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NBSB Pandemic Influenza Working Group
Detailed Report
Edward Cox, M.D., M.P.H.: We recognize how challenging it is to study drugs in
severe disease and in hospitalized patients, but it’s very important to understand the role
of drugs and their effects in those situations. Informative trial design is important. We
welcome other ideas, new ways to look at the issue.
In HIV, for example, we used surrogate endpoints, and that allowed us to identify early
predictors of clinical outcome. There’s been a lot of work in that area by [the Center for
Drug Evaluation and Research]. But it’s different for influenza. You can look at
virologic markers, and that’s useful, but the clinical endpoint is the effect on patient wellbeing,
and that’s right there in front of you, and you can measure it. So it’s different
from HIV.
There are real challenges in doing studies, but we all recognize the need. It may take
more to get studies to happen. We do need new treatment models, especially different
mechanisms that are not susceptible to resistance. Also combination therapy is an area to
study more. It’s important to plan for studies and try to answer questions.
Dr. Pavia: With H5N1, death is the common endpoint. The power to detect differences
is [poor]. It’s an overstatement to say the clinical endpoints are in front of us. Other than
fever or duration of hypoxemia or intubation, it’s too mixed, too subjective. Not enough
patients have those hard endpoints to measure.
Dr. Gellin: We heard about the European Medicines Agency (EMEA) approach. How is
this working outside the United States?
Dr. Ng-Cashin: With IV-zanamivir, the European regulators were the same as FDA. In
2007, they wanted to wait to find out what FDA said.
Ms. Birnkrant: We have an open dialogue with other regulators, and we want to hear
what they are doing.
Greg Martin, M.D.: In DoD, we’ve been approached to study combination therapy.
Would that be helpful? Especially for patients with severe influenza who are hospitalized
and we’re not sure what they’re resistant to.
Dr. Hayden: If you don’t know what they’re resistant to, it’s sensible to use
combination therapy, preferably dual therapy, which has been espoused by many. But
the routine use of combination therapy is problematic. Most good quality data say that if
the virus is amantadine-resistant, that doesn’t add anything to the combination, so you’re
just increasing the risk with no potential benefit. There are different issues there, so I
would not routinely embrace combination therapy. But there’s an argument for using
other agents with potential for value. I’d be cautious about using combination therapy
routinely without more evidence from independent labs.
Dr. Cantrill: We need to adapt our planning to current reality. We need to be ready in
2-4 months. Beyond that, we’re just preparing for the next pandemic. I hope NBSB’s
advice looks at the next steps. It requires some adjustment in where we stand between a
cautious and a bold approach. If we proceed in our normal cautious way, we’ll have a
good vaccine next summer. NBSB focuses on products, but there is planning beyond
products, e.g., major efforts on communications, plus effort to understand what’s going
on, surveillance, mitigation, and vaccination.
Dr. Pavia: Regarding the size of the stockpile, are we considering the right strategy? I
hope that’s being discussed. Dr. Robinson of BARDA echoed the urgency of the
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