Renewal of FDA's Prescription Drug User Fee Act could be complicated by a federal court ruling that the agency must take action on Sandoz' application for a follow-on version of Pfizer's recombinant human growth hormone Genotropin .

The court decision creates two questions that drafters of the renewal legislation will need to consider: whether the PDUFA goals should be written into statute and if follow-on biologics should be given a formal pathway.

The content of the new user fee legislation, which must be passed by end of fiscal year 2007, could also be influenced by the outcome of the November elections and headlines about drug safety issues. At this point, FDA and industry seem focused on creating mechanisms to streamline drug development meetings and post-marketing commitments (¹ Also see "PDUFA IV Negotiations Underway With FDA, Industry Working In Harmony" - Pink Sheet, 10 April, 2006., p. 24).

The decision in the Sandoz case, however, puts more energy behind those who would like to see the creation of a uniform approval mechanism for generic biologics.

Novartis subsidiary Sandoz filed the lawsuit in September, over two years after the company submitted the Omnitrope application under the 505(b)(2) pathway in June 2003 (² Also see "Omnitrope Lawsuit Could Further Delay FDA “Follow-On” Biologics Guidance" - Pink Sheet, 19 September, 2005., p. 21). The application was largely seen as a test case for the approval of follow-on biologics utilizing that pathway.

PDUFA Goals Are Not The Law

The court decision specifies that FDA violated its statutory requirements in not acting on the application within the 180-day time period specified by the Food Drug & Cosmetic Act. The agency had argued that under PDUFA it only needs to meet review goals for 90% of applications, but the court found that because the goals were contained in a document obliquely referenced in the law and not in the statute itself, the FD&C timetable held sway.

"The court rules that the 180-day statutory provision imposes a mandatory obligation on the FDA and that the FDA failed to so act," D.C. federal Judge Ricardo Urbina said in his April 10 ³ opinion granting Sandoz' motion for summary judgment.

"The reference document concerns FDA's goals, not the FDA's statutory obligations," Urbina said. "Had Congress meant to transmogrify section 355(c) from a mandatory statutory requirement to a non-mandatory goal, it most likely would have acted directly on the statute, changing for example 'shall' to 'may.'...The court is unwilling to alter the 180-day action requirement simply because the FDA cannot cope."

Placing the goals in statute would presumably insulate the agency from similar challenges, but that approach could be viewed with trepidation by an agency that already feels overstressed by the program's targets.

Von Eschenbach In Contempt?

More immediately, FDA must decide what its next steps will be. The agency feels it has three options following the ruling: approve Omnitrope, deny the application and offer the sponsor a hearing, or appeal the ruling. The agency has 60 days to file an appeal.

The judge emphasized in the opinion that if FDA does not want to approve Sandoz's application, it has to identify one of seven criteria, as stipulated by statute, as a basis (see chart: " ⁴ How 'No' Can FDA Go? ").

If the agency rejects the application, it must offer Sandoz the option of a hearing, in which an administrative law judge would likely preside. Although these hearings have been used for drugs, they have not been employed in the recent past.

A hearing could be inevitable, since the company is understood to be disinclined to accept the issuance of an "approvable" letter as part of a remedy.

If FDA takes no action, Sandoz can file a motion asking the court to issue an enforcement action, although the firm appears to want to avoid that route. "In upholding the statutory deadline, the ruling requires that FDA issue a decision on our pending new drug application for Omnitrope," Sandoz said in a statement. "We look forward to FDA's decision and expect a positive outcome."

If the agency does receive an enforcement order and fails to comply, the court can hold FDA in contempt. Resulting penalties could include fines and/or civil penalties for the commissioner.

FDA's decision on what course of action to pursue will depend in part on how successful it thinks an appeal could be. Urbina has had several high-profile decisions related to FDA's handling of generic drug applications overturned (⁵ Also see "BuSpar Generic Decision Favors Bristol: FDA Decision On ANDAs Pending" - Pink Sheet, 22 October, 2001., p. 17).

Urbina's Omnitrope decision carefully parses the statutory implications of the PDUFA goal letters and also dismisses the applicability of a potentially precedent setting case involving the speed of FDA's ANDA reviews.

The 1991 D.C. Circuit Court of Appeals ruling in Barr Labs v. FDA found that although the agency was in violation of law by missing the review deadlines for Barr's ANDAs, the company was not entitled to relief. The justices said FDA would have to transfer resources to review Barr's applications, which in turn would cause hardship for sponsors of other ANDAs, adding no net benefit to the public welfare (⁶ Also see "BARR's ATTEMPT TO FORCE FASTER ANDA REVIEWS DENIED BY APPELLATE COURT; FDA IS "SLUGGISH," COURT FINDS, BUT EXPEDITING BARR's ANDAs UNFAIR TO OTHER FIRMS" - Pink Sheet, 22 April, 1991., p. 10).

But the application of user fees to the drug approval process under PDUFA apparently changes judicial interpretation. "With additional funds now available to the FDA for its processing of NDAs, unreasonableness in agency's delay comes sooner than it did prior to the PDUFA. In short, with higher funds comes higher expectations," Urbina wrote.

Urbina's analysis would not seem to give comfort to the generic industry, which is resisting suggestions for a user fee program for ANDAs (⁷ Also see "FDA Faces Pricing Pressure As Generic Drug User Fee Debate Begins" - Pink Sheet, 27 February, 2006., p. 8).

Describing why Sandoz was entitled to FDA action, Urbina said, "an order expediting the plaintiff's NDA would not directly bottleneck other NDAs. The proper focus when considering delay is not whether other NDAs would be delayed by the prompt completion of this plaintiff's NDA, but whether the completion of this plaintiff's NDA has languished while other NDAs have been processed."

The judge referenced FDA's approval of "recombinant hyaluronidase, calcitonin, and glucagon, as well as other approved 505(b)(2) NDAs for naturally-sourced products."

Although the ruling could presumably be used by any new drug applicant wishing to seek a quick FDA decision, such a tactic should just as readily produce a rejection by the agency.

The Omnitrope ruling will have implications for another lawsuit with political ramifications: the Center for Reproductive Rights' lawsuit against FDA seeking a decision on Barr's Rx-to-OTC switch application for emergency contraceptive Plan B .

Generic Biologics: The Jury Is Still Out

The agency is obviously loathe to move forward with any activity that might be construed as a pathway for follow-on biologics, having shelved product-specific guidances in favor of creating a broader document. However, study areas under the Critical Path and recent approvals of minor products demonstrate that the agency is establishing many of the scientific elements for a pathway (⁸ Also see "FDA Sees Critical Path Opportunity To Address Follow-On Biologics" - Pink Sheet, 10 April, 2006., p. 13).

While the ruling suggests that 505(b)(2) could serve as a viable pathway for follow-on biologics, its utility is limited by the fact that so few "biologics" are approved as NDAs. The Omnitrope application also appears somewhat unique because of the large amount of clinical data Sandoz has generated, which is fueling the application's progress toward approval in Europe.

FDA cited the complexity of the Omnitrope application as one of the reasons for not making a decision (⁹ Also see "Omnitrope Lawsuit Could Further Delay FDA “Follow-On” Biologics Guidance" - Pink Sheet, 19 September, 2005., p. 21). Another remaining issue are the legal arguments in Pfizer's citizen petition from 2004 urging the agency not to approve the application (¹⁰ Also see "Sandoz Omnitrope NDA Is Test For Follow-On Biologics; Pfizer Says No" - Pink Sheet, 7 June, 2004., p. 6).

User Fee Program Renewal Gets Trickier After Ruling In Omnitrope Court Case

More from Archive

More from Pink Sheet