FDA offers guidance on testing drugs for smallpox-shot side effects

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Mar 12, 2004 (CIDRAP News) – The Food and Drug Administration (FDA) this week published guidelines for the development of drugs to treat the side effects of smallpox vaccination, an area in which the federal government is investing substantial research funds.

In a Mar 8 announcement, the FDA said it wants to help commercial and research sponsors plan appropriate studies for developing such drugs. "Today's guidance should reduce the cost and uncertainty of developing medicines that will harden our defenses against one of the most dangerous bioterrorism agents," said FDA Commissioner Mark McClellan.

The vaccinia virus used in smallpox vaccine can cause rare but serious complications, such as a generalized rash, eye infection, encephalitis, and myopericarditis, the FDA noted. People with an increased risk of serious side effects include those with a weak immune system because of HIV or immunosuppressive drugs, those with a history of eczema or atopic dermatitis, and pregnant women.

Federal health agencies launched a research program in 1998 to develop drugs for treating both smallpox and complications of smallpox vaccination, according to Catherine Laughlin, PhD, of the National Institute of Allergy and Infectious Diseases (NIAID). Because the smallpox virus is so closely related to vaccinia, "We think the vast majority of drugs that work against smallpox will also work against complications of vaccination that involves vaccinia," she told CIDRAP News. Laughlin is chief of the virology branch in the NIAID's Division of Microbiology and Infectious Diseases.

"We have an active grant portfolio with between 10 and 15 different approaches being tried to discover new drugs," Laughlin said. Efforts include screening of candidate compounds in cell cultures, evaluation of drug candidates in animals, and research on the existing drug cidofovir, currently approved for treatment of cytomegalovirus infection, she said.

The FDA's draft guidance, a 40-page document, recommends nonclinical studies for the early stages of drug development, the FDA said. The document includes information on chemistry, manufacturing and controls, nonclinical toxicology, microbiology, and clinical pharmacology.

"The guidance also focuses on the acquisition of in vivo data through the use of animal models, an approach that may be necessary because of the low occurrence of serious complications in the vaccinated population," the FDA announcement said. The guidelines also discuss the gathering of human efficacy and safety data, issues in the design of clinical trials, long-term follow-up of patients, and other topics. The FDA said it will accept comments on the guidance document for 60 days.

The FDA didn't give a reason for issuing the guidelines now, other than the general one of improving bioterrorism preparedness. Laughlin commented, "There is a lot of interest on the part of pharmaceutical firms to consider development of drugs for both treatment of smallpox and treatment of complications of vaccination." She said she suspects the FDA has been getting questions about how to proceed, given the difficulty of doing clinical efficacy studies for these kinds of drugs and the need to rely heavily on testing in animals.

"There's a lot of uncertainty about what the requirements will be, so I imagine they thought it would be helpful to try to clarify the requirements as much as they could," she said. "I think they'll be issuing similar guidelines for drugs for treating smallpox itself soon."

Cidofovir remains the most promising drug for treating smallpox vaccination complications at this point, according to Laughlin. But cidofovir must be given intravenously, and it can cause serious kidney toxicity. Consequently, a California chemist named Carl Hostetler has modified the drug by adding lipids so that it could be administered orally, which would be a "huge advantage" in an emergency, she said. Hostetler has licensed his cidofovir "analogs" to Chimerix, Inc., based in La Jolla, Calif., which is developing them further, she added.

In September 2003, Chimerix received a $36.1 million NIAID grant to develop its modified version of cidofovir, called CMX-001, for treating smallpox and complications of smallpox vaccine, according to a company news release. The company said the drug has shown activity against a variety of pox viruses, including smallpox and monkeypox, and it prevented death in mice exposed to a pox virus.

Laughlin said other candidate drugs for vaccinia complications are in early stages of development. She noted that the NIAID is collaborating with the Centers for Disease Control and Prevention and the Department of Defense in promoting development of the drugs.

See also:

Mar 8 FDA news release
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108260.htm

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