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Perspective on How the FDA Should Review Diagnostic Radiopharmaceuticals

This article provides readers with some background on concerns raised by Dr. Marcus about the evaluation of radiopharmaceuticals in this issue of The Journal of Nuclear Medicine (1). In 1975, the U.S. Food and Drug Administration (FDA) removed the exemption given to the Atomic Energy Commission for diagnostic radiopharmaceuticals and began regulating these drugs (2). This change was due to the increased use of radiopharmaceuticals and reimbursement by insurance companies and the resulting increased need for controlled production. The approval process of the FDA—whose mission is the safety and efficacy of drugs, including diagnostic drugs—was then applied to radiopharmaceuticals, with filing of an Investigational New Drug (IND) application being required for any new radiopharmaceutical developed (3). The IND primarily includes a chemistry manufacturing and controls section, a toxicology/pharmacology section, and a clinical protocol, including a consent form. Generally, the toxic portion of a drug is the mass present in the formulation, and as Dr. Marcus points out, for radiopharmaceuticals this mass is a very small quantity of the drug (in the range of micrograms to milligrams). In addition, a patient would typically receive only a single injection, again reducing the toxicity issue. For this reason, since the 1990s the nuclear medicine community has worked with the FDA to encourage the reduction of toxicity testing for these diagnostic radiopharmaceuticals. In 1996 the FDA published a guidance document on single-dose acute toxicity testing for pharmaceuticals (4), followed in 2006 by a guidance document that defined a microdose as less than 1/100th the dose of a test substance calculated (on the basis of animal data) to yield a pharmacologic effect of the test substance with a maximum mass dose of no more than 100 mg or, for a protein product, no more than 30 nmol (5). This document reduced the toxicology requirement from the 2 species required for therapeutic drugs to 1 species. The exploratory IND was originally intended for phase 0–1 studies, but in September 2017, with the issuance of draft guidance on nonclinical microdoses, the FDA expanded the reduced toxicology requirements to include traditional IND phase 2–3 studies for diagnostic radiopharmaceuticals (6). Additionally, toxicology studies could be performed not only in good-laboratory-practice laboratories but also in other types of laboratories, such as university comparative anatomy or veterinary medicine departments, further reducing cost. The field of nuclear medicine expanded from SPECT into PET in the 1990s, and by 1995 the primary PET drug used was 18FFDG, which was often produced at academic PET centers. The FDAwanted a controlled process for the production of this widely used PET drug and, in 1995, required that PET drugs be regulated under current good manufacturing practices (CGMPs), as had been mandated in 1975 for SPECT drugs. The PET community stepped forward to define the way the CGMPs would be applied to PET, since the mass of drug present in PET drugs is typically in the nanogram-to-milligram range, the half-life of the radionuclides is very short compared with typical SPECT drugs, and the 511-keV energy photon emitted requires significant shielding. The Food and Drug Modernization Act was signed by President Clinton in 1997. This act constituted the foundation of the FDA regulatory involvement in PET and provided that separate CGMP standards must be written specifically for PET. As a result of this congressional mandate, a radiopharmaceutical committee was formed to work with the FDA, including participation by the Academy of Molecular Imaging, the Society of Nuclear Medicine and Molecular Imaging (SNMMI), and the American College of Nuclear Physicians. In 2003, this interaction between the FDA and the committee resulted in the first 3 FDA approvals of PET radiopharmaceuticals— for 18F-FDG, 18F-sodium fluoride, and 13N-ammonia. The FDA met with the nuclear medicine community from 1995 until the final proposed rule on CGMPs for PET drugs was published in 2009. A workshop was convened at the FDA headquarters, and the community was invited to attend. A Coalition for PET Drug Approval was formed in 2010, involving multiple U.S. professional societies and commercial entities in nuclear medicine, including, but not limited to, the SNMMI, the World Molecular Imaging Society, the Society of Molecular Imaging, the National Association of Nuclear Pharmacies, the Society of Radiopharmaceutical Sciences, the American Pharmacists Association, the American Society of Nuclear Cardiology, United Pharmacy Partners, LLC, and the Council on Radionuclides and Radiopharmaceuticals. The FDA coalition meeting was collegial, and significant dialogue ensued, resulting in clarification and changes to the proposed rule; the final rule became effective in title 21 of Code of Federal Regulations, part 212 (21 CFR x212), in 2011 (7). In 2004 a critical event occurred: hepatitis C contamination of a radiopharmaceutical kit formulation compounded at a centralized nuclear pharmacy (8). This contamination was the result of reusing Received Jan. 2, 2018; revision accepted Mar. 22, 2018. For correspondence or reprints contact: Sally W. Schwarz, Washington University School of Medicine, Department of Radiology, Box 8225, St. Louis, MO 63110. E-mail: schwarzs@wustl.edu Published online Mar. 30, 2018. COPYRIGHT© 2018 by the Society of Nuclear Medicine and Molecular Imaging. DOI: 10.2967/jnumed.117.204446