By Lisa Seachrist

Washington Editor

WASHINGTON — The goal of having a single technical document to support pharmaceutical applications in the U.S., Europe and Japan has moved one step further with the negotiators developing draft guidelines describing a standard battery of genotoxicity tests.

The guidelines, published by the FDA in the Federal Register April 3, describe the series of tests that establish a drug's ability to cause damage to genetic material under the International Conference on Harmonization of Tech-nical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

"Basically these guidelines are designed to save money, time and animals — that is the whole impetus," said Robert Osterberg, pharmacology team leader for the FDA's anti-infective drug division and the agency's safety coordinator for ICH negotiations. "If we can get drugs on the market faster with less expense, we can spur innovation in the drug development area and people will benefit by it."

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. The goal of the harmonization efforts, which began three years ago, is to use sound science to coordinate the technical requirements for the registration of pharmaceutical products in the three regions.

The process proceeds via a series of steps. The first is the identification of areas in need of harmonization. Expert working groups examine the scientific state of the art to establish guidelines in the second step. Step three is a comment period during which the individual regions make modifications to the guidelines. The regions then reconvene to hammer out any lingering differences. Harmonization occurs in the final step: each region publishes the final guideline.

The FDA is publishing these guidelines and accepting comment on them until June 2 in order to be prepared for the Fourth International Conference on Harmonization, in Brussels in July.

The expert working group developed these guidelines in September 1996. The group agreed that registration of new pharmaceuticals requires a comprehensive assessment of their ability to cause large-scale damage to chromosomes and to cause mutations in genes. The guidelines aren't concerned with biologics, but with small molecule drugs.

The standard battery of tests will include bacterial, mammalian cell and in vivo genotoxicity studies. The group agreed upon the Ames test, which checks a compound's ability to generate mutations that restore viability to mutated salmonella as the bacterial screen.

Several different tests for mammalian cell genotoxicity will be considered acceptable. However, Osterberg noted that the regulators preferred the mouse lymphoma thymidine kinase assay. "This is a very sensitive assay," Osterberg said. "Some in industry say too sensitive."

The guidelines suggest that examining the peripheral blood erythrocytes or the bone marrow of rodents exposed to the drug for chromosome damage satisfies the requirement for an in vivo test.

While the expert working group established this three-test schema for testing genotoxicity, it recognized that some tests were inappropriate for different situations and that some drugs may require more rigorous testing. For example, it is a waste of time and money to perform an Ames test on antibiotics that are known to kill salmonella bacteria, Osterberg said.

The guidelines suggest compounds that have some structural entities known to cause mutations have additional testing. In addition, the guidelines recommend that drugs with a unique chemical structure undergo additional testing. This provision, however, is unlikely to make it through the July meeting of the ICH.

"The problem is that it is not easy to come up with a definition of a unique chemical entity," Osterberg said, noting that he attempted to do just that in a working group meeting in Japan last month. "Basically, of the 17 new drugs that I picked from the Physicians' Desk Reference, only one showed toxicity in a fourth test after proving non-genotoxic in the first three."

As a result, Osterberg said, the FDA is going to support removing this guideline — which the agency originally insisted upon.

Osterberg noted that while the goal of harmonization is to allow companies to work on a single set of safety data for submission in all three regions, each region retains autonomy when it comes to its regulatory decisions. For example, approval in Japan will have no bearing on approval in Europe and the U.S. *