New FDA Regulations for the Production of PET Radiopharmaceuticals
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Small facilities in jeopardy
In section 121 of the Food and Drug Modernization Act, the FDA was required by Congress to establish procedures for the approval of PET drugs and appropriate current good manufacturing practice (cGMP) requirements for such drugs. In response, the FDA worked alongside the PET community to establish rules to regulate PET radiopharmaceuticals, as the drug manufacturing rules which were already in existence were found to be unattainable as far as many PET radiopharmaceutical manufacturers where concerned. It also was determined they offered no significant benefit to the safety and efficacy of their PET product.“The new regulations for production of PET radiopharmaceuticals are the product of almost two decades worth of back and forth discussion between FDA and the PET imaging community,” says John Sunderland, PhD, director of the PET Imaging Center of the department of radiology at the University of Iowa. “[The] FDA felt they needed to regulate PET, but existing regulations didn’t really fit.”
Some aspects of the standardization are new for facilities and manufacturers, while most have been known and expected within the PET community for the past several years, Sunderland says.
“Most manufacturers have incrementally been upgrading their laboratories and procedures in anticipation of these regulations, [and the] FDA has sponsored several workshops and published a series of draft guidance documents over the years,” he explains.
However, the new requirements for manufacturers and facilities may be potentially onerous for smaller manufacturers, notes Sunderland. In particular, each producer of PET radiopharmaceuticals must register with the FDA as a drug manufacturer and FDA fees for New Drug Applications are required for each manufacturing entity and license. These fees are considerable expenses for the small facility, says Sunderland. For example, fees for FY2010 for an application requiring clinical data are $1,405,500, while an application not requiring clinical data or a supplement requiring clinical data costs $702,750. The establishment fees cost $457,200, while product fees are $79,720.
“It appears that the fee structure favors the major manufacturers over the smaller producers,” says Sunderland. “The larger manufacturers will likely feel the pinch less from the implementation of the new regulations than the smaller manufacturers.”
Barry Siegel, MD, chair of the ACRIN PET imaging core laboratory and professor of radiology and chief of nuclear medicine at the Mallinckrodt Institute of Radiology at Washington University in St. Louis agrees with Sunderland. “The costs may prove to be burdensome for academic institutions that manufacture PET radiopharmaceuticals for clinical practice,” he says.
“Incremental cost increase will likely result from the fees FDA levies to drug manufacturers, for laboratory upgrades associated with creating clean room environments for some of the manufacturing processes and increased personnel costs largely associated with record keeping burdens,” explains Sunderland, who notes that many small facilities may be forced to hire PET cGMP consultants to comply with the new regulations. New record-keeping procedures could be costly to implement as well.
While both Sunderland and Siegel believe it’s too soon to tell whether or not small manufacturers will be driven out by the new standards and cGMP costs, leaving only large agencies to produce PET drugs, Siegel hopes the latter is not the case.
“I think for many of the research institutions that do a lot of the important, innovative work with PET radiopharmaceuticals, the ability to supply FDG has provided important revenue to keep those facilities solvent so that they can do the things they are really interested in,” he says.
“I suspect the costs will make it more difficult for the smaller manufacturers to compete,” says Sunderland. “They are already at a disadvantage due to manufacturing economies of scale. It largely depends on how hard facility modification costs hit, and whether the large producers want to take this opportunity to expand their marketing territory into smaller markets.”
Consequences for clinical outcomes
Clinical outcomes should not be affected with the implementation of the regulations. Sunderland notes that while the “purity” and “strength” of PET radiopharmaceuticals should remain unchanged, he believes that FDA regulation will result in added cost and effort with no discernable benefit for patients or patient outcomes.Siegel does not expect a boost in clinical outcomes thanks to the new regulations, and notes that in the 12 years it took for the regulations to come into effect, most or all institutions have come into compliance with the United States Pharmacopeia (USP) chapters for quality of PET radiopharmaceuticals that they have been manufacturing for years. “To some extent, not having ‘FDA approval’ in some way increased the diligence necessary for an individual academic provider, for example, because you don’t have the umbrella of the FDA to stand behind, so you feel like you have to take it on yourself to make sure you are doing a good job,” he says.
“Operation in most PET production laboratories is almost certainly more standardized than it was in the past, but I still do not believe there will be any measurable benefit in the area of clinical outcome,” Sunderland notes. “The record, to date, is virtually spotless from this perspective.”