AIDS Campaign Spotlights Global Clinical Research

The campaign to combat the AIDS epidemic and other major diseases prevalent in developing nations is spurring development of a global clinical research infrastructure and focusing attention on international research policies and practices. These developments have been praised and debated at numerous international conferences during the past year that aim to spur investment in developing new vaccines and medicines to treat AIDS, malaria, and tuberculosis.

According to a recent report from PhRMA (Pharmaceutical Research and Manufacturers of America), sponsors are testing 83 new AIDS medicines, including 14 vaccine candidates, with one in Phase 3 clinical trials in Thailand and other countries. International health experts and patient advocates, however, insist that much more needs to be done.

Delegates at the World AIDS Conference in Barcelona in July 2002 heard reports from scientists on progressand disappointmentin developing new vaccines and therapies. While participants booed Health and Human Services secretary Tommy Thompson for failing to provide more funds to global anti-AIDS efforts, the gathering also reflected continued tension between those medical and patient groups that want more funds to treat the millions already infected by AIDS, and organizations that want to invest primarily in prevention and vaccine research.

Further discussion of these issues took place at the World Summit on Sustainable Development in Johannesburg in September, where Secretary of State Colin Powell similarly drew criticism for the Bush administrations inadequate funding of disease treatment in Africa. World AIDS Day in December prompted additional pledges from major nations to increase support for international disease prevention and treatment programs.

Establishing networks
This growing support for global disease research is enabling donor organizations and health foundations to invest more in research programs and in establishing international clinical trial networks to test promising therapies. A major roadblock to developing new medicines to combat diseases in developing countries is the lack of clinical research capability in those countries, according to a report on the State of the Worlds Vaccines and Immunization from the World Health Organization (WHO), UNICEF, and the World Bank.¹ The report points out that progress on vaccines for developing nations is stalled because of a limited number of research centers with the capacity and experience needed to conduct large-scale vaccine trials in poorer nations. It urges additional support for public-private partnerships to support clinical studies in developing nations, as is being done by the Malaria Vaccine Initiative (MVI) and the International AIDS Vaccines Initiative (IAVI).

Parallel clinical trials in industrial nations and developing countries are essential, the WHO report notes, to evaluate key differences in how vaccines affect differing populations. Vaccines often have to treat variations in the serotype or strain of a disease-causing organism, and population differences may affect dosage regimens. Clinical studies in developing nations should be carried out at an early stage in a drug development program to establish accurate forecasts of demand and to avoid gaps between when a new vaccine is available in wealthy and poor nations.

Overcoming obstaclesOpportunities and roadblocks to research in developing nations were discussed at the Partnering for Global Health Forum 2002 sponsored by the Biotechnology Industry Organization (BIO) and the Bill & Melinda Gates Foundation in Washington, D.C., in December. The forum brought together public- and private-sector funding organizations, such as the Gates Foundation and groups associated with the World Bank and the United Nations, with biotech companies seeking support for research and development programs that address AIDS and other diseases prevalent in developing nations.

Presentations described a host of initiatives for conducting research and for improving local clinical trial infrastructures.

The Global Alliance for TB Drug Development is forming an international clinical trial site network to test promising therapies. The aim is to provide support for a range of compounds and treatments to broaden chances for success.

IAVI is creating AIDS Vaccine Development Partnerships (VDPs) with pharma companies, biotech firms, and contract organizations that provide overall management and coordination of multiple research programs. IAVI is now building a regulatory team, in addition to its clinical team, to help small companies navigate the regulatory and oversight process. It also has established core laboratories that meet global quality standards to provide test data.

The INDEPTH Network, based in Ghana, has field sites in 16 countries in Africa and Asia. The network (www.indepth-network.net) monitors almost two million people, providing a platform for evaluating a wide range of health-care innovations and for conducting multisite research studies, particularly for testing vaccines and drugs for AIDS, tuberculosis, and malaria. The organization is training study monitors and investigators, improving local health facilities, and establishing ethics committees.

Vast changes
The INDEPTH network is one sign of considerable improvement in clinical trial operations in Africa over the last 30 years, observed Brian Greenwood of the London School of Hygiene and Tropical Medicine. Speaking at the forum, he noted that multiple ethics committees and viable consent procedures now exist, and that the number of trained investigators has increased noticeably. Logistics and transportation remain major problems, however. Solar power development is important for facilitating vaccine refrigeration and mobile phone communications, which greatly improves clinical data management.

Sponsors acknowledge the need to provide medical care to clinical trial participants, but the debate continues over whether that care has to meet standards of Washington, D.C., or London, or adhere to local conditions. An even trickier issue is what kind of continuing medical care a sponsor should provide to trial participants after a study is over. The pharmaceutical industry cannot use developing countries as a testing ground for products for the industrial world, Greenwood commented. But who does have long-term responsibility for caring for large patient populations (see sidebar) is unclear.

Boosting production
As programs to develop new vaccines and therapies show promise, health experts and funding organizations also are recognizing the need to plan for global manufacturing of any new treatments. Large-scale production is needed to provide vaccines for Phase 3 trials, which can involve thousands of participants. And to be able to produce a vaccine as soon as it is licensed, plant construction has to begin before sponsors have assurance that a test product will work. Construction of a vaccine manufacturing plant that meets GMP (good manufacturing practices) standards often requires several years and at least $50 million, but the numbers can be much higher for an AIDS vaccine that would be needed by much of the world.

IAVI is devoting considerable resources to formulating a plan for massive AIDS vaccine production. The nonprofit organization aims to link academic research efforts with networks able to conduct clinical trials in developing nations and with the product development skills found in the vaccine industry. To speed vaccines to Phase 1 trials, IAVI uses contract manufacturers to produce pilot lots for preclinical testing and for early clinical studies. Now it is beginning to map plans for constructing vaccine facilities able to supply millions of vaccine doses for developing nations.

Push and pull
While clinical research and other initiatives move forward, industry and health policy experts are examining economic and political factors likely to spur or discourage research and development of new vaccines and other treatments for global diseases. These include push approaches such as tax breaks and research grants that provide incentives for private sector investment in research. In addition, experts are increasing their focus on pull strategies that involve guaranteeing markets and future prices to promote private sector investment.

The Global Alliance for Vaccines and Immunization (GAVI) is promoting accelerated development and introduction plans (ADIPs) to help countries establish credible vaccine demand forecasts that are key to securing long-term financing for vaccine programs. The aim is to develop these forecasts early in the vaccine development cycle, before manufacturers undertake scale-up to encourage construction of production facilities sufficient to meet future demand.

WHO is helping to strengthen national regulatory authorities by assisting them in developing clear requirements for product licensing, field surveillance programs, lot release systems, laboratory testing capabilities, and regular manufacturer inspection programs to ensure compliance with GMPs.

Patient advocates and developing countries continue to complain that industrial nations are not providing enough support for the campaign against AIDS and other diseases prevalent in developing nations. Last fall, Congressional committees expanded funding for international AIDS programs in foreign aid funding bills for 2003, but were unable to reach final agreement on the budget plan. The Bush administration recently unveiled a new foreign aid plan that could expand the pool of funds available to support treatment and research for AIDS and other diseases. Political leaders in the United States and other countries increasingly recognize that the high economic and political costs imposed by the AIDS epidemic create a serious threat to stability and growth in Africa and other parts of the world.

References
1. www.unicef.org/noteworthy/sowvi/ sowv_en_2002_rev.pdf.

SIDEBAR: Promoting fair benefits for research populations
To avoid exploiting inhabitants of a poor country who agree to participate in a research program, current policy calls for sponsors to make safe and effective products developed through local testing reasonably available to those involved in a study. Defining how to meet such commitments has been very difficult and has raised questions about what standard of care sponsors should provide to study participants and broader patient populations in developing countries.

To address the issue, participants in a conference on Ethical Aspects of Research in Developing Countries, which was held in Malawi in March 2001, developed a new approach for dealing with these complex issues.¹ They offer the populations of developing nations a new framework for providing fair benefits, which include:

1. benefits to study participants during research, such as health care and collateral health services.
2. benefits to a broader population while research is going on, such as additional health services, improvements in public health programs, and employment and economic activity generated by the study.
3. benefits to a population after the research has been conducted. This may include access to an effective intervention, improvements in local medical care and public health, future opportunities for research collaboration, and possible financial gains from research results.

In determining what constitutes fair benefits, the framework calls for researchers to form a collaborative partnership with the local population in developing and evaluating a research program. And it emphasizes the need for transparency and local consultation in defining agreements and policies. An entire region or country may not share equally in the distribution of benefits or in making decisions on the program, and the policy emphasizes fairness over equality in assessing benefits or possible exploitation.

References
1. Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries, ETHICS: Fair Benefits for Research in Developing Countries, Science, 298: 2133 (2002); also available from www.sciencemag.org/cgi/content/full/298/5601/2133.