FDA issues proposed change in rules governing PET agents

The FDA wants to alter how PET radiopharmaceuticals are regulated, though the proposed changes may not take effect until 2008.

A draft of rule changes regarding the production of these drugs, a so-called current good manufacturing practices (cGMP) regulation, has been released to the industry, which has until the end of this year to comment.

"Our first step is to review input from that 90-day comment period," said Dr. George Mills, director of the FDA Division of Medical Imaging and Radiopharmaceutical Drug Products. "Once we have a final rule, we'll have about a two-year interval to final implementation."

After that, PET pharmaceuticals producers must follow the final rule when submitting new drug applications before going to market with a new PET agent.

The proposed regulation would establish minimum standards for production and testing of PET pharmaceuticals, taking into account particular properties of the drugs not adequately covered in existing cGMP regulations, according to the FDA. One such property is the short half-life of PET drugs, which requires that they be used within hours or minutes after production. This affects how they are produced and distributed.

The genesis of the proposed regulation goes back to 1997, when Congress passed the FDA Modernization Act, a law that mandated that the agency establish appropriate approval procedures and cGMP requirements for PET drugs by taking into account their special characteristics, the operational and production processes, and any relevant differences between not-for-profit and commercial manufacturers of such drugs. Since 1997, the FDA has carefully evaluated these elements to ensure that PET agents are safe and effective and of adequate quality.

"Essentially, the FDA was told it had two years to develop a mechanism for regulating PET radiopharmaceutical production, and the PET community would have two years to comply," said Dr. R. Edward Coleman, a professor of radiology and director of nuclear medicine at Duke University. "Those two years turned into eight, with several iterations and some back-and-forth with the PET community."

During that time, the FDA kept a close eye on the rapidly evolving PET pharmaceutical industry. At first, PET drugs were developed as a research tool and produced in academic institutions. While that remained the case, the agency didn't consider them a top priority. However, the FDA's regulatory interest increased when radiopharmaceuticals started entering routine clinical practice. In the ensuing years, commercialization of production and reimbursement came into play.

"Industry growth has been driven by government and third-party payer reimbursement for some PET studies. This increased demand and the requirement for additional supplies of radiopharmaceuticals, which in turn generated the need for additional outlets and producers," said Ken Breslow, senior regulatory affairs specialist for Siemens Medical Solutions, a major PET drug producer.

As the number of facilities using PET has increased, so has the number of PET drug production facilities. Producers now include both corporate and independent entities.

"The industry can be broadly broken into two categories: the academic institutions that do PET and prepare their own radiopharmaceuticals, and companies, both large and small, that manufacture and distribute the drugs on a commercial basis," Breslow said.

In reviewing the current PET drug production environment, the FDA concluded that standards and controls are needed to ensure the production of quality PET drugs, no matter the type or size of the production facility. The regulation is not intended to focus on one production setting but is designed to support all.

"That is why we are taking input from the various communities, to be able to understand how we could meet the needs of all of those areas," said Mills, who has served at the FDA for more than a decade.

Industry response to the agency's approach has been positive.

"The FDA is making sure everyone uses the same sort of testing, specifications, process control, and quality control, as well as the distribution of the final product," said Scott Thompson, corporate director of quality control for Eastern Isotopes, a Virginia-based producer of PET pharmaceuticals.

The impact of the new regulation is expected to be about equal for the two production sectors, industry and academia. If so, it will be a substantial change from the present situation.

"Currently, commercial companies operate under the practice of pharmacy," said Steve Zigler, senior director of technical development for Siemens. "But when the FDA finalizes these rules, we'll be required to operate under an FDA-regulated environment."

In effect, this will force PET drug producers to become drug manufacturers in the strictest sense. The rule change may have the greatest effect on academia.

"It will take academic institutions into the realm of being drug manufacturers, at least for this class of drugs," Breslow said.