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Clinical Trials Go Global

Overseas locations offer huge benefits—but also pose complex challenges.

BUSINESS PLANNING & TECHNOLOGY DEVELOPMENT

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The practice of medicine is constantly evolving, and medical practitioners and researchers around the world continue to develop and evaluate new ways to treat human illness. At any given time, thousands of pharmaceuticals and medical devices are being evaluated for potential benefits to patients. In fact, the registry of federally and privately supported clinical trials maintained by the National Institutes of Health, www.clinicaltrials.gov, currently lists approximately 50,000 clinical trials taking place in more than 150 countries around the world.

For pharmaceutical and medical device companies in the United States, clinical trials are increasingly taking place overseas as a prelude to the extensive FDA approval process at home. Ten years ago, 86% of all clinical trials were conducted in the United States. Today, only 57% are conducted in the United States, with almost a third of the trials being conducted in countries outside of the United States and Europe.1

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As with many business ventures in today's globalized economy, pharmaceutical and medical device companies see lower costs as a major benefit of taking clinical trials overseas. Manufacturers that take their trials beyond U.S. borders also stand to reap other benefits associated with efficiency and patient access.

At the same time, there are potential drawbacks to conducting clinical trials overseas that must be weighed against the benefits. Among such challenges are the myriad regulations that may trip up unwary companies with unfamiliar requirements, both medical and nonmedical. Failing to pay appropriate attention to both types of challenges may result in delays or even the derailment of an overseas clinical trial.

Taking Trials on the Road

The popular perception among the public is that every clinical trial is focused on validating the next new wonder drug or device. However, at any given moment, thousands of trials being conducted around the world are focused on testing slight differences in treatment protocols, experimenting with new ways to use existing devices, and measuring the impact of different drug combinations.

Over the past decade, the number of medical companies taking trials overseas nearly doubled, increasing from 956 in 1997 to nearly 1800 in 2006.1 Medical device clinical trials being conducted by U.S. companies vary greatly in scope, encompassing both large studies in multiple regions of the world and smaller operations in one or two countries. For example, current studies of medical devices listed at www.clinicaltrials.gov include the following.

  • A postmarket evaluation by Abbott Vascular (Redwood City, CA) of the Xience V everolimus-eluting coronary stent system in up to 150 study centers. Locations include countries in Europe (Austria, Belgium, France, the Czech Republic, Germany, Greece, Italy, Ireland, The Netherlands, Poland, Portugal, Spain, Sweden, Switzerland, and the United Kingdom), as well as Canada, China, India, Israel, Jordan, Kuwait, Malaysia, New Zealand, the Russian Federation, Saudi Arabia, Singapore, South Africa, and Thailand.
  • A study by Light Sciences Oncology (Bellevue, WA) of the use of interstitial light-emitting diodes to treat hepatocellular carcinoma compared with standard-of-care therapies. Locations include Hong Kong, India, South Korea, Malaysia, the Philippines, Singapore, and Thailand.
  • An analysis by Serica Technologies Inc. (Medford, MA) of the benefits of the SeriACL device for anterior cruciate ligament reconstruction compared with ligament autografts. Investigations are under way in Germany and Norway.
  • A registry in Belgium sponsored by Cordis Corp. (Miami Lakes, FL), a Johnson & Johnson company, to demonstrate the safety of the company's Enterprise vascular reconstruction device and delivery system.

Although Europe has long been a setting for U.S. clinical trials, China and India are the currently recognized hot spots. Large drug companies spent $2.2 billion in China and India on research and development during 2006—double the amount spent during the prior year.1 And China recently edged out India, which had been leading multinational clinical trials. In November 2007, China had 510 studies under way or completed for the year, compared with 471 in India.2

Central and Eastern Europe is another growth area for clinical trials. While clinical trials in Asia increased 29% annually between 2001 and 2006, Central and Eastern Europe increased 16% annually during the same period, outpacing Latin America's 13% annual growth.3

The Pros and Cons

Companies can realize a number of advantages by using overseas locations for clinical trials, with perhaps the most notable benefit being lower costs. A report by consultant A. T. Kearney estimated that using China as a clinical trial locale may cut costs in half compared with the United States.4 Consultant Frost & Sullivan puts the cost even lower, estimating clinical trials may cost as little as 15% of the tab in the United States or Europe.5 For example, a 2007 article in BusinessWeek cited a Chinese clinical trial of an artificial liver as an example of such cost savings.5 The trial's sponsor, Vital Therapies Inc. (San Diego), reported a per-patient cost of $15,000 in China compared with $50,000 in the United States (see Table I).

Cost in China ($)
Cost in United States ($)
One-day stay in hospital
40–100
750–1000
Magnetic resonance imaging
150–300
1500–3500
Yearly salary for senior oncologist
40,000
225,000
Typical cost to develop new drug
120 million
1 billion
Table I. Comparative costs of clinical trials in China and the United States.5

Benefits of overseas clinical trials extend beyond the financial realm as well. In particular, China and India offer large populations with a wide variety of diseases when compared with populations in the United States, where clinical trials often compete for a limited number of the same—and sometimes reluctant—patients. In countries with poor populations that lack access to routine, affordable medical care, clinical trials represent an opportunity for improved health. Thus, enrollment proceeds quickly. In addition, some countries have streamlined processes so that bureaucratic barriers are fewer or less time-consuming, contributing to a faster time-to-market cycle for new technologies.

Conducting clinical trials in other countries can also facilitate product approval in those countries, thereby generating sales more quickly. In fact, approval of a drug or device in a foreign country can spur sales and generate revenue that can then be used to fund U.S. clinical trials.

In clinical studies involving seasonal diseases, international sites can help shorten the time needed to obtain results by spanning climate zones and enabling year-round testing. International sites can also give companies access to uncontaminated populations in which patients have not been given other treatments that might interfere with testing. Likewise, certain conditions may be more widespread in international locations than they are in the United States. China, for example, is reported to have 160 million cases of hepatitis and 44% of the world's cancer cases.5

Despite the long list of potential benefits, there is an equally lengthy list of potential drawbacks to conducting overseas clinical studies. Some include questions related to the medical usefulness of studies. For example, it may not be possible to generalize results if the clinical study population base is different from that in the United States. In addition, cultural, environmental, or other factors may potentially skew a study's results. Likewise, certain countries may lack adequate clinical facilities and medical expertise to conduct the trial properly and with accuracy. They may also lack an adequate population base that presents the disease or condition being studied, thereby making it difficult or impossible to recruit the appropriate number of volunteers.

Furthermore, the standards imposed by certain foreign settings may not be rigorous enough to pass FDA scrutiny, eventually requiring the trial work to be repeated.

(click to enlarge)
Figure 1. Geographical comparison of time required to secure approval to begin a clinical trial. Source: Wyeth Research and Development.

Other potential pitfalls include various nonmedical considerations. For example, some foreign destinations have lower levels of protection for intellectual property and data confidentiality than those found in the United States. (To address such concerns, both China and India recently revised their laws to provide more protection for companies conducting clinical studies on their soil.) Other potential pitfalls include unstable political environments, ever changing regulatory processes, language barriers, and lengthy review times (see Figure 1). There are also ethical concerns about the possible exploitation of low-income, less-educated, unsophisticated populations and the potential lack of rigor regarding informed consent.

However, perhaps the biggest stumbling block to overseas clinical trials is the wide variety of regulations and requirements that medical companies must take into consideration when they take their trials on the road.

Daunting Complexity despite Standardization

To reduce inconsistency among standards for clinical trials, in 1964 the World Medical Association adopted what is known as the Declaration of Helsinki.6 FDA incorporated the document into its clinical trial standards in 1975. The World Medical Association updated its standards in 1975, 1989, and 2000. Currently, FDA is considering the 2000 revisions but has not yet adopted them.

In addition, the European Union issued a clinical trials directive in 2001 with the goal of reducing red tape, speeding up research, harmonizing procedures across Europe, enforcing patient protection measures, and increasing the transparency of the clinical research process. However, the goal of uniform standards is somewhat undercut by the fact that clinical trials are still subject to the legal codes of each member state of the European Union.

Despite efforts toward clinical trial standardization, much variation remains. Thus, conducting clinical trials overseas requires special attention to pertinent details in each host country. Some areas requiring attention involve medical issues, such as arranging for appropriate informed consent, providing investigators with standardized protocols, and arranging for on-site monitoring. None of these factors is likely to be overlooked when an experienced company is in the early stages of planning its clinical trial.

Other less-obvious issues, however, may catch companies by surprise. Insurance is one such area. Each country has its own standardized protocols and requirements for how insurance is handled and for covering the liability involved in running a clinical trial. International requirements include the following.

  • Germany has two laws addressing clinical trials for medical products: one for devices and one for drugs. The laws stipulate the type and amount of insurance a sponsor organization must carry—?500,000 per patient and ?5 million per trial for trials involving medical devices—and require the coverage be provided by a German insurer.
  • Switzerland requires coverage by local insurers. Most ethics committees within the country require a minimum of 1 million Swiss francs per patient and 10 million Swiss francs per trial. The local center where the trial is conducted must be included as a legal entity on the policy.
  • Australia has no compulsory insurance law. However, most hospitals and other sites where trials are conducted may require that coverage be placed through an Australian insurer, with coverage of $10 million Australian.

As these examples demonstrate, even countries with consistent, high standards for conducting clinical trials may differ greatly in their rules governing insurance coverage and other nonmedical issues. Therefore, when dealing with insurance and other considerations, it is critical that companies undertaking overseas clinical trials get started early with their planning. Arranging for insurance through foreign carriers is not always a speedy process, and failure to obtain the right kind of coverage may delay a trial or prohibit a trial from commencing.

In addition, insurance for overseas clinical trials must go beyond the entity conducting the trial. Coverage must be considered for employees who travel to foreign countries to monitor the site, as well as for the expensive equipment that might be shipped overseas as part of the trial or for local offices that are maintained while the trial is being conducted.

Conclusion

The advantages of going overseas as part of the clinical trial process outweigh the challenges for many companies; the rapid growth in globalized trials is testament to the many benefits. However, the complexity of meeting a variety of local requirements while still holding trials to the rigor required to pass U.S. regulatory scrutiny means that medical companies must plan early and thoroughly. This is especially true for nonmedical considerations that can easily be overlooked in the rush to secure sites and get a trial started. The end result of proper advance planning is not only good medicine, but also good business.


References

1. G Lopes, “Drug Makers Look East for Testing,” The Washington Times (December 8,, 2007): A01; available from Internet: www.washingtontimes.com/apps/pbcs.dll/article?AID=/20071208/BUSINESS/112080024/1001

2. “India Industry: Slipping to Second Place for Clinical Trials,” The Economist Intelligence Unit: Country ViewsWire [subscription data service] (5 November 2007).

3. K Getz, “Global Clinical Trials Activity in the Details,” Applied Clinical Trials, vol. 16, no. 9 (2007): 42; available from Internet: www.pharmainfo.net/global-clinical-trials-activity-details.

4. W Bailey, C Cruickshank, N Sharma, “Make Your Move: Taking Clinical Trials to the Best Location,” Executive Agenda (Chicago: AT Kearney, 2006); available from Internet: www.atkearney.com/main.taf?p=5,1,1,116,3,1.

5. “The Rush to Test Drugs in China,” Business Week vol. 4036, (2007): 60; available from Internet: www.businessweek.com/magazine/content/07_22/b4036076.htm.

6. Ethical Principles for Medical Research Involving Human Subjects (Ferney-Voltaire, France: World Medical Association, updated 2004); available from Internet: www.wma.net/e/policy/b3.htm.

Michael Thoma is assistant vice president for global technology underwriting at Travelers (St. Paul, MN).

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