An IND for a PET radiopharmaceutical is approved by the FDA for human use following a submission by a sponsor of the preliminary data of the radiopharmaceutical in humans and animals, technical details of the project, the clinical protocol, and the credential of the sponsor. There are three phases in the IND clinical investigation of a radiopharmaceutical. In Phase I, only pharmacologic and biodistribution data of the radiopharmaceutical are obtained in a limited number of humans and no therapeutic and diagnostic evaluation can be made. In Phase II, clinical effectiveness of the radiopharmaceutical is evaluated for a specific disease only in a limited number of patients. In Phase III, a large number of patients involving many trial centers are included in the clinical trial to establish the safety and clinical effectiveness of the radiopharmaceutical for a specific disease. Annual reports must be submitted on the progress of the project. Any serious adverse reaction from the product must be reported immediately to the FDA.

After a radiopharmaceutical is proven by clinical trials under an IND to be safe and efficacious for a specific clinical indication, an NDA is submitted with all clinical data by a commercial vendor to the FDA for approval to market it. Many clinical trial centers are sponsored by the vendor to collect the data, which are then submitted in the application. After scrutiny of the data, if the FDA is convinced of the safety and efficacy of the radiopharmaceutical for a clinical indication, it approves the product for marketing. It takes a long time (at times, a couple of years) from an IND to an NDA for approval of a particular radiopharmaceutical for clinical use in humans.

PET radiopharmaceuticals are uniquely different from conventional radiopharmaceuticals because they are short lived and are produced on site at the cyclotron facility. Synthesis of these tracers by radiolabeling with positron emitters is accomplished in automated synthesis boxes. Several lengthy quality control tests are often performed on an “after-the-fact” basis. The production methods and their technical details may vary from facility to facility. For these reasons, the FDA treats PET radiopharmaceuticals somewhat differently and attempts to standardize the techniques employed in all PET facilities. In the mid-1990s, the FDA published the regulations and guidelines for the manufacture of PET radiopharmaceuticals in the Federal Register. These regulations provided guidance for submission of NDAs and abbreviated NDAs (ANDAs) to the FDA for PET radiopharmaceuticals, and the guidelines gave details of the current good manufacturing practice (CGMP) to follow in the manufacture of PET radiopharmaceuticals.

However, the above regulations and guidelines were considered too costly and burdensome by the nuclear medicine community, particularly the commercial vendors. Also, other radiopharmaceuticals and conventional drugs were subjected to strict scrutiny by the FDA, resulting in a very long waiting time for marketing approval. Following strong lobbying by the nuclear medicine community, drug manufacturers, and other stakeholders, the US Congress enacted the FDA Modernization Act (FDAMA) (Public Law 105–115) in 1997 to overhaul several aspects of the drug manufacturing industry, which took effect on November 21, 1997. Under the Act, the existing regulations regarding PET radiopharmaceuticals were retracted and new provisions were introduced.

In the FDAMA, PET radiopharmaceuticals are categorized as positron-emitting drugs compounded by, or on the order of, a licensed practitioner following the state’s regulations and meeting the specifications of the official monographs of the US Pharmacopeia (USP). The FDAMA directed the FDA to develop approval procedures and guidance for the manufacture of PET radiopharmaceuticals within a time frame of 4 years. In this 4-year time line, all PET tracer-producing facilities in the USA were to be registered as drug manufacturers. In the first 2 years, the FDA was to consult with patient advocacy groups, professional associations, manufacturers, physicians, and scientists who prepare or use PET drugs, in developing approval procedures and CGMP for PET radiopharmaceuticals. The remaining 2 years were allowed for all PET radiopharmaceutical manufacturing facilities to comply with the new PET drug CGMP and register as manufacturers. During these 4 years, the FDAMA prohibited the FDA to require the submission of NDAs or ANDAs for PET radiopharmaceuticals produced according to the USP specifications. However, voluntary submissions of NDAs or ANDAs were not prohibited.

Based on the literature survey of PET data, the FDA concluded that certain PET radiopharmaceuticals, when produced under specific conditions, are safe and effective for certain clinical indications. Based on this survey, three PET radiopharmaceuticals, ¹⁸F-sodium fluoride for bone imaging, ¹⁸F-FDG for use in oncology and for assessment of myocardial viability, and ¹³N-NH₃ for evaluation of myocardial blood flow, were approved by the FDA in 2000. ⁸²Rb-rubidium chloride was approved by the FDA for evaluation of myocardial perfusion in 1989. Recently ¹⁸F-florbetapir has been approved for amyloid-plaque imaging in AD and ¹¹C-choline for prostate cancer.

The FDA also published in the Federal Register a draft guidance for industry entitled, “PET Drug Applications—Content and Format for NDAs and ANDAs” (March 10, 2000; 65 Fed.Reg. 13010), citing the safety and effectiveness of ¹⁸F-FDG, ¹⁸F-soodium fluoride, and ¹³N-ammonia. It is intended to assist manufacturers of these radiopharmaceuticals in submitting ANDAs, instead of full NDAs, simply referring to this guidance for product information. Following a period of comments from various stakeholders, the final rule was adopted. The guidance gives the details on the criteria for when to apply for an NDA or an ANDA and what to include in the application. In addition, this 2000 Federal Register addressed user fees against the applicants of NDAs for the application, manufacturing facilities, and drug products.

A traditional Phase I IND requires a very comprehensive and detailed application for any human research protocol for evaluation of a drug. In 2006, the FDA has instituted a new approach, called the “Exploratory IND,” or “eIND,” to ease the application process as well as expedite the research progress. An eIND is a clinical trial that is conducted early in Phase I, involves a limited radiation exposure, and has no therapeutic or diagnostic intent.

An eIND containing the following information must be submitted to the FDA:

It should be noted that an eIND is meant for quick assessment of pharmacokinetics, pharmacological effects, and mechanism of action of a drug for its potential clinical use. For pharmacokinetics study, microdosages of the product are used not to induce any pharmacological effect. A microdosage is defined as less than 1/100th of the dosage calculated to yield a pharmacological effect of a test product with a maximum dosage of ≤100 μg. Microdosage studies performed in animals for pharmacokinetics are acceptable to the FDA for extrapolation to human studies. For pharmacological studies, toxicity of the test product is established in animals (e.g., rats) by repeated administration of the product over a 7-day period and observing the pathological changes in tissues. The study can be extended to a 2-week repeat study. The aim of the experiment is to establish the starting dosage and the maximum dosage of the test product for safety and efficacy in the clinical trial. The dosage and the dosing regimen determined in the animal experiments for pharmacokinetics and pharmacologic effects are extrapolated to the human clinical trial to establish the mechanism of action for a given target. The study must be withdrawn after the completion of the proposed protocol. Readers are referred to “Guidance for Industry, Investigators and Reviewers Exploratory IND Studies” at http://​www.​fda.​gov/​cder/​guidance for further information.

The radiation dose to the critical organs (effective dose, dose to the lens and blood-forming organ) of a patient cannot exceed 3 rem (0.03 Sv) from a single dosage and a sum of greater than 5 rem (0.05 Sv) per year during the entire study. Only 30 patients over the age of 18 are allowed for study per protocol, and a special summary report must be submitted to the FDA, if the number exceeds 30 and the age is greater than 18. The pregnant women are not allowed to participate in the study under the RDRC.

An investigator in an institution formally submits a research protocol to its RDRC with detailed description of the study, but prior to submission, the protocol must be approved by the Institutional Review Board. The RDRC meets at least quarterly if active research is pursued, with at least 50% membership present. Members with conflict of interest in a protocol must excuse themselves from voting on the protocol. Based on the critical review of the protocol, the study may be or may not be approved by the RDRC. If approved, the study will be regularly monitored by the committee on the progress. Any adverse effects encountered during the study must be immediately reported to the FDA. The chairman of the RDRC is the primary contact person with the FDA and must submit an annual report on all projects. Also any change in the membership must be reported to and approved by the FDA.

The following major differences between the two processes are noted:

Expanded Access IND (eaIND) has been designed by the FDA to provide access to investigational drugs on an emergency basis for serious or life-threatening diseases. Pursuant to the FDAMA, 1997, specific provision for the eaINDs was included in a final rule on CGMP published in 2009 (see below). Although eaIND drugs were meant for therapeutic drugs, the FDA has included the diagnostic PET radiopharmaceuticals in eaIND groups because of the short half-lives and difficulty in commercial production.

An eaIND can be applied for an individual patient, a small group of patients, or a large group of patients. eaINDs are most useful for individual patients and the submission of an application to the FDA is simplistic. The required information for application includes pharmacology data, previous experience, evidence from literature, etc. For an individual patient, only direct cost can be recovered, whereas for a larger group, both direct cost and indirect cost (e.g., administrative costs) can be charged to the patients. PET eaINDs do not pose any potential risk, because of the diagnostic nature of the ingredients. eaINDs are not applicable to FDA-approved drugs such as ¹⁸F-FDG and ¹³N-ammonia.