September 2005

VACCINES

US Government Orders 2M Doses of Avian Flu Vaccine

The US National Institute of Allergy and Infectious Diseases (NIAID, Bethesda, MD, www3.niaid.nih.gov) announced it will order two million doses of an avian influenza vaccine from Sanofi-Pasteur (Swiftwater, PA and Lyon, France, www.sanofipasteur.com). In April, the NIAID began a Phase I trial to evaluate the vaccine's safety and ability to generate immunity against the H5N1 strain of avian flu, an illness that leads to severe disease and possible death in birds and humans. The government also contracted with Chiron Corporation to make 10,000 doses of similar vaccines, but production has not begun because of contamination found previously in its Liverpool plant (see D. McCormick, "Chiron Continues; Compounding Crackdown," Pharm. Technol. 29 [2], 17 [2005]).

Though the first 115 volunteers of the study's 450 subjects exhibited a strong immune response to the vaccine, NIAID's director, Anthony S. Fauci, MD, cautioned in a recent New York Times article, "We don't have all the vaccine we need to meet the possible demand. The critical issue now is, can we make enough vaccine, given the well-known inability of the vaccine industry to make enough vaccines."

Mass production of flu vaccines has been a challenge for vaccine manufacturers because the supply of chicken eggs (in which the vaccine is made) is limited. To help speed production, the vaccine was developed by reverse genetics using a seed virus "for vaccine production in a matter of weeks, a process that usually requires several months," Fauci said in an article he prepared for The Washington Times in March. The lack of manufacturing capacity is another problem that makes mass production difficult. According to Fauci, the vaccine maker will manufacture flu vaccine in shifts, with next winter's flu vaccine production ending this month and the avian vaccine production beginning in mid-September at the earliest.

Studies will continue on the remaining 335 volunteers, and additional tests are needed to determine the appropriate dosage of the vaccine and whether dose-sparing techniques can be used to stretch available supplies. Though the vaccine is not ready for use by the general public, the government plans to stockpile the vaccine and distribute doses in the event of a US pandemic.

–Kaylynn Chiarello

MANUFACTURING

GSK Releases Flu Vaccine Production Strategies

GlaxoSmithKline (Uxbridge, UK, www.gsk.com) is actively pursuing several strategies for meeting worldwide demand for the development, manufacture, and accessibility of flu vaccines.

As announced in the company's second-quarter report and at a vaccines seminar in June, the company is taking steps to boost its existing "Fluarix" flu vaccine production capacity. GSK also is continuing trials of an "improved" flu vaccine formulation, developing a new cell culture-based production system (for projected introduction in 2010), and preparing for a possible flu pandemic.

During the seminar, Bruce Innis, MD, GSK's vice-president of Clinical Research and Development and Medical Affairs for Vaccines for Virus Diseases, said the company plans to expand its Dresden, Germany facility to manufacture 35 million doses of Fluarix for the 2005–2006 season—up 5 million from 2004. Long-term plans include more than doubling Fluarix production to 80 million doses in the next three years.

The company estimates a worldwide flu vaccine manufacturing capacity of 300 million doses for the 2005 season, of which 51% are attributed to Sanofi Aventis, 25% to Chiron (assuming it manages to operate at full capacity), and 11% to GSK. These numbers will most likely shift, however, as Chiron (Emeryville, CA, www.chiron.com) prepares to respond to the list of Form 483 observations it received on July 21 following FDA inspection of its Liverpool facility, which produces the company's "Fluvirin" vaccine.

During his presentation, Innis also revealed clinical safety and immunogenic data from completed Phase I and II studies conducted for the "improved" flu vaccine formulation. The drug combines flu antigens and a "novel adjuvant" to enhance T-cell responses to the flu virus. Results of the studies conducted on elderly clinical trial subjects showed "improvements in T-cell responses are being achieved."

The company also briefly outlined its preparation plans for a possible flu pandemic, including technology that would allow for "surge" production and stockpiling.

–Maribel Rios

VACCINES

Acambis and Bavarian Nordic Vie for Smallpox Vaccine Contract

The US Department of Health and Human Services (Washington, DC, www.hhs.gov) issued a request for proposals (RFP) on Aug. 15 to acquire 20 million doses (in single-dose vials) of modified vaccinia Ankara (MVA) vaccine, a highly attenuated live smallpox vaccine. The two companies expected to compete for the contract are Acambis plc (Cambridge, UK, www.acambis.com) and Bavarian Nordic A/S (Copenhagen, www.bavarian-nordic.com). Both companies have conducted early clinical trials on MVA vaccines under contracts with the US National Institute of Allergy and Infectious Diseases.

MVA is based on a strain of the smallpox vaccine that does not replicate effectively in human cells. This modified form is being developed for use in individuals with compromised immune systems or atopic dermatitis (eczema) who cannot take the standard smallpox vaccine. Animal studies and Phase I and II clinical trials have shown MVA to be safe and immunogenic. Although FDA has not granted marketing approval to these investigational vaccines, the Centers for Disease Control and Prevention could authorize their emergency use in the event of a bioterrorist attack.

Manufacturing capacity is a key competitive element in the bidding process. Bavarian Nordic began pilot production of its MVA vaccine, "Imvamune," at its plant in KvistgÃ¥rd, Denmark in July. The company says it will begin manufacturing under good manufacturing practices (GMP) regulations at the facility in September, with an initial capacity of approximately 40–60 million doses per year that can be expanded to 180 million doses per year. In the meantime, Bavarian Nordic has produced its clinical trials materials at a plant in Berlin, Germany, which it acquired from Schering AG in May 2003. Bavarian Nordic also has a global commercial manufacturing and marketing agreement with GlaxoSmith-Kline (GSK, Uxbridge, UK, www.gsk.com), which includes back-up manufacturing capacity for government contracts.

Acambis has partnered with Baxter International, Inc. (Deerfield, IL, www.baxter.com) for process development and manufacturing services. "To us, manufacturing is a real strength because we have Baxter in place, who really know what they are doing in this area," says Lindsay Wright, vice-president of communications for Acambis. Baxter declined to say which manufacturing sites it would use or to talk specifically about capacity. Wright would say, however, that Acambis previously has supplied the US national stockpile with more than 180 million doses of its full-strength smallpox vaccine, "Acam2000," which replaced the "Dryvax" vaccine used until the disease was eradicated in 1980.

While noting that the bidding is highly competitive, Wright acknowledged that multiple contracts might be issued to avoid government reliance on a single source of a strategic vaccine. Such concerns were raised when the US government first awarded a single contract for the supply of anthrax vaccine to VaxGen in Nov. 2004.

Under the MVA vaccine contract, the Department of Health and Human Services would buy a minimum of 20 million doses over two years, with an option to buy an additional 60 million doses. The United States also will pay the contract winners to maintain CGMP manufacturing capability, referred to as a "warm-base."

–Laura Bush

COMPLIANCE

FDA Forces Pharmakon Lab Shutdown

On Aug. 2, the US Food and Drug Administration (Rockville, MD, www.fda.gov) slapped Pharmakon Laboratories (Tampa, FL) with a permanent injunction, thereby forcing the company to shut down operations. The company manufactures and distributes cough and cold liquids, tablets, and capsules.

Following inspections by FDA and a trial in US District Court, Judge Richard A. Lazzara found that drug products sold by Pharmakon did not meet current good manufacturing practice (CGMP) standards and other legal requirements. This isn't the first time Pharmakon's manufacturing practices have been questioned. In Sept. 2001, the company received a warning letter citing failure to label proper dosage; failure to establish qualification for manufacturing equipment ancillary systems; failure to validate or establish written procedures for the validation of equipment operations, water quality, or computer software used to calculate batch formulations; and failure to periodically monitor the quality of water used for manufacturing and cleaning.

Judge Lazzara stated in a release that he was "simply unwilling as a court of equity to place the health, safety, and welfare of the general public at risk in order to accommodate the economic well-being of defendants." The defendants were ordered to halt manufacturing and distributing drugs until they meet FDA's CGMP standards and receive marketing approvals.

"This action by Judge Lazzara sends a strong signal that FDA will take action against drugs that fail to meet quality standards," stated FDA Commissioner Lester M. Crawford. "As the nation's top enforcer of manufacturing standards, the FDA will continue to ensure that drugs being sold in this country meet those crucial requirements."

REGULATION

Q9 Establishes Common Terminology for Risk Management

On Aug. 8, the US Food and Drug Administration (Rockville, MD, www.fda.gov) published the draft of International Conference on Harmonization's (ICH) Q9 guidance, Quality Risk Management, for review and comment.

The draft outlines risk-management principles for drug development and manufacturing and describes common methods such as hazard analysis and critical control points and failure-mode effects analysis. The document also suggests pharmaceutical operations and regulatory activities to which the approaches can be applied, including areas such as quality management, drug development, and regulatory inspection and assessment of postapproval manufacturing changes.

David J. Horowitz, director of the Office of Compliance at FDA's Center for Drug Evaluation and Research (CDER), says the document's utility is that it standardizes terminology and conceptual models. "It will facilitate dialogue about what risk means in the context of pharmaceutical quality, and what some of the approaches to controlling quality risk are," he says. The guidance will facilitate industry acceptance of risk management, he adds, by giving manufacturers confidence that they'll be able to explain their approaches to international regulators using common terminology.

The risk-management guidance also will help industry and regulators apply concepts outlined in other ICH guidance documents, Horowitz says. "A risk-based approach is very important for implementation of quality-by-design," he says, referring to the concept underlying the ICH Q8 guidance, Pharmaceutical Development. "It's also very important for the implementation of quality systems, which is going to be the ICH Q10 document." FDA issued its own draft guidance on the same topic in October of last year.

The publication of the draft guidance in the three ICH regions is part of step two of the four-step ICH process. Horowitz declined to venture a guess about when the process would be completed. "This guidance is relatively straightforward and has a fairly discrete scope," he commented, "so I'm hopeful that we can get this done relatively quickly for ICH."

–Laura Bush

WARNING LETTER

Merck & Co.

On July 22, the US Food and Drug Administration sent a warning letter to Merck and Company (Whitehouse Station, NJ, www.merck.com) concerning the company's manufacture of an asparaginase intermediate used in the drug "Elspar" to treat acute lymphocytic leukemia.

The agency cited the company for failing to submit a supplement for a change in the production process and quality controls. Specifically, Merck prepared production cell culture from a pre-existing production cell culture instead of from the master cell culture, a change that required the company to file a prior-approval supplement. The company also instituted a re-isolation procedure for selecting cells for use in production of asparaginase intermediate without characterizing the new isolate before use in production.

FDA cited these violations in a Form 483 following a February inspection of the company's plant in Riverside, Pennsylvania. FDA issued the warning letter because it found the company's responses to the Form 483 to be inadequate.

–Laura Bush

FDA

FDA Announces Top Personnel Changes

US Food and Drug Administration (Rockville, MD, www.fda.gov) Commissioner Lester M. Crawford has solidified the agency's temporary management structure as one of his first actions in his new post.

Most significant for drug manufacturers, the commissioner made Janet Woodcock, MD, his permanent deputy commissioner for operations and chief operating officer, ending any speculation that she might return to her old job as the head of the Center for Drug Evaluation and Research (CDER). Steven Galson, MD, gets that position at CDER on a permanent basis as a result. Galson has been CDER's acting director for almost two years, since Woodcock was detailed to the commissioner's office. Galson was appointed CDER deputy director in 2001, coming from the Environmental Protection Agency, where he was involved with product safety and risk-management activities. He faces the daunting task of overseeing CDER's move to White Oak, Maryland and other related organizational changes.

Crawford also named Murray Lumpkin, MD, the permanent deputy commissioner for international and special programs, which includes pediatric therapeutics, combination products, and public health issues. Associate Commissioner for Legislation Patrick Ronan becomes Crawford's chief of staff and liaison to the Department of Health and Human Services. Scott Gottlieb, MD, who served as a deputy to former commissioner Mark McClellan, MD, and followed McClellan to the Center for Medicare and Medicaid Services, returns to FDA as deputy commissioner for medical and scientific affairs. Gottlieb is well positioned to help FDA access Medicare drug safety data and deal with drug coverage and cost issues.

–Jill Wechsler

FDA

PDUFA Application Fees Rise 14% for 2006

The US Food and Drug Administration (Rockville, MD, www.fda.gov) will raise most prescription drug user fees by 14% for fiscal year 2006, according to an Aug. 1 Federal Register announcement. Applications requiring clinical data will cost $767,400; other drug applications will require a payment of half that amount. Fees for establishments and products will increase only 1% to $264,000 and $42,130, respectively.

The increases for 2006 were adjusted to account for inflation as well as workload. The Prescription Drug User Fee Act (PDUFA) of 1992 authorized these fees with the aim of accelerating FDA review times by providing the agency with more resources. According to statutory amendments in 1997 and 2002, fees are adjusted annually so that total revenues from each category approximate the levels established in the statute, after first being adjusted for inflation and workload. Through the 2006 fees, the agency expects to generate a total of $296,988,623, divided approximately evenly among the three categories of fees.

The application fees apply to new drug applications (NDAs), biologics license applications (BLAs), commercial investigational new drug application (INDs), efficacy supplements, and manufacturing supplements. The new rates take effect Oct. 1, 2005.

–Laura Bush