Sandoz' pending NDA for Omnitrope appears ripe for an FDA decision.

Novartis' generic division submitted the application for Omnitrope (somatropin 5.8 mg) under the 505(b)(2) process; the NDA was accepted for review by FDA in July 2003, Sandoz said.

Sandoz is not commenting on the status of the application or the potential timeline for a decision.

However, a citizen's petition submitted by Pfizer (marketer of Genotropin ) May 13 seeking to block the application is one clear indication that a decision may be near.

The NDA does "not adequately address the safety, effectiveness and manufacturing considerations for recombinant human growth hormone products or the specific product differences between Genotropin and" the Sandoz product, Pfizer maintained. "Pfizer requests that FDA immediately deny approval" of the NDA (identified by Pfizer as number 21-426).

FDA's decision on the Omnitrope application will be a landmark in the evolution of a regulatory pathway for follow-on biologics.

The Future Of Follow-On Biologics

The agency is drafting a guidance on follow-on biologics, which it hopes to issue soon. The guidance will take a broad view, but is expected to address the specific issue of using the 505(b)(2) process for versions of human growth hormone and insulin (¹ Also see "“Follow-On” Biologics Guidance Will Limit Use Of Data To “Public Domain”" - Pink Sheet, 10 May, 2004., p. 3).

Novartis has been open about its efforts to pursue "generic" biologics - but secretive about the specific plan in the U.S. (² Also see "Novartis Pursuing Generic Biologics; Says Brand And Generic Lines Co-Exist" - Pink Sheet, 3 February, 2003., p. 23).

Pfizer's petition expresses uncertainty regarding details, including the exact brand name. Pfizer's petition refers to the drug as Omnitrop ; Sandoz, however, said the brand is spelled Omnitrope.

Sandoz describes Omnitrope as similar to Pfizer/ Pharmacia's human growth hormone brand Genotropin in its physio-chemical attributes and biologic effect.

The product was filed in Europe in May 2001 and received a positive opinion from the Committee for Proprietary Medicinal Products in June 2003.

Sandoz' decision to pursue a follow-on version of Genotropin rather than one of the other hGH brands reflects the commercial significance of the product in Europe.

Pfizer reported first quarter sales of Genotropin of $179 mil.: $58 mil. in the U.S. and $121 mil. in international markets.

The Pfizer Petition

Sandoz said that Genotropin loses patent protection in the U.S. in 2004; Pfizer, however, has two additional patents listed in the FDA Orange Book for the 5.8 mg strength.

³ Pfizer's petition notes that the company received a "patent certification" in conjunction with the 505(b)(2) NDA filing.

Pfizer makes two basic arguments against the approval of Genotropin: (1) that the 505(b)(2) NDA inevitably relies on proprietary Pfizer data which cannot be used to support approval; and (2) that Omnitrope and Genotropin have important clinical differences that rule out approval even if FDA allows Sandoz to rely on Pfizer data.

"It is scientifically and legally improper for FDA to rely on, reference, or otherwise use the clinical and manufacturing information establishing the safety and effectiveness of Genotropin(somatropin, rDNA origin, for injection)" to approve Omnitrope, Pfizer said in the citizen petition.

The Rules For 505(b)(2)

FDA has already taken a position on the legal issues surrounding use of the 505(b)(2) process.

The agency responded in October to citizen's petitions filed by Pfizer, the Biotechnology Industry Organization and Apotex by stating that the 505(b)(2) process could be used to pursue approval of a follow-on version of insulin or hGH - though the response was explicitly limited to the regulatory process question, not scientific issues (⁴ Also see "Generic Biologics: 505(b)(2) Route Still Open, But Scientific Issues Unresolved" - Pink Sheet, 20 October, 2003., p. 8).

Center for Drug Evaluation & Research Acting Director Steven Galson subsequently made a clear declaration on one point that appears to support Pfizer's petition: 505(b)(2) applications will have to rely solely on data in the public domain, not on proprietary data in another NDA (⁵ Also see "“Follow-On” Biologics Guidance Will Limit Use Of Data To “Public Domain”" - Pink Sheet, 10 May, 2004., p. 3).

Pfizer maintains that the Omnitrope NDA cannot overcome that hurdle.

"The only way for FDA to determine the similarity of the Omnitrop structure and characteristics would be for the agency to reference the non-public, proprietary chemistry, manufacturing and control information in the Genotropin NDA and supplements," Pfizer declared.

"Recombinant proteins such as Genotropin have extremely complex structures and characteristics, such that the only way to potentially evaluate the similarity of follow-on products would be on the basis of detailed CMC information in the innovator NDA," Pfizer said.

"The only way theoretically to approve a follow-on recombinant protein product would be in reliance on or through use of this proprietary data."

Approval Would Rely On Proprietary Data

"Specifically, FDA would need to compare, among other factors, the products' recombinant plasmids, master cell banks, and working cell banks," Pfizer said.

"Both the sequence of the recombinant plasmid used to manufacture Genotropin and the Genotropin information necessary to ascertain the impact of variations in the master and working cell banks, however, are proprietary."

Pfizer's argument is similar to a more general case laid out by Genentech in an April 18 citizen petition. Genentech maintains that FDA's effort to craft a guidance on follow-on biologics inevitably will be based on an illegal use by the agency of proprietary manufacturing data in all biotech applications.

Even if FDA were to rely on proprietary data, Pfizer declared, the two products "have so many important chemical and formulation differences - including molecular weight, genetic sequence of the recombinant plasmid, master and working cell banks and preservatives - that FDA cannot make a scientifically-rational decision."

Pfizer cites two specific differences between Genotropin and the Sandoz agent: (1) molecular weight; and (2) formulation differences, particularly the absence of mannitol.

According to Pfizer, Genotropin has a molecular weight of 22,124 daltons, while Omnitrope's molecular weight is 21,125 daltons.

"The molecular weight of many of the rhGH products approved by FDA is 22,125 daltons," Pfizer notes. Both Omnitrope and Genotropin have 191 amino acids.

Manufacturing, Formulation Differences

"The chemical basis for the differences in the molecular weights between Genotropin and Omnitrop has not been established, but it is likely due to differences in the manufacturing processes," Pfizer suggested.

Differences in formulation include "the lyophilized drug powder and the preservative in the diluent used to reconstitute the product for injection," Pfizer said.

"Mannitol is present in the drug powder and diluent of Genotropin, but not for Omnitrop," Pfizer said. The company "has proprietary data demonstrating the importance of mannitol to product characteristics, including stability."

"These and other formulation differences...can significantly affect the quality and safety of Omnitrop."

No Phase II

"Sandoz apparently has also failed to conduct adequate pre-clinical studies of Omnitrop, including suitable pharmacological and toxicological testing in animals and cell lines, as well as Phase II dosing studies, the latter being essential in view of the differences in the drug delivery systems for Genotropin and Omnitrop."

Sandoz says it conducted Phase I and Phase III studies to support the Omnitrope NDA.

Pfizer notes that FDA has already approved eight hGH products based on full NDAs. "If FDA approves the Omnitrop Sec. 505(b)(2) application, FDA will improperly and unjustifiably be lowering its rigorous approval standards that have served patients well for these products," the company declared.

Finally, Pfizer asks FDA to agree that there should be no basis for awarding an "A" therapeutic equivalence rating to the Sandoz product.

Sandoz Omnitrope NDA Is Test For Follow-On Biologics; Pfizer Says No

More from Archive

More from Pink Sheet