Pragmatic Clinical Trials: �Future Directions and Design Considerations����Cynthia Hau, MPH, DrPH Candidate�Cooperative Studies Program Coordinating Center�VA Boston Healthcare System�November 1, 2024

Office of Research and Development

Cooperative Studies Program

Pragmatic Clinical Trial (PCT) – VA Point Of Care Research

Healthcare providers

Electronic delivery systems

Electronic clinical and administrative data

Health System

Clinicians

Data

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Learning Health System

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Randomized trials

integrated within routine clinical practice

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PCT Design

Veterans Affairs Cooperative Studies Program (VA CSP)

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Boston CSP Coordinating Center – specialized in pragmatic trials

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• 1^st pilot study, 2011
• 1^st large-scale study, 2016-2022
• 1^st hybrid study, 2024
• 1^st target trial emulation, planning

CSP Central office, DC CSP Coordinating Centers

Today’s Presentation

Reality

Optimal

• Examples from the Diuretic Comparison Project (DCP)
• The role of pragmatic clinical trials
• Challenges with practical application

Diuretic Comparison Project (DCP)�Jun 2016 – Jun 2022

N Engl J Med 2022;387:2401-10. DOI: 10.1056/NEJMoa2212270

N Engl J Med 2023; 388:1341-1342�DOI: 10.1056/NEJMc2301922

Consideration: fit for a pragmatic design

• Treatment available in usual care settings
• Well-established safety profile
• Validated algorithms for safety and outcome monitoring

N Engl J Med 2022; 387:2462-2463�DOI: 10.1056/NEJMe2215744

Response by Authors

DCP Consent and Randomization Procedures

Agreed to have their patients approached for trial recruitment

Confirmed patients could undergo study randomization

Prescribed through usual care

(VA outpatient pharmacy)

Consideration: Trial requirements can be completed with usual setup

DCP Recruitment

Boston VA Healthcare System

Consideration: Flexible EHR

DCP Study

Consideration: Flexible EHR, supporting community and aligned incentive

Benefit: ↑ Clinical Trial Access

Locations of the 72 main VA medical centers

(72 VA Healthcare Systems composed of 72 medical centers and 537 outpatient clinics) 

Puerto Rico

Hawaii

Alaska

JAMA Netw Open 2023 Sep 5;6(9):e2332049.

DOI: 10.1001/jamanetworkopen.2023.32049

Benefit: ↑ Geographic Reach

Rural or Highly Rural Residential Areas (45%)

Urban Residential Areas (55%)

Puerto Rico

Hawaii

There were 55 patients from Alaska (not displayed in the figure)

JAMA Netw Open 2023 Sep 5;6(9):e2332049.

DOI: 10.1001/jamanetworkopen.2023.32049

Benefit: ↑ Patient Representation

¹ Finding from the VA Office of Health Equity: Black or African American Veterans comprise 16% VHA user in FY16 – FY19.

² Finding from US Census: 43% Veterans from the South and 14% from Northeast.

NIH Grand Rounds Feb 2024: Pragmatic recruitment of underrepresented groups (Cynthia Hau, MPH)

Benefit: �↑ Capacity

Randomized

JAMA Netw Open 2023 Sep 5;6(9):e2332049.

DOI: 10.1001/jamanetworkopen.2023.32049

Challenge: Outcome Ascertainment

Decisions supported by the DSMB:

• Source-specific approach
• Applied quarterly Medicare data before the release of final data
• Utilized available clinical notes to classify cancer relatedness, before the release of NDI data

J Biomed Inform 2024 Feb:150:104587.

DOI: 10.1016/j.jbi.2024.104587

472 patients, 16.2 months

Added 298,

= 770 patient, 15.6 months

90% agreement

J Biomed Inform 2024 Feb:150:104587.

DOI: 10.1016/j.jbi.2024.104587

Challenge: Adherence Monitoring

Data-driven approach

Refill patterns and actual scenarios

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Classify patients as

• Lapse
• Switch
• Discontinue

Patient #1

Patient #2

Future Direction

Leveraging healthcare systems for large-scale clinical trials is feasible

• Clinical trial access
• Patient representation
• Generalizability of study results

? Phase III trial

? Facilitate registration

? Label expansion

Pragmatic Clinical Trials (since 1967)

NEJM 2022;387:2401-2410

JAMA 1967;202(11):1028-1034

VA RCT

143 Patients: HCTZ Combination vs Placebo

VA PCT

13 523 Patients: HCTZ vs Chlorthalidone

• Current Challenges
• Within a health system
• Use of routine care data

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• Future challenges (working on)
• Collaborations
• Target trial emulation
• Data sharing
• Digital innovations

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Conclusion

Helpful Links

NIH Pragmatic Trials Collaboratory Grand Rounds Presentations

NIH Grand Rounds Oct 2016: Chlorthalidone Versus Hydrochlorothiazide (Frank Lederle, MD)

NIH Grand Rounds May 2018: An Overview of the VA Point of Care Program (Ryan Ferguson, ScD MPH)

NIH Grand Rounds Aug 2022: The Diuretic Comparison Project: A Large Pragmatic Clinical Trial (Areef Ishani, MD, MS)

NIH Grand Rounds Feb 2024: Pragmatic recruitment of underrepresented groups (Cynthia Hau, MPH)

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Publications

Chlorthalidone vs. Hydrochlorothiazide for Hypertension–Cardiovascular Events | NEJM | Ishani et al (2022)

Design of a pragmatic clinical trial embedded in the Electronic Health Record: The VA's Diuretic Comparison Project | Contemp Clin Trials| Ishani et al. (2022)

A Centralized EHR-Based Model for the Recruitment of Rural and Lower Socioeconomic Participants in Pragmatic Trials | JAMA Network Open | Hau et al. (2023)

Practical issues in pragmatic trials: the implementation of the diuretic comparison project | Clin Trials | Ferguson et al. (2023)

The impact of COVID-19 on a large pragmatic clinical trial embedded in primary care | Contemp Clin Trials | Leatherman et al. (2023)

Strategies for secondary use of real-world data for outcome ascertainment in pragmatic clinical trials | J Biomed Inform | Hau et al. (2024)

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Thank you

Cynthia Hau (presenter)

Biostatistician

VA Cooperative Studies Program Coordinating Center

VA Boston Healthcare System

cynthia.hau@va.gov

DCP Acknowledgement

Co-Authors:

Cynthia Hau, Jimmy Efird, Sarah Leatherman, Oleg Soloviev, Peter Glassman, Patricia Woods, Areef Ishani, William Cushman, and Ryan E. Ferguson

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Other DCP team and VA members:

Grant Huang, Mary Brophy, Louis Fiore, Addison Taylor, Alison Klint, Jade Fiotto, Maura Flynn, Amanda Guski, Robert Hall, Colleen Hynes, Srihari Raju, Gregory Robben, Christal Sadatis, Linda Sweeney, Liang Zhu, Olivia Taylor, Jacob McPherson, Eustacia Ikeri, Abhinav Tella, William Vang, Katherine Perkey, Alicia Zhang, and Danne Elbers

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In memoriam: Frank Lederle, MD

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Data and Safety Monitoring Board Committee:

Drs. Christopher Cannon, Cynthia Coffman, Larry Fine, and Gina Wei