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Streamlining cardiovascular clinical trials to improve efficiency and generalisability
  1. Faiez Zannad1,
  2. Marc A Pfeffer2,
  3. Deepak L Bhatt3,
  4. Denise E Bonds4,
  5. Jeffrey S Borer5,6,
  6. Gonzalo Calvo-Rojas7,
  7. Louis Fiore8,
  8. Lars H Lund9,
  9. David Madigan10,
  10. Aldo Pietro Maggioni11,
  11. Catherine M Meyers12,
  12. Yves Rosenberg4,
  13. Tabassome Simon13,14,
  14. Wendy Gattis Stough15,
  15. Andrew Zalewski16,
  16. Nevine Zariffa17,
  17. Robert Temple18
  1. 1 Clinical Investigation Center, Centre Hospitalier Universitaire de Nancy, Nancy, France
  2. 2 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  3. 3 Brigham and Women's Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts, USA
  4. 4 National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
  5. 5 The Howard Gilman Institute, New York, New York, USA
  6. 6 State University of New York Downstate Medical Center, Brooklyn, New York, USA
  7. 7 Department of Clinical Pharmacology, Hospital Clínic, University of Barcelona, Barcelona, Spain
  8. 8 Department of Veterans Affairs, Cooperative Studies Program, Boston, Massachusetts, USA
  9. 9 Department of Medicine, Unit of Cardiology, Karolinska Institute, Stockholm, Sweden
  10. 10 Department of Statistics, Columbia University, New York, New York, USA
  11. 11 ANMCO Research Center, Florence, Italy
  12. 12 National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, Maryland, USA
  13. 13 Assistance Publique-Hôpitaux de Paris, Saint Antoine Hospital, Paris, France
  14. 14 Université Pierre et Marie Curie, Paris, France
  15. 15 Campbell University College of Pharmacy and Health Sciences, Research Triangle Park, North Carolina, USA
  16. 16 Glaxo Smith Kline, King of Prussia, Pennsylvania, USA
  17. 17 AstraZeneca, Cambridge, UK
  18. 18 Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA
  1. Correspondence to Professor Faiez Zannad, Clinical Investigation Center, Centre Hospitalier Universitaire de Nancy, Université de Lorraine and INI-CRCT (F-CRIN); Institut Lorrain du Coeur et des Vaisseaux, Nancy 54500, France; f.zannad{at}chru-nancy.fr

Abstract

Controlled trials provide the most valid determination of the efficacy and safety of an intervention, but large cardiovascular clinical trials have become extremely costly and complex, making it difficult to study many important clinical questions. A critical question, and the main objective of this review, is how trials might be simplified while maintaining randomisation to preserve scientific integrity and unbiased efficacy assessments. Experience with alternative approaches is accumulating, specifically with registry-based randomised controlled trials that make use of data already collected. This approach addresses bias concerns while still capitalising on the benefits and efficiencies of a registry. Several completed or ongoing trials illustrate the feasibility of using registry-based controlled trials to answer important questions relevant to daily clinical practice. Randomised trials within healthcare organisation databases may also represent streamlined solutions for some types of investigations, although data quality (endpoint assessment) is likely to be a greater concern in those settings. These approaches are not without challenges, and issues pertaining to informed consent, blinding, data quality and regulatory standards remain to be fully explored. Collaboration among stakeholders is necessary to achieve standards for data management and analysis, to validate large data sources for use in randomised trials, and to re-evaluate ethical standards to encourage research while also ensuring that patients are protected. The rapidly evolving efforts to streamline cardiovascular clinical trials have the potential to lead to major advances in promoting better care and outcomes for patients with cardiovascular disease.

  • clinical trials as topic
  • cardiovascular disease
  • pragmatic clinical trials as topic

https://doi.org/10.1136/heartjnl-2017-311191

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    Footnotes

    • Contributors FZ: Developed workshop agenda and participated in workshop discussion of this topic; drafted the paper; revised the paper for important intellectual content; approved the final submitted version; agrees to be accountable for all aspects of the work. MAP, DLB, DEB, JSB, GC, LF, LHL, DM, APM, CMM, YR, TS, AZ, NZ, RT: Participated as a participant and discussant during the workshop from which this paper was developed; drafted the paper; revised the paper for important intellectual content; approved the final submitted version; agrees to be accountable for all aspects of the work. WGS: Drafted the paper; revised the paper for important intellectual content; approved the final submitted version; agrees to be accountable for all aspects of the work.

    • Funding This work was generated from discussions during the 11th Global Cardiovascular Clinical Trialists (CVCT) Forum held in Washington, DC in December 2014. CVCT was organised by the Clinical Investigation Center (CIC) Inserm, CHU, and the University of Lorraine, France, and INI-CRCT (F-CRIN), Nancy, France, and funded by an unrestricted educational grant from Association de Recherche et d'Information en Cardiologie (ARISC), a non-profit educational organisation in Nancy, France. ARISC had no involvement in preparation, review or approval of the manuscript for publication.

    • Competing interests DLB: Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St Jude Medical; Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda. DB: This work was done while Dr. Bonds was an employee of the National Heart, Lung and Blood Institute. JSB: Personal fees from Cardiorentis (DSMB), AstraZeneca (event adjudication committee), Novartis (DSMB), ARMGO (advisory board), Celladon (DSMB), BioTRONIK (Trial Executive Committee), Boerhinger-Ingelheim (consultant), Abbott Laboratories (consultant), Sarepta (consultant), Amgen (consultant), Servier (Trial Executive Committee, consultant), GSK (DSMB), Pfizer (DSMB). LHL: Consultant to Bayer Pharma, Novartis, AstraZeneca, Vifor Pharma; Research grants from AstraZeneca, Boston Scientific; Honoraria for lectures or speaker's bureaus from Novartis, St Jude. DM: Within the past 4 years, DM has been a paid consultant to Endo, Jarvik Heart, Lilly, Merck and Pfizer. In addition he has testified on behalf of plaintiffs in litigation related to pharmaceutical products and medical devices. APM: Research grants from Novartis, Cardiorentis, Bayer; Honoraria for lectures from Servier. TS: Research grants from AstraZeneca, Daiichi-Sankyo, GSK, MSD, Novartis; Personal fees (board and consultancy) from AstraZeneca, Astellas, Bayer, BMS, Lilly, MSD, Novartis, Sanofi. WGS: Consultant to Overcome (travel expense reimbursement to attend CVCT and professional time related to preparation of this paper), European Society of Cardiology, Heart Failure Association of the European Society of Cardiology, Heart Failure Society of American, Relypsa, Stealth Peptides, Celyad and Respicardia. AZ: Employee of GSK. NZ: Employee of AstraZeneca.

    • Provenance and peer review Not commissioned; externally peer reviewed.