FDA advisory panel backs new method of anthax vaccine research

An FDA advisory panel has backed a new strategy for anthrax vaccine researched developed by its Center for Biologics Evaluation and Research.

The new strategy also provides for an important precedent for future applications of the "animal rule."

"The 'animal rule' is legislation that allows products to be licensed based on demonstration of efficacy in animals - rather than humans - for products for which human efficacy trials are not feasible or ethical," Gary S. Nabors, the vice president of product development and site operations at Emergent BioSolutions, Inc., said.

The animal rule uses two species, stating that, "The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans."

The animal rule has been in place since 2002 but is not usually applied to drug developments. The FDA's new stance on the rule shows a victory for its application, Nabors said.

"This was a victory of sorts, but it is really more of a step towards a greater goal," Nabors said. "There are still many challenges remaining for the great variety of products in development that would need to be licensed under the animal rule. As more and more animal rule products are put in front of FDA, the agency is more focused on choosing how the animal rule should be interpreted, which in the end is helpful for industry.

"The FDA's backing of the Center for Biologics Evaluation and Research's strategy clarifies more specifically how animals should be used to derive a serological correlate of protection for anthrax. This is a key step in being able to predict efficacy of anthrax vaccines for the post-exposure prophylaxis indication in humans, and will likely be an important consideration for new vaccines seeking a pre-exposure indication.  Once a correlate of protection for Emergent's anthrax vaccine is agreed upon by FDA, the agency will likely look at the performance of new vaccines in the light of this correlate, but may make companies with follow-on vaccines independently derive a correlate for their specific products."

To date, two drugs have been approved using the animal efficacy rules, FDC Reports, Inc., reports - Merck Sante's Cyanokit for use against cyanide was approved in December 2006 and a U.S. Army's pyridostigmine for use against the nerve agent Soman in February 2003.

"The precedents that are set for the first products to be licensed using the animal rule may allow for faster product development for follow-on products, because the requirements for licensure will be more clear," Nabors said.

There are three animal study designs to assess the level of protection an anthrax vaccine offers under the animal rule - general use prophylaxis, post-exposure prophylaxis and passive immunization.

"General use prophylaxis is equivalent to pre-exposure protection," Nabors said. "The vaccine is administered before challenge with the infectious agent. Circulating antibody levels present prior to challenge are then correlated with probability of survival.

"Post-exposure prophylaxis is when animals are first infected and then are treated with either antibiotic alone or antibiotic plus vaccine. The goal is to show that vaccination provides an added survival benefit compared to antibiotic treatment. This study is primarily used to demonstrate the added benefit of vaccination over the benefit provided by antibodies alone. These studies are done because this provides a demonstration of efficacy of the vaccine for the proposed indication.

"Passive immunization is when antibodies raised to the vaccine are administered to an animal prior to infection. The level of antibody int he serum at the time of challenge is then correlated to survival probability. Passive immunization studies have a very limited role, as they have been shown to overestimate how much antibody is really required to protect against anthrax in an active vaccination (pre-exposure) setting. Nevertheless, passive immunization studies do fundamentally demonstrate the concept that antibodies protect against the infection."