice, and its relevance to the Institute's mission. Protocols that are of special concern to the general public may be forwarded to the DDIR for review and concurrence prior to implementation in the CC.
The Federal regulations codified in 45 CFR 46 apply to all human-subjects research conducted and supported by institutions – foreign or domestic – that receive funds from DHHS. They require prospective continuing review and approval of human-subjects research by a committee, usually called an IRB. The primary mandate of an IRB is to protect and safeguard the rights and welfare of human research subjects. The NIH IRB's approve research if they determine that the following minimum requirements are satisfied:
- The risks to subjects are minimized.
- The risks are reasonable in relation to anticipated benefits, if any, to subjects, and to the importance of knowledge that may reasonably be expected to result.
- The selection of subjects is equitable.
- Informed consent will be sought from the subjects or their authorized representatives.
The IRB's of the Institutes that perform patient-oriented research in the CC are listed in figure 4. The CC and some other NIH components do not generate enough protocols to warrant their own IRB's. These entities submit their protocols to the IRB with the appropriate scientific expertise. Members and Chairs of IRB's are appointed by the DDIR to 1- to 3-year renewable terms, following nomination by the Institute Clinical Director, in consultation with the Institute Scientific Director. Each NIH IRB has at least five members, whose varying backgrounds promote complete and adequate review of the research activities commonly performed by that Institute. Each IRB must have at least one member whose primary interest is in a nonscientific area (e.g., law, ethics, religion) and at least one member who is not affiliated with the Public Health Service. These two attributes may be combined in the same member. Each IRB must also have a statistician, an ethics consultant from the CC Department of Clinical Bioethics, and a representative from any other CC department. To ensure adequate representation of all disciplines during IRB proceedings, a quorum is necessary for decision-making. A quorum is defined as a majority of the voting membership, including at least one member whose primary concerns are in a nonscientific area. The IRB may appoint nonvoting, ad hoc members who have specialized knowledge to assist with reviewing complex issues that require expertise beyond that usually found on the IRB.
The minutes of the IRB meetings record attendance, actions taken by the IRB, votes taken on the actions, the reasons for stipulated or recommended changes in a protocol or for tabling or disapproving the protocol, and discussion of controversial issues and their resolution. Unless the research activity is determined to be exempt from the requirements of the NIH MPA, all research activities involving human subjects must be approved by an appropriate IRB of one of the NIH Institutes before any research activity occurs at the CC or at a non-NIH performance site.
The Human Subjects Research Advisory Committee (HSRAC) advises the DDIR, who chairs the Committee, on policies and procedures for conducting human-subjects research at NIH. Other members include the OHSR Director (Executive Secretary); all NIH IRB Chairs; the CC Director; the Chief of the Department of Clinical Bioethics; and a lay member. The HSRAC meets every 2 months.
At the discretion of the DDIR, the HSRAC may serve as the IRB of record for reviewing, approving, and monitoring intramural research involving human subjects covered by the NIH MPA. If the HSRAC convenes as an IRB, its membership must be appropriately augmented to meet the requirements of 45 CFR 46; the membership list is then submitted to OPRR for approval.
The Medical Executive Committee (MEC) advises the CC Director, and develops policies governing standards of medical care in the CC. The MEC represents and acts for the medical staff and other clinical professionals in the CC. The MEC meets at least once a month. The following functions of the MEC may directly or indirectly affect the development, implementation, and monitoring of a protocol:
- developing and coordinating policies concerning medical practice at the CC;
- making recommendations to the CC Director on all matters relating to medical staff appointments, clinical privileges, and corrective action;
- assessing the overall quality of patient care on a continual basis;
- recommending the resources needed to provide, maintain, and improve quality clinical care to CC patients and Institutes providing clinical services;
- serving as a hearing body for adverse actions; and
- providing oversight of the consultative services provided at the CC.
The MEC adopts rules governing the work of the medical staff. The rules take effect when approved by the CC Director, and are codified in Policy and Communication Bulletins under the CC's Medical Administrative Series (MAS). These policies are designated by an M for medical, two digits that represent the year of publication, followed by a hyphen and one or two digits that indicate the place of the policy in the sequence of those published that year. MAS policies of particular interest to investigators writing a protocol include M97-2, Subject: "Guidelines for Writing Research Protocols," and M77-2, Subject: "Informed Consent."
Scientists and investigators are permitted to use radionuclides and certain radioactive sources under licenses granted to the NIH by the Nuclear Regulatory Commission (NRC). The Radiation Safety Program is conducted under the authority and supervision of the Radiation Safety Officer (RSO). The RSO, appointed by the NIH Director, is responsible to the Director for the content and execution of the Radiation Safety Program. The RSO is also the chief of the Radiation Safety Branch. The staff of this Branch conduct the daily activities required by the program.
The Radiation Safety Committee (RSC), a campus-wide committee responsible to the NIH Director, advises and consults with the RSO on the conduct of the Radiation Safety Program. The RSC is also responsible for reviewing all protocols in which uses of radiation or radioactive materials do not meet the criteria for "medically indicated," but rather are regarded as "indicated for research." The RSC establishes policies and procedures for using radioactive material safely at NIH and is NIH's chief instrument for carrying out the regulations of the NRC. The NRC regularly inspects NIH to determine if activities with licensed materials or sources are being conducted in accordance with applicable NRC regulations and the conditions of the licenses issued. The inspections focus not only on the Radiation Safety Program, but also on individual laboratories, authorized users, and individual users. The NRC can withdraw the overall license under which NIH operates if the NRC determines that individuals or groups working here are violating the regulations.
The Radiation Safety Branch and the RSC are responsible for every isotope on the NIH campus. They certify, authorize, and empower investigators to hold and use the isotopes in test tubes and humans.
The FDA regulates the use in human subjects of radioactive drugs that are not approved nor under an IND exemption as codified in title 21, Code of Federal Regulations, part 361 (21 CFR 361). An example would be a radioiodinated lipoprotein used in lipid metabolism research that has no diagnostic or therapeutic intent. The RSC passes all protocols of this nature to the Radioactive Drug Research Committee for review. This subcommittee of the RSC is responsible for adherence to FDA regulations on such agents.
The Institutional Biosafety Committee is charged with protecting the NIH campus and the community at large from infectious agents that might produce illness in humans. It has no fewer than five members, so selected that they collectively have experience and expertise in recombinant-DNA technology and the capability to assess the safety of recombinant-DNA research. They are called upon to evaluate, for example, every vector used in DNA samples. Fundamentally, their concern is with the attendants, nurses, and physicians working with the patients receiving such a vector, as well as the community at large.
The Recombinant-DNA Advisory Committee (RAC) is the public advisory committee that advises the DHHS Secretary, the DHHS Assistant Secretary for Health, and the NIH Director on matters concerning recombinant-DNA research. The RAC, a diverse group of 18-20 persons (including physicians, geneticists, lawyers, and ethicists), registers all new protocols that involve exposure of patients to recombinant genetic material. The RAC formally discusses only those protocols involving new gene-transfer vectors, or methodology thought to have a potential impact on the public at large or to present unusual risks that have not been considered previously, thus requiring a public forum (as opposed to the confidential FDA review process). The authority for approval of all such protocols was relinquished by the RAC to FDA in October 1997.
The Office of Recombinant-DNA Activities (ORDA) serves as the main point of contact for information on recombinant-DNA activities and provides advice within and outside NIH. The ORDA is responsible for carrying out functions that may be delegated to it by the NIH Director. The ORDA serves as the focal point for data management of NIH- and FDA-approved human gene-transfer protocols, administers the annual data-reporting requirements for human gene-transfer experiments, and maintains an inventory of NIH- and FDA-approved human gene-transfer experiments. In addition, ORDA decides whether human gene-transfer protocols require a review by the RAC. The ORDA selects two or three members of the RAC to review the proposed protocol to determine if it should be subjected to a full review at a full public meeting of the RAC. The FDA in turn may approve the protocol or elect to have it reviewed by the RAC.