Sandoz' lawsuit against FDA over the human growth hormone product Omnitrope could further complicate the agency's efforts to define a potential approval route for "follow-on" biologics.

The lawsuit, filed by Novartis' generic subsidiary Sept. 13, asks a D.C. federal judge to declare that the 505(b)(2) approval pathway "can be used for protein-based biologic drugs regulated under Section 505 of the FD&C Act."

The Omnitrope NDA has largely been seen as a "test case" at the agency for approval of follow-on biologics under the 505(b)(2) pathway. However, FDA appears to be waiting for further clarification of issues surrounding generic biologics before issuing an action letter on the NDA, which was originally filed more than two years ago.

During that time, the agency has worked to sort out scientific issues relating to follow-on biologics, and a historical white paper and guidance documents on the subject are under development.

However, the broader legal and public policy debate surrounding follow-on biologics has stymied the agency's efforts to set forth scientific guidelines.

The issue also has been percolating on Capitol Hill, where legislators are pondering whether to introduce measures that would create an approval pathway.

Sandoz' lawsuit now seeks to put the issue of an approval pathway in the hands of the judiciary - at least with regard to biologics such as human growth hormone and insulin that are regulated under the FD&C Act.

FDA Fails To Act

The ^FDL-1 lawsuit alleges that the agency violated the FD&C Act and Administrative Procedure Act by failing to act on Sandoz' NDA for the recombinant human growth hormone product in a timely fashion.

Sandoz filed the Omnitrope (somatropin) NDA on July 30, 2003 under section 505(b)(2) "after extensive discussion with FDA's professional scientists and reviewers in the reviewing division responsible for approving metabolic and endocrine drug products like Omnitrope," the complaint states.

The filing was based on Sandoz' preclinical, clinical and comparability testing; literature references; and "FDA's prior determination on the public record of the safety and efficacy" of the reference listed drug, Pfizer's Genotropin (somatropin), the complaint says.

The user fee deadline for the Omnitrope application was extended by three months due to a major chemistry amendment; the extended deadline was Aug. 31, 2004.

In September 2004, Sandoz said that FDA was unable to reach a decision on Omnitrope due to "unresolved scientific and legal issues" relating to follow-on proteins (¹ Also see "Follow-On And Wait: FDA Defers Action On Sandoz’s Human Growth Hormone" - Pink Sheet, 6 September, 2004., p. 35).

One Year Later: Still Waiting

"One year after the Aug. 31, 2004 extended PDUFA date, the defendants have yet to act upon the Omnitrope application by issuing as required under the FD&C Act and the user fee statutes a complete action letter either approving the product, or detailing specific deficiencies and any actions necessary to clear the way for an approval," the complaint states.

"There has been no substantive correspondence from the defendants to Sandoz relating to NDA 21-426 since Aug. 31, 2004, despite Sandoz' two resubmissions and renewed requests for approval of its application."

Sandoz says it has exhausted all available administrative remedies. FDA's "actions on and failure to approve the Omnitrope NDA constitute final agency action," the complaint alleges.

"It is futile for Sandoz to seek any further administrative relief, and any new or further administrative proceedings before the agency also would be futile, as the defendants have confirmed as recently as Sept. 12, 2005 that no timetable will be given by or for FDA to act on the Omnitrope NDA."

Sandoz also asserts that agency inaction on Omnitrope constitutes "constructive granting" of Pfizer's May 2004 citizen petition, which requested that FDA deny approval of Sandoz' application (² Also see "Sandoz Omnitrope NDA Is Test For Follow-On Biologics; Pfizer Says No" - Pink Sheet, 7 June, 2004., p. 6).

Disparate Treatment Alleged

Sandoz' complaint references several other biologic product approvals under 505(b)(2) to support its position that FDA is subjecting the Omnitrope NDA to "disparate treatment."

Among the examples cited is FDA's June 1998 approval of NovoNordisk's GlucaGen (glucagon [rDNA origin] for injection).

The complaint also points to FDA's approval of NDAs for two hyaluronidase products: Ista's Vitrase in May 2004 and Amphastar's Amphadase in October 2004.

FDA has acknowledged that the hyaluronidase 505(b)(2) approvals could serve as a model for established biologics (³ Also see "Ista Tries To Void Vitrase NME Status: Will Less Exclusivity Mean More?" - Pink Sheet, 25 April, 2005., p. 31).

More recently, Sandoz cites FDA's Aug. 12 approval of Unigene's 505(b)(2) for Fortical (recombinant calcitonin-salmon). The Fortical NDA relied, in part, on the safety and effectiveness findings for Novartis' Miacalcin NS .

The hyaluronidase and Fortical approvals followed FDA's October 2003 response to a Biotechnology Industry Organization citizen petition, in which the agency left open the possibility that the 505(b)(2) pathway could be used for approval of biologics under the FD&C Act.

However, the agency limited its response to legal and regulatory questions, saying it would address scientific issues at a later date (⁴ Also see "Generic Biologics: 505(b)(2) Route Still Open, But Scientific Issues Unresolved" - Pink Sheet, 20 October, 2003., p. 8).

"Uncodified Policy" Barring 505(b)(2) Route

Sandoz warns that FDA's handling of the Omnitrope NDA could have a far-reaching impact on follow-on biologic products.

"The defendants' actions could result in the effective institution of an uncodified policy that the existing 505(b)(2) pathway cannot be used prospectively for protein-based technologies under Section 505."

Sandoz further asserts that its reputation and operations will be irreparably harmed because FDA's failure to approve Omnitrope will create doubts in the minds of others about the company's biopharmaceuticals R&D operations.

Furthermore, the launch of Sandoz' biopharmaceuticals business in the U.S. is being delayed because of the Omnitrope regulatory issues, the complaint states.

Novartis has said it intends be a leader in the area of follow-on biologics. In a move toward that goal, the pharma giant recently has increased the size of its Sandoz unit with the purchase of the generic firms Eon and Hexal (⁵ Also see "Novartis Seeks To Be Generics “Powerhouse” With Eon, Hexal Acquisitions" - Pink Sheet, 28 February, 2005., p. 21).

Congressional Threat?

Sandoz' complaint suggests that Congress could use the appropriations process to prevent FDA approval of follow-on biologics under the 505(b)(2) pathway.

Although Sandoz paid $533,400 in user fees in connection with the Omnitrope NDA, those funds were "effectively expended by the defendants when the FDA professional scientists and reviewers fully completed their review of the Omnitrope NDA in August 2004," the complaint states.

Consequently, a regulatory action on Omnitrope would be funded through FDA's appropriated monies, the complaint implies.

"Legislation governing...expenditure of FDA's appropriated funds during fiscal year 2006 potentially may be amended prior to enactment to include some form of a prohibition on FDA's expenditure of appropriated funds for the review and approval of any Section 505(b)(2) NDA for any biologic drug like human growth hormone (and thus Omnitrope) that FDA regulates under the FD&C Act," the complaint states.

The FY 2006 Agriculture appropriations bill, which funds FDA, has passed the House and is awaiting action on the Senate floor (⁶ Also see "FDA Report On Citizen Petition Impact On ANDAs Sought By Senate Panel" - Pink Sheet, 27 June, 2005., p. 14).

Plan B Comparisons

The Omnitrope case has prompted speculation that FDA could soon face a lawsuit over its failure to take regulatory action on another high-profile, although non-biologic, NDA.

In August, FDA announced that it would defer a decision on Barr Labs' application to switch the emergency contraceptive Plan B over-the-counter due to "unresolved regulatory and policy" questions (⁷ Also see "Plan B Delay Draws Criticism From Congress, Academia, FDA Official" - Pink Sheet, 5 September, 2005., p. 6). The agency, which has missed the user fee deadline for acting on Barr's NDA, issued an advanced notice of rulemaking on the issue of whether a drug can be marketed OTC for some patients and Rx for others, based upon age.

Omnitrope Lawsuit Could Further Delay FDA “Follow-On” Biologics Guidance

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