On May 8, 2015, FDA approved a new antibacterial treatment for plague, Avelox® (moxifloxacin). Plague is a deadly infectious disease caused by the enterobacteria Yersinia pestis, which can be spread in the air, by direct contact, or by contaminated undercooked food or materials, depending on lung infection or sanitary conditions. In particular, plague may be spread to humans through bites from infected fleas, contact with infected animals or humans, or laboratory exposure. Until June 2007, plague was one of the three epidemic diseases (along with cholera and yellow fever) that was specifically reportable to the World Health Organization, and is still endemic in some parts of the world. Plague manifests itself with a variety of host infections, for example, bubonic plague in lymph nodes, septicemic plague in blood vessels, and pneumonic plague in lungs. Plague is treatable if detected early. Plague is also considered weaponizable, which was one of the topics I undertook at FDA as a de facto member of the Working Group on Civilian Biodefense, which resulted in the Journal of the American Medical Association (JAMA) article: Plague as a Biological Weapon. At that time, early treatment and prophylaxis treatment for plague was streptomycin or gentamicin or the tetracycline or fluroquinolone classes of antimicrobials.
Avelox® was approved utilizing the Agency’s “Animal Efficacy Rule”: New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible, Parts 314 and 601, 67 Fed. Reg. 37,988 (July 1, 2002). This was a rule that I worked on in a similar capacity at FDA, given the challenges that were presented when it is unethical or not possible to conduct adequate and well-controlled clinical efficacy studies for certain indications. At this point, plague is a rare disease that does not lend itself to the conducting such trials in humans, given the potentially fatal consequences of non-treatment. The concept behind the animal efficacy rule is that for certain new drug and biological products that are intended to reduce or prevent serious or life-threatening conditions, FDA may approve these products for marketing based on traditional evidence of safety (typically from clinical studies in healthy subjects taking the proposed product) combined with effectiveness derived from appropriate studies in animals and any additional supporting data. Specifically, the rule provides that FDA can rely on evidence from animal studies to provide substantial evidence of the effectiveness of these products when:
- There is a reasonably well-understood pathophysiological mechanism for the toxicity of the chemical, biological, radiological, or nuclear substance and its amelioration or prevention by the product;
- 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 (meaning the model has been adequately evaluated for its responsiveness) for predicting the response in humans;
- The animal study endpoint is clearly related to the desired benefit in humans, which is generally the enhancement of survival or prevention of major morbidity; and
- The data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information in animals and humans is sufficiently well understood to allow selection of an effective dose in humans, and it is therefore reasonable to expect the effectiveness of the product in animals to be a reliable indicator of its effectiveness in humans.
Avelox® was approved based on an animal efficacy study utilizing African green monkeys infected with Yersinia pestis in a laboratory setting. Here, 20 monkeys were randomly selected to receive a 10-day course of either Avelox® or placebo (10 for each arm) at least four hours after fever onset following Yersinia pestis exposure. For this study, the primary endpoint was survival at the end of the study, and while all 10 monkeys treated with Avelox® survived, none of the 10 monkeys treated with placebo survived. More information about the animal efficacy rule and additional product approved under this rule may be found here.