Global Health Concerns Create Business Opportunities

Even before the emergence of the swine-flu pandemic, policymakers and pharmaceutical companies were paying more attention to diseases affecting the poorer people in the world. Americans and Europeans have long recognized that they are vulnerable to infections and contamination from overseas, and that development of new medicines and vaccines is critical to ensuring public health at home and abroad.

Jill Wechsler

Funding to bolster healthcare systems in developing countries and to improve treatments for infectious diseases has increased in the last decade. US support in this area has grown exponentially, beginning with AIDS, and is now helping to combat malaria, tuberculosis (TB), and many neglected tropical diseases.

Pharmaceutical companies have responded by supporting public–private partnerships that strive to develop new vaccines and medicines and improve healthcare delivery systems in developing countries. The international financial crisis has squeezed resources for these efforts, however. US initiatives have suffered from delays in appointing a permanent director of the Agency for International Development as well as looming cuts in foreign aid. Although the list of promising drug and vaccine candidates for neglected diseases is growing, competition among donor agencies and multiple public–private partnerships threatens success in bringing new therapies through the costly development and registration process.

Shift from the West

The slowdown in the growth of pharmaceutical sales in the industrial world is a prime factor encouraging manufacturers to expand their presence in emerging markets and developing nations. In announcing quarterly earnings in July, GlaxoSmithKline (GSK, London) CEO Andrew Witty highlighted the company's reduced reliance on "white pill, western market" sales and rising investment in younger, growing markets.

Similarly, Pfizer (New York) has established an emerging-markets business unit to build sales in Brazil, China, India, Mexico, Russia, and Turkey. sanofi aventis (Paris) has made a series of acquisitions in recent months to expand its drug and vaccine portfolio in emerging markets. Other pharmaceutical companies are taking similar tacks.

While newly industrialized nations offer sales potential, manufacturers also are tackling neglected tropical diseases. Merck (Whitehouse Station, NJ) announced in June that it would provide proprietary information about drug candidates to the Drugs for Neglected Diseases Initiative to develop treatments for Chagas and leishmaniasis, among other diseases. Roche (Basel) is working with the Institute for OneWorld Health to develop new treatments for diarrheal disease from leads uncovered in Roche's cystic-fibrosis research.

Treatments for tuberculosis

The US Food and Drug Administration plays an important role in facilitating the development of new vaccines and drugs to protect against global infectious diseases. Its role may expand under Commissioner Margaret Hamburg, who built a strong record in public health and TB-control efforts as head of New York City's public-health department in the 1990s. That experience will help FDA encourage research on new TB treatments and counter a resurgence in multidrug-resistant and extensively drug-resistant TB strains.

In Washington this month

The good news is that new TB-drug development and international collaborations are taking place. The trend demands clearer FDA guidelines on TB-drug testing. Current therapies are decades old, involve lengthy treatment courses, result in poor compliance, and generate resistant TB strains.

An FDA advisory-committee meeting in June supported establishing a research pathway with early endpoints for drugs to treat multidrug-resistant TB. The panel agreed that reduced bacterial count in sputum culture, followed by confirmatory trials to document low relapse rates, could accelerate the research and development (R&D) process, an approach that could be useful for the new compound being developed by Johnson & Johnson's (New Brunswick, NJ) Tibotec subsidiary with support from the Global Alliance for TB Drug Development (TB Alliance).

FDA followed up with a two-day workshop in July that delved into clinical-trial design challenges for drug-susceptible TB. The panel evaluated noninferiority study designs, combination-therapy regimens, problems of missing data, and early study endpoints. TB Alliance President Melvin Spigelman emphasized the importance of testing new combination-drug regimens that combat resistance and lead to individualized therapy. Gail Cassell, vice-president of Eli Lilly (Indianapolis), advocated "boldness in clinical-trial design," along with better postapproval adverse-event monitoring.

Market incentives

Because not all desired clinical trials can be funded, the global health community is tapping 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 spur production of artemisinin-based combination therapies (ACTs) that are effective, but require subsidies to be affordable in developing counties.

The Global Fund to Fight AIDS, Tuberculosis, and Malaria recently launched the Affordable Medicines Facility—malaria (AMFm) to make ACTs available in Africa and Asia at a nominal cost. The AMFm will subsidize the purchase of fixed-dose combination ACTs or combinations in coblistered packages approved by FDA or European authorities or on the World Health Organization's (WHO) prequalified drug list. By expanding the market for these effective, high-quality therapies such as Novartis's (Basel) Coartem (artemether-lumefantrine) and sanofi aventis's ASAQ (artesunate-amodiaquine), the program aims to drive older, ineffective products out of the market.

Another AMC project supports the development of new pneumococcal vaccines that protect against pneumonia and other diseases that claim the lives of millions of children each year. A broad coalition of public and private donors have committed $1.5 billion to guarantee a price for pneumococcal vaccines suitable for use in developing countries.

FDA's priority-review voucher program offers another inducement for manufacturers to support R&D on neglected disease treatments. The program provides a voucher to sponsors who seek approval of a treatment for one of 16 neglected 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 large sales potential.

The first voucher was recently awarded to Novartis in conjunction with the approval of the antimalarial Coartem in the US. The move drew criticism because the program is supposed to reward companies for developing brand-new treatments, and Coartem has been available for more than a decade around the world. The Novartis application got the program going, however, while FDA develops guidance and weighs whether to expand the list of tropical diseases that qualify for review vouchers.

The search for new vaccines

The holy grail for global health initiatives is to spur R&D on new vaccines that prevent lethal infections, and public–private partnerships are making progress in this area. PATH's Malaria Vaccine Initiative is launching Phase III trials of a malaria vaccine developed by GSK, and the Aeras Global TB Vaccine Foundation has several candidates in early clinical trials. Rotavirus vaccines recently received a strong push from WHO, which in June recommended including this preventive in national immunization programs for infants and children.

Vaccine development also is strong in industrialized nations, as new preventives for human papillomavirus, rotavirus, and shingles have hit the market. FDA anticipates a slew of license applications in coming months, and they could be overwhelming if they coincide with filings for the new pandemic H1N1 vaccine that is being tested and produced as fast as possible. The US expects to spend some $8 billion for testing and purchase of 100 million doses of the flu vaccine from GSK, Novartis, Sanofi Pasteur (Lyon), Astra-Zeneca's (London) MedImmune, and CSL (Victoria, Australia). Billions more will come from the United Kingdom, France, Germany, and other nations.

FDA and industry face several challenges in developing and producing the new pandemic vaccine, as discussed at a July meeting of FDA's Vaccines and Related Biological Products Advisory Committee. To speed the preventive 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, though, companies must conduct clinical trials to ensure safety and to determine the necessary dose strength and number for effectiveness. Another question is whether the swine-flu vaccine should be administered separately or with a seasonal flu shot, which manufacturers already have produced in large quantities.

In addition, the National Institutes of Health (NIH) is conducting clinical trials to test dosing options for various age groups, as well as the need to mix the new vaccine with an adjuvant to achieve the desired immune response. If adjuvant is needed, FDA plans to use its emergency use authority to expedite access to what would be a new vaccine.

Even if all the test results are positive, it's not clear how quickly industry will produce the millions of doses needed. Companies experienced difficulties cultivating antigen from the available H1N1 strains, but yields began to rise last month, bolstering hopes for initial supplies in September. MedImmune reported great success in producing bulk quantities of its FluMist vaccine, which is made from live virus, but doesn't have enough nasal spray devices to deliver the inhaled product.

Broader impact

Vaccine makers are parlaying the current demand surge into new production and distribution. Sanofi Pasteur gained FDA licensure for its new Swiftwater, Pennsylvania, vaccine-manufacturing facility earlier this year. Chinese manufacturers have geared up to expand flu-vaccine production at home, GSK recently opened a large vaccine production facility in Singapore that is slated to begin commercial production of pneumococcal conjugate vaccine in 2011.

Demand for pandemic flu vaccine also has spurred the 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 developing cell-based manufacturing technology for the influenza vaccine, the long-desired approach for accelerating seasonal flu-vaccine production.

A squeeze on funding

Despite significant increases in funding for global health during the past decade, international health officials fear a major budget squeeze. A May 2009 Institute of Medicine report recommends nearly doubling US financial commitments to global health to $15 billion per year by 2012. The panel urges US academic institutions and biomedical companies to help strengthen research and medical infrastructure in other nations and to support patent pooling and the open exchange of information and tools to spur research.

Unfortunately, the US may be hard-pressed to maintain the current level of funding for global health. In May, the Obama administration unveiled a $63-billion, six-year global initiative to combat AIDS, TB, malaria, and other health problems that affect developing countries. The initiative aims to build on the current $48-billion, five-year funding plan for the President's Emergency Plan for AIDS Relief (PEPFAR), which has been praised for slowing the rising death rate from AIDS in Africa and poor nations. Obama's broader and longer funding plan, however, may reduce the annual budget for PEPFAR and other international health programs.

White House policy advisor Gayle Smith acknowledged funding shortfalls at a July meeting sponsored by the Kaiser Family Foundation. She emphasized the need to assess how money is spent and to combine government resources with private funding before trying to "grow the numbers."

The funding decline is squeezing resources at public–private partnerships just as they are poised to harvest the rewards of more than a decade of research efforts. A study by the International Federation of Pharmaceutical Manufacturers Associations in 2007 estimated that full testing and registration of those projects now in public–private partnership pipelines would require $8.3 billion in funding, but that less than $1 billion was available. The situation has generated interest in market-incentive strategies and increased calls for newly industrialized nations such as China and India to invest more in disease research that stands to benefit their nations.

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