Although the US Food and Drug Administration’s (FDA) 2015 approval of the vaccine BioThrax for postexposure prophylaxis (PEP) for inhalational anthrax wasn’t the first approval under the rarely used Animal Rule, researchers in Nature explained on Thursday why it is a “significant step forward” in the approval of new vaccines and other medical countermeasures under the pathway.
The Animal Rule pathway (codified here) was designed to allow companies to bring medical countermeasures against dangerous pathogens, like anthrax and the plague, without actually testing the efficacy of the treatments on human subjects.
Instead, as the University of Texas Medical Branch researchers point out in their perspective piece, the regulations allow for approval of a product based on “adequate and well controlled” animal studies that suggest a treatment is “reasonably likely to produce clinical benefit in humans” and have an acceptable safety profile from human clinical studies.
The pathway is unique to the US, though the authors note that Health Canada can approve vaccines and other treatments under the regulations for “Extraordinary Use New Drugs,” which have similarities to the FDA’s Animal Rule.
And in the EU, the European Medicines Agency (EMA), which does not have an animal rule equivalent, has stated that this gap does not preclude “the possibility that animal models data in principle could have a critical role in the assessment” for approval of a product via their conditional marketing authorization or marketing authorization under exceptional circumstances pathways.
Under the Animal Rule in the US, however, companies are subject to requirements for postmarketing studies to demonstrate clinical efficacy when such studies become feasible (more on the Ebola trial feasibility below), as well as restrictions to ensure safe use and labels that indicate FDA’s approval was based solely on animal studies.
The Texas researchers also note that for developers pursuing licensure under the Animal Rule, FDA “emphasizes the importance of ‘early and ongoing communications’ with the agency regarding the applicability of this pathway, suitability of proposed animal models and design of studies to demonstrate product efficacy.”
Although the Animal Rule doesn’t require compliance with the regulations for Good Laboratory Practice for Nonclinical Laboratory Studies (GLP), the authors say that FDA “expects that pivotal studies for model definition, efficacy evaluation and that support determination of dose regimen for humans comply with GLP ‘to the extent practicable.’”
According to the Focusarchive, FDA approved Johnson & Johnson's Levaquin (levofloxacin) as the first treatment under the Animal Rule in April 2012. In December 2012, FDA approved the first biologic under the rule: GlaxoSmithKline's raxibacumab to treat inhalation anthrax. And a botulism antitoxin manufactured by Cangene was also approved in March 2013.
For BioThrax, the researchers note, “A key aspect of the process for anthrax vaccine approval via the Animal Rule was bridging of animal and human data to establish the effective dose for humans, which was defined by the FDA Center for Biologics Evaluation and Research [CBER] as requiring that the ‘vaccine dose in humans elicit an immune response comparable to that of animals protected by the vaccine.’”
In addition, the authors say that for developers under the Animal Rule, “the immune markers selected for bridging studies are not expected to be robust correlates or surrogates of protection, or approval via other mechanisms would be possible.”
But a key factor in bridging the immunological data from animal efficacy studies to humans is the use of validated or well-qualified assays.
And though the pivotal efficacy study for BioThrax was not performed as a GLP-compliant study, it was reviewed by FDA, including via an inspection of the testing facility to assess whether deviations from GLP adversely impacted the study.
As potential Ebola vaccines continue their way through development, the authors say they think such vaccines, when submitted for FDA approval, will provide further clarification of FDA’s expectations under the Animal Rule or Accelerated Approval pathways, and will provide opportunities to evaluate specific requirements for clinical and animal data.
“However, due to these trials occurring at the tail end of the outbreak, collection of efficacy data sufficient to support traditional licensure of any products was limited, which has prompted further discussions regarding the path to licensure for filovirus vaccines,” the authors write.
A May 2015 meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee singled out three potential pathways: approval via traditional clinical efficacy, which the authors say “currently seems unlikely in the absence of further large outbreaks of Ebola disease;” Accelerated Approval (which allows for surrogate or clinical intermediate endpoints and is used for therapies for serious conditions “as soon as it can be concluded that [their] benefits justify their risks”); or the Animal Rule.
“For Ebola vaccines, this surrogate endpoint may be levels of total or neutralizing antibodies and would need to be defined on the basis of immunological data from animal studies, and naturally infected or exposed/protected humans, including data from the West African clinical trials,” the authors say.
But a significant question, according to the Texas researchers, for application of the Animal Rule or Accelerated Approval pathways is whether the combined animal and clinical data now available for Ebola are sufficient to identify an immunological or another endpoint that can serve as an acceptable surrogate for predicting protective efficacy in humans.
Priority Review Vouchers
In addition to the Animal Rule, Congress is also trying to incentivize the development of new medical countermeasures via priority review vouchers (PRVs), which would grant an expedited review of a new drug application to a company that successfully won approval for such a countermeasure.
Before leaving for summer recess, the House Energy & Commerce Committee in mid-July moved forward a bill, first considered in February, that would create the medical countermeasure PRV program.
The bill would also establish a new user fee program under which a sponsor of a drug application that is the subject of a PRV shall pay to FDA, in addition to other fees required to be submitted by the sponsor. Sponsors of medical countermeasures would also have to write a report on the approved product no more than five years after the product's approval.
Nature Perspective: First vaccine approval under the FDA Animal Rule