Overview of Review Processes Related to UM Human Use of Radioisotope Studies

USE OF RADIOACTIVE MATERIAL AND RADIATION-PRODUCING EQUIPMENT AT THE UNIVERSITY OF MICHIGAN
The U.S. Nuclear Regulatory Commission (NRC) is responsible for regulating the use of radioactive materials and the Michigan Department of Licensing and Regulatory Affairs (MD-LARA) is responsible for regulating the use of radiation-producing equipment including x-ray machines, x-ray diffraction units, cyclotrons, medical linear accelerators, and electron microscopes. The University of Michigan (U-M) has applied for and has been granted licenses by the NRC to use radioactive material and registration certificates by the MD-LARA to operate x-ray producing equipment. As an NRC licensee and MD-LARA registrant, the U-M must follow the applicable NRC and MD-LARA regulations as well as any specific requirements stated in a license or registration certificate. Copies of NRC and MD-LARA regulations are available for review at Radiation Safety Service (RSS) / Occupational Safety & Environmental Health (OSEH).

The Nuclear Regulatory Commission and the Food and Drug Administration (FDA) have regulatory responsibilities concerning medical devices, drugs, and biological products utilizing radioactive material. On August 26, 1993, the NRC and FDA signed a Memorandum of Understanding that describes the roles and coordination between the two regulatory agencies. Both agencies agree to promptly inform each other whenever they receive a report or otherwise become aware of a potential public health problem such as a malfunction, failure, reportable event, or a misadministration involving products of mutual regulatory concern.

The FDA is responsible for assuring the safety, effectiveness, and proper labeling of medical products, such as drugs, devices, and biologics. The FDA functions intended to ensure the effectiveness, safety, and quality of drugs for human use include, but are not limited to, the following: (1) review of clinical and bioavailability studies, manufacturing processes, and testing methods; (2) review of voluntary and mandatory adverse reaction reports and drug product defect reports; and (3) enforcement activities such as routine and directed inspections, product removals, recalls, warning letters, and case actions such as seizure, injunction, prosecution, and civil penalties.

RADIATION SAFETY SERVICE (RSS) / OCCUPATIONAL SAFETY & ENVIRONMENTAL HEALTH (OSEH)
Radiation Safety Service / OSEH is responsible for ensuring that radiation-producing equipment and radioactive materials are used safely and in accordance with applicable regulations. RSS/OSEH is also responsible for ensuring that doses to employees and research subjects are maintained As Low As is Reasonably Achievable (ALARA).

In addition, RSS/OSEH provides administrative and technical assistance to the U-M Radiation Policy Committee (RPC) and the Radioactive Drug Research Committee (RDRC) / Subcommittee on the Human Use of Radioisotopes (SHUR).

RADIATION POLICY COMMITTEE (RPC)
The RPC is responsible for implementing, maintaining, and overseeing radiation safety at the University of Michigan. It establishes policies and enforces compliance with the program. NRC regulations mandate that a radiation safety (policy) committee is in place at medical and research & development institutions that use radioactive materials.

The committee provides advice through the Associate Vice President for Facilities & Operations to the Executive Vice President & Chief Financial Officer regarding the regulatory compliance and the safe, authorized use of ionizing radiation.

The RPC, along with the Radiation Safety Officer (RSO), are responsible for approving the use of radioactive material and radiation-producing devices and evaluating the training and experience qualifications of applicants who request such authorizations. The RPC or RSO can revoke or suspend a user’s authorization for health, safety, environmental, or regulatory compliance concerns.

The committee consists of faculty and staff appointed by the Executive Vice President & Chief Financial Officer, who, by their knowledge and experience, are qualified to make judgments and formulate policy with respect to radiological safety and regulatory compliance.

Specifically, the RPC will consist of U-M administration, the U-M Radiation Safety Officer (RSO), representatives from clinical and research disciplines, and various other U-M program areas.

The Executive Director of Occupational Safety & Environmental Health (OSEH) and the Associate Vice President for Facilities & Operations will serve as ex officio members of the RPC. The RPC meets on at least a quarterly basis.

RADIOACTIVE DRUG RESEARCH COMMITTEE (RDRC)
The Radioactive Drug Research Committee (RDRC) is a subcommittee of the U-M's Radiation Policy Committee. The RDRC reviews certain research protocols involving radiopharmaceuticals as required by Food and Drug Administration (FDA) regulations (21 CFR 361.1).

The RDRC research pathway involves the oversight of basic human research for the purpose of advancing scientific knowledge. The research is intended to obtain basic information regarding the metabolism of radioactive drugs including kinetics, distribution, dosimetry, and localization or obtain basic information regarding human physiology, pathophysiology, and biochemistry of radioactive drugs. Only basic research studies are permitted under 21 CFR 361.1.

The FDA regulations specified in 21 CFR 361.1 explain when radioactive drugs for basic science and medical research in humans would be generally recognized as safe and effective, and would therefore not be subject to the same requirements for investigational use as other new drugs. Under 21 CFR 361.1, basic science and certain medical research may be conducted without an IND if approved by an institution’s RDRC. The term radioactive drug as used in 21 CFR 361.1 includes radioactive biological products labeled with a radionuclide.

Research conducted under the RDRC approval process is NOT intended for the immediate therapeutic, diagnostic, or preventive benefit to the human research subjects involved. In addition, RDRC research is NOT intended to determine the safety and effectiveness of a radioactive drug in human research subjects as a therapy, diagnostic, or preventive medical product.

Any protocol submitted to the RDRC for review and approval is also required to receive Institutional Review Board (IRBMED) approval. IRBMED approval is contingent upon RDRC/SHUR review and approval. For protocols undertaken at the U-M, the Office of Research Regulatory Affairs (RRA) will ensure the coordination of eResearch application reviews by the RDRC and other ancillary committees. Any revisions or modifications required by the RDRC/SHUR must be incorporated into the protocol before final, full approval by the IRB will be granted.

RDRC Responsibilities

  • Review, approve, request modification or clarification, or defer approval of human research protocols involving the administration of radioactive material to subjects solely because they are involved in a research study
  • Ensure that radioactive drugs are only administered to human research subjects by or under the direct supervision of physicians meeting the specific training and experience requirements specified in the NRC medical regulations (10 CFR 35)
  • Document meeting minutes including voting results
  • Communicate comments and expectations to the Principal Investigator
  • Submit an annual report by January 31st to the FDA as required by 21 CFR 361.1. The annual report must include a summary of each RDRC-approved study and a list of the current U-M RDRC membership
  • Maintain approval by the FDA and ensure compliance with 21 CFR 361.1. The FDA monitors the activities of each institution’s RDRC through on-site inspections, notification of deficiencies, and withdrawal of RDRC approvals.

Protocols the RDRC is Authorized to Review
FDA Research Protocols (21 CFR 361.1)
The RDRC reviews human research protocols involving radioactive drugs without: (1) a New Drug Application (NDA) filed with the FDA, (2) an approved Investigational New Drug (IND) application, or (3) an IND Exemption may be subject to review by the RDRC in compliance with 21 CFR 361.1.

To be eligible for review by the RDRC under 21 CFR 361.1, a protocol must:

  • Involve certain radioactive compounds generally recognized as safe and effective
  • Be designed to use radioactive compounds to obtain basic information regarding the metabolism of the compound or regarding human physiology, pathophysiology, or biochemistry
  • Not be intended for immediate therapeutic use, diagnostic use, diagnostic studies, or clinical trials
  • Not be intended to determine the safety and effectiveness of a drug (carry out a clinical trial)
  • Not be designed as part of the routine clinical medical management of patients
  • Not allow a pharmacological dose to cause a clinically detectable effect
  • Be limited with respect to the annual and total radiation dose commitment to the numerical limits specified in 21 CFR 361.1

Example of a RDRC Study: ‘An investigator wants to study the expression of a specific neurotransmitter receptor in the brain of normal elderly.’

RDRC Membership

  • The RDRC is comprised of the identical membership as the SHUR; thus, RDRC/SHUR.
  • The RPC Chair will appoint the members and chairperson of the RDRC/SHUR
  • In accordance with FDA regulations (21 CFR 361.1), an RDRC must have at least five members that include the following professional disciplines:
  1. The U-M Radiation Safety Officer
  2. A physician recognized as a specialist in nuclear medicine
  3. An individual qualified by training and experience to formulate radioactive drugs, and
  4. An individual with special competence in radiation dosimetry
  5. The remainder of the membership may consist of individuals that have special training and experience in various disciplines pertinent to the need of the committee in reviewing a research project. These individuals may be from the field of radiology, internal medicine, radiation therapy / radiation oncology, clinical pathology, hematology, endocrinology, radiation physics, radiation biophysics, health physics, medical physics, cardiology, pediatrics, nuclear pharmacy, biochemistry, and other fields related to the safe use of radioactive drugs.

Summary
Under the FDA’s RDRC regulations (21 CFR 361.1), human research using a radioactive drug or biological product may be conducted under an RDRC only (without an IND) when that research is basic science research, and not research that is intended for immediate therapeutic, diagnostic, or similar purposes, or to determine the safety and effectiveness of the radioactive drug or biological product for such purposes (meaning, the research cannot constitute a clinical trial for the product).

The FDA regulations list three additional requirements for human subject research that may be conducted under an RDRC:

  1. The research must be approved by an institution’s RDRC that has been approved by the FDA.
  2. The dose to be administered must be known not to cause any clinically detectable pharmacological effect in humans.
  3. The total amount of radiation to be administered as part of the study must be the smallest radiation dose practical to perform the study without jeopardizing the benefits of the study, and must be within specified limits.

SUBCOMMITTEE ON THE HUMAN USE OF RADIOISOTOPES (SHUR)
The Subcommittee on the Human Use of Radioisotopes (SHUR) is a subcommittee of the U-M's Radiation Policy Committee and is comprised of the identical membership as the RDRC. The SHUR is responsible for the review and approval of applications for the clinical use of radioactive materials in or on humans submitted by medical authorized users and the review of human research subject protocols involving the administration of radiopharmaceuticals to research subjects that are not covered under 21 CFR 361.1.

SHUR Responsibilities

  • Review, approve, request modification or clarification, or defer studies involving FDA-approved New Drug Applications (NDA)
  • Review, approve, request modification or clarification, or defer studies involving FDA-approved Investigational New Drugs (IND)
  • Review, approve, request modification or clarification, or defer studies involving IND Exemptions
  • Review, approve, request modification or clarification, or defer the clinical administration of radiopharmaceuticals intended for therapeutic use, diagnostic use, or similar purposes or to determine the safety and effectiveness of a drug (clinical trials)
  • Ensure that radioactive drugs are only administered to patients or human research subjects by or under the direct supervision of physicians meeting the specific training and experience requirements specified in the NRC medical regulations (10 CFR 35)
  • Document committee meeting minutes including voting results
  • Communicate committee members comments and expectations to the Authorized User Physician or Principal Investigator
  • Ensure compliance with Nuclear Regulatory Commission (NRC) medical regulations (10 CFR 35) and the Food and Drug Administration (FDA) research subject regulations for studies conducted under an IND, NDA, or IND exemption. Both the NRC and FDA will monitor the activities of the SHUR and RDRC, respectively, through on-site inspections and notification of deficiencies or non-compliance issues.

Example of a SHUR Study: ‘An investigator wants to study a new radioligand to monitor the treatment response of a brain tumor.’

Any human research subject protocol submitted to the SHUR for review and approval is also required to receive Institutional Review Board (IRBMED) approval. IRBMED approval is contingent upon SHUR review and approval. For protocols undertaken at the U-M, the Office of Research Regulatory Affairs (RRA) will ensure the coordination of eResearch application reviews by the SHUR and other ancillary committees. Any revisions or modifications required by the SHUR must be incorporated into the protocol before final, full approval by the IRB will be granted.

RDRC/SHUR Meetings
RDRC/SHUR meetings are typically scheduled on the third Monday of every month and the FDA requires traditional face-to-face meetings when reviewing new RDRC applications. The FDA does not approve of teleconferencing or e-mail correspondences for the initial review of new RDRC applications.

The RDRC/SHUR members vote on each protocol reviewed at the meeting. Any member having involvement in a protocol or some other conflict of interest must abstain from voting on it.

For each protocol, members may vote to do the following:

  • Approve unconditionally
  • Approve pending minor changes in the protocol which may be approved after review by the Chair of the RDRC/SHUR
  • Defer, requiring substantial or major changes or more information which will be reviewed at another committee meeting
  • Disapprove

Committee meeting minutes will be drafted by the RDRC/SHUR secretary and signed by the RDRC/SHUR Chair. The minutes will include a listing of the members who were present for the meeting, voting results and committee members comments regarding the reviewed protocols.

The RDRC/SHUR reports to the RPC. Subsequent to RDRC/SHUR approval, the RPC Chair reviews and approves RDRC/SHUR applications.