Global health concerns generate new therapies for home and abroad

Even before the emergence of the swine flu pandemic, biopharmaceutical companies were investing in vaccines and treatments for lethal diseases that plague much of the world. There is growing recognition that Americans and Europeans are vulnerable to infections from overseas, and that development of new medications is critical to ensuring public health.

Key Points

Even before the emergence of the swine flu pandemic, biopharmaceutical companies were investing in vaccines and treatments for lethal diseases that plague much of the world. There is growing recognition that Americans and Europeans are vulnerable to infections from overseas, and that development of new medications is critical to ensuring public health.

Over the last decade, there has been an increase in US funding designed to bolster healthcare systems in less developed countries and to improve treatments for infectious diseases. From a focus on AIDS, US support in this area has greatly expanded to include malaria, tuberculosis (TB), and many neglected tropical diseases.

One sign of this trend is increased support for a number of public-private partnerships, which have been established in recent years to develop new therapies and to improve third-world healthcare delivery systems.

The PATH Malaria Vaccine Initiative is launching phase 3 trials for a promising malaria vaccine developed by GlaxoSmithKline. Progress has been slow in discovering a vaccine for TB, but 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 (WHO), which recommended in June that this preventive measure be included in national immunization programs for infants and children.

At home, new preventive agents for human papillomavirus (HPV), rotavirus, and shingles have emerged in recent years. FDA approved 3 vaccines last year, and several important applications have been filed, including a new meningitis vaccine from Novartis and Wyeth's updated pneumococcal conjugate product.

FDA anticipates a flood of license applications in coming months, which could be overwhelming if too many coincide with filings for the H1N1 vaccine, which is in priority production. The United States expects to spend approximately $8 billion to test and purchase nearly 200 million doses of pandemic flu vaccine from GlaxoSmithKline, Novartis, Sanofi Pasteur, AstraZeneca's MedImmune, and Australia-based CSL Ltd. Billions more will come from other nations seeking vaccine supplies.

FDA and industry face several challenges in developing and testing the new pandemic vaccine, as discussed at a July meeting of FDA's Vaccines and Related Biological Products Advisory Committee. To speed the agent to patients, FDA is allowing licensed manufacturers to file manufacturing supplements for a strain change, similar to what vaccine makers do each year for new seasonal flu vaccines. Because the H1N1 vaccine is a slightly different single strain vaccine, companies must conduct clinical trials to ensure safety and to determine effective dose strength. Other issues are whether 1 or 2 doses are needed and whether swine flu vaccine should be given separately or with a seasonal flu shot.

In addition, investigators at the National Institutes of Health (NIH) are conducting clinical trials to test dosing options for various age groups and to test whether the new vaccine needs to be mixed with an adjuvant to achieve the desired immune response.

Even if all of the testing comes out well, it's not clear how quickly industry will be able to distribute millions of needed doses. Vaccine-makers experienced difficulties cultivating antigen from the available H1N1 strains, but yields began to increase last month, bolstering expectations that initial supplies will be available in September for high-priority populations.

TACKLING TB

In addition to fueling vaccine development, R&D partnerships are expanding the range of treatments that can attack infectious diseases that cripple third-world nations. Merck announced a collaboration with the Drugs for Neglected Diseases Initiative in June to provide propriety information on drug candidates that will lead to development of treatments for Chagas and leishmaniasis, among others. Roche is working with the Institute for OneWorld Health to develop new treatments for diarrheal disease based on research leads related to Roche's cystic fibrosis research.

FDA has taken a lead role in development of new TB treatments to counter a surge in multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains. That may expand under the leadership of FDA Commissioner Margaret Hamburg, who has a strong background in public health and who spearheaded TB control efforts when she was the head of New York City's public health department in the 1990s. Fast development of more effective drugs and diagnostics for identifying TB infection and strains is critical for preventing a global health catastrophe, warned Partners in Health founder Paul Farmer at an Institute of Medicine (IOM) forum in February.

The good news is that there's a mini-surge in new TB drug development and international collaborations, a trend that demands clearer FDA guidelines on TB drug testing. Current therapies are decades old, involve lengthy treatment courses, and result in poor compliance that only generates TB strains resistant to available medications. An FDA advisory committee meeting in June supported establishing a research pathway with early end points for drugs being investigated for the treatment of MDR TB. The panel agreed that reduced bacterial count in sputum culture, followed by confirmatory trials to document low relapse rates, could accelerate the R&D process. This kind of approach could be useful for testing new compounds, such as the one being developed by Johnson & Johnson's Tibotec subsidiary with support from the Global Alliance for TB Drug Development (TB Alliance).

FDA followed up this meeting with a 2-day workshop in July that delved into clinical trial design challenges for drug-susceptible TB. The panel weighed the use of noninferiority study designs, combination therapy regimens, and missing data, as well as early study end points. Sequella Chief Medical Officer Gary Horwith urged consideration of phase 0 and adaptive clinical trials to accelerate development. TB Alliance President Melvin Spigelman emphasized the importance of testing new combination drug regimens that may lead to individualized therapy. Gail Cassell, vice president at Eli Lilly, advocated "boldness in clinical trial design," along with better postapproval monitoring of adverse events.

Despite significant increases in global health funding over the past decade, these programs could face major budget cuts. The Obama administration has proposed a $63 billion, 6-year global initiative to combat AIDS, along with TB, malaria, and other third-world health problems. That turns out to be less per year than Bush's $48 billion, 5-year funding plan for PEPFAR, the President's Emergency Plan for AIDS Relief, praised for slowing the growth of AIDS in Africa and other poor nations. The funding decline is squeezing resources at public-private partnerships just as they are poised to harvest some rewards from more than a decade of research. One response may be more investment from newly industrialized nations, such as China and India, in infectious disease research that could directly benefit their populations.

Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.