The RDRC is responsible for determining whether or not the proposed research study constitutes basic research and if so, whether the following requirements are met. The RDRC Protocol Review Checklist may be used by the RDRC when reviewing proposed research studies.
Radiation dose to subject
- The radiation dose to research subjects is as low as practical to perform the study without jeopardizing the benefits to be obtained from the study and meets the limits specified in § 361.1(b)(3). This requirement is evaluated by the following:
- absorbed dose calculations based on biologic distribution data from valid studies (e.g., published data)[§ 361.1(d)(1)(i)].
- an acceptable method of radioassay of the radioactive drug prior to its use to assure that the dose calculations actually reflect the administered dose [§ 361.1(d)(1)(ii)].
- information that demonstrates that the radioactive drug chosen for the study has the half-life, types of radiation emitted, radiation energy, metabolism, chemical properties, etc. that result in the lowest dose to the whole body or specific organs with which it is possible to obtain necessary information [§ 361.1(d)(1)(iii)].
- identification of adequate and appropriate instruments for the detection and measurement of the specific radioactive drug [§ 361.1(d)(1)(iv)].
- For adult subjects: Radiation dose from a single study or cumulatively from a number of studies conducted within 1 year does not exceed the following [§ 361.1(b)(3)(i)]:
|Organ or System||Single Dose|
|Annual and Total Dose|
|Whole body||0.03 (3)||0.05 (5)|
|Active blood-forming organs||0.03 (3)||0.05 (5)|
|Lens of the eye||0.03 (3)||0.05 (5)|
|Gonads||0.03 (3)||0.05 (5)|
|Other organs||0.05 (5)||0.15 (15)|
- For subjects under 18 years of age: Radiation dose does not exceed 10 percent of dose set forth above [§ 361.1(b)(3)(ii)]. For additional requirements for studying subjects under 18 years of age see Human Research Subjects: Age.
- Determination of total radiation doses and dose commitments includes [§ 361.1(b)(3)(iii)]:
- All radioactive material included in drug either as essential material or as significant contaminant or impurity.
- X-ray procedures that are part of the research study.
- Possibility of follow-up studies
- The numerical definitions of dose are based on absorbed fraction method of radiation absorbed dose calculation (e.g., system set forth by Medical Internal Radiation Dose Committee of the Society of Nuclear Medicine or by the International Commission on Radiological Protection)[§ 361.1(b)(3)(iv)].
- The radiation exposure is justified by the quality of the study being undertaken and the importance of the information it seeks to obtain [§ 361.1(b)(1)(iii)].
Pharmacological dose to subjects
- The amount of active ingredient or combination of active ingredients is known not to cause any clinically detectable pharmacological effect in humans [§ 361.1(b)(2)].
- If the same active ingredients (exclusive of the radionuclide) are to be administered simultaneously (e.g., under an IND or for a therapeutic use), the total amount of active ingredients including the radionuclide is known not to exceed the dose limitations applicable to the separate administration of the active ingredient excluding the radionuclide [§ 361.1(b)(2)].
These requirements are evaluated by pharmacological dose calculations based on clinical data in the published literature or from other valid human studies [§ 361.1(d)(2)].
Qualifications of investigators
Investigators are qualified by training and experience to conduct the research studies [§ 361.1(d)(3)].
License to handle radioactive materials
The investigator or institution is licensed by the appropriate State, local, and/or Federal authorities.
- For reactor-produced isotopes, the investigator or institution is licensed by the Nuclear Regulatory Commission or Agreement State to possess and use the specific radionuclide for research use or is a listed investigator or institution under a broad license [§ 361.1(d)(4)].
- For non-reactor-produced isotopes, the investigator or institution is licensed by other appropriate State or local authorities when required by the State or local law [§ 361.1(d)(4)].
- Approval by IRB: The research study has the approval of an Institutional Review Board (IRB) and the consent of the subjects or their legal representatives must be obtained [§ 361.1(d)(5)].
- Age: The research subjects must be 18 years of age and legally competent. Exceptions are permitted only if the study:
- represents a unique opportunity to gain information not currently available,
- requires the use of research subjects less than 18 years of age, and
- is without significant risk to the subject [§ 361.1(d)(5)].
- Research studies involving minors must be reviewed and approved by a qualified pediatric consultant to the RDRC [§ 361.1(d)(5)]. In addition, a special summary must be submitted to the FDA at the time a research study is approved that involves subjects less than 18 years of age [§ 361.1(c)(3)].
- Women of Child-Bearing Potential: Female research subjects must state in writing that they are not pregnant or on the basis of a pregnancy test be confirmed as not pregnant [§ 361.1(d)(5)].
- Number of subjects: If the number of proposed subjects exceeds 30, a special summary must be submitted to FDA [§ 361.1(c)(3)].
Quality of radioactive drug
- The radioactive drug used in the research study meets the appropriate chemical, pharmaceutical, radiochemical, and radionuclidic standards of identity, strength, quality and purity as needed for safety and be of such uniform and reproducible quality as to give significance to the research study conducted [§ 361.1(d)(6)].
- Radioactive materials for parenteral use are prepared in sterile and pyrogen-free form [§ 361.1(d)(6)].
- Scientific knowledge and benefit is likely to result from the study [§ 361.1(d)(7)].
- A rationale for the research is derived from appropriate animal studies or published literature [§ 361.1(d)(7)].
- The protocol is of sound design such that information of scientific value may result [§ 361.1(d)(7)].
- A justification that the radiation dose is sufficient and no greater than necessary for measurement [§ 361.1(d)(7)].
- A justification that the number of research subjects is sufficient and no greater than necessary for the purpose of the study. The number of subjects is limited to that needed for basic research and not for immediate therapeutic, diagnostic, or similar purposes, or to carry out a clinical trial to determine the safety and effectiveness of the drug [§ 361.1(d)(7)].
- The investigator must immediately report to the RDRC chairperson all adverse effects associated with the use of the radioactive drug in the research study [§ 361.1(d)(8)].
- The RDRC chairperson must immediately report to FDA all adverse reactions probably attributable to the use of the radioactive drug in the research study [§ 361.1(d)(8)].
The packaging, label, and labeling of the radioactive drug are in compliance with Federal, State, and local law regarding radioactive materials [§ 361.1(f)]. The label of the immediate container and the shield container, if any, must bear the following
- The statement "Caution: Rx only" [§ 361.1(f)(1)];
- The statement: "To be administered in compliance with the requirements of Federal regulations regarding radioactive drugs for research use (21 CFR 361.1)" [§ 361.1(f)(2)];
- The established name (USAN name) of the drug, if any [§ 361.1(f)(3)];
- The established name and quantity of each active ingredient [§ 361.1(f)(4)];
- The name and half-life of the radionuclide, total quantity of radioactivity in the drug product’s immediate container, and amount of radioactivity per unit volume or unit mass at a designated referenced time [§ 361.1(f)(5)];
- The route of administration, if it is for other than oral use [§ 361.1(f)(6)];
- The net quantity of contents [§ 361.1(f)(7)];
- An identifying lot or control number from which it is possible to determine the complete manufacturing history of the package of the drug [§ 361.1(f)(8)];
- The name and address of the manufacturer, packer, or distributor [§ 361.1(f)(9)];
- The expiration date, if any [§ 361.1(f)(10)];
- If the drug is intended for parental use, a statement as to whether the contents are sterile [§ 361.1(f)(11)];
- If the drug is for other than oral use, the name of all inactive ingredients [§ 361.1(f)(12)], except that:
- Trace amounts of harmless substances added solely for individual product identification need not be named [§ 361.1(f)(12)(i)].
- If the drug is intended for parental use:
- The quantity or proportion of all inactive ingredients, except those ingredients added to adjust pH or to make the drug isotonic may be declared by name and a statement of their effect [§ 361.1(f)(12)(ii)];
- If the vehicle is Water for Injection, USP, it need not be named [§ 361.1(f)(12)(ii)].
In the case of containers too small or otherwise unable to accommodate a label with sufficient space to bear all such information, the information required by “A” and “L” above may be placed on the shielded container only [§ 361.1(f)(12)(ii)].