“Similar” Biologics Could Use One Clinical Trial For All Indications – Teva

Abbreviated applications for "similar" follow-on biologics could include clinical data in one indication to support approval in all innovator indications, Teva Senior Director Global Clinical Research Yafit Stark, PhD, said.

"Once we have demonstrated therapeutic equivalence in a selected indication, it should be extended to other indications," Stark said at an FDA public workshop on follow-on proteins Sept 14.

Studies of "similar" follow-on biologics in multiple innovator indications would be redundant, she argued. "If we can show clinical comparability, why do we need to duplicate it?"

FDA held the public workshop to hear comments on the scientific and technical considerations of follow-on proteins. [Editor's Note: To ¹ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.].

The agency is developing a guidance on a follow-on biologic approval pathway, and cited unresolved scientific issues as one reason for its decision to defer approval of Sandoz' human growth hormone application (² (Also see "Follow-On And Wait: FDA Defers Action On Sandoz’s Human Growth Hormone" - Pink Sheet, 6 Sep, 2004.), p. 35).

Stark laid out a conception of follow-on biologics divided into two types: "identical" and "similar."

"Identical...is referring to products that are identical in terms of structure and share the same bioactivity," Stark explained. "When it comes to biosimilar products, they may have some slight differences in the structure, but share the same bioactivity."

For biosimilar products, Stark acknowledged some clinical data will likely be necessary to show therapeutic equivalence. "We feel that clinical data probably will be needed when analytical comparison is not 100% identical," she said.

In addition to allowing clinical data from one indication to support broader efficacy claims, "only one clinical trial will be performed for one indication," she proposed.

Follow-on biologic safety would primarily be assessed after marketing under Teva's approach. "Safety must be monitored closely in ongoing comparisons, but we recommend you put more effort during the post-marketing," Stark said. "During the post-marketing, we can expose large-scale patient populations, we can detect rare events."

Teva also suggests immunogenicity outcomes be studied after approval. "In clinical studies, it will be very difficult to detect subtle differences in immunogenicity. So we would like to recommend to do more during the post-marketing, through which we can expose more patients and detect antibodies to the product," Stark said.

FDA repeatedly raised concerns about immunogenicity over the course of the meeting (see ³ ).

Approval of "identical" follow-on biologics would be largely based on Phase I pharmacokinetic/pharmacodynamic data under Teva's model.

"We propose to do a comparative Phase I study to establish pharmacokinetic/pharmacodynamic" equivalence, Stark said. "We must use the same dose, route of administration...similar to an ANDA."

MDS Pharma proposed that favorable PK/PD data could allow a company seeking approval for a "switchable" biologic to concentrate on safety, not efficacy, in Phase III (see ⁴ (Also see "Follow-On Biologics Studies Depend On “Switchability”, MDS Pharma Says" - Pink Sheet, 20 Sep, 2004.) ).

Teva's proposal for "identical" generic biologics would rely on analytical studies to show the equivalence of two proteins. At the meeting, representatives from Teva, Barr and the companies' respective subsidiaries, Sicor and Duramed, professed a belief that current analytical techniques are rigorous enough to make that possible.

The Pharmaceutical Research & Manufacturers of America, the Biotechnology Industry Organization, Johnson & Johnson, Wyeth and Pfizer presented an opposite viewpoint.

"Protein products are difficult to characterize. Even a relatively small and simple protein product is difficult to characterize, and the molecular structure of many proteins cannot be fully characterized fully with current technology," BIO Managing Director-Scientific & Regulatory Affairs Sara Radcliffe said.