NDAs FOR PET RADIOPHARMACEUTICALS WOULD COVER USE OF CYCLOTRONS

NDAs FOR PET RADIOPHARMACEUTICALS WOULD COVER USE OF CYCLOTRONS and "black boxes" under a current FDA proposal, FDA Medical Imaging Drugs Group Leader Eric Jones, MD, said at a March 5 FDA public hearing on regulatory approaches to positron emission tomographic (PET) radiopharmaceuticals. "Accelerators and cyclotrons used to produce radioactive atoms for PET radiopharmaceuticals [would be] considered components of processing to produce PET radiopharmaceuticals and [would] be embodied within the" new drug application, Jones said. "We would review the cyclotron as part of the NDA, and we would consult with the Center for Devices and Radiological Health as needed," the FDAer noted. "The automated synthesis systems [black boxes] would also follow a similar approach [as] we would have those [embedded] within the NDA...and we would seek consultation from [CDRH] as needed." The current proposal differs from one contained in a paper recently released by the agency for comment. The hearing was held to get feedback on the paper, which sets out FDA's plan for regulating these products. The prior proposal called for a 510(k) or a premarket approval application to be submitted for the processing equipment in addition to an NDA for the PET radiopharmaceutical. FDA also is proposing that PET radiopharmaceuticals be regulated as "new drugs" and therefore would need investigational new drug clearance and NDAs or abbreviated NDAs. At the hearing, FDA issued a statement saying that the agency has "an NDA for a finished PET radiopharmaceutical in which the cyclotron and associated...black box are described in the NDA as components of the manufacturing process." The Methodist Medical Center in Peoria, Illinois filed an NDA on Jan. 15 for the widely-used PET radiopharmaceutical, fludeoxyglucose F 18. The agency's medical imaging drugs advisory committee determined at its May 1992 meeting that FDG is effective in evaluating suspected brain tumors, localizing the site of epilepsy and establishing myocardial viability based on a clinical drug master file (DMF) submitted to FDA by the Institute for Clinical PET (ICP) ("The Gray Sheet" June 1, 1992, p. 27). Steven Zigler, PhD, operational director at Methodist's PET center, commented negatively on the length of time required to put the FDG regulatory package together. "The development of our NDA at Methodist has easily required five man-years of effort since October 1991," Zigler said, adding: "I believe the collective effort to assemble our NDA and see it through to conclusion...has literally strained the resources of the entire PET community." FDA Medical Imaging Drugs Division Supervisory Chemist Eric Sheinin, PhD, asked past ICP President Edward Coleman, MD, if the lessons learned from the FDG NDA would make it easier for the next application. Coleman responded: "We have learned that the efforts that we have made have not been met with equal efforts by the FDA to have any compromise or to be able to work with us on developing an appropriate position for the use of FDG in the hospital." The major limitations, Coleman continued, "relate to GMP standards; we are not manufacturers of drug products," and FDA has "not been able to show any leniency in the hospitals producing these products concerning GMP standards." He added: "As a matter of fact, the mechanisms that are put before us today...are even more stringent than [those] we were working with in 1988." FDA's Jones pointed out that "documents for FDA field investigators allow for modified GMP requirements as they apply to PET radiopharmaceuticals and will include separate, alternative procedures for inspections." The consensus of attendees representing radiopharmaceutical medicine, pharmacy and industry remained unchanged: they feel FDA regulation of PET radiopharmaceuticals is unnecessary since adequate regulation already exists. Steven Larson, MD, Society of Nuclear Medicine, noted that the U.S. Pharmacopoeia "has established standards for PET tracers in general clinical use; the USP Drug Information Branch has published monographs that serve the usual function of package inserts." In addition, "the American Pharmaceutical Association's Nuclear Pharmacy Section is expected to approve pharmacy compounding practices for PET radiotracers this month," Larson said. ICP President Henry Wagner, MD, said PET producers and users have recommended that FDA appoint a working group of staffers and outside experts to develop specific recommendations and standards for PET. CDRH Office of Health Affairs Director Gordon Johnson, MD, said: "I think Dr. Wagner's suggestion of putting some people together...is helpful."