By Lisa Seachrist
WASHINGTON — By their nature, biotech products raise distinct issues when it comes to preclinical testing. Efforts at international harmonization of the types of preclinical testing needed for these products will remain a case-by-case endeavor, according to draft guidelines released by FDA.
The guidelines, published by the FDA in the Federal Register April 4, describe the principles that regulators and industry should use in determining the appropriate type of preclinical testing under the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
"Biotech products are different from standard pharmaceuticals," said Joy Cavagnaro, senior pharmacologist in the office of the director in the Center for Biologics Evaluation and Research and representative for the agency to ICH on this issue. "It is too easy to simply subject biotech products to the standard battery of tests used with conventional pharmaceuticals. The problem with that approach is that it may not result in relevant information."
The ICH was organized to provide tripartite harmonization initiatives for the world's major pharmaceutical producers — the U.S., Europe and Japan. The discussions include input from both the regulatory bodies and the regulated industries of all participating regions. Cavagnaro noted that all of the regions originally reported that they dealt with preclinical testing of biotech products on a case-by-case basis.
"Further examination of practices indicated that regulatory agencies and industry weren't really dealing with these products much differently from standard pharmaceuticals," Cavagnaro said. "With biotech, one really has to think about the action of the product to decide which tests to perform. We should be able to design studies more appropriate to biotech."
For example, Cavagnaro pointed out that biotech products are very unlikely to cause genotoxicity and it is a waste of time and resources to perform genotoxicity tests on the products.
In addition, the guidelines suggest circumstances where toxicity studies could be done in single species rather than the two species used in preclinical testing of standard pharmaceuticals. Because immunotoxicity to biotech products is species specific, the guidelines suggest that companies focus on pathology associated with immunocomplexes rather than simply the production of antibodies.
The document also mentions the value of testing the product in animal models of disease. Cavagnaro noted that testing in an appropriate animal model will not only address safety, but could also give sponsors information about efficacy. "It is possible that surrogate endpoints could be determined from testing in animal models of disease," Cavagnaro said.
"Basically, the guidelines are pretty much common-sense types of stuff," said Alan Goldhammer, vice president of government relations at the Biotechnology Industry Organization. "And this isn't going to change the way that most companies are doing business."
Cavagnaro pointed out that the emphasis on a case-by-case consideration for biotech products means companies need to establish a dialogue with the regulatory agencies, because testing biotech products requires rational study design, not blind animal studies. "We don't want to overuse animals."
Cavagnaro also noted that most biotechs are taking the opportunity to discuss trial design early with agencies whether it is the FDA or one of the other agencies represented in ICH, and establish the necessary working relationships.
"That is exactly right," Goldhammer said. "In general, there is a lot less preclinical testing that one has to do with biotech products than ordinary pharmaceuticals and that is really what this document emphasizes."
Harmonization occurs through a series of steps. Identifying areas needing harmonization represents the first step. The second begins when expert working groups examine the scientific state of the art to establish guidelines. Step three is a comment period where the individual regions make modifications to the guidelines. The regions then reconvene to hammer out any lingering differences. Harmonization occurs in step five, where each region publishes the final guideline.
This document represents step two in the international harmonization process, and Cavagnaro noted she expected the document to come out of the July meeting in Brussels in step four. The FDA is taking comments on the document until June 3 in order to come to the meeting with a step-three document in hand.
Goldhammer noted that he expected the guidelines to come to harmonization with relative ease. *