FDA's Critical Path opportunities list suggests that the agency is actively working to lay the scientific groundwork for follow-on biologics.

The opportunities list proposes two projects - Novel Approaches to Characterizing and Standardizing Biological Products and Enabling Manufacturing Changes for Well-Characterized Proteins - that could clarify some of the underlying scientific issues complicating development of agency policy on follow-on biologics.

The Critical Path projects will be carried out in the context of FDA's evolving approach to follow-on biologics, which has shifted from a product-specific strategy to broadly applicable guidances.

"After re-assessing these 'product-specific' documents, FDA has decided that it would be more appropriate to publish guidances that are more broadly applicable to [follow-on protein products] in general," the agency told Sen. Orrin Hatch (R-Utah) and Rep. Henry Waxman (D-Calif.) in a March 17 letter.

[Editor's note: In-depth analysis of FDA's follow-on biologic strategy shift appeared in ¹ "The Pink Sheet" DAILY April 5. To read the article and sign up for a free trial, visit our website, www.ThePinkSheetDAILY.com.]

FDA had previously indicated that guidance could come in the form of interlocking documents on different scientific areas (² Also see "FDA Generic Biologics Short-Term Plan Includes Immunogenicity Document" - Pink Sheet, 7 March, 2005., p. 33). Last fall, however, the agency delayed the release of regulatory documents, citing unresolved scientific, legal and regulatory questions (³ Also see "Follow-Ons Off? FDA Shelves Near-Term Plans For Biologics Documents" - Pink Sheet, 10 October, 2005., p. 14).

FDA described its shift to favoring broadly applicable guidances in response to a Feb. 10 letter from Waxman and Hatch that requested release of FDA guidance documents on generic insulin and human growth hormone.

FDA's proposed Critical Path projects would address some of the key underlying scientific questions impeding regulatory progress on follow-on biologics.

A major obstacle in developing a general approval pathway for follow-on biologics is that proteins are often so complex that they cannot be sufficiently characterized.

As part of its Critical Path effort to improve biologics manufacturing, FDA advocates that research be undertaken to qualify new approaches to characterizing large molecules.

"New methods of measuring the physical characteristics of biological products, such as nuclear magnetic resonance, x-ray crystallography, and/or mass spectroscopy could be used to provide a link between the physical characteristics measured by these tests and the clinical outcomes," the agency said.

"Today, these techniques remain underused, pending scientific consensus development work to understand how physical characteristics predict the purity and performance of biological products," FDA's opportunities list states.

The characteristics of large-molecule products are closely linked to specific manufacturing processes, a major hurdle to approval of follow-on biologics.

Brand companies have argued that due to the connection between product and process, clinical evaluation similar to that necessary for BLA approval should be required for biologic products that have undergone manufacturing process changes.

Amgen's large-scale trials of Aranesp and Enbrel following manufacturing changes have been cited by innovator firms as the standard of evidence necessary to support generic biologics (⁴ Also see "Amgen Trials For Manufacturing Changes Touted As Model For Bio-Generics" - Pink Sheet, 21 February, 2005., p. 32).

Generics firms generally contend that product characterization and pharmacokinetic/ pharmacodynamic studies should be sufficient.

ANDAs for Sanofi-Aventis' complex small-molecule drug Lovenox (enoxaparin sodium) could be the next demonstration of FDA's willingness to approve generic versions of complex molecules. A June 2005 court ruling removed a 30-month stay of approval on enoxaparin ANDAs from Teva and Amphastar.

Momenta, a company attempting to characterize Lovenox using polysaccharide sequencing, has suggested that unless generics companies can fully characterize the low molecular weight heparin product, FDA will not approve generic versions.

Although FDA's proposed Critical Path project to enable manufacturing changes for well-characterized proteins is focused on production scale-up, the development of tools to facilitate changes in manufacturing processes for biological products could support the case for approval of generic biologics.

"New tools are needed to predict and assess the effect of manufacturing changes on product performance and to assess comparability to product made using previous processes," FDA says.

Inclusion of biologic manufacturing projects in FDA's opportunities list suggests that the agency believes that answers to scientific questions are within reach. The list identifies 76 research projects "intended to improve product development in the short- and mid-terms" (⁵ Also see "FDA To Provide Updates On Critical Path Opportunities List Projects" - Pink Sheet, 20 March, 2006., p. 5).

Although FDA appears to be moving forward in resolving outstanding scientific issues surrounding large-molecule products, the agency has yet to establish an approval pathway for follow-on biologics.

The agency has made limited use of the 505(b)(2) approval pathway for biologics such as hyaluronidase and Unigene's Fortical (recombinant calcitonin-salmon) but has not adopted the mechanism as a general pathway for follow-ons.

The prospects for follow-on biologics guidances could improve with the confirmation of FDA Commissioner nominee Andrew von Eschenbach. However, guidance on follow-on biologics is not on the Center for Drug Evaluation & Research's 2006 agenda (⁶ Also see "Drug Safety Stays At Top Of FDA’s Agenda With New Guidances In The Works" - Pink Sheet, 13 March, 2006., p. 25).

In the absence of FDA action, an approval pathway for generic biologics could be established through legislative or legal action.

Sandoz has sued FDA over its delay in acting on the NDA for the human growth hormone Omnitrope , and is asking the court to declare that the 505(b)(2) pathway can be used for the approval of biologics (⁷ Also see "Omnitrope Lawsuit Could Further Delay FDA “Follow-On” Biologics Guidance" - Pink Sheet, 19 September, 2005., p. 21).

Omnitrope was the first product to receive a European Medicines Agency recommendation for approval under its new regulatory pathway for approval of similar biologics.

Congress may be tempted to include legislation addressing follow-on biologics as part of the upcoming Prescription Drug User Fee Act reauthorization, Wyeth Exec VP-Business Practices & Compliance Bruce Burlington told a March 29 FDA-industry dialogue conference. "The industry doesn't want it to, [but] it may be there," he said.

FDA Sees Critical Path Opportunity To Address Follow-On Biologics

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