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Partnerships launched 63 research projects that may translate into nine or 10 new drugs by 2010.
During the past few years, it has become good business and good politics for pharmaceutical companies to invest in the research and development (R&D) of drugs and vaccines to treat a host of deadly diseases plaguing the poorer nations of the world. The Bill and Melinda Gates Foundation deserves much credit for putting this important issue at the top of the agenda for donor nations, nonprofit organizations, and pharmaceutical manufacturers. The spread of the AIDS epidemic around the world and the looming pandemic flu crisis have brought home the threat of health problems in distant continents, prompting wealthy governments to focus more on global biomedical research and treatment programs.
The challenges for pharmaceutical manufacturers are considerable. The industry's high profits and research successes boost pressure to devote more corporate resources to third-world medical needs. But, such initiatives often require new skills and knowledge and need different procedures for conducting research. Despite much public attention, the level of support from national governments remains fairly meager and uncertain.
In the past, pharmaceutical companies often gave away available drugs for third-world diseases, but this has not encouraged investment in research on needed treatments that have little market value in industrial states. A more recent strategy has been to establish artificial commercial markets. US and European governments have offered tax breaks and patent extensions to push R&D. They also have provided advance purchase commitments (APCs) to "pull" new products to market. But, analysts now consider these tactics only minimally effective because they often yield treatments with low value for patients in poor countries. Some products still are too expensive for widespread purchase and have dosing and distribution requirements that undermine access and compliance.
Although governments and international agencies continue to back the push–pull drug development model, there is growing support for new partnership arrangements that aim to speed drug research by reducing the risk for pharmaceutical companies. This approach has altered the landscape for developing new drugs to treat neglected diseases, according to an important study by a research group at the London School of Economics headed by Mary Moran, MD. Published in September 2005 by the Wellcome Trust, the report documents how public–private partnerships (PPPs) during the past five years have spurred R&D on new treatments for third-world health conditions such as malaria, tuberculosis (TB), leprosy, leishmaniais, schistosomiasis, dengue fever, and others.*
Promoting global drug quality oversight
Although pharmaceutical companies developed only a handful of new drugs to treat neglected diseases in the previous 25 years, Moran finds that from 2000 to 2004, partnerships involving large and small companies and nonprofit organizations launched 63 research projects that should translate into nine or 10 new drugs by 2010. This investment has occurred largely outside normal government health funding programs and has been supported substantially by Gates, the Rockefeller Foundation, and other private donors.
In the 1990s, multinational pharmaceutical companies closed down neglected disease research, according to Moran. Now, they are joining PPPs such as Medicines for Malaria Venture, the TB Alliance, Drugs for Neglected Diseases, and the Institute for OneWorld Health (iOWH) and investing their own resources in this area to address objectives such as:
In addition, a growing number of niche biotechnology companies regard small infectious disease markets similarly to orphan drug development. R&D partnerships provide the means for many small companies to parlay expertise in genomics, bioinformatics, and other innovative technologies into new development programs and also to license out intellectual property to larger partners.
Reducing research risk
Consequently, multinational pharmaceutical companies are supporting more research in third-world diseases. In the lead are major manufacturers such as GlaxoSmithKline (GSK), Novartis, AstraZeneca, and Sanofi-Aventis, which have established separate neglected-disease R&D units. These corporate initiatives do not expect to make a profit, but seek to conduct R&D in a way to avoid large losses. This "no profit–no loss" approach, says Moran, requires a new research model. Large pharmaceutical companies traditionally have obtained promising drug leads from research organizations and biotech companies and then stepped in to underwrite late-stage clinical development.
The partnership approach encourages pharmaceutical manufacturers to be more involved in relatively low-cost, early-stage research to identify and run preliminary tests on promising compounds. The more expensive and risky task of conducting clinical trials and seeking product registration in multiple countries is assumed largely by the nonprofit partner, which benefits from local research networks and experience negotiating national regulatory requirements.
The private sector's prime expertise is finding drugs, explained Moran at a conference sponsored by the Brookings Institution in Washington, DC last April. "Where they're less interested and less expert is doing large-scale trials with pregnant women and children in remote developing countries in diseases that they don't know about." So the new model "swaps roles round," she explained. "Industry moves upstream" to do high-level innovation that carries less liability risk, and public groups move downstream to clinical development and dealing with regulatory authorities and patient groups. Lower expenditures produce drugs at not-for-profit prices and with higher health value to patients in developing countries.
The collaborative models differ. Some PPPs are establishing their own laboratories to conduct research without any industry partner, often contracting out clinical research, product formulation, and manufacturing to separate entities. Contract research organizations are involved in more than one third of PPP projects and most often are asked to handle specific tasks such as animal testing and local clinical trial monitoring.
An "industry mindset" is an important characteristic of these collaborative organizations. Medicines for Malaria Venture president Chris Hentschel, who comes from the biotech industry, explained at the Brookings conference that being able to drop unsuccessful projects is key. "If they're not meeting milestones, we have to kill them," he said, "and we operate exactly like industry in that way."
Manufacturability is another important consideration for identifying potentially successful products, noted Jerald Sadoff, president of the AERAS Global Tuberculosis Vaccine Foundation and formerly with Merck. Most projects fail because they can't be made at an acceptable cost or in a reliable way for millions of doses. The PPPs have expertise in the field, he said, but experience in good manufacturing practices (GMP) reporting and data management comes from industry.
Consequently, most collaborative projects rely on a large pharmaceutical partner to handle the manufacturing and packaging of final drug products. Actual production often is outsourced to a developing-country partner, frequently a local generic-drug manufacturer. Lynn Marks, senior vice-president of the GSK Medicine Development Center, noted that voluntary licensing of products allows manufacturing in low-cost plants in developing countries to "get outside our cost structure."
Fairly sophisticated generics firms in India, China, and South Africa have considerable expertise in formulation chemistry, low-cost scale-up, and product distribution in Africa and Asia. Some of these larger generic manufacturers also are moving more into R&D as PPPs provide opportunities to expand from basic productions to new drug development.
More efficient and innovative formulations and manufacturing approaches may be one beneficial outcome of the search for new treatments. For example, iOWH is partnering with researchers at the University of California, Berkeley and a spin-off company, Amyris Biotechnologies, to develop a large-scale, low-cost commercial microbial drug production process for artemisinin, the key ingredient in new antimalarials. Berkeley scientists are refining the production process, Amyris is developing a large-scale industrial fermentation process needed for commercialization, and iOWH will perform the testing to demonstrate bioequivalence of microbially produced artemisinin with the natural product.
Growing expectations that these R&D partnerships will yield effective vaccines and drugs during the coming decade is prompting some organizations to address anticipated manufacturing needs. AERAS is testing multiple TB vaccine candidates in a new $10-million research and manufacturing facility in Maryland, which can produce candidate vaccines that meet GMP standards for use in clinical trials. Sadoff acknowledges that a new vaccine may not be available for widespread use until 2012, but believes that these early efforts will set the stage for scaling up to produce the 150 million doses or more that would be needed annually of a successful product.
Ensuring drug quality
While pharmaceutical companies and research entities seek new treatments for disease, other organizations are helping third-world nations establish systems for monitoring and ensuring the quality and safety of new and existing medicines. An April report from the World Health Organization's (WHO) Commission on Intellectual Property Rights, Innovation, and Public Health supports efforts to build third-world regulatory capacity as one of its many recommendations for expanding access to needed medicines in developing countries. The report, which was presented to the World Health Assembly in May, notes the need to strengthen oversight of clinical trials conducted in poorer countries, ensure adherence to GMPs, and manage supply chains effectively to ensure product quality and curb the circulation of counterfeit products.
WHO also assists developing nations in obtaining high-quality and effective medicines through its prequalification program for ensuring that drugs to treat AIDS, malaria, and TB meet established standards. WHO reviews manufacturer dossiers, inspects production facilities for GMP compliance, and conducts surveillance to detect substandard or counterfeit drug production. Since 2001, WHO has prequalified 152 products, almost all for treating AIDS, explained WHO program coordinator Lembit Rago at the Drug Information Association annual meeting in June. As many dossiers are now in the pipeline, including more for TB and malaria treatments.
USP goes global
To help developing countries establish effective registration and inspection programs, the US Pharmacopeia issued a guide for "Ensuring the Quality of Medicines in Low-Income Countries" last fall (see sidebar, "Promoting global drug quality oversight"). This project is part of USP's expanding international program for promoting the quality and proper use of medicines around the world. For the last decade, USP has worked with the US Agency for International Development (USAID) to develop a Drug Quality and Information (USP DQI) program, which now has projects in 31 countries in four regions.
A recent project has established standards for ensuring the quality of zinc supplements now considered important for reducing childhood diarrhea. USP also is working with the Medicines for Malaria Venture and manufacturers to develop monographs and reference standards for malaria treatments. Tests of antimalarial drug samples in Guyana and other countries found high rates of substandard and counterfeit products. Similarly, USP may develop monographs for TB therapies and drugs for other neglected diseases not marketed in the United States. These monographs will be posted on the USP Web site, but not published in official USP publications. In Asia, USP is participating in a drug quality monitoring project in five countries in the Mekong subregion and has provided technical assistance on similar activities in China. A new Asian Network of Excellence in Quality Assurance of Medicines, which is supported by USP DQI, will promote technical expertise, skills, and information-sharing on drug quality.
USP also is expanding its own program for testing the quality and consistency of medicines, dietary supplements, and active pharmaceutical ingredients around the world. Last February, USP Executive Vice-President Roger Williams cut the ribbon on a USP office and laboratory in India. The site will be used for testing and establishing reference standards on active ingredients and drugs produced in India. A similar operation is slated to open early next year in Shanghai.
Push for funding
The limiting factor on all these initiatives still is inadequate funding from most wealthy nations. The Moran report notes that more than half of the nearly $255 million contributed to PPPs as of April 2005 came from the Gates Foundation. The United States provided $16 million, more than other governments, but still very little.
Most of the public funding for third-world health currently goes to treatment programs such as the Global Fund to Fight AIDS, Tuberculosis, and Malaria and the President's Emergency Plan for AIDS Relief, which is providing $15 billion over five years to support prevention, antiretroviral treatment, and patient care in 16 target nations in Africa and elsewhere.
Moreover, recent efforts to expand support for third-world health programs by industrialized nations have been disappointing. A special United Nations session on HIV and AIDS in June failed to gain commitments from donor nations to higher treatment goals and funding levels. And, at their July summit, leaders of the Group of Eight industrialized nations sidestepped a proposal for a multibillion-dollar advance market commitment fund to support development of new vaccines.
Fortunately, private donors have remained generous. The Gates Foundation announced in July that it will award $287 million in grants over five years to 16 scientific teams around the world that aim to develop the long-sought AIDS vaccine. The subsequent announcement that Warren Buffett will donate $31 billion to the Gates Foundation is likely to further expand the organization's support for multiple research efforts. Researchers believe that if governmental aid programs matched these levels, many new treatments would emerge fairly quickly.