FDA Issues Warning Letter to Chiron Over Flu Vaccine Production Issues
Chiron officials on Friday announced that FDA regulators have sent the company a warning letter requesting more information about contamination issues at a Liverpool, England, plant that led to the suspension of the plant's manufacturing license and the subsequent U.S. flu vaccine shortage, the New York Times reports (Pollack, New York Times, 12/11). British Medicines and Healthcare Products Regulatory Agency officials in October suspended the plant's license for three months because of contamination issues. MHRA last week extended the suspension from January to April.
Chiron was expected to produce about half of the United States' flu vaccine supply for this season, but because of the suspension it will not ship any doses. U.S. officials initially anticipated having about 100 million flu vaccine doses this flu season. France-based Aventis Pasteur has provided the United States with 58 million flu vaccine doses, and Maryland-based MedImmune provided about three million doses of the nasal-spray flu vaccine FluMist. HHS officials on Tuesday also agreed to import 1.2 million doses of GlaxoSmithKline's flu vaccine Fluarix, manufactured in Germany, after the vaccine received provisional FDA approval. U.S. officials could purchase an additional 2.8 million doses from GSK if demand for flu shots continues.
Regulatory officials have said that Chiron's extended license suspension was anticipated and was not the result of new findings. FDA and MHRA officials will visit the factory to verify its progress. The suspension could be lifted immediately if Chiron is able to show it has remedied the site's problems. FDA Acting Commissioner Lester Crawford next week is expected to meet with British regulators to discuss the situation. Crawford in November told the House Committee on Government Reform that FDA will inspect the plant in February or March (California Healthline, 12/9).
The FDA warning letter gives Chiron 15 working days to respond. The letter asks Chiron to provide details about flaws that FDA regulators found in an October inspection of the plant following its license suspension. The October FDA inspection report cited violations of bacterial contamination of vaccine batches; inadequate cleaning procedures; microbial growths on equipment used to fill vaccine vials; unacceptable levels of bacterial toxins in some vaccine preparations; and contamination in some viral seed cultures used to produce the vaccine (Tansey, San Francisco Chronicle, 12/11).
The letter asks Chiron officials to provide more detail about the actions it plans to take to remedy the problems (New York Times, 12/11). Chiron last month submitted a remediation plan to FDA officials (Leinwand, USA Today, 12/13). According to the New York Times, FDA's warning "could indicate that the agency was not totally satisfied with the company's plans for fixing the problems" (New York Times, 12/11). FDA regulators will inspect the plant after the company verifies that it has addressed all the issues. Crawford is meeting with MHRA officials this week to "discuss and assess the status of Chiron's remedial actions," according to FDA spokesperson Lenore Gelb (Leinwand, USA Today, 12/13).
An FDA spokesperson said that it is standard agency procedure to issue warning letters after regulators find serious violations during an inspection (New York Times, 12/11). FDA policy indicates that such a letter is required when official action is necessary to remedy violations. According to the Los Angeles Times, the warning letter demanding official action is "considered more serious" than encouraging voluntary improvements (Los Angeles Times, 12/11).
Congress members last month during a government reform hearing "harshly criticized" FDA for not issuing a warning letter after finding problems at the plant in June 2003, relying instead on voluntary corrections by company officials, the New York Times reports (New York Times, 12/11). Chiron on Friday issued a press release but would not provide a copy of the warning letter. FDA will post the warning letter on its Web site on Tuesday after proprietary information is concealed (Leinwand, USA Today, 12/13).
Chiron spokesperson Alison Marquiss said the warning letter would not affect the company's schedule to produce vaccine for the 2005 flu season (New York Times, 12/11). Chiron officials have said that the company must begin production in March to deliver vaccine by October and November 2005 (California Healthline, 12/9). According to the New York Times, Marquiss "characterized the letter as a formality" and said it did not contain any information not already included in FDA's inspection report (New York Times, 12/11).
Marquiss said, "The warning letter is based on findings from the October inspection and a review of Chiron's response to those findings. It is not the result of any newly identified safety issues or findings by the FDA." She added, "We aim to achieve full remediation in time for the 2005-06 flu season. We are committing significant resources and expertise to this matter" (Los Angeles Times, 12/11).
According to the New York Times, many experts have said that Chiron's sales could be "sharply limited" even if it were to resume production next year because more suppliers are considering entering the U.S. market (New York Times, 12/11). Even if British officials lift Chiron's license suspension, the company must still comply with U.S. regulations. If U.S. regulators are unsatisfied with Chiron's solution, they could revoke Chiron's U.S. license permanently (Leinwand, USA Today, 12/13). Canada-based ID Biomedical last week announced that it expects to sell vaccine in the United States by 2007 through 2015. If the company receives FDA approval, the deal could reach as much as $2.3 billion.
Analysts and health officials also said last week that the FDA's limited approval this year of GSK's Fluarix vaccine may help the company win a permanent U.S. license. If approved, GSK plans to sell 10 million to 20 million doses next year and has the capacity to produce additional doses. A MedImmune spokesperson on Wednesday said the company could provide as many as 10 million doses of FluMist for next season (California Healthline, 12/9).
Several states have eased or eliminated guidelines on who should be given priority to receive a flu vaccine shot as demand for the vaccine has declined (Schmit, USA Today, 12/13). Following the shortage announcement in October, CDC officials recommended that people 65 years and older, people with chronic diseases, children six months to 23 months, pregnant women, nursing home residents and those in contact with very young children be considered high risk for contracting the flu and be given priority for the flu shot (Cook, AP/Hartford Courant, 12/13).
However, a mild beginning to the flu season and the U.S. government's ability to secure additional flu vaccine from Europe has lowered demand. Michigan and Utah have lifted all restrictions while encouraging those in the high-risk group to receive the shot. Minnesota extended the priority group to include those ages 50 and older, and Massachusetts lowered the minimum age it considered high priority. California, Arkansas and Colorado are all considering loosening restrictions. CDC officials have said that it is premature to relax all guidelines, noting that flu season has peaked as late as February in previous years. According to USA Today, the decrease in demand "points out the disparity of the flu vaccine shortage" as some states have an excess and some are still looking for additional supplies (Schmit, USA Today, 12/13).
National Institute of Allergy and Infectious Disease officials on Thursday announced that they hope to enroll about 1,000 people by Dec. 23 in late-stage trials to test the effectiveness and safety of GSK's Fluarix. U.S. regulators issued Fluarix an investigative new drug license for this flu season in an effort to mitigate the shortage. The vaccine already is distributed in 70 other countries. In the trials, four out of five participants will receive the vaccine and the remaining enrollees will receive a placebo (AP/Richmond Times-Dispatch, 12/10). Participants' blood will be tested for influenza antibodies after three weeks (Stanforth, Rochester Democrat and Chronicle, 12/13).
Participants who receive a placebo will be given a dose of U.S.-licensed vaccine at the conclusion of the study. The testing will be conducted at the University of Rochester Medical Center, Cincinnati Childrens Hospital, University of Maryland School of Medicine and Baylor College of Medicine (AP/Richmond Times-Dispatch, 12/10). The study might allow GSK's Belgian division to become a permanently licensed U.S. distributor next year (Rochester Democrat and Chronicle, 12/13).
Baxter International ended a late-stage trial of its flu vaccine PreFluCel that was being conducted in Europe because participants showed relatively high rates of fever (Reuters/Los Angeles Times, 12/10). Baxter planned to test the vaccine in the United States next year, and hoped to enter the U.S. market for the 2007-08 flu season. The vaccine is manufactured using animal cells rather than the traditional chicken egg method.
Baxter spokesperson Deborah Spak noted that vaccines for other diseases that were manufactured using the same cell culture process have been successful (New York Times, 12/11). Baxter was estimated to have made the most progress using the cell method (Jaspen, Chicago Tribune, 12/9).