As drug discovery and development capabilities continue to expand globally, pharmaceutical companies are increasingly interested in understanding the most efficient way to bring drugs to the US market based on a global clinical development strategy. This trend is not limited to established multi-national corporations, as an increasing number of emerging iopharmaceutical companies are seeking a global presence to better address unmet medical needs and to maximize their commercial opportunity.
From a US regulatory perspective, the typical rule of thumb cited by experts is that “at least 20% of the supporting clinical data should be from patients in the US.” To accommodate this assumption, clinical trial strategy must include the US as a key and potentially rate limited country, which can have significant implications in terms of higher trial costs, longer study timelines, delays for achieving approval, and ultimately impacts the probability of success of the drug development program.
However, the conventional wisdom of the “20% rule” is in contrast to stated US Food and Drug Administration (FDA) regulations related to foreign clinical data.
For example, since 2008, 21 CFR Part 312.120 has permitted FDA acceptance of foreign clinical studies not conducted under an investigational new drug application (IND) as support for an IND or a marketing application, provided that these studies are conducted under Good Clinical Practices (GCP). Moreover, under 21 CFR 314.106, FDA may grant marketing approval based solely on high quality foreign clinical data.
The question that therefore faces pharmaceutical companies seeking regulatory approval for a drug in the US is: “what proportion of my study population needs to be from the US?” According to a review done by the Department of Health and Human Services, Office of the Inspector General, in fiscal year 2008, the majority of subjects and sites in trials supporting NDA and BLA approvals that year were located outside the United States (Office of Inspector General, 2010). This paper takes a closer look at FDA’s more recent track record with respect to approving drugs based on studies that were conducted with primarily non-US patient populations and examines the information FDA has accepted to demonstrate that foreign clinical data are applicable to the US patient population.
FDA’S TRACK RECORD OF ACCEPTING NON-US CLINICAL DATA TO SUPPORT MARKETING APPROVALMETHODOLOGY
A comprehensive list of drugs and biological products approved by FDA between 2013 and 2017 was collected from the FDA website. The analysis included only new drug and biological product approvals, and not reformulations or 505(b)(2) products. For each new approval, we reviewed the statistical review memorandum published as part of the approval documentation.
Through this review process, we developed a dataset by recording key elements of the study design including: number of pivotal trials submitted for review, total number of participants completing each pivotal trial, and the geographic location of each trial participant. Lastly, internal IQVIA experts reviewed the database and coded each approval into a relevant therapeutic area grouping. Through this analysis, of the 181 new drug approvals from 2013 – 2017, the percent of all participants in pivotal trials from the United States was calculated for 176 new drugs and biological products. Five approvals were excluded from analysis given lack of reporting on specific geographic mix of trial participants.RESULTS AND ANALYSIS
For the five-year period of 2013-2017, the 176 pivotal clinical studies that supported approval by FDA, had on average, 41% of study participants from the US. While this is significantly higher than the hypothesized 20% rule-of-thumb threshold, in each year there was significant variation from this mean – in every year from 2013 to 2017, some products were approved based on pivotal studies with 100% of participants from the US and others were approved based on studies with less than 10% of participants from the US.