Downing et al. Trials (2016) 17:199 DOI 10.1186/s13063-016-1322-4
RESEARCH
Open Access
Participation of the elderly, women, and minorities in pivotal trials supporting 2011– 2013 U.S. Food and Drug Administration approvals Nicholas S. Downing1, Nilay D. Shah2, Joseph H. Neiman3, Jenerius A. Aminawung4, Harlan M. Krumholz1,5,6 and Joseph S. Ross1,6,7*
Abstract Background: Pivotal trials, the clinical studies that inform U.S. Food and Drug Administration (FDA) approval decisions, provide the foundational evidence supporting the safety and efficacy of novel therapeutics. We determined the representation of the elderly, women, and patients from racial and ethnic minorities in pivotal trials and whether the FDA is making subgroup efficacy analyses among these subpopulations available to the public. Methods: We conducted a cross-sectional study of novel therapeutics approved by the FDA between 2011 and 2013. Using publicly available FDA documents, we collected information on the demographic characteristics of pivotal trial participants (age ≥65 years, sex [male, female], race [white, black, Asian, other], and ethnicity [Hispanic, non-Hispanic]) and determined the availability of subgroup analyses by age, sex, race, and ethnicity. Results: We identified 86 novel therapeutic that were approved by the FDA between 2011 and 2013 for 92 indications on the basis of 206 pivotal trials. The median age of pivotal trial patients was 53.1 years (interquartile range 40.6–60.6), and the mean proportion of patients ≥65 years of age was 28.9 % (95 % CI 23.5–34.4 %). Similar proportions of pivotal trial participants were male (mean 50.3 %, 95 % CI 45.3–55.2 %) and female (mean 49.7 %, 95 % CI 44.7–54.7 %). Most participants were white (mean 79.2 %, 95 % CI 75.9–82.6 %), while the mean proportion of black patients was 7.4 % (95 % CI 5.5–9.3 %), that of Asian patients was 7.4 % (95 % CI 5.2–9.7 %), and that of patients of other races was 5.9 % (95 % CI 4.4–7.5 %). Information about ethnicity was available for only 59.8 % of indications, and where such data were available, the mean proportion of Hispanic participants was 13.3 % (95 % CI 10.3–16.3 %). FDA reviewers performed and made available subgroup efficacy analyses by age, sex, and race for at least one of the pivotal trials used as the basis of approval for over 80 % of indications. Conclusions: Although women are equally represented in pivotal trials supporting recent novel therapeutic approvals by the FDA, elderly patients and those from racial and ethnic minorities are underrepresented. FDA reviewers generally perform subgroup efficacy analyses by age, sex, and race and make these subgroup analyses available to the public.
* Correspondence: [email protected] 1 Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, CT, USA 6 Department of Health Policy and Management, Yale University School of Public Health, New Haven, CT, USA 7 Section of General Internal Medicine and the Robert Wood Johnson Foundation Clinical Scholars Program, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA Full list of author information is available at the end of the article © 2016 Downing et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Downing et al. Trials (2016) 17:199
Background Clinical trials provide the foundational evidence that supports U.S. Food and Drug Administration (FDA) approval and informs physicians and patients as they make decisions about the use of new therapies. For this evidence to inform both regulators and clinical practice, it is critical that the patients participating in these trials, wherever they are conducted, reflect the population of patients expected to use the novel therapeutic agent. This is particularly important for pivotal clinical trials, the late-stage clinical trials that are intended to demonstrate the safety and efficacy of novel therapeutics and upon which the FDA bases its approval decisions [1]. However, several groups of individuals, including the elderly, women, and persons from racial and ethnic minority groups, have historically been underrepresented in clinical research, limiting the ability of many studies to inform decisions about their care [2–8]. Over the years, the FDA has taken several measures aimed at improving and ensuring the representativeness of patients participating in pivotal clinical trials. First, in 1998, the FDA issued the “demographic rule,” requiring drug makers to report the age, sex, and race of clinical trial participants in their annual reports to the agency [9]. While the demographic rule ensured that this information was available to the FDA, it did not mandate its availability to the public. However, the 2012 FDA Safety and Innovation Act (FDASIA) urged the FDA to address this issue, and, in August 2013, the agency released a report describing the demographic characteristics of participants in trials of drugs and devices approved in 2011, as well as the availability of subgroup analyses for key age, sex, and race subgroups [10]. More recently, the FDA published an expanded investigation of the representativeness of clinical trials supporting drugs approved between 2010 and 2012 [11]. In this article, we describe the results of our research to characterize the demographic characteristics of patients participating in pivotal clinical trials for all novel therapeutics approved by the FDA between 2011 and 2013 and to determine the availability of subgroup efficacy analyses using publicly available data sources. Our research was similarly focused on participation in these trials by members of historically underrepresented populations: the elderly (defined as patients aged 65 years or older), women, persons of nonwhite race, and Hispanics. Although our study was initiated before the publication of the FDA’s initial report prompted by the FDASIA and subsequent research study [10, 11], there are three specific reasons that support the current dissemination of our work: (1) to validate the FDA’s findings of the age, sex, and race of clinical trial participants, exclusively using publicly available data sources, since the FDA’s study made use of internal documents submitted to the agency that are not available
Page 2 of 11
to the public; (2) to confirm the FDA’s findings among 2013 drug approvals, since the FDA’s study focused on 2010 through 2012 approvals; and (3) to provide a broader investigation of the issue by examining trial participation by ethnicity, since the FDA study focused only on age, sex, and race.
Methods Study sample
Using the Drugs@FDA database, a publicly available index of FDA regulatory actions, we identified all novel therapeutics (i.e., new molecular entities—drugs—and novel biologics) that were approved by the FDA between 1 January 2011 and 31 December 2013 [12]. Generic drugs, reformulations, combinations of nonnovel therapeutic agents, and nontherapeutic agents (i.e., diagnostic agents) were excluded. For each of the novel therapeutics included in our sample, we determined the indications for which it was first approved for use by reviewing the FDA’s approval letter and the initial drug label. All indications were classified into one of eight therapeutic areas (cancer, cardiovascular [including diabetes mellitus and hyperlipidemia], infectious disease, autoimmune and musculoskeletal disease, neurology, dermatology, psychiatry, and other). Next, we determined whether these novel therapeutics had been granted orphan status, indicating that they are primarily intended for the treatment of a rare disease. For small molecules, orphan status was determined using the Drugs@FDA database [12]; for biologics, we searched the Orphan Drug Product Designation Database [13]. Pivotal trials
The FDA makes a series of documents available in the Drugs@FDA database that correspond to the key components of the agency’s review process, explain the basis of its approval decision, and summarize notable information presented in sponsors’ applications. The “medical review” discusses the safety and efficacy of novel therapeutics, describing the pivotal trials in detail. For each of the novel therapeutics included in our sample, we manually searched the corresponding medical review documents to identify the pivotal trials that supported their approval and recorded the intention-to-treat (ITT) population (i.e., all participants who received at least one dose of the study drug or its comparator). If the medical review did not clearly identify the pivotal trials used as the basis of approval, we reviewed other FDA documents to identify such trials, such as the summary review and office director memos, and if necessary manually classified trials as pivotal following an established approach [1].
Downing et al. Trials (2016) 17:199
Demographic characteristics of pivotal trial participants
Information describing the age, sex, race, and ethnicity of the participants in each of the identified pivotal trials was abstracted from the FDA’s medical review documents. In circumstances when the medical review did not contain all of this information, the agency’s statistical reviews were searched. To characterize the ages of pivotal trial participants, we recorded the mean as a summary statistic; if the mean was unavailable, the median was used. When FDA documents provided such statistics for individual trial arms, but not in the aggregate, we used a weighted-average approach to estimate the corresponding statistic for the entire study population. In addition, we determined the number of elderly clinical trial participants, defined as those aged 65 years or older. Next, we recorded the number of male and female participants in each study. To characterize clinical trial participants’ race and ethnicity, we counted the number of participants in four racial subgroups (white, black, Asian, and other) and two ethnic subgroups (Hispanic and non-Hispanic). Two reviewers (JHN and JAA) independently abstracted this information from FDA documents. A second reviewer (NSD) validated the initial abstraction by reabstracting all data, and all discrepancies were resolved through discussion with the senior investigator (JSR). Availability of subgroup efficacy analyses
To determine whether FDA reviewers documented the efficacy of novel therapeutics for age, sex, and race as well as ethnic subgroups, we searched the medical and statistical reviews to identify the presence of subgroup analyses for each pivotal trial. Analyses of efficacy involving patients of any two age groups (e.g.,
RESEARCH
Open Access
Participation of the elderly, women, and minorities in pivotal trials supporting 2011– 2013 U.S. Food and Drug Administration approvals Nicholas S. Downing1, Nilay D. Shah2, Joseph H. Neiman3, Jenerius A. Aminawung4, Harlan M. Krumholz1,5,6 and Joseph S. Ross1,6,7*
Abstract Background: Pivotal trials, the clinical studies that inform U.S. Food and Drug Administration (FDA) approval decisions, provide the foundational evidence supporting the safety and efficacy of novel therapeutics. We determined the representation of the elderly, women, and patients from racial and ethnic minorities in pivotal trials and whether the FDA is making subgroup efficacy analyses among these subpopulations available to the public. Methods: We conducted a cross-sectional study of novel therapeutics approved by the FDA between 2011 and 2013. Using publicly available FDA documents, we collected information on the demographic characteristics of pivotal trial participants (age ≥65 years, sex [male, female], race [white, black, Asian, other], and ethnicity [Hispanic, non-Hispanic]) and determined the availability of subgroup analyses by age, sex, race, and ethnicity. Results: We identified 86 novel therapeutic that were approved by the FDA between 2011 and 2013 for 92 indications on the basis of 206 pivotal trials. The median age of pivotal trial patients was 53.1 years (interquartile range 40.6–60.6), and the mean proportion of patients ≥65 years of age was 28.9 % (95 % CI 23.5–34.4 %). Similar proportions of pivotal trial participants were male (mean 50.3 %, 95 % CI 45.3–55.2 %) and female (mean 49.7 %, 95 % CI 44.7–54.7 %). Most participants were white (mean 79.2 %, 95 % CI 75.9–82.6 %), while the mean proportion of black patients was 7.4 % (95 % CI 5.5–9.3 %), that of Asian patients was 7.4 % (95 % CI 5.2–9.7 %), and that of patients of other races was 5.9 % (95 % CI 4.4–7.5 %). Information about ethnicity was available for only 59.8 % of indications, and where such data were available, the mean proportion of Hispanic participants was 13.3 % (95 % CI 10.3–16.3 %). FDA reviewers performed and made available subgroup efficacy analyses by age, sex, and race for at least one of the pivotal trials used as the basis of approval for over 80 % of indications. Conclusions: Although women are equally represented in pivotal trials supporting recent novel therapeutic approvals by the FDA, elderly patients and those from racial and ethnic minorities are underrepresented. FDA reviewers generally perform subgroup efficacy analyses by age, sex, and race and make these subgroup analyses available to the public.
* Correspondence: [email protected] 1 Center for Outcomes Research and Evaluation, Yale–New Haven Hospital, New Haven, CT, USA 6 Department of Health Policy and Management, Yale University School of Public Health, New Haven, CT, USA 7 Section of General Internal Medicine and the Robert Wood Johnson Foundation Clinical Scholars Program, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA Full list of author information is available at the end of the article © 2016 Downing et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Downing et al. Trials (2016) 17:199
Background Clinical trials provide the foundational evidence that supports U.S. Food and Drug Administration (FDA) approval and informs physicians and patients as they make decisions about the use of new therapies. For this evidence to inform both regulators and clinical practice, it is critical that the patients participating in these trials, wherever they are conducted, reflect the population of patients expected to use the novel therapeutic agent. This is particularly important for pivotal clinical trials, the late-stage clinical trials that are intended to demonstrate the safety and efficacy of novel therapeutics and upon which the FDA bases its approval decisions [1]. However, several groups of individuals, including the elderly, women, and persons from racial and ethnic minority groups, have historically been underrepresented in clinical research, limiting the ability of many studies to inform decisions about their care [2–8]. Over the years, the FDA has taken several measures aimed at improving and ensuring the representativeness of patients participating in pivotal clinical trials. First, in 1998, the FDA issued the “demographic rule,” requiring drug makers to report the age, sex, and race of clinical trial participants in their annual reports to the agency [9]. While the demographic rule ensured that this information was available to the FDA, it did not mandate its availability to the public. However, the 2012 FDA Safety and Innovation Act (FDASIA) urged the FDA to address this issue, and, in August 2013, the agency released a report describing the demographic characteristics of participants in trials of drugs and devices approved in 2011, as well as the availability of subgroup analyses for key age, sex, and race subgroups [10]. More recently, the FDA published an expanded investigation of the representativeness of clinical trials supporting drugs approved between 2010 and 2012 [11]. In this article, we describe the results of our research to characterize the demographic characteristics of patients participating in pivotal clinical trials for all novel therapeutics approved by the FDA between 2011 and 2013 and to determine the availability of subgroup efficacy analyses using publicly available data sources. Our research was similarly focused on participation in these trials by members of historically underrepresented populations: the elderly (defined as patients aged 65 years or older), women, persons of nonwhite race, and Hispanics. Although our study was initiated before the publication of the FDA’s initial report prompted by the FDASIA and subsequent research study [10, 11], there are three specific reasons that support the current dissemination of our work: (1) to validate the FDA’s findings of the age, sex, and race of clinical trial participants, exclusively using publicly available data sources, since the FDA’s study made use of internal documents submitted to the agency that are not available
Page 2 of 11
to the public; (2) to confirm the FDA’s findings among 2013 drug approvals, since the FDA’s study focused on 2010 through 2012 approvals; and (3) to provide a broader investigation of the issue by examining trial participation by ethnicity, since the FDA study focused only on age, sex, and race.
Methods Study sample
Using the Drugs@FDA database, a publicly available index of FDA regulatory actions, we identified all novel therapeutics (i.e., new molecular entities—drugs—and novel biologics) that were approved by the FDA between 1 January 2011 and 31 December 2013 [12]. Generic drugs, reformulations, combinations of nonnovel therapeutic agents, and nontherapeutic agents (i.e., diagnostic agents) were excluded. For each of the novel therapeutics included in our sample, we determined the indications for which it was first approved for use by reviewing the FDA’s approval letter and the initial drug label. All indications were classified into one of eight therapeutic areas (cancer, cardiovascular [including diabetes mellitus and hyperlipidemia], infectious disease, autoimmune and musculoskeletal disease, neurology, dermatology, psychiatry, and other). Next, we determined whether these novel therapeutics had been granted orphan status, indicating that they are primarily intended for the treatment of a rare disease. For small molecules, orphan status was determined using the Drugs@FDA database [12]; for biologics, we searched the Orphan Drug Product Designation Database [13]. Pivotal trials
The FDA makes a series of documents available in the Drugs@FDA database that correspond to the key components of the agency’s review process, explain the basis of its approval decision, and summarize notable information presented in sponsors’ applications. The “medical review” discusses the safety and efficacy of novel therapeutics, describing the pivotal trials in detail. For each of the novel therapeutics included in our sample, we manually searched the corresponding medical review documents to identify the pivotal trials that supported their approval and recorded the intention-to-treat (ITT) population (i.e., all participants who received at least one dose of the study drug or its comparator). If the medical review did not clearly identify the pivotal trials used as the basis of approval, we reviewed other FDA documents to identify such trials, such as the summary review and office director memos, and if necessary manually classified trials as pivotal following an established approach [1].
Downing et al. Trials (2016) 17:199
Demographic characteristics of pivotal trial participants
Information describing the age, sex, race, and ethnicity of the participants in each of the identified pivotal trials was abstracted from the FDA’s medical review documents. In circumstances when the medical review did not contain all of this information, the agency’s statistical reviews were searched. To characterize the ages of pivotal trial participants, we recorded the mean as a summary statistic; if the mean was unavailable, the median was used. When FDA documents provided such statistics for individual trial arms, but not in the aggregate, we used a weighted-average approach to estimate the corresponding statistic for the entire study population. In addition, we determined the number of elderly clinical trial participants, defined as those aged 65 years or older. Next, we recorded the number of male and female participants in each study. To characterize clinical trial participants’ race and ethnicity, we counted the number of participants in four racial subgroups (white, black, Asian, and other) and two ethnic subgroups (Hispanic and non-Hispanic). Two reviewers (JHN and JAA) independently abstracted this information from FDA documents. A second reviewer (NSD) validated the initial abstraction by reabstracting all data, and all discrepancies were resolved through discussion with the senior investigator (JSR). Availability of subgroup efficacy analyses
To determine whether FDA reviewers documented the efficacy of novel therapeutics for age, sex, and race as well as ethnic subgroups, we searched the medical and statistical reviews to identify the presence of subgroup analyses for each pivotal trial. Analyses of efficacy involving patients of any two age groups (e.g.,
