Washington Report

Manufacturers Face New Challenges Battling Global Threats

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com

Although new drug development usually focuses on clinical and preclinical research, moving innovative products from clinical testing to market mainly involves overcoming manufacturing capabilities and production challenges. Ensuring access to consistently high-quality critical vaccines and therapies needed to counter bioterrorism attacks is a topic frequently debated. Product shortages are leading to policies that expand US drug and vaccine manufacturing and ensure that US regulatory and healthcare policies avoid erecting roadblocks to high-quality drug production (see sidebar, "Signs of progress"). Warnings of a global flu pandemic and of bioterrorist attacks in the next few years are increasing the focus on drug manufacturing. The World Health Organization (WHO) advises that the avian flu virus is likely to mutate and spread to humans, which could kill millions worldwide. Congress is weighing new "BioShield II" legislation to spur the development of countermeasures to biological threats and to fight infectious diseases. Such crises would stress national healthcare systems as well as international capacity to produce needed vaccines and medicines. Government agencies are looking to encourage research and development of new vaccines and other drugs to protect and treat influenza patients, a process which would involve new methods for testing and producing great quantities of new treatments. A key issue is whether the United States has sufficient capacity to produce vaccines and medical treatments needed to meet domestic needs in the event of a health emergency, particularly a global pandemic. This past year's flu vaccine shortage, precipitated by manufacturing problems at Chiron's United Kingdom vaccine production facility, focused national attention on vaccine quality control and regulation. Federal officials also acknowledge that in the case of a global flu pandemic, foreign governments very likely would curb exports of vaccines and drugs to the United States until the needs of local populations are met. Some manufacturers are looking to expand US production capacity of critical drugs and are developing more-efficient production methods for vaccines, but such undertakings are expensive and may take several years to accomplish. Seeking more antivirals To prepare for a potential global influenza crisis in the near future, the Department of Health and Human Services (HHS) plans to finalize its Pandemic Influenza Preparedness and Response Plan by fall. In the wake of this past year's highly disruptive flu vaccine shortage, plus regular supply problems with routine children's vaccines, policymakers are very nervous about how the nation will deal with such a global health crisis. A major flu pandemic would increase demand for medications to treat patients stricken by influenza, particularly during the period when vaccines are under production. At the forefront of this effort is rising international demand for Roche's antiviral Tamiflu (oseltamivir), which was approved by the US Food and Drug Administration and recommended by WHO for influenza treatment. In 2003, more than 1 million prescriptions were written in the United States for this neuraminidase inhibitor, which prevents flu virus replication. Roche reports that foreign governments are ordering millions of doses of Tamiflu for national stockpiles. The company is urging the Centers for Disease Control and Prevention (CDC) and other US agencies to follow suit or face shortages in the case of an international emergency. Last-minute orders will be difficult to fill because Tamiflu involves a complex manufacturing process that takes 8–12 months to progress from raw material to finished product, explained Roche Medical Director Dominick Iacuzio at a hearing in May before the House Energy and Commerce Committee on pandemic preparedness. The production process involves many intermediate steps, including use of a unique starting material and "a potentially explosive production step that may be carried out only in specialized and costly facilities," Iacuzio pointed out. Roche doubled production capacity at its European facility in 2004 and plans to increase production in 2006. One initiative would expand US output by shipping active ingredient to US manufacturing sites to produce finished drug product. In the United States, Roche also is adopting special packaging for stockpiled Tamiflu to extend expiration dating. These plans, though, may be blocked if Gilead Sciences follows through on its June announcement to end its 10-year licensing agreement with Roche for Tamiflu manufacturing and marketing. Meanwhile, Roche is advocating an increased Tamiflu order from HHS, which so far has purchased only 2.3 million courses of Tamiflu, enough to treat less than 1% of the US population. Other nations are stockpiling enough of the drug to cover up to 40% of their populations. Without further purchase commitments, the manufacturer might find itself in the uncomfortable position during a global pandemic of having to export Tamiflu to countries with advance orders. The Infectious Diseases Society of America (IDSA) recommends that the United States stockpile antivirals sufficient to treat 50% of the nation's population. It notes the need to support the development of antiviral production capacity in the United States as well as a strategy for distributing antivirals and vaccines to states, local health departments, and points of care. CDC is enhancing systems for monitoring adults hospitalized with influenza to detect signs of resistance to current antiviral drugs and to guide its policy for distributing scarce supplies of these medications. The National Institute of Allergy and Infectious Diseases (NIAID) is supporting research on new antivirals to precisely target viral proteins and to inhibit their functions as well as studies of new broad-spectrum therapeutics that might work against many influenza virus strains. IDSA points out that such innovation could be important in light of the potential for a pandemic influenza strain to become resistant to Tamiflu. (continued)