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GLOBAL APPROACHES to DRUG DEVELOPMENT: WHEN EX-US CLINICAL DATA CAN SUPPORT US DRUG APPROVALS Understand Factors That Drive Positive US FDA Review

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GLOBAL APPROACHES to DRUG DEVELOPMENT: WHEN EX-US CLINICAL DATA CAN SUPPORT US DRUG APPROVALS Understand Factors That Drive Positive US FDA Review White Paper GLOBAL APPROACHES TO DRUG DEVELOPMENT: WHEN EX-US CLINICAL DATA CAN SUPPORT US DRUG APPROVALS Understand factors that drive positive US FDA review ANN MEEKER O’CONNELL, MS, Vice President and Global Head, Quality Assurance, IQVIA ANTHONY F. ABRUZZINI, PhD, MSc, Vice President, Strategic Drug Development, IQVIA CAITILIN HAMILL, PhD, MBA, Senior Director, Regulatory Affairs, Cell and Gene Therapy Center, IQVIA JESSICA ZAKAR, Associate Principal, Consulting Services, IQVIA TABLE OF CONTENTS Executive Summary 3 FDA’s Track Record of Accepting non-US Clinical Data to Support Marketing Approval 4 I) Standards for Study Quality, Data Quality and Ethics 7 II) Establishing that Foreign Data can be Extrapolated to the US 9 Two Drug Approvals Using a Low Percentage of US Data 10 Radicava (Edaravone) to Treat Patients with Amyotrophic Lateral Sclerosis (ALS) 10 Entresto (Sacubitril/Valsartan) for Heart Failure 14 Conclusion 15 References 16 About the Authors 17 EXECUTIVE SUMMARY 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 biopharmaceutical 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 For example, since 2008, 21 CFR Part 312.120 has of thumb cited by experts is that “at least 20% of the permitted FDA acceptance of foreign clinical studies supporting clinical data should be from patients in the not conducted under an investigational new drug US.” To accommodate this assumption, clinical trial application (IND) as support for an IND or a marketing strategy must include the US as a key and potentially application, provided that these studies are conducted rate limited country, which can have significant under Good Clinical Practices (GCP). Moreover, under implications in terms of higher trial costs, longer 21 CFR 314.106, FDA may grant marketing approval study timelines, delays for achieving approval, and based solely on high quality foreign clinical data. ultimately impacts the probability of success of the drug The question that therefore faces pharmaceutical development program. companies seeking regulatory approval for a drug in the However, the conventional wisdom of the “20% rule” is US is: “what proportion of my study population needs in contrast to stated US Food and Drug Administration to be from the US?” According to a review done by the (FDA) regulations related to foreign clinical data. 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 “An application based solely on foreign clinical data approvals that year were located outside the United meeting U.S. criteria for marketing approval may be States (Office of Inspector General, 2010). This paper approved if: takes a closer look at FDA’s more recent track record (1) the foreign data are applicable to the with respect to approving drugs based on studies U.S. population and U.S. medical practice; that were conducted with primarily non-US patient (2) the studies have been performed by clinical populations and examines the information FDA has investigators of recognized competence; and accepted to demonstrate that foreign clinical data are (3) the data may be considered valid without the need applicable to the US patient population. for an on-site inspection by FDA or, if FDA considers such an inspection to be necessary, FDA is able to validate the data through an on-site inspection or other appropriate means.” 21 CFR 314.106 iqvia.com | 3 FDA’S TRACK RECORD OF 2013 to 2017, some products were approved based on pivotal studies with 100% of participants from the ACCEPTING NON-US CLINICAL DATA US and others were approved based on studies with TO SUPPORT MARKETING APPROVAL less than 10% of participants from the US. Figure 1 below summarizes the distribution of patients for each METHODOLOGY approved drug within the timeframe. 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 Figure 1: US Drug Approvals 2013-2017; not reformulations or 505(b)(2) products. For each % of Pivotal Clinical Trial Participants from the US new approval, we reviewed the statistical review 100% memorandum published as part of the approval 90% documentation. 80% om the US 70% 60% Through this review process, we developed a dataset by 50% recording key elements of the study design including: 40% 30% total patients fr number of pivotal trials submitted for review, total 20% % of 10% number of participants completing each pivotal trial, 0% 2017 2016 2015 2014 2013 and the geographic location of each trial participant. Lastly, internal IQVIA experts reviewed the database Source: IQVIA and coded each approval into a relevant therapeutic Of the 176 new drug and biological product approvals area grouping. Through this analysis, of the 181 new included in our analysis, 30 were approved based on drug approvals from 2013 – 2017, the percent of all pivotal clinical trials with less than 10% of patients from participants in pivotal trials from the United States was the US and 55 were approved based on trials with calculated for 176 new drugs and biological products. less than 20% of patients from the US. This represents Five approvals were excluded from analysis given 17% and 31% of all approvals during this time period lack of reporting on specific geographic mix of trial respectively. Each year, there was at least one approval participants. based on pivotal clinical trial data with less than 10% of patients from the US, with the highest number seen in RESULTS AND ANALYSIS 2013 (9 out of 27 approvals or 33%). This demonstrates For the five-year period of 2013-2017, the 176 pivotal that new drugs and biological products are routinely clinical studies that supported approval by FDA, had and consistently approved by the US FDA based on on average, 41% of study participants from the US. clinical trials that were conducted primarily at sites While this is significantly higher than the hypothesized outside of the US. 20% rule-of-thumb threshold, in each year there was significant variation from this mean – in every year from 4 | Global Approaches to Drug Development: When Ex-US Clinical Data Can Support US Drug Approvals 2013 2014 2015 2016 2017 Total 2013 to 2017 Total number of drug and biological product approvals included in the analysis 27 40 45 21 43 176 Number of drugs approved based on pivotal clinical trial data with <10% US patients 9 6 7 1 7 30 Percent of approvals based on pivotal clinical trial data with <10% US patients 33% 15% 16% 5% 16% 17% Number of drugs approved based on pivotal clinical trial data with <20% US patients 11 11 17 4 12 55 Percent of approvals based on pivotal clinical trial data with <20% US patients 41% 28% 38% 19% 28% 31% While each year the average percentage of pivotal in otolaryngology were based on pivotal clinical trials clinical trial participants from the US across all approvals in which 100% of participants were from the US, while is consistent at around 40%, there is significant the 14 approvals in cardiology were based on pivotal variance across therapeutic areas. As highlighted in clinical trials in which ~20% of participants were from Figure 2, the two approvals in ophthalmology and one the US on average. Figure 2: Average Percent of Participants from US by Therapeutic Area (Approvals 2013-2017) # approvals Ophthalmology 100% 2 Otolaryngology 100% 1 Genetic Disease 72% 4 Gastroenterology 71% 8 Nephrology 62% 2 Dermatology 59% 8 Musculoskeletal 57% 5 Womens Health 53% 6 Hepatology 51% 9 Hematology/Oncology 46% 8 Neurology 43% 16 Other 43% 2 Oncology 36% 42 Infections and Infectious Diseases 34% 16 Pulmonary/Respiratory 33% 9 Immunology 31% 5 Endocrinology 29% 11 Cardiology/Vascular 22% 14 Hematology 22% 5 Rheumatology 20% 3 Source: IQVIA Oncology saw the highest number of total approvals less than 20% of patients from the US. Among these 14 (42), 14 of which were based on pivotal clinical data with trials, the average percent of US patients was just 8%. iqvia.com | 5 While the initial hypothesis might have presumed that revealed that there is no correlation between the the acceptance of non-US clincial trial data would be percent of participants from the US and the overall trial limited to smaller trials evaluating treatments for rare size, as seen in Figure 3. diseases that are not prevalent in the US, further analysis Figure 3: Relationship Between Overall Trial Size and Percent of Participants from the US (Approvals 2013-2017) Total Number of Subjects* 5,000 Infectious Disease 4,500 Other 4,000 Oncology 3,500 Neurology Cardiology/Vascular 3,000 2,500 2,000 1,500 1,000 500 0 % US Subjects 0510 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 * Note: represents the total number of all subjects from all geographic regions across all pivotal trials; excluding 14 trials larger than 5,000 patients Source: FDA Novel Drug Approvals; IQVIA Analysis Further, across the 5 years examined there were 30 approvals that included less than 10% of pivotal clinical trial participants from the US. These studies included, Figure 4: Average Total Pivotal Trial Participants; all on average, 1,811 total patients across the series of approvals vs.
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