Proposal to Test Smallpox Vaccine in Young Children Sets Off Ethics Debate

By SHERYL GAY STOLBERG

ASHINGTON, Nov. 4 — Federal health officials are proposing to test the smallpox vaccine in toddlers and preschoolers, a proposal so fraught with ethical questions that the Food and Drug Administration is seeking comment from the public before allowing the experiment to proceed.

The vaccine is made of a live virus called vaccinia and poses a risk of serious complications, even death. At issue is whether the threat of a bioterrorist attack using smallpox — a disease that was eradicated in humans two decades ago — is serious enough to warrant exposing children to those risks.

"Everyone agrees that the risk of smallpox through a bioterrorism event is not zero," said Dr. Karen Midthun, who supervises vaccine research for the food and drug agency. "But how small or how large is that risk? Given that it is so difficult to quantitate, it makes it difficult to know whether there is potentially any benefit to these children."

Dr. Midthun said the agency would take public comment on the proposal through the end of this month. After that, she said, Tommy G. Thompson, the secretary of health and human services, and Dr. Mark B. McClellan, the new commissioner of food and drugs, will decide whether to approve the study.

The proposed pediatric study comes as President Bush is considering whether, and how, to make smallpox vaccine available to the public for the first time since 1972, when routine vaccinations were suspended. Mr. Bush is considering proposals to make the vaccine available first to health care workers and eventually to all Americans.

The pediatric study would enroll 40 children, ages 2 to 5, at Children's Hospital Medical Center in Cincinnati and Harbor-U.C.L.A. Medical Center in Los Angeles. Because the vaccinia virus can spread, posing serious risk to people with immune deficiencies or skin conditions like eczema, the children will be required to stay home from day care or preschool for a month after inoculation.

The National Institutes of Health has been testing the government's aging stockpile of 15.4 million doses of smallpox vaccine to see if it can be used safely in adults, and to see if it remains effective when diluted; research suggests that it does. The goal of the pediatric study is to determine if the same is true in children.

"If we had an attack and we had to use the vaccine in children, you would see a lot of eyebrow-raising if we didn't know the effects," said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, the branch of the N.I.H. that is proposing the study.

But the study is drawing objections from some experts. Among them is Dr. Paul A. Offit, chief of infectious diseases at Children's Hospital of Philadelphia, who believes the benefits of testing the vaccine do not outweigh the risks. Noting that the vaccine offers protection when given up to four days after exposure, Dr. Offit said he believed testing in children was ethical only after an actual case of smallpox had been reported.

"Smallpox doesn't exist in this world, so the benefits are solely theoretical," said Dr. Offit, who serves on a panel of experts that advises the Centers for Disease Control and Prevention on vaccine policy. "That, in combination with the fact that the vaccine has known and, albeit rarely, severe side effects leads one to question whether you can ethically do that study."

When the smallpox vaccine was last in use, 15 people out of every million who received it experienced potentially life-threatening complications — a risk that experts have said holds true for both adults and children. In children, Dr. Fauci said, the most serious risk is encephalitis, a potentially deadly disorder that causes inflammation of the brain.

Dr. Fauci cited statistics from a 1968 study that tracked 5.6 million people who received smallpox vaccine, 3.3 million of them children between the ages of one and four. Among these youngsters, 10 developed encephalitis and three — all under the age of one — died from it.

Federal regulations impose strict oversight on clinical trials in children. If studies pose more than minimal risk to children, they may go forward only if they offer direct benefit to the child or enhance understanding of the child's disorder. If those conditions are not met, the studies are subject to federal review, including an evaluation by outside experts and public comment of the sort the F.D.A. is seeking.

Among the experts consulted for the pediatric smallpox trial is Dr. Neal Halsey, director of the Institute for Vaccine Safety at Johns Hopkins University in Baltimore. Dr. Halsey said he had concluded that the study was ethical, but only if it was "done very carefully and done in a very limited number of children."

But he said he had chosen not to take part in the national institutes' trial. "I did not care to be involved in exposing children to the known risks of the vaccine in the absence of clear benefit," Dr. Halsey said.

Although the government has contracted with the pharmaceutical industry to buy a new version of the smallpox vaccine, the vaccine to be used in the pediatric study comes from an aging stockpile of 15.4 million doses manufactured by Wyeth-Ayerst and donated to the government.