eFigure. Cardiovascular Clinical Trial Selection Process on ClinicalTrials.gov
eReferences. Cardiovascular Disease Trials Included in This Analysis
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Nanna MG, Chen ST, Nelson AJ, Navar AM, Peterson ED. Representation of Older Adults in Cardiovascular Disease Trials Since the Inclusion Across the Lifespan Policy. JAMA Intern Med. 2020;180(11):1531–1533. doi:10.1001/jamainternmed.2020.2750
Older adults traditionally have been underrepresented in cardiovascular disease (CVD) trials,1,2 requiring extrapolation of evidence from younger populations.3 In response, the National Institutes of Health (NIH) established the Inclusion Across the Lifespan Policy in January 2019 to expand representation of older adults and children in clinical research.4,5 The policy requires NIH studies to include individuals across the lifespan and to justify age-based exclusions. We set out to assess the early impact of this policy for the inclusion of older adults in CVD trials with a variety of funding sources.
For this review, we identified all phase 3 and phase 4 CVD interventional studies in the US for coronary artery disease, congestive heart failure, atrial fibrillation, peripheral artery disease, and valvular heart disease starting on or after January 25, 2018, and registered on ClinicalTrials.gov as of February 11, 2020. Trials were classified as prepolicy if they commenced enrollment 1 year before the NIH policy (January 25, 2018, to January 24, 2019) and as postpolicy if they commenced enrollment on or after January 25, 2019. We excluded 8 trials that were withdrawn, suspended, or terminated and 4 trials that were targeted at pediatric or pregnant populations (eFigure and eReferences in the Supplement).
Inclusion/exclusion criteria were abstracted, including age limits, trial type, study intervention, location, sponsoring agency, target study size and duration, and the study’s primary and secondary end points. These were compared using the χ2 test or Fisher exact test for categorical variables and the Mann-Whitney test for continuous variables. Inclusion of patient-centric end points most relevant to geriatric populations was assessed, including health status, function, quality-of-life measures, mobility assessments, and patient-reported outcomes. Exclusion criteria that may disproportionately affect older adults were also examined, such as physical disability, decreased life expectancy, and cognitive impairment.1
We identified 97 eligible CVD trials, including 47 prepolicy and 50 postpolicy trials. Aggregate study characteristics for prepolicy and postpolicy trials are presented in the Table. Most trials did not include age limits in the prepolicy or postpolicy eras (14 of 47 [30%] vs 16 of 50 [32%]; P = .81). However, most postpolicy trials lacked geriatric-centric outcomes as first- or second-degree end points (32 of 50 [64%]), and exclusion criteria disproportionately affecting older adults were common both prepolicy (35 of 47 [75%]) and postpolicy (35 of 50 [70%]) (P = .62) (Figure).
Trial sponsorship was similar in the prepolicy vs postpolicy periods, with a trend toward fewer publicly funded studies (Table). The proportion of studies that included age limits was similar among industry-funded and publicly funded studies (18 of 48 [38%] vs 4 of 15 [27%]; P = .54), and it was also similar prepolicy and postpolicy in both publicly funded studies (3 of 10 [30%] prepolicy vs 1 of 5 [20%] postpolicy; P > .99) and industry-funded studies (9 of 26 [35%] prepolicy vs 9 of 22 [41%] postpolicy; P = .65). When the small number of NIH-funded trials was compared with all others, the proportion with age limits was similar (1 of 5 [20%] vs 29 of 92 [32%]; P > .99).
Inclusion of measures of health status, function, or quality of life (16 of 47 [34%] prepolicy vs 16 of 50 [32%] postpolicy; P = .83), gait-speed and mobility assessments (9 of 47 [19%] prepolicy vs 9 of 50 [18%] postpolicy; P = .88), and patient-reported outcomes (18 of 47 [38%] prepolicy vs 17 of 50 [34%] postpolicy; P = .66) was similar in all studies before and after the enactment of the policy.
One year after adoption of the Inclusion Across the Lifespan Policy, challenges remained in ensuring adequate representation of older adults in CVD trials. One-third of trials included explicit age limits, with no difference before or after the policy, and two-thirds of trials used exclusion criteria that disproportionately affect older adults. In addition, only a minority of studies included patient- and geriatric-centric clinical trial end points after adoption of the policy.
Although this study highlighted early opportunities for improvement in representation of older adults in CVD trials, it was limited by the data available on ClinicalTrials.gov. Moreover, a given clinical trial might not explicitly exclude participants based on chronological age alone, but that does not necessarily translate into adequate enrollment of older participants. Further tracking of actual enrollment by age group will be critical to monitoring the success of the policy. Future policy changes that extend beyond just NIH-funded studies may also be necessary to improve the collection of evidence among older adults with CVD.
Accepted for Publication: May 22, 2020.
Corresponding Author: Michael G. Nanna, MD, Duke Clinical Research Institute, Duke University School of Medicine, 200 Morris St, Durham, NC 27710 (email@example.com).
Published Online: September 8, 2020. doi:10.1001/jamainternmed.2020.2750
Author Contributions: Dr Nanna had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Nanna, Chen, Nelson, Navar.
Drafting of the manuscript: Nanna, Chen.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Nanna.
Administrative, technical, or material support: Chen, Peterson.
Supervision: Nanna, Navar, Peterson.
Conflict of Interest Disclosures: Dr Nanna reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Navar reported receiving personal fees from Amgen, AstraZeneca, Janssen, Esperion, Amarin, Sanofi, Regeneron, Novo Nordisk, Novartis, The Medicines Company, and Pfizer and grants from Amgen, Janssen, Amarin, Sanofi, and Regeneron outside the submitted work. Dr Peterson reported receiving grants from Amgen, Sanofi, AstraZeneca, Merck, and Janssen and personal fees from Amgen, AstraZeneca, Merck, Novartis, Pfizer, Janssen, and Sanofi outside the submitted work. No other disclosures were reported.
Funding/Support: This study was supported by training grant T32-HL069749 from the National Institutes of Health (Dr Nanna) and grant NIH K01HL133416-01 from the National Institutes of Health (Dr Navar).
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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