Pre-approval testing for "follow-on" biologics should focus on determining product factors with the greatest risk of immunogenicity, the Generic Pharmaceutical Association said.

"One might consider taking a risk management approach in which resources are focused on assessing product factors with the greatest risk of immunogenicity," GPhA says in its Dec. 8 ¹ white paper, "Biopharmaceuticals ("Follow-On" Protein Products): Scientific Considerations for an Abbreviated Approval Pathway."

Pre-approval testing should include aggregation assessment, GPhA said. "Since aggregates are the primary product factor associated with immunogenicity, analytical testing of biopharmaceutical products for aggregation could minimize the potential for immunogenicity."

Other factors that have been cited as possible causes for immunogenicity - novel epitopes, impurities other than aggregation, glycosylation changes and oxidation - "have never been demonstrated to be actually associated with immunogenicity," the white paper says.

GPhA advocates including the measurement of aggregates as part of a product's characterization.

"Immunogenicity of reference protein products and other new therapeutic proteins could be minimized if aggregation is monitored systematically," GPhA says

GPhA questioned the utility of small clinical comparator trials in assessing immunogenicity.

"Clinical trials done solely to evaluate differences in immunogenicity in a limited patient population would not be scientifically valid and therefore may be of limited utility," GPhA says.

During FDA's public workshop on follow-on proteins in September, Teva suggested immunogenicity outcomes should be studied post-market due to the difficulty in detecting subtle differences in immunogenicity (² Also see "“Similar” Biologics Could Use One Clinical Trial For All Indications – Teva" - Pink Sheet, 20 September, 2004., p. 21).

The Pharmaceutical Research & Manufacturers of America takes issue with any sort of risk analysis approach for assessing immunogenicity of follow-on biologics, including reduced clinical testing.

"There should be no differential application of any of these principles and testing requirements regarding immunogenicity to innovative and follow-on products that might otherwise result in an increased risk being assumed by patients taking a follow-on product," ³ PhRMA's comments state.

GPhA's white paper asserts that characterization of follow-on biologics should include the critical aspects of the products.

"An appropriate suite of such tests can provide comprehensive comparative characterization of all clinically meaningful properties of a biopharmaceutical," GPhA said.

"It is generally acknowledged that no 'one' analytical method is currently capable of such comprehensive analysis."

GPhA distinguished between the need for "absolute" and "comparative" characterization of biologics.

"Comparability of the fingerprints of the two products can...provide a high level of assurance that the two products are indeed comparable without necessarily completely elucidating either product in absolute terms," the white paper states.

GPhA continues to believe that analytical characterization can allow for an approval pathway that precludes clinical studies. "The results of analytical characterization are often more sensitive to product changes than are clinical studies," GPhA said.

Most reported characterization problems are due to inappropriate or misinterpreted tests, GPhA noted.

"GPhA is not aware of any instances of a good faith and thorough application of a comprehensive suite of modern analytical methods failing to detect a significant change in a product's safety or efficacy qualities."

The manufacturing process can be used to determine the scope of a suite of tests, GPhA said. "Similarities or differences in the two manufacturing processes being compared should be considered in deciding the scope of characterization testing needed."

GPhA Offers Risk-Based Approach To “Follow-On” Biologics Immunogenicity

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