Regulatory With Radiopharmaceuticals By Jerome A. Halperin Since ince the first radionuclides became available for civilian medical use following World War II, the development, production, and marketing of human drugs containing radionuclides (radiopharmaceuticals) have been different from nonradioactive drugs. The radiopharmaceutical marketplace is characterized by about a dozen firms. Only two or three of these are large multiline pharmaceutical manufacturers for whom radiopharmaceuticals is but one product line. Most are small specialty firms whose sole products are radiopharmaceuticals. To a large extent, radiopharmaceutical manufacture is still a cottage industry, especially in the production of generic copies of approved or commonly used radiopharmaceutical products. Innovation occurs at the bench of the end product userthe nuclear medicine physician working closely with a support staff of nuclear pharmacists, nuclear chemists, radiation physicists, and other specialists-rather than in the laboratory of a large manufacturer. The nuclear medicine team conceives and develops a new radioactive diagnostic agent, tests it in a number of patients to determine whether it works, reports its find Pharmacist Jerome A. Halperin is dep uty director of FDA's Bureau of Drugs. This article is based on a speech presented to the Nuclear Pharmacy Session at the 1980 APhA Annual Meeting in Washington, DC. American Pharmacy Vol. NS20, No. 8, August 1980:444 ings at professional meetings or publishes a paper, and is off and working on a new agent while other physicians and nuclear pharmacists start preparing and using the agent. Much of this work is done without adherence to FDA's Investigational New Drug regulations. The large radioactive drug manufacturers become involved for the most part only when an agent shows sufficient commercial potential. Until recently, these manufacturers had not been involved much in the de velopmental phase of the products. Into Line Since 1975, when FDA terminated the 1963 exemption to the new drug provisions of the Federal Food, Drug, and Cosmetic Act, FDA policy has been to bring the development, production, and marketing of radiopharmaceuticals into line with other sectors of the pharmaceutical marketplace. This is necessary not only for legal reasons, but also to assure the safety and effectiveness American Pharmacy Vol. NS20, No. 8, August 1980/445 of products, to assure their quality, to improve diagnostic medicine, and to minimize radiation exposure. The primary thrust has been to see that radiopharmaceuticals meet the new drug provisions of the law, i.e., that products have approved NDAs or INDs. The Bureau of Drugs has published guidelines for the clinical evaluation of radiopharmaceuticals both in adults and in children and now is preparing guidelines for the manufacturing and controls information in radiopharmaceutical new drug applications, for conformance with the good manufacturing practices, regulations for radiopharmaceutical manufacturing, and finally, for determining when nuclear pharmacies must register as drug establishments. Slowly, the differences between radioactive and nonradioactive drugs are disappearing, and the development, production, and marketing of radioactive drugs are becoming like other drugs. To a large extent, radiopharmaceutical manufacture is still a cottage industry..... In bringing about these regulatory changes, FDA needs the support of the nuclear pharmacists whose professional goal is the same as the agency's: providing the highest quality radiopharmaceutical product to the patient with the minimum possible risk. Radiopharmaceuticals are still different enough to give pharmaceutical manufacturers, investigators, and FDA some special problems. The differences can be described under the following headings: • Radioactive drugs vs. radiochemicals; • Commercialization of investigational drugs; • Manufacturing problems; 21 'Radiopharmaceuticals are still different enough to give manufacturers, investigators, and FDA some special problems.' • Adverse reactions and product defects; • Drug product quality; Pharmacy vs. manufacturing. 'Chemicals' vs. 'Pharmaceuticals' Certain manufacturers have characterized their products as "radiochemicals," claiming that FDA has no jurisdiction over them. They often maintain either that they have no knowledge of the ultimate use of their radiochemicals or, if they acknowledge that they are aware that the radiochemicals ultimately are used as a radioactive drug, that they are not responsible under the new drug regulations, stating that such concern is more properly the re Commercialization There continues to be widespread use of unapproved new radiopharmaceuticals, some covered by an IND and some not. In some cases, radiopharmaceutical manufacturers have supplied investigational products to physicians under the IND, with no attempt to require that these physicians conduct wellcontrolled trials necessary for valid clinical investigation and for approval of the drug for marketing. În at least one incidence, up to 30,000 doses of an investigational drug had been distributed under the pretext of a clinical investigation. FDA plans to issue a policy statement and a plan for curtailing commercialization of investigational products and assuring proper development and clinical testing of such products. The reasons for our concern are not merely that widespread commercialization of investigational products is not legal. It is, more important, that until the agent can be shown to be safe and effective through appropriate clinical trials, physicians lack the full information required to demonstrate the proper use of the agent, and patients may be exposed to unnecessary risk. A variant of this problem is that of distribution of a new drug without an approved New Drug Application. This situation occurs where nuclear pharmacies and radioactive drug manufacturers produce their own versions of already approved marketed drug products but do not obtain approval of their products. In the nonradioactive drug marketplace, this is analogous to the marketing of a generic product. The system for accomplishing this is that generic marketers obtain either an ANDA (abbreviated New Drug Application) or full NDA (if the innovator product is approved after 1962). To assure the integrity of the mar American Pharmacy Vol. NS20, No. 8, August 1980/447 ketplace and the quality of all prod- Like all drug manufacturers, mak- 'The agency does not consider seizure to be a useful approach in the case of short-lived products.' Failure in some cases to validate sterilization procedures; Failure to maintain and check HEPA filters; • Failure to monitor environmental conditions; • Failure to observe aseptic techniques, especially in the preparation of parenterals; Failure to investigate complaints of product problems adequately; Failure to control raw materials (inventory records and development of appropriate specifications); Failure to maintain and/or utilize master production and control records; 223 Regulatory Actions When FDA notes discrepancies or noncompliance with the GMPs, it usually issues, as a first step, a regulatory letter requiring that practices be brought into compliance. In the last three years, FDA has issued 10 regulatory letters to radiopharmaceutical manufacturers. Two of the letters were later followed up with injunctions for failure to correct the problems identified. It is interesting to note, however, that even the firms that have been enjoined continue to have manufacturing problems. Some of these problems have resulted from rapidly evolving technology, but others seem to stem from the manufacturer's difficulty in making the transition in regulatory requirements from radiochemical manufacturer to radiopharmaceutical manufacturer. Although seizure is an important regulatory tool for FDA, there have been no seizures of radiopharmaceuticals. The agency does not consider seizure to be a useful approach in the case of short-lived products. By the time a seizure is processed and invoked by the courts, the radiopharmaceutical either will have been used up or will have decayed to the point where it has no commercial value. In addition to these regulatory actions, there have been several recalls of radiopharmaceutical products for problems such as improper biodistribution, improper radioactive labeling, incorrect formulation, and lack of stability. FDA recognizes that radiopharmaceuticals present some problems that are different from nonradioactive pharmaceuticals, but in spite of the special handling requirements required by radiopharmaceuticals, the general Good Manufacturing Practice regulations are suitable requirements and are generally appropriate for the preparation of radioactive drug products. Product Problem Reporting FDA, in cooperation with the Society of Nuclear Medicine (SNM) and the United States Pharmacopeia, initiated the SNM Drug Product Problem Reporting Program in 1976. Since that time, nearly 400 reports have been submitted. An analysis of the 371 reports received as of December 31, 1979 (see Adverse Reactions table), discloses that there were 176 reports of adverse reactions and 195 reports of drug product problems. Most of the adverse reaction reports were of allergic reactions, especially from labeled human serum albumins. A few possibly could be attributed to pyrogens. The most common problems encountered in terms of product defects have been poor labeling efficiency of technetium 99m products, particle size of aggregated albumins and sulfur colloids, and stability. The radiopharmaceutical defects are described in the table at right. Product Quality The quality of radiopharmaceuticals is important to nuclear pharmacists, to physicians in nuclear medicine, and especially to the patients who receive them. For this reason, FDA has analyzed a number of products as part of our ongoing surveillance programs. A regrettable finding, and one of concern, is that the incidence of out-of-limit samples of radiopharmaceuticals is far greater than that of nonradioactive drugs. In FY 1977, for example, out-of-limit samples were found in 11 of 56 analyzed (19.6%). In FY 1978, out-of-limit samples were found in 26 of 85 (30.6%), and in FY 1979, 8 of 79, or 10.1% of the samples, were out of limits. By way of comparison, the out-of-limit rates for nonradioactive drugs ranged from 0% to 1.6% in these fiscal years. The conclusion is clear. Greater attention must be paid to manufacturing problems and the quality of radiopharmaceuticals. Pharmacy vs. Manufacturing In 1975, FDA indicated that until it issued regulations governing manufacture of radiopharmaceuticals by nuclear pharmacies, it would take no enforcement action against nuclear pharmacies for failure to comply with certain requirements of the FDA regulations, providing that |