Clinical Trials Go Global

The conduct of clinical trials for U.S. Food and Drug Administration (FDA) drug approvals—whether they take place in an academic medical centers or private practices—is no longer the exclusive realm of the United States. A large percentage of trials today take place outside North America, with increasing numbers in developing countries.

The FDA says that at least 80% of approved marketing applications for drugs and biologics contain data from foreign clinical trials. A June 2010 Department of Health and Human Services (HHS) Office of the Inspector General report noted that, although Western Europe accounts for most foreign clinical trial participants and sites, Central and South America had the highest average number of participants per site.¹ Additionally, developing nations are aggressively seeking clinical trials.

Belimumab Approval Highlights Challenges of Global Trials

A recent example is the drug belimumab (Benlysta), approved by the FDA on March 10, 2011, for the treatment of systemic lupus erythematosus (SLE). According to research on the drug, at least half of which was conducted outside North America and Western Europe, benefits were lower for U.S. residents and Canadians.

The first therapy in more than 50 years to be FDA approved for SLE, belimumab is the first in a new class of drugs called B-lymphocyte stimulator-specific inhibitors. According to a briefing for the FDA Arthritis Advisory Committee, its efficacy was questioned in certain populations, including Africans and African-Americans.² Additionally, the briefing noted “an inconsistent efficacy trend across different geographical regions of the world with numerically smaller separation of efficacy measures between placebo and belimumab for patients from [the] U.S. and Canada compared to some other regions.”

The belimumab story illustrates a concern with foreign clinical trial participants: Results from populations outside of the United States, especially in developing countries, may not be generalizable to the U.S. population.

Concerns about International Studies

“In rheumatology, where we’re talking about immune-modifying types of drugs, we don’t know a lot about variation in pharmacogenomics across populations,” says Kevin Schulman, MD, MBA, director of the Center for Clinical and Genetic Economics at Duke Clinical Research Institute in Durham, N.C. “We don’t know a lot about disease severity or practice patterns. So, how do we interpret information that we get in these other environments where many of these issues are left unexplored in a clinical trial?”

Dr. Schulman was the senior author of a 2009 New England Journal of Medicine article entitled “Ethical and Scientific Implications of the Globalization of Clinical Research.”³ The article notes that “geographically distinct populations can have different genetic profiles, and these differences have been shown to be related to the safety and effectiveness of drugs and even medical devices.”

One example of how medications affect ethic groups differently is noted by John Cush, MD, director of clinical rheumatology at Baylor Research Institute in Dallas. “When you look at the use of many current drugs on the market, whether methotrexate, Arava [leflunomide], or [tumor necrosis factor] inhibitors, they are used at lower doses in Japanese and Chinese populations, as pharmacokinetics and tolerability is different in these populations.”

Another concern about outsourcing is whether the foreign site has proper regulatory oversight, even though all clinical studies are supposed to be conducted under guidelines established by the International Conference on Harmonization, which has met frequently since 1991 to develop technical requirements for safe, effective, and high-quality drug development.⁴

Interestingly, a number of foreign studies have shown higher response rates to both active and placebo treatment, notes Arthur F. Kavanaugh, MD, professor of medicine in the rheumatology, allergy, and immunology division at the University of California, San Diego. “It’s hard to know why,” he says. “There are multiple factors. When you’re analyzing data region by region, you’ll see dramatic variation in the active treatment and placebo responses in different parts of the world.” He says results could be skewed when patients suddenly have access to treatments not previously available. “There may be a huge incentive for patients to get access to a medication, for physicians to get medication for their patients, and even for physicians to get the remuneration and recognition that can come from being an investigator in clinical trials,” Dr. Kavanaugh notes.

A large percentage of trials today take place outside North America, with increasing numbers in developing countries.

The Who and Why Behind Clinical Trials

Today it is Contract Research Organizations (CROs) that have increasingly taken a larger role in preclinical through phase III studies. From about 4,900 in 2000, CRO-conducted trials numbered 8,600 in 2010, according to the Tufts Center for the Study of Drug Development in Boston. The Association of Contract Research Organizations (ACRO) notes that CRO revenue was about $20 billion in 2010, representing one-third of total pharmaceutical and biotechnology development spending.

John J. Lewis, ACRO vice president, says his organization represents the larger global companies, including nine of the top 10 and 60% of the CRO industry revenue. However, many small companies also call themselves CROs and, according to Lewis, they could easily number in the thousands globally.

“Countries have different levels of regulatory maturity, and we try to adjust for that,” Lewis says. “Our members are going with the sponsor to the FDA to present data. We’re working closer with sponsors and regulators to clearly define the lines of responsibility.”

According to numerous sources, pharmaceutical companies have outsourced trials to CROs and foreign countries largely due to economic pressures, time-consuming regulatory burdens in the United States, legal entanglements, and low or absent participation by treatment-naive American patients.

According to the ACRO, globalized trials can reduce development time by more than half.

“By gaining access to a global population of 7 billion rather than a U.S. population of 312 million, patient recruitment is vastly accelerated, leading to a cost savings in addition to drugs being made available to patients sooner,” Lewis says.

In a 2008 article in Harvard Business Review, GlaxoSmithKline CEO Jean-Pierre Garnier said that, “discovering and developing a new medicine takes at least 12 years, and the average cost is now more than $1 billion,” compared with less than $100 million almost two decades ago.⁵ “By switching 50% of its trials from high-cost places such as the United States and Western Europe to low-cost places such as India and South America, a mid-size pharmaceutical company with 60,000 patients in clinical trials could save $600 million annually.”

Ethics of International Trials

Jeremy Sugarman, MD, MPH, Harvey M. Meyerhoff Professor of Bioethics and Medicine at the Johns Hopkins Berman Institute of Bioethics in Baltimore, notes that, “having studies conducted in international locations is not necessarily a bad thing. It depends upon a variety of factors, including the quality of the site and the quality of the investigators doing the research, regardless of the location.”

Unfortunately, many of the foreign sites that got into the clinical trial business weren’t prepared, according to Dr. Schulman. “We moved into these markets very aggressively, and then the clinical research standards evolved. We’re not training physicians or regulatory people to get them up to speed before we do the research,” he says. “What we should do is share the clinical risk. If some country is not the niche market for the product, it shouldn’t have a disproportional burden of research on investigational products.”

Among the ethical considerations are disparities in education, economic and social status, and healthcare systems that may jeopardize the rights of research participants, according to a July 21, 2009 news release from ACRO.⁶

“Unfortunately, international research comes under almost constant attack, most often by those who make grand conclusions about ethics and quality based on a few anecdotes,” said Doug Peddicord, ACRO executive director, in April 2011.⁷

Still, concerns about the ethics of international clinical trials are not unfounded. Testing drugs on people in low-income countries incurs more risks than previously discovered, according to a report by the Centre for Research on Multinational Corporations in collaboration with the Latin American organization Salud y Fármacos and the Indian Center for Studies in Ethics and Rights.⁸ The report referenced “trade-offs between speed and costs of the clinical trial managed by CROs on the one hand, and the ethical quality of these trials on the other. The suggestion is that sponsors expect CROs to conduct the trial as quickly as possible, which might put pressure on the CROs to be lax on the ethics (e.g., by circumventing informed consent procedures, not reporting adverse events, etc.).”

Additionally, the report pointed to subcontracting by CROs, which “fragments clinical trial-related tasks further and squeezes budgets even more. Cost and time pressures combined with the fragmentation of clinical trials can easily lead to a lack of oversight over and comprehension of the full trial process.”

Who Is Responsible for Oversight?

If a drug is intended for the U.S. market, it must be approved by the FDA. Studies conducted under an Investigational New Drug (IND) designation are governed by FDA informed consent and Institutional Review Board requirements, while those foreign studies not conducted under an IND are governed by another rule.^9,10 The FDA has never had the resources to adequately police global and U.S. sites.

In its 2010 report, the HHS Office of Inspector General said the FDA inspected only 1.9% domestic clinical sites and 0.7% of foreign trial sites. The report noted that “logistical challenges and sponsors’ submission of clinical data in a nonstandard format also hinder FDA’s ability to monitor foreign clinical trials. FDA was also unable to account for all clinical trial information because application files were missing or the sponsors failed to provide site locations and subject enrollment in the clinical study reports.”

In the report, the HHS suggested that the FDA adopt and require standardized electronic clinical trial data and an internal database, monitor foreign clinical trials not conducted under INDs, and continue to explore ways to expand its oversight of foreign clinical trials.

At least 80% of approved marketing applications for drugs and biologics contain data from foreign clinical trials.

Oversight Is Evolving

According to Karen R. Mohoney, FDA spokesperson, inspections of clinical trials outside the United States have steadily increased, from 32 in FY 2003 to 112 in FY 2010. “We expect that trend to continue,” she says. In the past few years, the FDA has opened offices in China, India, Latin America, the Middle East, and South Africa. She says that “these offices were strategically chosen based on problems in the past and on the ability to leverage expertise and to build on past experiences. These offices were established following a special congressional appropriation in 2008.”

The FDA’s Center for Drug Evaluation and Research is currently developing a risk-based site selection computerized model to help choose sites for inspection. Additionally, there are efforts underway to assist in standardizing the way that data are collected and submitted to the FDA, Mohoney says. The FDA is conducting training activities in good clinical practice in research outside the United States and is collaborating with the European Medicine Agency to conduct joint inspections and share information on applications, inspections, and best practices.

Meanwhile, all involved entities are keeping an eye on the outsourcing of clinical trials. At a Reuter’s Health Summit held Nov. 8–11, 2010 in New York City, FDA Commissioner Margaret Hamburg said that caring for patients properly means that drug companies must do more than just enter a country, conduct a study, and leave. They need to recognize that patients have made a contribution, taken risks, and deserve to be respected and provided with broader aspects of care.

Sue Pondrom is a medical journalist based in San Diego.

References

1. Office of Inspector General, U.S. Department of Health and Human Services. Challenges to FDA’s ability to monitor and inspect foreign clinical trials (OEI-01-08-00510). June 2010. Available at oig.hhs.gov/oei/reports/oei-01-08-00510.pdf. Accessed October 10, 2011.
2. Briefing document for the Arthritis Advisory Committee meeting, for Benlysta (belimumab). November 16, 2010. Adelphi, Md.
3. Glickman SW, McHutchison JG, Peterson ED, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med. 2009;360:816-823.
4. International Conference on Harmonization. Available at www.ich.org. Accessed October 10, 2011.
5. Garnier J. Rebuilding the R&D engine in Big Pharma. Harvard Business Review. May 2008.
6. ACRO news release. Clinical research safety and ethical standards in developing world up to U.S. levels. July 21, 2009. Available at www.acrohealth.org/clinical-research-safety-and-ethical-standards-in-developing-world-up-to-u.s.-levels.html. Accessed October 10, 2011.
7. Piddicord D. Global clinical trials: Setting the record straight. ACRO News Release, April 26, 2011. Available at www.acrohealth.org/global-clinical-trials-setting-the-record-straight.html. Accessed October 10, 2011.
8. van Huijstee M, Schipper I. Putting contract research organizations on the radar. February 2011. Available at http://somo.nl/publications-en/Publication_3615/at_download/fullfile. Accessed October 10, 2011.
9. Code of Federal Regulations Title 21, Part 312, Subpart B. Investigational New Drug Application (IND).
10. Code of Federal Regulations Title 21, Part 312.120(C)(1).