Global Development Challenges Sponsors

The need to strengthen public health at home and abroad is bolstering research and development of new medicines and vaccines to prevent and treat infectious diseases. Donor nations and organizations have increased funding over the last decade to strengthen health care systems in less developed countries and to improve treatments for malaria, tuberculosis, and many neglected tropical diseases.

Jill Wechsler

Biopharmaceutical companies have joined public–private partnerships (PPPs) developing these therapies, attracted by the desire to expand sales globally while also improving the health of poor populations. In announcing quarterly earnings in July, GlaxoSmithKline Chief Andrew Witty highlighted the company's reduced reliance on "white pill/western market" sales. Pfizer has established an emerging markets business unit to build sales in Brazil, China, India, Mexico, Russia, and Turkey, and other pharma companies are taking similar tacks.

These developments are increasing the number of clinical trials being conducted outside North America and Western Europe, raising questions about how well sponsors can monitor and ensure adherence to good clinical practices (GCPs) around the world. Many PPPs are poised to harvest the fruit of over a decade of research efforts, but may be stymied by the international financial crisis, which is squeezing resources needed to underwrite the late-phase clinical trials necessary to register new treatments.

Facilitating research

The Food and Drug Administration is encouraging development of new vaccines and drugs for global diseases by providing guidance on ways to streamline preclinical and clinical studies for third-world conditions. These initiatives may expand under Commissioner Margaret Hamburg, who has a strong background in public health and spear-headed TB control efforts when head of New York City's public health department in the 1990s.

The FDA has been particularly active in efforts to combat the resurgence in multidrug resistant (MDR) and extensively drug resistant (XDR) TB strains. An FDA advisory committee in June supported a research pathway for drugs to treat MDR TB that utilizes early endpoints of reduced bacterial count in sputum culture, followed by confirmatory trials to document low relapse rates.

This approach could accelerate the R&D process for new compounds, such as that being developed by Johnson & Johnson's Tibotec subsidiary with support from the Global Alliance for TB Drug Development (TB Alliance).

A two-day FDA workshop in July delved further into clinical trial design challenges for drug-susceptible TB. The panel weighed noninferiority study designs, combination therapy regimens, and missing data problems, as well as early study endpoints. Sequella Chief Medical Officer Gary Horwith urged consideration of Phase 0, adaptive clinical trials, and surrogate endpoints to accelerate development.

TB Alliance President Melvin Spigelman emphasized the importance of testing new combination drug regimens to combat resistance. Gail Cassell, vice president at Eli Lilly, advocated "boldness in clinical trial design," along with better postapproval adverse event monitoring.

More vaccine studies

The holy grail for global health is to discover new vaccines that can prevent lethal infections, a task that raises new challenges for PPPs and sponsors of vaccine trials. After years of preclinical testing, there are signs of progress in this area. The PATH Malaria Vaccine Initiative is launching Phase III trials on a promising malaria vaccine developed by Glaxo, and the Aeras Global TB Vaccine Foundation has several candidates in early clinical trials.

Vaccine development is strong at home, too, as new preventives for HPV, rotavirus, and shingles have hit the market. FDA approved three vaccines last year, and several important applications are in the queue. However, the agency could be overwhelmed if too many submissions coincide with its review of filings for the new pandemic H1N1 vaccine, now being tested and produced as fast as possible.

The United States expects to spend some $8 billion for nearly 200 million doses of the new vaccine from Glaxo, Novartis, Sanofi Pasteur, Astra Zeneca's MedImmune, and Australia-based CSL Ltd., and European and other nations have placed comparable orders.

To meet this huge demand, FDA is allowing licensed manufacturers to file manufacturing supplements for a strain change, similar to what companies do each year for new seasonal flu vaccines, as explained at a July meeting of FDA's Vaccines and Related Biological Products Advisory Committee. Because the H1N1 vaccine is a slightly different single strain vaccine, though, companies have to conduct clinical trials to ensure safety and to determine the necessary dose strength for effectiveness. There also are questions about the need for one or two vaccine doses and whether to administer the swine flu vaccine 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, as well as the need to mix the new vaccine with an adjuvant to achieve desired immune response. If adjuvant is needed, FDA would then utilize its emergency use authority to expedite access to what would be a new vaccine.

Overseas challenges

This interest in global disease is expanding the volume of clinical research conducted outside the United States, generating concerns about adherence to GCPs and appropriate oversight in less regulated regions.

Wyeth had to shut down a clinical trial in India last year when an infant died after receiving a new vaccine through the study. Pfizer recently anted up $75 million to settle litigation related to 11 deaths linked to clinical trials in Nigeria in 1996 to test whether its antibiotic Trovan was effective against meningitis. A key issue was that Pfizer relied on oral consent from parents instead of obtaining written informed consent, a situation that raised questions about how well the sponsor explained study risks.

An article in the New England Journal of Medicine last February highlighted a number of ethical issues related to the globalization of clinical research (Feb. 19, 2009, 360, 816-823). Research taking place outside the United States is increasing, according to this review of studies listed on the www.ClinicalTrials.gov Web site, many occurring in Eastern Europe, Russia, and developing nations. The authors from Duke University questioned whether this trend compromised GCPs by opening the door to inadequate institutional review board oversight and lax monitoring. An important issue is whether patients participating in studies in third-world countries end up testing drugs that will be too expensive for local use, as opposed to treatments for prevalent infectious diseases.

These and other critics claim that industry conducts clinical trials overseas to cut costs and avoid strict regulatory oversight. Pharma companies and CROs respond that added outlays for management, data collection, and oversight offset much of the potential savings. But sponsors acknowledge that they are able to recruit patients more efficiently and conduct trials more quickly in other nations, which translates into valuable savings.

More clinical trials are being conducted overseas because it's increasingly difficult to enroll Americans in clinical trials, according to a July report from the Association of Clinical Research Organizations (ACRO). The study claims that clinical trials conducted in developing countries are as safe and ethical as those taking place in the West, and that taking research overseas brings new drugs to market more quickly and at lower cost.

The analysis notes that pharma companies actually conduct relatively few clinical trials in Africa or poor Asian nations, but that such undertakings can be highly beneficial to those regions. Clinical research offers access to better health care, improvements in local health system infrastructure, and training for investigators—not to mention the prospect of contributing to the discovery of important new medicines. International health authorities often press sponsors to test drugs and vaccines for infectious diseases in the target region to ensure that the therapy is effective against local disease strains.

ACRO would like FDA to conduct more inspections of overseas clinical research sites while trials are going on to ensure adherence to high safety and ethical standards. FDA already is increasing oversight of drug research and production "beyond its borders" with new offices in China, India, and other regions designed to facilitate monitoring of important clinical trials. The European Medicines Agency also has announced plans to increase GCP inspections of clinical trials in Africa, Asia, Latin America, and Russia.

Those efforts may expand under a more formal FDA-EMEA collaboration on GCP site inspections. The two authorities announced last month that they will conduct joint inspections and share findings regarding pivotal trials on drugs and biologics intended to support market applications in both regions. The regulators are looking for sponsors conducting such studies who are likely to benefit from more efficient joint oversight.

Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com