Washington Editor

GAITHERSBURG, Md. - FluMist should be used in children between 1 and 5 years old, a majority of FDA advisors recommended Wednesday, supporting MedImmune Inc.'s bid to expand use of the live influenza virus vaccine.

The company, of Gaithersburg, Md., has filed a supplemental biologics license application for pediatric use in that age group, save for children with a history of wheezing or asthma. Presently, the nasal spray's liquid formulation is approved for use in those between 5 and 49.

"We're quite pleased with the outcome of today's vote," said James Young, MedImmune's president of research and development, "which further for us endorses the efficacy and safety of this product, and hopefully provides the opportunity for the FDA to act in expanding the indication to include children below 5 years of age."

That presumably would lead to higher sales of FluMist, which has never come close to original hopes since first reaching the market three years ago, much less the nearly $2 billion the company has invested in it to date. It generated $36 million in sales last year.

Each one-year age group younger than 5 represents about 4 million children, Young said, and between 40 percent and 50 percent of them get a flu vaccine shot. But only about 17 percent of first-timers required to receive a follow-up get that second dose. "Under 5 is important now," Young said, "because that is the only healthy child population that's recommended to get the vaccine."

Members of the FDA's Vaccines and Related Biological Products Advisory Committee voted 9-6 in favor of FluMist's benefit-risk profile for MedImmune's proposed age range, and unanimously agreed that it's effective in that group. Committee members also agreed unanimously that the vaccine was safe and effective in children between 2 and 5, but they split their safety and efficacy recommendations for the youngest of kids in whom FluMist has been studied, those 6-23 months. They voted 12-3 against its benefit-risk profile in them, but 12-1 in favor of its efficacy.

In addition to casting votes, most panelists also recommended post-approval studies to better assess risks associated with FluMist in young children, such as trials that span multiple flu seasons and include large numbers of the youngest of kids receiving the vaccine, those 6-23 months, if the FDA signs off on the sBLA. MedImmune has proposed expanding a 60,000-patient Phase IV trial to also include 20,000 children younger than 5.

The agency, which typically follows the suggestions of its advisors, is scheduled to act on the application by May 28. Young said the company would begin meeting with the FDA next week to further discuss the review process and negotiate labeling.

During the advisory meeting, Edward Connor, MedImmune's executive vice president and chief medical officer, noted the "limited" flu vaccine options for children younger than 5 in making a case for FluMist. MedImmune largely has based its application on a large pivotal trial directly comparing the product to the trivalent inactivated vaccine (TIV, Sanofi-aventis) approved in children, with complementary data from other studies also informing the submission. Collectively, these data showed FluMist to be efficacious in preventing the flu, demonstrated a better overall efficacy compared to TIV and showed it confers better cross-protection against mismatched flu strains compared to TIV, Connor said.

Young attributed FluMist's better efficacy to better antibody responses in children getting the nasal spray than those who receive TIV, and such superior efficacy and related comparative data would be part of FluMist's package insert for the first time, he said.

"Kids just don't respond effectively to TIV," Young added. "They respond and make antibodies to FluMist very easily [and] very broadly. They make antibodies against the drifted strains, not just the strains that are in the vaccine, whereas you don't see that with TIV."

However, safety findings have proven more confounding, particularly data from the pivotal study. Children younger than 24 months who received FluMist had a statistically significant increase in protocol-defined wheezing, with those younger than 12 months accounting for most of the difference. In post hoc analyses, children 6-11 months had a significant increase in all-cause hospitalizations, mostly more than 42 days after vaccination.

In general, between 20 percent and 25 percent of children in that age group have issues with wheezing. Still, Connor conceded that "further evaluation is needed" in them.

An additional post hoc benefit-risk assessment in those 12-23 months without a history of wheezing or asthma suggested no increase in hospitalizations, a small but nonsignificant increase in wheezing after vaccination and a significant decrease in flu compared to TIV. That same assessment suggested a favorable profile for children younger than 24 months without a history of wheezing or asthma. Among those children, those treated with FluMist had significantly fewer cases of flu illness compared to TIV patients, and no increase in wheezing rates or hospitalizations.

All children received the same dose in the pivotal trial as adults receive, which isn't the case for the TIV product approved for kids, so Young suggested "dialing down" the dose in the youngest children to dampen safety signals.

For those 24-59 months, there was a significant benefit without wheezing or hospitalization risk, and for those 12-23 months, Connor concluded that a "significant benefit" was observed despite "some residual wheezing."

But FDA reviewers took issue with MedImmune's conclusions, cautioning against post hoc analyses that drew conclusions on children 12-23 months compared to those 6-11 months, given that no such distinction was pre-specified in the study protocol. Further, they noted concerns about hospitalizations, wheezing episodes and respiratory events such as pneumonia in FluMist-treated children younger than 24 months.

An agency staffer, Sang Ahnn, called "unclear" MedImmune's statistical reasoning to exclude kids 6-11 months but include those 12-23 months.

MedImmune plans to manufacture between 7 million and 8 million doses for the coming flu season, Young said. Only 7 million have been distributed in the past three years. In the background of the meeting, the company has accepted a $15.6 billion buyout by London-based AstraZeneca plc, a deal that's in the process of closing.

On Wednesday, shares in MedImmune (NASDAQ:MEDI) gained 6 cents to close at $57.14.