BIO “Follow-On” Biologics Risk-Based Proposal Would Require Clinical Tests

The Biotechnology Industry Organization's risk-based approach to a regulatory pathway for "follow-on" biologics would include a clinical testing requirement.

"The greater the risk that a clinically significant effect would arise from manufacturing differences between the follow-on and innovator products, and the more serious the potential risk is to patients, the more data should be required," ¹ BIO's comments, "Scientific Considerations Related to Developing Follow-on Protein Products," state.

BIO emphasizes that the extent of analytical, preclinical and clinical tests should depend on the risks to patients as well as overall scientific considerations.

"The scientific unknowns are too great and the potential risks to patients too high for FDA to approve any protein product without the full complement of preclinical and clinical testing," BIO states.

The Generic Pharmaceutical Association also supports using a risk-based approach but it differs in scope from the BIO proposal (² (Also see "GPhA Offers Risk-Based Approach To “Follow-On” Biologics Immunogenicity" - Pink Sheet, 20 Dec, 2004.), p. 28).

"One might consider taking a risk management approach in which resources are focused on assessing product factors with the greatest risk of immunogenicity," GPhA states in its Dec. 8 ³ white paper, "Biopharmaceuticals ("Follow-On" Protein Products): Scientific Considerations for an Abbreviated Approval Pathway."

The generics association holds the opposite view from BIO on the need for clinical testing.

GPhA's white paper states that a "suite" of appropriate analytical tests absent clinical studies can be used to fully characterize follow-on products.

The Pharmaceutical Research & Manufacturers of America is aligned with BIO on the need for clinical studies for follow-on products, yet in ⁴ PhRMA's comments, the organization takes issue specifically with any sort of risk analysis approach for assessing immunogenicity.

BIO acknowledges that an abbreviated regulatory pathway may be possible in the future for certain follow-on products.

"Under a future approval pathway for follow-on products, some applications may require less extensive preclinical and clinical studies than the innovator had to submit," BIO said.

However, in the war of words, BIO gives no quarter on terminology for "follow-on protein products."

The association has not proposed a particular nomenclature, but it opposes use of the terms "comparability" and "therapeutic equivalence" in describing follow-on biologics.

"BIO cautions against the use of the word 'comparability' in describing the relationship between innovator and follow-on proteins."

"Comparability is a term of art that long has been restricted to 'intra-manufacturer' situations," BIO maintained.

"'Therapeutic equivalence' is imprecise with respect to protein products because it fails to reflect the variability that inevitably exists between therapeutic protein products," BIO said.

The generics industry also has yet to commit to a particular nomenclature but opposes the use of the phrase "follow-on," and notes that FDA does not want to use the term "generic."

GPhA is gearing up for an advocacy campaign on generic biologics and will use focus groups to develop alternative terminology for "follow-on" biologics (⁵ (Also see "Flu Vaccine Shortage Shows Hazards Of Market Concentration – Sen. Leahy" - Pink Sheet, 11 Oct, 2004.), p. 31).

Whatever the result of that research, the association believes that non-interchangeable products would not require unique nomenclature, while "it may be preferable for biopharmaceutical products that are deemed to be interchangeable to utilize unique nomenclature that denotes that the products are 'biogenerics' or 'interchangeable' products."

During a Generic Pharmaceutical Association/FDA Technical Conference in October, Acting Deputy Commissioner for Operations Janet Woodcock, MD said she was not set on terminology for follow-on biologics except that it would have to include the term "proteins" (⁶ (Also see "FDA Follow-On Biologics Background Document To Be Released By Year-End" - Pink Sheet, 1 Nov, 2004.), p. 16).

BIO also believes that separate clinical studies will be necessary for different indications for the same product.

"If a protein is indicated for two patient populations, the protein may induce different immunogenic responses in the two populations," BIO said. "These differences would not be detected without clinical studies designed to detect them for each indication in each patient population."

BIO supports its position by referring to the European Union's 2003 directive on "biosimilars," which "specifies that for each claimed indication of a biosimilar product, the safety and effectiveness must be separately demonstrated."

During FDA's September public workshop on follow-on proteins, Teva presented the opposite view that abbreviated applications for "similar" follow-on products could include clinical data in one indication to support approval of all innovator indications (⁷ (Also see "“Similar” Biologics Could Use One Clinical Trial For All Indications – Teva" - Pink Sheet, 20 Sep, 2004.), p. 21).

Both BIO and GPhA have referred to the example of Biogen's multiple sclerosis therapy Avonex to support their arguments.

In its comments, BIO pointed to the reduction in immunogenicity for Avonex determined by a Phase IV trial following a manufacturing change as evidence that clinical studies are necessary to support approval.

GPhA cited the positive approval outcomes after manufacturing changes to the product as evidence that "the agency was willing to let something go through without further clinical testing based on not totally exact physical parameters" (⁸ , p. 9).

BIO's comments were submitted in anticipation of the upcoming Feb. 14-16 follow-on biologics workshop sponsored by FDA and the Drug Information Association.

Development of FDA's background document on follow-on biologics, which was intended to be released by year-end, has been delayed while senior management addresses drug safety issues raised during the year (⁹ 'The Pink Sheet' Jan. 3, 2005, In Brief).