Another significant barrier to conducting clinical trials in the United States is competition from sites in other countries; indeed, the clinical research footprint is shifting overseas. The number of active, FDA-regulated investigators based outside the United States has grown by 15 percent each year since 2002, while the number of U.S.-based investigators has fallen by 5.5 percent annually (Getz K. A., 2007). A recent study of industry-sponsored Phase 3 clinical trials for the 20 largest U.S.-based pharmaceutical companies found that approximately one third of the trials are being conducted entirely outside the United States and that over half of all study sites are located in other countries. The number of non-U.S. countries being used as trial sites more than doubled between 1995 and 2005, while the proportion of trials conducted in the United States and Western Europe decreased (Glickman, et al., 2009).
There are a number of factors driving this geographical shift. First, significant cost savings are possible, particularly in developing countries (Bailey, Cruickshank, & Sharma; Glickman, et al., 2009). One pharmaceutical company representative reported that a top-tier academic medical center in India charges around $1,500 to $2,000 per case report, which is less than a tenth of the cost at a second-tier center in the United States (Glickman, et al., 2009). Human labor accounts for much of the cost of clinical research, and salaries for physicians, nurses, and study coordinators in developing countries are lower than they are in the United States and other high-income countries (World Health Organization, 2006). Payment to clinical trial sites is also lower elsewhere than it is in the United States, and U.S.- based clinical trials are not as cost-effective (in terms of cost per patient visit) as trials based in other countries (English, Lebovitz, & Giffin, 2010).
Second, shorter timelines, due largely to faster recruitment, are also possible outside the United States. Countries such as China, India, and Russia have large potential patient pools that can help accelerate the otherwise time-consuming recruitment process (Bailey, Cruickshank, & Sharma; Glickman, et al., 2009). One industry representative said participants could be found in India in approximately half the time it takes to recruit in the West (Rai, 2005). For some diseases, such as malaria, sufficient numbers of patients can only be found in other countries (GlaxoSmithKline, 2011). Ultimately, U.S. investigators enroll only two-thirds as many patients as investigators elsewhere (English, Lebovitz, & Giffin, 2010).
Third, conducting trials in other countries allows drug sponsors to access more commercial markets for the drug they are testing. Increasingly, foreign regulatory agencies are demanding that drugs be tested on their own populations before they will allow the drug to be registered in their country; thus, sponsors conduct trials in those countries to fulfill those demands (Schmidt, 2001).
Fourth, conduct standards and intellectual property protection have improved in foreign countries, making these sites more attractive than they have been in the past. A key driver of this improvement has been the widespread adoption of the ICH Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice (ICH-GCP) guidelines (Bailey, Cruickshank, & Sharma; Glickman, et al., 2009; Schmidt, 2001; International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), 1996). The ICH-GCP guidelines establish a set of universal principles to which all clinical trials should adhere, including requirements to follow ethical standards, ensure scientific soundness, preserve the rights and safety of trial subjects, and maintain confidentiality of records, among others (Kramer, Smith, & Califf, 2012).
Fifth, the regulatory environment in wealthy countries, including the United States, has become increasingly burdensome to drug sponsors (Glickman, et al., 2009). More detailed discussion of regulatory barriers can be found in Section 4.5.
Given the factors listed above, it is easy to understand why drug sponsors might decide to shift part or all of their clinical research operations overseas. However, in doing so, they create a new set of potential scientific, ethical, and practical problems. From the standpoint of U.S. clinical care, there is concern that results from trials conducted in other countries may not be generalizable to the U.S. population. Indicators of standards of care for a particular site or country often are not reported, so it is difficult to tell whether different places are really comparable (Glickman, et al., 2009). Furthermore, some diseases may go untreated or undertreated in developing countries, making it easier to find trial participants whose outcomes will not be complicated by prior medications. Such patient populations are not representative of the types of people who would be using the drug in higher income countries, more specifically, patients for whom previous treatments have failed (Glickman, et al., 2009). Finally, geographically dispersed populations may have genetic differences that cause them to respond differently to drugs. Thus, a U.S. patient might have a different reaction to a drug compared to a patient from Asia or Eastern Europe, for example. These genetic differences are often not accounted for in study design or reporting of results (Glickman, et al., 2009).
Aside from the scientific concerns, conducting trials in other countries can also be ethically challenging. This is especially true in developing countries, where research involving human subjects is complicated by factors such as lack of education, poverty, and low health care standards. Participants may not fully understand the trial process or their role, or they may feel compelled to participate by the promise of financial compensation or access to health care that might otherwise be outside their reach (Glickman, et al., 2009). Beyond the generalizability concerns discussed above, it is also ethically questionable to conduct trials in places that are not intended to be major markets for the drug being studied (Glickman, et al., 2009). Lastly, there is a lack of transparency with regard to clinical research in many developing countries. The International Committee of Medical Journal Editors created the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication” (International Committee of Medical Journal Editors, 2010), but investigators in developing countries tend to be less well-versed in these guidelines and less experienced, which can be a barrier to obtaining trial data and publishing results (Glickman, et al., 2009).
Practically speaking, conducting trials at multiple sites across different countries magnifies the barriers associated with multicenter trials, including lack of harmonization among regulations across multiple jurisdictions and difficulties in enforcing consistency in protocol across multiple trial sites. Further discussion of these types of barriers can be found in the previous sections.