Apr 6, 2012 (CIDRAP News) – The intravenous antiviral peramivir was used in close to 1,300 severely ill patients under an emergency authorization during the 2009 flu pandemic, but its impact and safety profile remain unclear, in part because of patchy data collection, according to reports and commentary published in Clinical Infectious Diseases (CID) this week.
The Centers for Disease Control and Prevention (CDC) estimated that 1,274 patients received the IV drug under an Emergency Use Authorization (EUA). Food and Drug Administration (FDA) officials estimated that about 16% of the patients died, which is in the range of fatality rates reported for hospitalized H1N1 patients generally, according to the reports.
Also, many adverse events were reported in the treated patients, but those were generally attributed to their already-severe illness at the time of treatment and other factors. Rashes were the only adverse reactions that seemed clearly related to the drug, but data gaps left the overall safety picture incomplete.
"Despite extensive and thoughtful efforts, the post hoc data collection described in this issue provided a limited and incomplete view of the experience," wrote Andrew T. Pavia, MD, a pediatric infectious disease expert at the University of Utah, in a commentary. "The EUA mechanism as described in the Project BioShield Act of 2004 was not designed for prospective data gathering."
Peramivir is a neuraminidase inhibitor, like oseltamivir (Tamiflu, given orally) and zanamivir (Relenza, given by inhalation), but is not yet licensed by the FDA. The FDA issued an EUA for peramivir on Oct 23, 2009, for the sake of seriously ill patients who needed an IV antiviral. The EUA remained in force until June 2010. The CDC managed distribution of the drug to clinicians who requested it.
In one of the CID reports, CDC officials write that they received 1,371 clinician requests for peramivir and delivered 2,129 5-day adult-treatment course equivalents to 563 hospitals.
Data from three surveys were used to estimate how many patients were treated. The surveys included a reminder survey about reporting adverse events, a hospital pharmacy survey, and a clinician survey seeking patient data. From these, the CDC estimated that at least 1,274 patients, median age 49, received the drug.
The reminder survey results yielded data on 844 patients. Adverse events were reported in 260 (31%) of these, but most of the events could have been due to flu itself or underlying diseases, according to Pavia. Because of the survey design and the lack of a control group, the relationship of the adverse events to peramviir could not be determined, he said.
The clinician survey drew a response rate of only 12%, with data on 127 patients. "The results paint a picture of very ill patients and late treatment," Pavia commented. Ninety-two percent of the patients were on mechanical ventilation when peramivir treatment was started. When treatment ended, 30 (24%) of the patients had died. The available data did not permit a conclusion on whether the drug influenced outcomes.
The second CID report was written by FDA officials who analyzed reports submitted to the Adverse Events Reporting System (AERS) about peramivir patients. The FDA received 369 reports covering 900 adverse events in 344 patients.
The FDA investigators could not determine if any adverse events other than rash were due to peramivir, as missing data, severe illness, and other factors complicated the review, according to Pavia. The estimated overall mortality among the treated patients, about 16%, "did not differ from overall mortality of 14% to 46% in published series of hospitalized patients with pH1N1 influenza," he wrote.
Despite the limitations, the reports "highlight the first effective use of the EUA to provide a potentially lifesaving medication that was not yet licensed during a large-scale bioemergency," Pavia wrote. "The delivery of drug to more than 1,100 critically ill patients within 24 hours of the request represents an enormous effort and logistical tour de force."
But he adds that the EUA was not initiated until close to the peak of the second wave of the pandemic, "and there may have been missed opportunities to make the drug available earlier."
Pavia suggests that more complete clinical data on patients treated under an EUA could be collected by providing data forms or links to secure Web sites when the drugs are delivered. Clinical research networks established in advance of emergencies would also improve data collection.
The US House–passed version of the reauthorization for the Pandemic and All-Hazards Preparedness Act would expand the FDA's ability to plan in advance for EUAs and to collect data during and after an emergency, but the Senate version does not include those provisions, Pavia said. Passage of the language in the House version is critical, he said.
Yu Y, Garg S, Yu P, et al. Peramivir use for treatment of hospitalized patients with influenza A(H1N1)pdmo9 under Emergency Use Authorization, October 2009 – June 2010. Clin Infect Dis 2012 (early online publication) [Abstract]
Sorbello A, Jones SC, Carter W, et al. Emergency use authorization for intravenous peramivir: evaluation of safety in the treatment of hospitalized patients infected with 2009 H1N1 influenza A virus. Clin Infect Dis 2012 (early online publication) [Abstract]
Pavia AT. What did we learn from the Emergency Use Authorization of peramivir in 2009? (Commentary). Clin Infect Dis 2012 (early online publication) [Access page]
See also:
Oct 26, 2009, CIDRAP News story
