Overcoming Lack of Diversity in Cardiovascular Clinical Trials
2019; Lippincott Williams & Wilkins; Volume: 140; Issue: 21 Linguagem: Inglês
10.1161/circulationaha.119.041728
ISSN1524-4539
AutoresRebecca Ortega, Clyde W. Yancy, Roxana Mehran, Wayne Batchelor,
Tópico(s)Acute Myocardial Infarction Research
ResumoHomeCirculationVol. 140, No. 21Overcoming Lack of Diversity in Cardiovascular Clinical Trials Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBOvercoming Lack of Diversity in Cardiovascular Clinical TrialsA New Challenge and Strategies for Success Rebecca F. Ortega, MHA, Clyde W. Yancy, MD, MSc, Roxana Mehran, MD and Wayne Batchelor, MD, MHS Rebecca F. OrtegaRebecca F. Ortega Icahn School of Medicine at Mount Sinai, New York, NY (R.F.O., R.M.). , Clyde W. YancyClyde W. Yancy Northwestern University Feinberg School of Medicine, Chicago, IL (C.W.Y.). , Roxana MehranRoxana Mehran Icahn School of Medicine at Mount Sinai, New York, NY (R.F.O., R.M.). and Wayne BatchelorWayne Batchelor Wayne Batchelor, MD, MHS, Inova Heart and Vascular Institute, 3300 Gallows Rd, Fairfax, VA 32312. Email E-mail Address: [email protected] Inova Heart and Vascular Institute, Fairfax, VA (W.B.). Originally published18 Nov 2019https://doi.org/10.1161/CIRCULATIONAHA.119.041728Circulation. 2019;140:1690–1692The Importance of Heterogeneity in Clinical TrialsOur current cardiovascular research paradigm has served us well for decades, facilitating the approvals of new drugs and devices that have unequivocally advanced the treatment of cardiovascular disease. While it may be argued that patient heterogeneity is a nuanced, rather than critical, component of drug or device efficacy, it is unquestionable that the current standard of care emanates from randomized controlled trials that have failed to fully represent elderly patients, minorities, and women.1 The lack of adequate data for these relevant subgroups challenges the integrity of our evidence-based care algorithms and questions the replication of favorable safety and outcomes across all populations. These persistent missteps in our evidence-based generation could permit less than ideal health outcomes as a function of sex, age, race, and ethnicity. Given the rapidly changing demographics in our society, addressing these gaps in our evidence base is therefore not only a social imperative, but also a clinical necessity and important business consideration if we are to provide optimal care to an increasingly diverse US patient population.The Regulatory ConundrumAs part of the 2012 US Food and Drug Administration (FDA) Safety and Innovation Act, a legislative directive emerged to address diversity in clinical trials and the impact of age, sex, and race/ethnicity on the safety and efficacy of newly approved drugs. A key programmatic output was the FDA Drug Trials Snapshots program, which shed light on the demographics of patients enrolled in pivotal trials that lead to new drug approvals.1 Of the 53 533 patients who participated in FDA registered cardiovascular drug trials from 2015 to 2016, geography unexpectedly emerged as yet another disparate variable, with US enrollment representing only 16% of patients, while the outside US population constituted 84% of patients enrolled in pivotal trials.Though expediting enrollment, the unintended consequence of the continued globalization of clinical trials is an even more stark underrepresentation of US patient populations. For example, for all FDA drug trials completed in 2015 to 2016, only 1.3% of non-US study participants were African American, while this proportion was nearly 15% for participants enrolled in the United States1 (a proportion that mirrors current US Census Bureau demographics and is indicative of progress in US-based clinical trial enrollment). For cardiovascular drug trials, only 2.5% of all trial participants were African American, again primarily attributable to non-US enrollment.1 Thus, a paradox emerges: to address the need for more efficient and less costly clinical trials, what has transpired are trials with even less representation of real-world US populations.With the ever-increasing economic pressure to rapidly complete clinical trials, efforts to include underrepresented patient populations such as African Americans, Hispanics, Native Americans/Alaskan Natives, Asian Americans, South Asians, Native Hawaiian/Pacific Islanders, women, and the elderly are now at even greater risk. Taken together, these groups represent at least 50% of all patients at risk for cardiovascular diseases. Despite strongly emphasizing diverse patient enrollment, the FDA does not mandate it. The result is that cardiovascular drugs and devices have a pathway to FDA approval without meaningful inclusion of important demographic groups who form a large portion of the US population and may also represent those with the most need for newly indicated drugs or devices. A compelling example is the FDA approval of ivabradine for heart failure with reduced ejection fraction. Less than 1% of the patients studied in randomized trials testing the efficacy of ivabradine self-identified as African American, yet African American patients in this country are disproportionately afflicted by the condition.2Strategies for SuccessSeveral vanguard cardiovascular studies have attempted to generate evidence among patient subgroups historically underrepresented in randomized controlled trials by focusing exclusively on those groups. An early, notable example in cardiovascular research is the African American Heart Failure Trial, which enrolled 1100 African American patients with advanced heart failure exclusively in US-based sites3 and demonstrated the benefit of hydralazine/isosorbide dinitrate. More recently, the PLATINUM Diversity study enrolled 1501 women and minorities across 52 US sites in under 10 months, efficiently providing useful phase IV outcomes data addressing newer drug eluting stent platforms and highlighting the complex interplay between race/ethnicity, sex and social determinants of health.4While race-only or sex-only recruitment works if a unique hypothesis is being tested, it does not otherwise represent a reasonable standard of clinical trial design. However, these kinds of enriched cohort studies, especially when conducted in the United States, may generate important safety and efficacy data in groups who are otherwise poorly represented in international randomized controlled trials.Another approach is to seek race/ethnicity/sex/age-specific data from existing databases that aggregate information from multiple trials or registries. For example, the WIN-DES study (Women in Innovation and Drug-Eluting Stents) pooled disparate data sets across 26 drug-eluting stent studies where women were otherwise underrepresented, creating a sample size of more than 11 000 women and illustrating how certain populations might be more equitably represented in clinical trial databases.5 Electronic health records and large digital data warehouses also hold promise, but new methods will be needed to analyze such large nonrandomized datasets with an expected high degree of missing data. Any of these new research methods will require careful evaluation and determination if these nontraditional study models are to constitute an adequate level of evidence, particularly for clinical practice guidelines.The Path ForwardIn this era of global clinical trials, recruiting a patient cohort representative of US patient demographics is a new challenge and a critical need. Strategies to effectuate this goal must be rigorously tested, but we believe candidate initiatives include the following:Consideration of economic incentives (or penalties) by the FDA (or payers) that would enable greater inclusion of diverse patients in clinical trials.Commitment by industry and the clinical science community to revisit the design of trials, selection of investigators and sites, and geographic balance of US and non-US subjects.Engagement with peer investigators outside of the United States to target more race/ethnicity diversity and gender balance in clinical trial recruitment.Exploration of enhanced cohort recruitment in phase IV or postapproval studies to address important safety and implementation questions.Recruitment and training of more diverse coordinator and investigator research teams.Incorporation of novel information technology strategies, including use of electronic health data, social media, gamification, and other digital health technologies as unique steps to expand the pool of potential research subjects.Revision of the informed consent process, assuring that language matches literacy levels and that consent is culturally sensitive.Education at the societal level to advance the overall "research IQ" of the populace, thus overcoming a legacy of mistrust of the research enterprise and reducing barriers to participation in clinical trials.There are legitimate concerns with a major reengineering of the clinical trial design and execution process, and obligatory costs may be incurred. But what price do we pay for our continued uncertainty of the effectiveness of new therapies as a function of race/ethnicity/sex/age? Today, the decision-making process for 50% or more of our patient population is based on empiricism and/or extrapolation of results obtained in patient populations that they do not reflect. This is an untenable clinical model.The efficiency derived from incorporation of non-US sites into randomized controlled trials is applauded and needed, but exquisite caution must now be exercised to avoid further exacerbation of the current gaps in evidence. Within US research sites, there is awareness of the need for more diversity, and progress has been made, but our efforts should be redoubled. We implore all stakeholders to engage in this thought paradigm and target greater inclusion as a new top-level research priority.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circWayne Batchelor, MD, MHS, Inova Heart and Vascular Institute, 3300 Gallows Rd, Fairfax, VA 32312. Email Wayne.[email protected]orgREFERENCES1. Food and Drug Administration (FDA). 2015-2016 Global Participation in Clinical Trials Report.2015. https://www.fda.gov/downloads/Drugs/InformationOnDrugs/UCM570195.pdf. Accessed June 15, 2019.Google Scholar2. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.Lancet. 2010; 376:875–885. doi: 10.1016/S0140-6736(10)61198-1CrossrefMedlineGoogle Scholar3. Taylor AL. The African American Heart Failure Trial: a clinical trial update.Am J Cardiol. 2005; 96(7B):44–48. doi: 10.1016/j.amjcard.2005.07.033CrossrefMedlineGoogle Scholar4. Batchelor W, Kandzari DE, Davis S, Tami L, Wang JC, Othman I, Gigliotti OS, Haghighat A, Singh S, Lopez M, et al. Outcomes in women and minorities compared with white men 1 year after everolimus-eluting stent implantation: insights and results from the PLATINUM Diversity and PROMUS Element Plus Post-Approval Study Pooled Analysis.JAMA Cardiol. 2017; 2:1303–1313. doi: 10.1001/jamacardio.2017.3802CrossrefMedlineGoogle Scholar5. Stefanini GG, Baber U, Windecker S, Morice MC, Sartori S, Leon MB, Stone GW, Serruys PW, Wijns W, Weisz G, et al. Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials.Lancet. 2013; 382:1879–1888. doi: 10.1016/S0140-6736(13)61782-1CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Spielman D, Schlosser R, Liebowitz A, Sharma R, Overdevest J, Mattos J and Gudis D (2021) Do Federal Regulations Affect Gender, Racial, and Ethnic Disparities in Chronic Rhinosinusitis Research?, Otolaryngology–Head and Neck Surgery, 10.1177/01945998211021011, 166:6, (1211-1218), Online publication date: 1-Jun-2022. Albosta M, Dangl M, Vergara-Sanchez C, Ergui I, Inestroza K, Vincent L, Ebner B, Maning J, Grant J, Hernandez R and Colombo R (2022) The association of racial differences with in-hospital outcomes of patients admitted for sinus node dysfunction, Heart Rhythm O2, 10.1016/j.hroo.2022.05.010, Online publication date: 1-Jun-2022. 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Lanfear D, Neaton K, Lu C, Liu Y and Dent-Acosta R (2020) A Phase 4, Open-Label, Single-Arm Study Assessing the Efficacy and Safety of Ivabradine in African American Patients with Heart Failure and Reduced Ejection Fraction, Cardiology and Therapy, 10.1007/s40119-020-00196-1, 9:2, (561-568), Online publication date: 1-Dec-2020. November 19, 2019Vol 140, Issue 21 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.041728PMID: 31738602 Originally publishedNovember 18, 2019 Keywordsstandard of carecardiovascular diseaseswomenUnited States Food and Drug Administrationminority groupsPDF download Advertisement SubjectsClinical Studies
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