VI. PROTOCOLS USING RADIATION FOR RESEARCH
PI's and their associates are responsible for obtaining approval of the RSC for clinical research studies that involve exposure to ionizing radiation when the exposure is not medically indicated or when such use is experimental.
The majority of protocols use radiation or radioactive materials in a medically indicated fashion, that is, for diagnosis or treatment when such use is considered to be standard patient care. However, it is important to recognize that a procedure with radiation exposure that is readily accepted as standard patient care, when done more than once, may become classified as "for research purposes." If the radiopharmaceutical or x-ray procedures in a protocol are of the appropriate type and number used in the practical management of the condition, the radiation exposure is considered medically indicated and does not require RSC review.
If uses of radiation or radioactive materials do not meet the criteria for "medically indicated," they are regarded as "indicated for research." Then the RSC must review the protocol. Any radiation exposure of healthy clinical research volunteers, as well as protocols conducted with certain radioactive research drugs (radiopharmaceuticals that are not FDA-approved drugs nor used under an IND or New Drug Approval [NDA]), must be reviewed by the RSC. If there is any question about the category in which a protocol's radiation may fall, the PI should confer with the Chair or Executive Secretary of the RSC.
The IRB makes the final decision of whether radiation exposure is medically indicated or indicated for research purposes. If the IRB determines that the protocol involves radiation exposure for research purposes, the Institute Clinical Director and the IRB have the authority to require the PI to send the protocol to the RSC for review and approval. Investigators are encouraged to submit their applications to the RSC as soon as possible; in many cases, it is clear that research-related radiation is involved in the proposed research. Submission of applications to the RSC in parallel with submission to an IRB shortens review times considerably.
The use of radiation sources in clinical applications is conducted under the supervision of physicians who are specifically authorized by the RSC. Information about this process is available in the "NIH Radiation Safety Guide," available on the web at http://www.nih.gov/od/ors/ds/rsb/rsguide/appe.htm.
An authorized user, also known as an "applicant," may also be the person who orders radioactive materials and is responsible for their safe and proper use and disposal. The authorized user, who may be the PI, is also responsible for ensuring compliance with conditions of the protocol and other procedures relating to safe use of radiation sources. Commonly, however, the PI may not be authorized to use radionuclides in human subjects, and thus he or she will enlist a physician who is authorized. The investigators are responsible for minimizing the radiation dose to the research participant consistent with obtaining the desired research information.
The issue of what and how much to tell a prospective research participant is an important judgment to be made by the PI, the IRB, and the RSC for each new protocol involving radiation exposure.
The RSC established the following guidelines to assist PI's with preparing a protocol consent document for a protocol that involves radiation exposure for research purposes.
Examples are presented below of acceptable and suggested wording of statements of risk that have been developed by the RSC for consent documents. The statements must accurately and completely reflect the sources of radiation exposure and the radiation doses to be received by research subjects participating in a specific protocol.
Consent and assent statements must be modified appropriately for child participants, taking into account that dose guidelines generally are 1/10th of those for adults.
When drafting consent statements, it is helpful to seek the counsel of experienced authorized users or PI's, RSC members, or the Executive Secretary of the RSC.
Form NIH-88-23(a), "Application for Authorization to Use Radiation in Research Involving Human Subjects" (appendix F), the protocol consent, and, in the case of radiation exposure of minor subjects, assent statements are to be submitted to the RSC for research studies that use radiation indicated for research purposes.
The NIH-88-23(a) form is available in PC-format from the RSC. A physician who is authorized by the RSC to use radiation in clinical applications must complete this form. It must be completed accurately and thoroughly, including the signatures of all authorized users and the identification of the PI on the first page of the application. Applications to the RSC must be signed by a clinician authorized by the RSC and by the PI, with the exception that the signature of the PI is sufficient for protocols that involve only radiographic procedures indicated for research.
Under policies developed by the RSC to ensure compliance with licenses granted to NIH by the NRC, and to ensure the safety of research subjects, the RSC reviews the dosimetry calculations on the form and written in the protocol for all protocols using radiation for research purposes. Dosimetry information and assistance are available from the Executive Secretary of the RSC. The applicant or PI must present valid dosimetric estimates that reflect up-to-date methodologies, ensure that dosimetry calculations are arithmetically correct, and cite references or provide assumptions upon which the dosimetry is based. The protocol and protocol consent and assent documents must include a description of the radiation doses and their risk to the human subject. The PI should ensure that these values are consistent on the NIH-88-23(a) form, in the protocol, and in the protocol consent and assent documents.
To expedite the review process, a completed NIH-88-23(a) form, the protocol, and the protocol consent and assent documents should be submitted together as the "application package" to the RSC, the appropriate IRB, and the RDRC (if applicable) simultaneously. These review bodies will evaluate the application package concurrently, communicating with each other by way of memos and advising one another of any changes or stipulations required of the PI. The applicant or PI must submit 14 copies of the application package – including the original NIH-88-23(a) form – to the Executive Secretary of the RSC at least 7 days before the scheduled meeting, to allow for distribution to the RSC members. The RSC typically meets on the last Thursday of each month. Applicants or PI's are not required to attend the RSC meetings. Applicants may expect one of the following actions to be taken by the RSC:
After applicants have met the RSC's requirements, final approval of the application package is given, with the RSC Chair signing the radiation authorization form and the Executive Secretary signing the NIH-88-23(a) form. The application package is assigned a Rad Authorization Number. The original approval is transmitted to the PCSC, along with the NIH-88-23(a) form. Copies of the RSC approval are forwarded to the applicant, PI, and other interested parties (figure 10). A copy is maintained in the RSC files. The responsibilities of the PI are to ensure that approval of the protocol by the RSC and the IRB has been obtained before seeking final approval by the CC Director; to ensure that changes required by reviewers are reconciled; and to advise the RSC, through the Executive Secretary, of changes mandated by other reviewers (usually an IRB) that relate materially to the conduct of radiation studies.
The RSC handles exclusively "in-house" protocols. Radiation exposure in protocols carried out at other NIH units, such as the Phoenix National Institute of Diabetes and Digestive and Kidney Diseases Field Station research program, are evaluated and approved by the radiation safety committees at those units. However, clinical studies conducted in National Institute on Aging and National Institute on Drug Abuse facilities in Baltimore, Maryland, do fall under the purview of the RSC.
The FDA permits the use under very restrictive rules of certain radioactive drugs that are not in routine clinical use. These radioactive agents are neither approved drugs nor available under an IND or NDA, but they may be used in studies involving basic research that is not intended for diagnostic or therapeutic purposes. For example, a clinical researcher may wish to use a radioactive drug to study the metabolism of a given organic molecule or its precursors or metabolites. Such studies must be reviewed and approved by the RDRC, a subcommittee of the RSC.
Applicants are required to submit five copies of their application to the RDRC for review. The RDRC considers such issues as radiation dose to subjects; quality control procedures; and tests to ensure purity, sterility, and apyrogenicity, as well as freedom from physiologic effect. Applicants are not required to attend the RDRC meetings. As mentioned above, RDRC reviews are coordinated with those of the RSC, and applicants must submit applications simultaneously to the two committees as well as the IRB.
An application for amendment to the radiation authorization must be submitted if the procedures previously approved by the RSC are changed. Investigators are responsible for obtaining RSC approval for changes to radiation authorizations that affect the following: number or age of subjects, patient population, radiation dose or models used to estimate radiation dose, wording in protocol consents and assents related to administration of radiation, regimen for administration of radiation, and change or departure of the PI. This is true irrespective of the IRB's choice of review method – expedited or regular review. Relatively minor changes and emergency compassionate exemptions may be requested via an explanatory memorandum if the information previously submitted on NIH-88-23(a) form is not changed substantially, for example, a request for change of authorized user or PI. If the amendment requests substantive changes, such as an increase in the radiation dose to human subjects, the PI must submit a new NIH-88-23(a) form, the amended protocol, and the protocol consent and assent documents for review by the full committee. In all cases of protocols conducted under the auspices of the RDRC, all amendments must be reviewed and approved by the RDRC and the RSC. The Executive Secretary of the RSC may be consulted to assist the applicant or PI with determining the extent of the amendment. Investigators seeking expedited review should contact the Executive Secretary for guidance, since exceptions are handled on a case-by-case basis.
Licenses granted to NIH by the NRC require periodic RSC review of all protocols for which it has granted radiation authorization. All Rad Authorizations must be reviewed and renewed every 3 years after the initial approval by the RSC. It is appropriate to coordinate RSC reviews with IRB review. The RSC review requires a written protocol that incorporates all amendments approved since the last triennial review of the application package and that clearly reflects the current nature of the protocol, for example, current methods and procedures used in the protocol and valid dosimetric estimates that reflect up-to-date methodologies. When the dosimetry has not changed since the last triennial review, the applicant or PI may use current dose tables, but the first few pages of the NIH-88-23(a) form must still be prepared; this requires new original signatures of the current applicant and PI identified on the first page of the application. When submitting applications for triennial review, the PI should follow the procedures outlined above for new studies.Previous | Index | Next
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