Given the high cost of moving a promising drug candidate through years of clinical trials, it’s no wonder that more and more drug and device manufacturers have begun conducting at least some of their clinical trials in foreign countries. In 2008, 80% of marketing applications for drugs and biologics approved by the U.S. Food and Drug Administration (FDA) included at least some data from foreign clinical trials, and it is estimated that 40% to 65% of all trials are conducted outside the United States, according to a recent report.1
The U.S. Office of the Inspector General (OIG) has raised concerns about the increasing prevalence of foreign clinical trials, particularly when they are conducted in developing countries with minimal regulatory supervision. Although these trials provide lower costs and faster completion times, some worry about the ability of local institutional review boards to adequately monitor data integrity and protect the privacy and welfare of study participants. Others question the degree to which results from developing nations can be applied to the U.S. population.
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guideline, entitled “Ethnic Factors in the Acceptability of Foreign Clinical Data”, notes that while some medications have comparable characteristics across ethnicities, in other cases ethnic differences may affect safety, efficacy, and metabolism.
Intrinsic ethnic factors include genetic or physiological factors that are inherent to the drug, its class, or the disease under study. These include genetic polymorphism of drug metabolism, racial differences in disease manifestation (such as multiple sclerosis, irritable bowel syndrome, fibromyalgia, etc.), and genetic differences in receptor sensitivity. Extrinsic ethnic factors such as climate, socioeconomic and educational status, lifestyle, prevailing medical factors (diagnostic criteria or social acceptance of the disease), and therapeutic approaches (such as non-medicinal therapies) may also contribute to differences in trial results.
The increasing use of foreign trial data has led to a better understanding of requirements for extrapolating data from region to region, while expanding medical knowledge has allowed an improved characterization of the influence of ethnic factors on a given drug.
Which drug candidates can be effectively pursued using foreign trial data is partly a matter of choosing compounds that are less likely to be sensitive to ethnic factors (Table 1).
Compounds that are more likely to be sensitive to ethnic factors are more likely to be a regulatory red flag (Table 2).
If the FDA determines that a compound is not ethnically sensitive, bridging studies may not be required or pharmacologic studies (PK/PD) may suffice. If ethnicity is a factor, controlled clinical trials may be needed to confirm the findings in an ethnically-relevant group of patients.
Ethnicity, however, is not the only concern for sponsors considering global trials and incorporating foreign trial data. The huge rise in the number of foreign trials—India, for example, had 50 trials for U.S. Investigational New Drug (IND) applications in 2002 and is expected to have over 1,850 in 2010—has also led to a large rise in the number of complaints regarding the conduct of trials.2
According to the FDA’s Center for Drug Evaluation and Research, complaints pertaining to foreign research sites include informed consent issues, failure to follow protocol, inadequate records, unqualified personnel, failure to get review board approval, drug accountability, and recruitment practices, among many others.
The OIG report indicated that the FDA had conducted inspections on only 0.7% of foreign trial sites, but of those, some countries stand out for all the wrong reasons. In India, 40% of inspections resulted in an FDA 483 warning; in Russia, 60% received a 483; in China, of eight inspections, seven received a 483. On the other hand, Brazil had a 483 issued on just 10% of trials, and there is significant cooperation and compliance in Western Europe where the vast majority of foreign data is collected.
What’s important in conducting trials, where most or all of the data will come from outside the United States, is to choose a research partner that is sensitive to the issues surrounding globalization and is capable of managing a study that takes this into account. It is especially important to look for a partner with global experience, a site-centric approach to study management, and the flexibility to work under multiple types of contractual and operational requirements. Technology systems and worldwide communications capabilities are also critical when dealing with probable requirements for a standardized electronic format for data collection.
|Table 2. Compounds more likely to be sensitive to ethnic factors|
|High inter-subject variation in bioavailability|
|Low bioavailability, thus more susceptible to dietary absorption effects|
|A steep pharmacodynamic curve for both efficacy and safety|
|A narrow therapeutic dose range|
|Highly metabolized, especially through a single pathway|
|Metabolism by enzymes known to show genetic polymorphism|
|High likelihood of use in a setting of multiple co-medications|
Because more than 86% of U.S. principal investigators fail to meet their enrollment needs, the globalization of clinical trials was inevitable. It has followed the same pattern as the earlier globalization of manufacturing, and improvements in worldwide connectivity have only accelerated the process.
The pharmaceutical industry needs to accept this new reality and take steps to integrate it into more effective drug development research. For example, characterizing the product early in the program as ethnically sensitive or not, planning ahead to mitigate potential ethnic differences, and incorporating potential bridging data in the program will be essential for success. Choosing a partner, countries, and sites appropriate to specific trials is crucial. Working closely with the FDA throughout the trial to ensure the acceptability of data is only logical, and seeking ways to expand FDA oversight of foreign clinical trials is something that will benefit the industry and, ultimately, worldwide health.
The world is diverse and incorporating diversity in clinical trials allows drug developers to further harmonize regulatory requirements between countries, aid in the transfer of technology, develop global treatment guidelines, and facilitate the development of best practices.
Global trial data is undoubtedly changing the way things work. Only by accepting and embracing this fact, can the industry move forward.
1. Daniel Levinson. “Challenges To FDA’s Ability To Monitor And Inspect Foreign Clinical Trials.” Department of Health and Human Services, Office of Inspector General (June 2010): 22 Oct. 2010. https://oig.hhs.gov/oei/reports/oei-01-08-00510.pdf
2. ClinicalTrials.gov. Available at www.ClinicalTrials.gov. Accessed On January 4, 2011.
Ken Phelps is an expert in global drug development, specifically through the 505(b)(2) regulatory approval pathway. He has lead in the successful FDA approval of numerous compounds.
Vijai Kumar has 40 year experience as a clinician, investigator, pharmaceutical physician, and consultant in the pharmaceutical industry. He provides trial management services in India and pharmaceutical consulting services globally.
This article was published in Drug Discovery & Development magazine, January, 2011, Vol. 14, No. 1, pp. 30-32.
Filed Under: Drug Discovery