FDA finalises guidance on smallpox drug development

As part of critical preparedness efforts, the United States (US) Food and Drug Administration (FDA) have published a final guidance to assist sponsors in the clinical development of drugs for treatment and prevention of smallpox (variola virus) infection.

The primary aim of smallpox research is to address three areas that are essential for public health:

  • Finding better antiviral drugs to treat smallpox disease.
  • Making safer vaccines.
  • Improving tests to detect the variola virus

The World Health Organisation (WHO) declared smallpox eradicated in 1980, however there have been concerns that the virus could still exist in undeclared or unknown locations, with the potential for it to be utilised as a biological weapon.

“Despite recent advances in developing an effective treatment for smallpox, drug developers still face challenges in bringing forward these medical countermeasures, which are critical should smallpox ever be used as a biological weapon.”

The main challenge is the fact that there are no new naturally occurring cases of smallpox in the wild, which has led to a lack of data on the pathophysiology of human smallpox, the restricted nature of variola virus samples and the “ethical issues that preclude human smallpox challenge studies”. Clinical efficacy trials of drugs for treating or preventing smallpox are not feasible, and challenge studies in healthy subjects are unethical. Hence, the FDA states that prospective smallpox drugs should be developed and approved under the regulation known as the Animal Rule (21 CFR part 314, subpart I, for drugs and 21 CFR part 601, subpart H, for biologics).

The most significant changes made from the draft to the final guidance, are clarifications regarding the “recommended immunological characterisations of animals in key studies”. Specifically, sponsors should perform a direct serologic analysis for larger animals or indirect analysis for rodents “to monitor for any prior orthopoxvirus exposures in the test animals”. Cellular immune assays should be considered when feasible and appropriate. The guidance also recommends sponsors to consider the differences in disease development between human and animal models, when designing study protocols.

The final guidance also emphasises that the recommendations made also apply to monoclonal antibodies, and it also states that any study involving variola virus “must be conducted in collaboration with the Centres for Disease Control and Prevention (CDC), and will require approval from the World Health Organization.”

Sponsors interested in developing antivirals, small molecules, therapeutic proteins, or monoclonal antibodies for smallpox are encouraged to discuss their approach with the FDA as early as possible and to communicate with the FDA through the Pre-Investigational New Drug Application (Pre-IND) Consultation Program.

Click here to access the full guidance.