Latest Drug Approval Via the Animal Rule: The Black Death


To clarify the somewhat misleading title, the latest drug approval using FDA’s Animal Rule is to expand the approved indications for Levaquin to the treatment and prevention of plague due to pulmonic or systemic infection with Yersinia pestis. Although other antibiotics are indicated as treatment for Y. pestis infection, the novel component of the Levaquin indication is its potential widespread use as a preventive agent in emergency situations. Y. pestis only infrequently causes plague at this time in history, several thousand cases worldwide and very rarely in the U.S. However, with the Center for Biologics Evaluation and Research’s efforts over the past decade to develop and license vaccines and treatments for agents of potential bioterrorism, Y. Pestis has now joined pathogens such as anthrax, smallpox and others as selected biowarfare targets of interest. Given the limited natural occurrence of plague and the ethical impossibility to test drugs in human volunteers with experimental exposures, the development program for such therapeutics falls to the Animal Rule.

The Animal Rule, issued in 2002, established guidelines for development of drugs as “medical counter-measures” against chemical, biologic, and radiologic threats based principally on animal data. The pathway sounds rather simplistic, i.e., provide evidence of the drug’s efficacy and safety in a relevant animal model with only limited requirements for human clinical safety information, including pharmacokinetic and pharmacodynamic data which would aid in establishing human dosing directions. As one might expect, the logical first candidates for such an agent would be a marketed drug, with an established safety profile and evidence of therapeutic activity, now to be approved for the supplemental indication via the Animal Rule. However, drug development according to this paradigm has been limited, with previous approvals only to cyanokit for cyanide poisoning and pyridostigmine for nerve gas poisoning. Each of these drugs brought along considerable human prior experience.

As discussed in a recent review (P. Aebersold. 2012. FDA experience with medical countermeasures under the Animal Rule, Adv Prevent Med vol. 2012, article ID 507571), development of a third potential drug via this pathway (a specific monoclonal antibody therapy for the infectious agent of anthrax) has been languishing for several years. The reasons for this situation appear to include several scientific issues, some of which should have been successfully resolved via better communication between the pharmaceutical sponsor and FDA. Although the anthrax drug is actually available via the Strategic National Stockpile, the nation’s repository of selected antibiotics, vaccines and various antidotes if the need arises in the setting of a natural pandemic or act of bioterrorism, it suggests a somewhat unfortunate conclusion: development of truly novel medical countermeasures may prove to be too costly to be practical. Given that the probability of a drug’s human efficacy and safety based on extrapolation from animal data is at best a scientific judgment, perhaps never to be confirmed with human data, it would seem reasonable for FDA to facilitate development of the broadest possible variety of therapeutic agents in the arsenal. The successful development and subsequent approval of Levaquin for the treatment and prevention of plague is the first approval via the Animal Rule of an anti-infective agent, and perhaps will set the stage for the approval of the anthrax agent as well. Bioterrorism continues to be a realistic risk, and it is reassuring to know that treatment options based on strong science are in progress.

Posted by Bob Roth, Vice President and Worldwide Medical Director. For more information, please contact Bob at bob.roth@weinberggroup.com.