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The FDA is encouraging manufacturers to invest in research and development for new vaccines and therapeutics to combat third-world diseases.
The need to strengthen public health at home and abroad is expanding the development of new medicines and vaccines to prevent and treat infectious diseases around the world. Donor nations and organizations have increased funding over the last decade to bolster healthcare systems in less developed countries and to improve treatments for malaria, tuberculosis, and many neglected tropical diseases. Biopharmaceutical companies have joined public-private partnerships (PPPs) developing these therapies, attracted by the desire to expand sales globally as well as opportunities to improve third-world health. Many PPPs are poised to harvest rewards from over a decade of research efforts, but require billions in additional resources to finance costly research and clinical trials.
A main thrust of these initiatives is to spur research and development (R&D) on new vaccines to prevent infections that kill millions of people every year. The PATH Malaria Vaccine Initiative is launching Phase 3 trials for a promising malaria vaccine developed by GlaxoSmithKline (GSK), and the Aeras Global TB Vaccine Foundation has several candidates in early clinical trials. Rotavirus vaccines recently received a strong push from the World Health Organization's decision to add this preventive to national immunization programs for infants and children.
Vaccine development is strong at home as well, as new preventives for human papillomavirus, rotavirus, and shingles have hit the market. The US Food and Drug Administration approved three vaccines last year, and several important applications are in the queue. Meanwhile, the agency has its hands full reviewing filings for the new pandemic H1N1 vaccine, now being tested and produced as fast as possible. The US expects to spend some $8 billion for nearly 200 million doses of the flu vaccine from GSK, Novartis, Sanofi Pasteur, Astra-Zeneca's MedImmune, and Australia-based CSL Limited. European and other nations have placed comparable orders.
The FDA and the industry face several challenges in meeting the demand for H1N1 vaccines, as discussed at a July meeting of FDA's Vaccines and Related Biological Products Advisory Committee. The agency is allowing licensed manufacturers to file manufacturing supplements for a strain change, similar to what companies do each year for new seasonal flu vaccines. Because the H1N1 vaccine is a slightly different single-strain vaccine, companies have to conduct clinical trials to ensure safety, determine the necessary dose strength for effectiveness, and decide whether one or two doses are needed. Another question is whether the swine flu vaccine should be administered separately or with a seasonal flu shot.
The National Institutes of Health is conducting additional clinical trials to test dosing options for various age groups and the need to mix the new vaccine with an adjuvant to achieve the desired immune response. If an adjuvant is needed, the FDA plans to use its emergency authority to expedite access to what would then be a new vaccine. The agency took this route earlier in the year to permit treatment of infants with antivirals not yet labeled for that age group, but has not used this approach for a new vaccine.
Even if all the testing comes out well, it's not clear how quickly the industry will produce the millions of needed doses. Companies experienced difficulties cultivating antigen from the available H1N1 strains, but yields began to rise last month, generating hopes for initial supplies in September. MedImmune reported great success in producing bulk quantities of its FluMist vaccine, which is made from a live virus, but doesn't have enough nasal spray devices to deliver the inhaled product.
MedImmune's excess supply, though, may lead to overseas sales, as vaccine makers capitalize on the opportunity created by the flu pandemic to expand production and distribution. Sanofi gained FDA approval for its new Swiftwater, PA, vaccine manufacturing facility earlier this year, while foreign manufacturers, such as Sinovac Biotech in China, have geared up to conduct clinical trials and expand production of a influenza vaccine at home. Struggling Connecticut-based Protein Sciences Corporation has received federal funding to develop new flu vaccine development methods, leading to testing for its experimental PanBlok vaccine. Inovio Biomedical of San Diego has gained attention from positive animal studies on its DNA-based flu vaccine, although it will take several years to bring such a product to market.
The demand for a pandemic flu vaccine also has spurred development of novel antigens and testing standards. Earlier this year, FDA scientists unveiled a new antigenic fingerprinting approach for testing the potential protective activity of vaccines under development. Vaccine makers are moving forward with the development of a cell-based manufacturing technology for influenza vaccine, the long-desired approach for accelerating seasonal flu vaccine production.
While vaccines to prevent disease are the holy grail for tackling global health problems, a number of initiatives support development of new treatments for tuberculosis (TB), malaria, and multiple neglected diseases that cripple third-world countries. Efforts to combat multi-drug resistant (MDR) and extensively-drug resistant (XDR) TB strains is high on the global research agenda and has attracted considerable attention at the FDA. Efforts to streamline clinical research approaches for TB drugs could expand under Commissioner Margaret Hamburg, who launched a major TB control campaign when head of New York City's public health department in the 1990s.
An FDA advisory committee meeting in June discussed early trial endpoints for drugs to treat MDR TB, such as reduced bacterial count in sputum culture, followed by confirmatory trials to document low relapse rates, to accelerate the R&D process. The FDA followed up with a July workshop that examined noninferiority study designs, combination therapy regimens, and missing data issues for research involving drug-susceptible TB. Sequella Chief Medical Officer Gary Horwith urged consideration of Phase 0 and adaptive clinical trials and surrogate endpoints, and Gail Cassell of Eli Lilly advocated "boldness in clinical trial design."
Because there will always be limits on funds available to support costly clinical trails, the neglected disease community is testing the stimulus power of market-based "pull" mechanisms, such as advance market commitments (AMCs) that guarantee prices for new vaccines and drugs with low profit potential in the US or Europe. This approach is being used to fight malaria by subsidizing the purchase of artemisinin-based combination therapies (ACTs) that are effective, but too costly for most third-world health programs. By expanding the market for these more effective therapies, the program aims to encourage the production of quality ACTs and drive older, ineffective products out of the market.
Another AMC project supports the development of new pneumococcal vaccines that can protect against pneumonia and other diseases that claim the lives of millions of children each year. A broad coalition of public and private donors has committed $1.5 billion to guarantee a price for a vaccine suitable for third-world use, while also encouraging companies to invest more broadly in research and expanded manufacturing capacity for effective vaccines.
The FDA's priority review voucher initiative offers another type of inducement for manufacturers to support R&D of neglected disease treatments. The program provides a voucher to sponsors seeking approval of a treatment for one of 16 designated tropical diseases. The voucher is good for a future priority, six-month review (instead of the usual 10 months or more), which should be highly lucrative to any company seeking market approval for a new medicine with a large sales potential.
The first voucher was recently awarded to Novartis in conjunction with approval of its antimalarial drug Coartem (artemether-lumefantrine) in the US. The drug already was available in most of the world, but the application got the program going while the FDA develops guidance and weighs whether to expand the list of topical diseases that qualify for review vouchers. Several manufacturers appear poised to file applications, with the hope of gaining vouchers they can use or sell to support speedy drug approvals.
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, firstname.lastname@example.org