guide for preparing and conducting clinical research study

VI. PROTOCOLS USING RADIATION FOR RESEARCH

Ionizing Radiation Usage: Medically Indicated or Indicated for Research Purposes

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.

Authorized User and Individual User of Radioactive Materials

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.

Informed Consent for Radiation Exposure

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.

  • Specify the source and amount of radiation by giving the following:
    • The source or sources of radiation exposure, including x-ray exposures.
    • The dosage of any radionuclide in units of activity, e.g., millicurie or microcurie.
    • The radiation doses in rem or the equivalent, to the organs and tissues that receive the higher doses. The use of radiation dose to the "whole body" is an important value only for certain radionuclides where the "whole body" dose is one of the higher organ-dose values. The "whole body" or "total body" radiation dose generally is not an indicator of the overall potential radiation hazard or risk.
  • Relate the radiation doses to the appropriate guideline or regulatory limit (the following apply to adults – 18 years of age and older; the limits for minors generally are 1/10th of those for adults):
    • NIH radiation safety guidelines for radiation exposure to research participants, both patients and healthy clinical research volunteers: 3 rem to any tissue within a 13-week period (quarter of a year) and 5 rem annually.
    • FDA regulatory limits for exposure to research participants from the use of "radioactive research drugs": 3 rem per single administration or study, and 5 rem per year to the whole body, blood-forming organs, lens of the eye, and gonads; for other organs the limits are 5 rem per single administration or study and 15 rem annually.
  • Estimate the risks of the radiation doses in general terms and, as appropriate, relate the estimated risk to other types of risk.
  • State that the radiation exposure to be received by participating in the protocol is for research purposes and is not medically indicated for the benefit of the research participant.
  • State that the use was reviewed and approved by the RSC and, if applicable, the NIH Radioactive Drug Research Committee (RDRC).
  • Include a statement that the pregnancy status of female subjects in their childbearing years will be determined, and that pregnant subjects may not participate in research with radiation involving human subjects. Example: "For women who have started menstruation, a negative urine pregnancy test is required because pregnant subjects may not participate in this study." An age-appropriate statement should be added to assent statements for minor female participants. In certain cases, this requirement may be waived; e.g., when including low doses of x-rays to the extremities and when the radiation dose to the fetus is negligible.
  • Include the following sentences: "Please advise your doctor if you have participated in research studies at the NIH or other institutions that involved the use of radiation so that it may be determined that the total radiation dose from all studies is not excessive. Examples of such studies include x-ray studies conducted in radiology departments, cardiac catheterization, and fluoroscopy, as well as nuclear medicine studies, e.g., technetium and PET scans."

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.

  • "The radiation doses that you will receive as a result of participating in this study include radiation from the administration of [XXX millicurie] of [radiolabeled preparation] and [specify any research-related radiographic (x-ray) procedures required by the study]."
  • "Using the standard way of describing radiation dose, you will receive [XXX rem] to your [greatest-dosed organ], [XXX rem] to your [next organ], and [XXX rem] to your [next organ]." (List at least the three organs receiving the highest radiation doses.)
  • "Please be aware that the radiation exposure is necessary for this research study only, and is not essential for your medical care. The NIH Radiation Safety Committee, a group of experts on radiation matters, has reviewed the use of radiation in this research study and has approved the use as being necessary to obtain the research information desired."
  • "The radiation dose you will receive (choose the applicable statement from those below, applicable for adults – 18 years of age and older):
    • "is within the NIH radiation safety guidelines for research subjects, that is, 3 rem to any tissue in a 13-week period and 5 rem in 1 year." (Note: This statement is to be used only for radioactive research drugs used in clinical research studies approved by the RDRC in accordance with FDA regulations.)
    • "is within FDA regulatory limits for the use of radioactive research drugs, i.e., 3 rem per administration and 5 rem in 1 year to the whole body, blood-forming organs, lens of the eye, and gonads."
    • "exceeds [or slightly exceeds, if appropriate] the radiation doses usually permitted to research subjects at NIH, but the NIH Radiation Safety Committee has approved the higher dose in view of the value of the scientific information to be obtained. The radiation dose usually permitted to research subjects at NIH is 3 rem to any tissue in a 13-week period and 5 rem in 1 year."
  • "The potential long-term risk from the radiation doses is uncertain, but the doses have never been associated with any definite adverse effects. Thus, the risk to you is estimated to be slight." (Note: For extremely high radiation doses, this statement of risk may not be correct and should be modified to reflect actual estimated adverse effects.)
  • "Please advise your doctor if you have participated in research studies at the NIH or other institutions that involved the use of radiation so that it may be determined that the total radiation dose from all studies is not excessive. Examples of such studies include x-ray studies conducted in radiology departments, cardiac catheterization, and fluoroscopy, as well as nuclear medicine studies, e.g., technetium and PET scans."

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.

Radiation Safety Committee Review

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:

  • Approval
  • Approval with recommendations

    The applicant or PI should respond to the recommendations. If the protocol is approved with or without recommendations, the RSC Chair immediately signs the approval memorandum and forwards the approval to the applicant or PI within 1 or 2 working days after the RSC meeting. Simultaneously, the RSC notifies the PI, the IRB Chair, and the PCSC of the RSC approval.

  • Approval with stipulations

    The applicant or PI must provide the RSC with a written response to the stipulations. The applicant or PI will receive a memorandum identifying the stipulations of the RSC within 7 to 10 days after the RSC meeting. In the case of simple stipulations, an electronic message may be sent to the applicant or PI to help expedite the application.

    Once the stipulations have been addressed as requested by the RSC, the applicant or PI should submit the revised application package and a "Response to RSC Stipulations" memorandum to the Executive Secretary of the RSC, for review and approval by the RSC Chair. Depending on the extent of the stipulations, the RSC Chair may review and approve the revised application package without full committee review. At this stage, additions to the application that go beyond the scope of the original application or stipulations may result in referral of the application to the full committee for review.

  • Table

    The RSC determines that approval cannot be granted until further information is provided or specific changes are made in the proposed protocol. When the applicant or PI submits new information, the protocol is reviewed again by the RSC.

  • Disapproval

    The RSC sends a notice to the applicant or PI identifying the reasons for disapproval of the protocol. The applicant or PI may then submit a revised application package that reflects due consideration of the reasons for disapproval of the original application.

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.

Figure 10: Authorization to Administer Radiation in Research Involving Human Subjects

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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.

Radioactive Drug Research Committee

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.

Amendment and Triennial Reviews

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.

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