In an effort to support the development of antiviral drugs to treat or prevent smallpox (variola virus) infection, the US Food and Drug Administration (FDA) on Tuesday updated its decade-old drug development guidance.
After extensive vaccination efforts, the World Health Organization formally declared smallpox to be eradicated in the wild in 1980. Prior to that, outbreaks of the virus, especially the more severe variola major
, caused millions of deaths each year.
Despite the successful eradication of the disease, FDA and health officials around the world are concerned that smallpox could be used as a biological weapon or in terrorist attacks. Routine smallpox vaccination was also phased out in the US during the 1970s, leaving most of the population susceptible to the virus were an outbreak to occur.
According to FDA, antiviral drugs to treat or prevent smallpox are needed, as, “The usefulness of vaccination in a biothreat situation depends on the ability to vaccinate exposed and at-risk persons" and whether the vaccine will protect against the specific variola strain.
The guidance, which updates the agency's 2007 draft guidance Smallpox (Variola Virus) Infection: Developing drugs for Treatment or Prevention
, discusses issues related to nonclinical development, study design considerations for animal efficacy studies and considerations for developing a human safety database.
FDA also says the guidance incorporates input from two public meetings, a 2009 public workshop and a 2011 meeting of its Antiviral Drugs Advisory Committee, which helped formulate the agency's proposed regulatory pathway for antivirals to treat or prevent smallpox.
Because there are no new naturally occurring cases of smallpox, and because it would be unethical and highly dangerous to conduct challenge studies in healthy volunteers, FDA anticipates sponsors will need to conduct animal efficacy studies under the so-called Animal Rule
to support new drug application (NDA) or biologics license application (BLA) submissions for smallpox antivirals.
The changes to the guidance include revised considerations for preliminary assessments of antiviral activity in animal models, study design considerations for animal efficacy studies and recommendations for dose selection in humans.
FDA also says the guidance includes clarification on nonclinical virology, pharmacology and toxicology and recommendations for clinical trials in humans, such as safety studies in healthy volunteers and clinical trials in the event of a public health emergency.
Additionally, the guidance includes a discussion on expanded access to investigational new drugs and considerations for emergency use authorization for smallpox antivirals.
, Federal Register Notice