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NBSB Pandemic Influenza Working Group Detailed Report Therefore, Hoffman-La Roche is supporting two ongoing investigator-led studies in Canada in hospitalized patients: one in uninfected patients who required intubation and mechanical ventilation, and one in patients infected with <strong>H1N1</strong> who have severe respiratory syndrome. The company is discussing with FDA the possibility of IV TamiFlu for emergency use. It can produce a limited clinical supply by the third quarter of 2009. The first batch could be available by August, and 4,000 treatment courses could be produced by the end of 2009. Hoffman-La Roche is also studying oseltamivir in immunocompromised patients and kids under age 1. Two studies have been initiated to assess the efficacy and safety of oseltamivir in transplant patients—one is focused on treatment, and the other focuses on prophylaxis. Both are double-blind, randomized, multicenter trials. The prophylaxis study is complete, and found that oseltamivir prophylaxis reduced the incidence of laboratory-confirmed infection (by viral culture or PCR) by 79.9%. The 12-week dosing regimen was well tolerated, and the AE profile was similar to placebo. No cases of resistance were identified. The company is collaborating with NIH/NIAID on a study of infants less than 2 years. The study takes a cohort approach. Younger groups are enrolled if pharmacokinetic and safety profiles raise no concerns in older groups. As of April 2009, 40 patients were enrolled, mostly male and Caucasian. The youngest cohort—under 2 months—had four kids enrolled as of April. As of late April, 57 AEs had been reported; all but three were considered unrelated to treatment, and no seizures or neurological concerns were reported. The pharmacokinetic measures and other preliminary findings are promising. The study is ongoing. In the fall, the company is conducting a similar study in Europe. Discussion Dr. Pavia: There is frustration, clearly, around this topic. So let’s explore that, recognizing that we’re in a difficult position. Debra Birnkrant: We have concerted efforts to communicate on antivirals for influenza. Regarding [FDA’s] published draft guidance, we have received comments and will address those. In addition to frustration by pharmaceutical companies doing research, we have also heard how much we are communicating with them. Our goal is to develop perennial antivirals for the seriously ill, ensure adequate supplies of current products, and encourage development of new antivirals. Dr. Pavia: There are considerations about study design and endpoints. Elizabeth Higgs, M.D.: We are working internationally, and we are aware of the need for novel treatments for influenza. We were reminded last season when we saw the resistance. We are one point mutation from having no systemic treatment for pandemic influenza, so it’s urgent to address. I’ve been in the middle of this, and I think we can work together, but we need some novel thinking. There are not a lot of treatment options because it’s challenging, as we’ve discussed. Endpoints are good place to start: perhaps replication of the virus in a high-risk population, or maybe strain-specific endpoints. Maybe virologic clearance in high-risk populations is something to revisit. Dr. Pavia: What models have we used in other diseases—with better endpoints? 80
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 81
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