Manufacturers of unapproved positron emission tomography drugs working toward getting formal FDA approval are pleased that the agency is stressing the availability of an "expanded access" investigational new drug process, as opposed to filing a full NDA.

The expanded access IND pathway was discussed alongside the NDA and ANDA filing process at a day-long workshop on PET drug approvals FDA hosted at its White Oak headquarters March 2. In a revised draft guidance issued last month, FDA said sponsors should submit applications by Dec. 12. By Dec. 9, 2015, all PET drugs still in commercial clinical use must have approval.

According to the guidance, sponsors have the option of submitting an NDA or an ANDA based on one of the approved drugs, but the discussion of the IND application option at the workshop is a godsend for certain types of products, Jenny Keppler, president and COO of PET tracer development company ImaginAb, said in an interview after the workshop.

An ordinary IND offers access to drugs with the primary purpose of studying the drug's effects, while the primary purpose of an expanded access IND is to diagnose or monitor a patient's disease or condition, Lucie Yang of CDER's Division of Medical Imaging Products said at the workshop. Sponsors can file a request with FDA to be allowed to charge for such "investigational" expanded access drugs.

Avoiding "The Exception That Swallows Up The Rule"

Keppler called this "incredibly forward-thinking" of the agency, because certain kinds of PET imaging drugs, such as methionine C11 injection for brain tumors, will probably never be made by a commercial sponsor, due to their lack of patentability and the fact that these radioactive products have a 20-minute half-life and must therefore be made on the spot or very near where they will be used.

Methionine C11 "is absolutely critical for patients with brain tumors," she said. "It's all about serving the patients," and making this regulatory pathway available will allow hospitals to continue to do so.

However, there are limitations on this process, Jane Axelrad, CDER's associate director for policy, said. "We don't want expanded access with charging to be the exception that swallows up the rule," she said.

Any request to charge needs to be prominently highlighted in an IND submission to FDA, and while the agency is emphasizing its flexibility, having a lot of PET sponsors use this approach will as put pressure on FDA to ensure they are all generating meaningful data.

Moreover, Yang pointed out that already approved drugs are not appropriate for expanded access INDs. These include the three PET drugs covered in the draft guidance - fludeoxyglucose F 18 injection, sodium fluoride F 18 and ammonia N 13 injection - as well as rubidium chloride Rb82. Besides methionine C11, other drugs that may qualify for expanded access due to their low levels of use are carbon monoxide C11, fluorodopa F18 injection, flumazanil C11 injection, mespiperione C11 injection, raclopride C11 injection, sodium acetate C22 injection and water O15 injection.

More Than 100 PET Producers

To date, FDA has approved six PET drugs of the three types covered by the draft guidance - three fludeoxyglucose F18 injection products, two sodium fluoride F18 injection drugs and one ammonia N13 injection drug. However, there are more than 100 PET production facilities, each one of which produces multiple drugs, Axelrad said in an interview before the workshop.

The reason for this state of affairs has to do with the history and method of manufacture of these drugs, which first came into use in the 1970s, originally in research, and later in clinical practice to diagnose a variety of different diseases and conditions. The radioactive isotopes they contain are made in cyclotrons that have to be located near where they are to be used, because the radioactive components of the drugs decay rapidly. The radioactive components have very short half-lives ranging from a few minutes to hours.

The 1997 FDA Modernization Act required the agency to develop a cGMP regulation for PET drugs and set forth procedures on filing NDAs and ANDAs for them (Also see "FDA Develops Separate Set Of GMP Requirements For PET Drug Makers" - Pink Sheet, 21 December, 2009.).

Axelrad said the purpose of the revised draft guidance on PET drug approval - an earlier version came out in March 2000 - is to make the NDA or ANDA submission process easier, and added that the agency will issue final guidance as soon as possible. Following the upcoming public meeting and other future meetings, the agency may add questions and answers to the Web page it maintains on PET drugs.

Meanwhile, although the boilerplate language FDA adds to all draft guidances states that they are "distributed for comment purposes only," given the approaching deadline FDA says that the revised draft guidance "may be used to guide submissions while FDA obtains comments on it."

Keppler said the workshop was very useful for sponsors, clarifying for them how to do comparisons to reference-listed drugs, the amounts of user fees, cGMP regulations and the working of the compliance inspection program. FDA called the meeting to allow all stakeholders to air their views, which they did through an ad hoc group called the Coalition for PET Drug Approval. Within this coalition, which includes nine organizations, Keppler represented the Academy of Molecular Imaging at the workshop.

-Martin Berman-Gorvine (m.berman-gorvine@elsevier.com)

PET Drugs May Get Shorter Path To FDA Approval

More from Archive

More from Pink Sheet