FDA makes progress with PET guidance plans

Agency to outline findings in Federal Register

The Food and Drug Administration continues to move toward establishing regulatory guidelines for the PET industry, particularly the manufacture of PET pharmaceuticals. In a Federal Register notice the agency expects to publish by the end of this year, it will further outline the safety and efficacy of N-13 ammonia for heart rest and stress perfusion imaging, and F-18 fluorodeoxyglucose (FDG) for evaluating malignancy in patients with known abnormalities and myocardial perfusion. Only three PET drugs have been approved by the FDA to date: sodium fluoride F-18, rubidium-82, and FDG.

Since the early 1990s, the FDA has been evaluating the development of PET technology as it moved out of the research sphere and into the medical arena. In 1995, the agency published a regulatory approach that set an 18-month implementation period, during which the PET industry would be required to comply with the FDA’s investigational new drug application (IND) and new drug application (NDA) requirements, to register as PET manufacturers, and to observe current good manufacturing practice (CGMP) regulations.

“PET facilities have been producing and marketing drugs that have never been approved,” said Jane Axelrad, associate director for policy at the agency’s Center for Drug Evaluation and Research. “We’ve been trying to get them under regulatory control.”

In 1997, Congress passed the FDA Modernization Act, which required the FDA to withdraw the protocol it had developed in 1995 and produce new guidelines within two years. The agency was to consider the unique characteristics of PET drugs, such as their short half-lives, the techniques necessary to produce them, and the fact that many PET products had been in research use for years. In the meantime, PET drug manufacturers were to abide by U.S. Pharmacopeia guidelines.

The agency began to develop its new guidelines by focusing on the most commonly used PET drugs, such as F-18 FDG, N-13 ammonia, and O-15 water. It has been working with an advocacy group, the Institute for Clinical PET of Foothill Ranch, CA, and others to formulate conclusions about these radiopharmaceuticals’ safety and efficacy, based on clinical literature. In June, the FDA convened a meeting between its Medical Imaging Drugs Advisory Committee and PET industry advocates in Gaithersburg, MD, to present its initial findings and gather feedback. The agency then continued its review and plans to publish its conclusions, as well as a protocol for filing NDAs, later this year in the Federal Register.

“The Advisory Committee agreed with (the findings presented at the June meeting). Now we’re completing our reviews and expect to publish the results, which will form the basis of NDA submissions, in the Federal Register,” Axelrad said.

In addition to its safety and efficacy findings, the FDA is developing CGMPs for the industry. Once the FDA’s new guidelines for PET have been established and published in a final rule—which will include both safety and efficacy research and CGMPs—FDAMA’s two-year implementation period, during which companies must come into compliance with the rule, will begin. But the FDA doesn’t want PET drug manufacturers to wait until that final rule is published to begin submitting NDAs or abbreviated applications, and will encourage them to begin submitting once the agency issues its safety and efficacy findings, Axelrad said.