Review of the Drug Trials Snapshots Program of the US Food and Drug Administration

Abstract

This review of FDA’s Drug Trials Snapshots Program evaluates the sex-specific findings reported as part of the approval process for all cardiovascular drugs that the FDA approved in 2015.

Over the last 20 years, there have been concerns that too few women and minorities are enrolled in clinical trials to provide confidence about drug safety and effectiveness. Women’s advocacy groups, in particular, have called for more representation in trials of cardiovascular diseases. In 2012, the US Food and Drug Administration (FDA) Safety and Innovation Act (FDASIA 907) was enacted and required the FDA to report on the diversity of participants in clinical trials and the extent to which safety and effectiveness data are based on demographic factors such as sex, race, and age. In response, the FDA piloted a new transparency initiative called the Drug Trials Snapshots Program. Snapshots are data posted online in a standardized format after approval of a “new molecular entity” (NME). They show who participated in the pivotal clinical trials used to approve the drug by sex, race, and age subgroups. Snapshots also provide statements on observed demographic subgroup differences in safety and efficacy. The FDA releases a Snapshot for every NME approved after January 2015 within 30 days of the approval date.

Methods

Reviewing the first year of Snapshot data from January 1, 2015, through December 31, 2015, we documented the reported number of women in cardiovascular drug trials and whether any statements of subgroup difference were made. We compared the sex-specific safety and efficacy statements in Snapshots (http://www.fda.gov/Drugs/InformationOnDrugs/ucm412998.htm) with those made in the corresponding prescribing information (PI) accessed on Drugs@FDA: FDA Approved Drug Products (http://www.accessdata.fda.gov/scripts/cder/daf/) (and also linked on the Snapshots page).

Results

In 2015, there were 9 NMEs with cardiovascular indications. Of these, the number of women enrolled in the trials was 22 621, accounting for 35% of the 64 611 total participants (Table 1). Inclusion of women ranged from 24 participants to 8006 (mean of 2262 and median of 1691). Nine Snapshot statements concluded that men and women responded similarly. Seven PI statements concluded that men and women responded similarly, and 2 did not provide efficacy statements on sex. Two Snapshot statements concluded that there were safety differences between men and women; 6 concluded that the risk of adverse effects appeared to be similar in men and women; and 1 concluded there were not enough participants to determine the difference. The PI did not include any statements on adverse effects differences between men and women (Table 2).

Table 1. Women and Men in Pivotal Trials^a of Cardiovascular Snapshots (2015) Compared With Percentage of Women in Disease Population^b.

Drug	Indication	Participants, No. (%)		Cardiovascular Disease Area	Women in the Disease Population, %b
		Women 22 621 (35)	Men 41 990 (65)
Ivabradine	To reduce hospitalization from worsening heart failure	1535 (24)	4970 (76)	Heart failure	53c
Secubitril/valsartan	Treatment of heart failure	1847 (22)	6595 (78)	Heart failure	53c
Cangrelor	For prevention of coronary artery blood clot formation in patients undergoing PCI	3121 (28)	8024 (72)	Acute coronary syndrome	39d
Alirocumab	Treatment of certain patients with high cholesterol	1507 (40)	2245 (60)	Hypercholesterolemia	58e
Idarucizumab	Reversal of the anticoagulant effects of dabigatran during emergency situations or when there is a need to reverse its blood-thinning effects	58 (47)	65 (53)	Reversal agent	NA
Evolocumabf	Treatment of certain patients with high cholesterol	2079 (50)	2098 (50)	Hypercholesterolemia	58e
Evolocumabg	Treatment of certain patients with high cholesterol	24 (49)	25 (51)	Hypercholesterolemia	58e
Edoxaban	Prevention of stroke in patients with atrial fibrillation	8006 (38)	13020 (62)	Atrial fibrillation	43h
Edoxaban	Reduction of risk of VTE in patients with previous VTE	3524 (43)	4716 (57)	VTE	52i
Selexipag	For the treatment of adults with PAH	920 (80)	232 (20)	PAH	80j

Abbreviations: FDA, US Food and Drug Administration; PAH, pulmonary arterial hypertension; PCI, percutaneous coronary intervention; VTE, venous thromboembolism; WHO, World Health Organization.

^aIn the FDA Report “Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products, August 2013,” the FDA defines pivotal clinical trials as the clinical investigations designed to collect definitive evidence of the safety and effectiveness of a medical product for a specified intended use (http://www.fda.gov/downloads/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/UCM365544.pdf).

^bThe percentage of women in the disease population for each of the disease areas was estimated by dividing the prevalence of the disease among women by the total prevalence, obtained from the cited scientific literature.

^cBased on self-reported data from National Health and Nutrition Examination Survey (NHANES) 2009 to 2012 and National Heart, Lung, and Blood Institute of adults aged 20 years or older.

^dBased on the American College of Cardiology’s National Cardiovascular Data Registry of patients referred after admission for an acute coronary syndrome, including acute myocardial infarction or unstable angina between 2000 to 2002 at 388 US hospitals.

^eBased on patients 20 years or older who had high total cholesterol levels, defined as 240 mg/dL or higher, from National Center for Health Statistics/NHANES 2011 to 2012 data.

^fClinical trial of patients with heterozygous familial hypercholesterolemia.

^gClinical trial of patients with homozygous familial hypercholesterolemia.

^hBased on a cross-sectional study of adults 20 years or older who were enrolled in a large health maintenance organization in California and who had atrial fibrillation diagnosed between July 1, 1996, and December 31, 1997.

ⁱBased on national VTE prevalence patterns in the US population within a 5-year period from 2002 to 2006 and real-world data from patients in the MarketScan Commercial and Medicare databases.

^jBased on data from the REVEAL Registry, a multicenter prospective cohort design involving 54 centers in the United States that screened patients for suspected or confirmed World Health Organization group I pulmonary arterial hypertension between March 2006 and September 2007.

Table 2. Sex Subgroup Statements Made for Cardiovascular Indications in Drug Trials Snapshots and Prescribing Information^a.

Drug: Indication	Drug Trial Snapshotsb		Prescribing Informationb
	Subgroup Efficacy	Subgroup Safety	Subgroup Efficacyc
Ivabradine: reduce hospitalization from worsening heart failure	Ivabradine appeared to be similarly effective in men and women	The risk of overall adverse effects was similar in men and women	None found
Sacubitril/valsartan: treatment of heart failure	Sacubitril/valsartan worked similarly in men and women	The risk of adverse effects appeared to be similar in men and women	None found
Cangrelor: prevention of coronary artery blood clot formation in patients undergoing PCI	Cangrelor was similarly effective in men and women	More bleeding was seen in women taking Cangrelor than in men taking Cangrelor; in the trial, all patients (men and women) treated with Cangrelor had more bleeding than patients given clopidogrel, another blood thinner	Cangrelor pharmacokinetics are not affected by sex, age, renal status or hepatic function; no dose adjustment is needed for these factors
Alirocumab: treatment of certain patients with high cholesterol	Alirocumab worked similarly in men and women	The risk of adverse effects was similar in men and women	Age, body weight, sex, race, and creatinine clearance were found not to significantly influence alirocumab pharmacokinetics; no dose adjustments are recommended for these demographics
Idarucizumab: reversal of the anticoagulant effects of dabigatran during emergency situations or when there is a need to reverse its blood-thinning effects	Idarucizumab worked similarly in men and women	The number of patients in the main trial was small; differences between men and women could not be determined	Age, sex, race (white vs Asian) and body weight had no clinically important effect on systemic exposure of idarucizumab based on population pharmacokinetic analyses in a healthy volunteer cohort of 201 male and 19 female participants
Evolocumab: treatment of certain patients with high cholesterol	Evolocumab worked similarly in men and women	The risk of adverse effects was similar in men and women	The pharmacokinetics of evolocumab were not affected by age, sex, race, or creatinine clearance, across all approved populations
Edoxaban: prevention of stroke in patients with atrial fibrillation	Edoxaban was similarly effective in men and women	The risk of major bleeding was similar among men and women	In a population pharmacokinetic analysis, after accounting for body weight, sex had no additional clinically significant effect on edoxaban pharmacokinetics
Edoxaban: reduction of risk of VTE in patients with previous VTE	Edoxaban was similarly effective in men and women	The overall incidence of bleeding was greater in women, primarily owing to an increase in vaginal bleeding	In a population pharmacokinetic analysis, after accounting for body weight, sex had no additional clinically significant effect on edoxaban pharmacokinetics
Selexipag: treatment of PAH, WHO group I, to delay disease progression and reduce the risk of hospitalization for PAH	Selexipag worked similarly in men and women	The risk of adverse effects was similar in men and women	No clinically relevant effects of sex, race, age or body weight on the pharmacokinetics of selexipag and its active metabolite have been observed in healthy subjects or patients with PAH

Abbreviations: FDA, US Food and Drug Administration; PAH, pulmonary arterial hypertension; PCI, percutaneous coronary intervention; VTE, venous thromboembolism; WHO, World Health Organization.

^aSometimes referred to as the drug product label or package insert, the prescribing information is an established regulatory document that contains a summary of the essential scientific information needed for the safe and effective use of the drug (Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products; 21 CFR 201.56; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=201.56). It should be noted that “Snapshots” should not be used exclusively to make decisions about whether to take a drug and are not designed to substitute for the prescribing information; rather, they are intended to promote discussion about clinical trial participation and variability in drug response.

^bData are available at the FDA Drug Trials Snapshot home page (http://www.fda.gov/Drugs/InformationOnDrugs/ucm412998.htm), where each Snapshot is listed with subgroup statements and a link to the corresponding Prescribing Information statements.

^cNo sex subgroup safety statements were found in the prescribing information for these drugs.

Discussion

Previous investigations into the number of participants by sex were limited to aggregate data and broad therapeutic area. The FDA Drug Trials Snapshots Program represents the first time that pivotal trial demographic information and subgroup analysis statements for safety and efficacy of all newly approved NMEs are consistently reported and readily available in 1 place. Cardiovascular disease appears to be an area where enrollment of women is disproportionately low. The FDA plans to work with the cardiology community to address this issue.

A comparison of the statements made in Snapshots and PI statements shows more consistency in efficacy statements than safety statements. For the 2015 cardiovascular NMEs, Snapshots documented 2 safety statements related to increased bleeding risk and 1 statement where there were not enough participants to determine the difference, whereas the PI did not have any sex subgroup statements related to safety. These differences may be owing to the legal requirements imposed on the PI, for which sex demographic labeling is not a required subsection.

With only a year’s worth of Snapshot data, we are limited in understanding if these data are comparable to those of other years. Beyond the demographics of sex, variability in response to drugs may also be caused by a large number of factors including diet, concomitant medications, genetic traits, and other factors. As a transparency initiative, the Snapshots Program intends to catalyze a broader discussion on ways to improve our understanding of biologic variability in drug response, when it should be measured, and how best to design clinical trials to capture it.