Regulatory Beat: Vaccine Manufacturers face New Opportunities, Additional Scrutiny

A small but rising number of deaths from avian flu in Asia is prompting health experts to predict a global flu pandemic in the next few years. The World Health Organization (WHO) warns that the avian flu virus is likely to mutate and spread to humans, which could potentially kill millions worldwide and stress health care systems, as well as the international capacity to produce needed vaccines and medicines.

Jill Wechsler

At home, the Department of Health and Human Services (HHS) is developing a Pandemic Influenza Preparedness and Response Plan, issued in draft form last August. Members of Congress now want a final plan and evidence of progress in developing vaccines and treatments to cope with a major flu pandemic. Coming in the wake of last year's devastating flu vaccine shortage, plus regular supply problems with routine children's vaccines, policymakers are very nervous about how the nation will deal with a global health crisis.

FRAGILE SYSTEM

In preparing for a serious flu outbreak, an important challenge is to ensure an adequate and timely supply of influenza vaccine, according to Congress' Government Accountability Office (GAO), [GAO-05-760T, May 26, 2005]. However, US preparedness efforts are hampered by a lack of domestic vaccine manufacturing capacity. Only five manufacturers produce vaccines for the US market, and only one company makes conventional seasonal flu vaccine entirely in the US. At a hearing on pandemic flu preparedness before the House Energy and Commerce Committee in May, Julie Gerberding, director of the Centers for Disease Control and Prevention (CDC), described the US vaccine manufacturing system as "fragile." She noted that pandemic flu vaccine produced in other countries probably will not be available in the US because other governments "may prohibit export of the vaccines produced in their countries until their domestic needs are met."

The National Institutes of Health (NIH) are supporting research efforts geared toward new vaccine production methods as well as disease analysis. FDA is developing policies to facilitate new vaccine approval and ensure that manufacturing facilities meet all quality standards. While vaccine manufacturing is a tricky business in any situation, fast production of a vaccine for a novel virulent influenza strain raises additional challenges. It now takes six to eight months to identify prevalent flu strains each season, to develop effective vaccines, and to ramp up production of millions of doses.

Policy makers recognize that efforts to expand the nation's vaccine manufacturing infrastructure and to stabilize the market for routine and seasonal vaccines will lay a foundation for responding to a national or global pandemic. Last year's shortages, to some extent, may help improve the process by boosting funding for new programs and removing regulatory and legal obstacles to vaccine development. A number of NIH and CDC initiatives have been launched that support vaccine R&D and expanded production capacity:

• Improved egg production methods. Sanofi-Pasteur (Swiftwater, PA) has a five-year $40 million contract with HHS to provide a secure, year-round supply of eggs suitable for full capacity flu vaccine production.

• Development of cell-based vaccine production methods that eliminate the need for eggs altogether to produce other vaccines in the US and Europe. HHS seeks proposals from additional manufacturers to test cellular and recombinant vaccines and has awarded Sanofi-Pasteur a grant in this area.

• Support for new vaccine production facilities. Sanofi has committed to expand its current manufacturing operation to produce up to 300 million doses of monovalent pandemic vaccine, a process that will take at least five years.

• Improved vaccine manufacturing processes at existing facilities. HHS offers funding for manufacturers to develop more efficient methods for viral master seed production; egg inoculation; growing, purifying and harvesting vaccine; formulating the vaccine product; and loading vials or syringes.

• Development of dose-stretching strategies that decrease the amount of flu virus antigen needed in each dose, such as adding an adjuvant to a formulation to stimulate immune response.

• Pilot testing of pandemic flu manufacturing capacity. Under a contract with the National Institute of Allergy and Infectious Diseases (NIAID), Sanofi-Pasteur produced pilot lots of a new H5N1 vaccine for testing in clinical trials. Even before obtaining study results, Sanofi will produce two million doses of the vaccine to ensure satisfactory large-scale manufacturing and production techniques and conditions.

APPROVALS AND OVERSIGHT

Meanwhile, FDA's Center for Biologics Evaluation and Research (CBER) has put vaccine licensing and product quality assurance at the top of its priority list. CBER Director Jesse Goodman recently named Norman Baylor as the permanent head of the Office of Vaccine Research and Review (OVRR), providing more stability for that operation. To speed access to new vaccines, CBER will regard a vaccine for a pandemic flu strain as merely a product undergoing a routine change, thus requiring only a supplemental, rather than a new application to obtain approval. The agency may also offer accelerated approval to new vaccine sponsors based on antibody levels as surrogate markers for efficacy.

Another CBER goal is to become more aware of possible manufacturing problems that could curtail vaccine production, as seen at Chiron's UK facility last year. The agency plans to conduct good manufacturing practices (GMP) inspections of flu vaccine manufacturers annually instead of every two years. This recognizes that complex manufacturing issues may arise when producing a "new" influenza vaccine each year. And the hope is that recently inspected manufacturers will be well positioned to quickly develop and produce a vaccine in the event of a pandemic.

FDA also has signed information-sharing agreements with British and other foreign regulators in countries where vaccines are produced for the US market. The goal is to facilitate access to information on problems arising from manufacturing inspections, and to better communicate information on new technologies in manufacturing operations.

One sign of progress is Glaxo-SmithKline's May 2005 announcement that it has filed a license application for its Fluarix vaccine, which is produced in Europe. Glaxo plans to provide 10 million doses of the product for the 2005–2006 flu season once the application is approved.

There also has been a flurry of activity in developing new vaccines for adults and children. FDA recently approved new pertussis booster vaccines for adolescents from Glaxo and Aventis. Last month, researchers made headlines in releasing promising data on a vaccine being developed by Merck that would protect adults from developing shingles, a painful skin disease.

REMAINING CHALLENGES

While US regulators and research organizations are supporting new vaccine development and production, manufacturers point to a number of factors that make the US vaccine market unstable and less attractive to industry. The distribution system is complex, government purchasing imposes a ceiling on prices, and demand for adult vaccination has remained fairly weak. Manufacturers and others have identified a number of policy changes that could strengthen the flu vaccine market and the vaccine industry overall:

• Offer tax credits to manufacturers that build new vaccine manufacturing facilities in the US.

• Expand government guarantees to buy a set amount of vaccine each season and to buy back a percentage of unsold vaccine at the end of each season.

• Strengthen liability protections for manufacturers of pandemic flu vaccine distinct from the existing Vaccine Injury Compensation Program (VICP).

• Resolve the accounting issue with the Securities and Exchange Commission that is blocking several major vaccine companies from selling products to vaccine stockpiles.

Further Reading

The May/June issue of the journal Health Affairs (vol. 24, no. 3) focuses on vaccine R&D and features several articles on incentives and obstacles to vaccine production. See

www.healthaffairs.org

.

Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634, jwechsler@advanstar.com.