AATS Grant Writing Workshop Developing a Clinical Research Program, Trial Design, Patient Enrollment Timothy J. Gardner MD Christiana Care Health System.

AATS Grant Writing Workshop

Developing a Clinical Research Program, Trial

Design, Patient Enrollment

Timothy J. Gardner MDChristiana Care Health System

Wilmington Delaware

Clinical Professor of Surgery

University of PennsylvaniaBethesda

March 4, 2011

Why should I develop a Clinical Research Program?Importance of research in the triad of

excellence as a surgeon (skilled surgeon, effective teacher, thoughtful and productive researcher)

Primary importance of our clinical work mandates attention to surgical methods and outcomes

Clinical research is achievable by virtually all cardiac and thoracic surgeons

Clinical research has become even more relevant in this current environment

Traditional progression of clinical research activities

Case Reports of small number of patients. Provides anecdotal evidence of efficacy

Case Series, usually retrospective reports from a single center: Suggestive evidence

Observational Reports, larger number of cases, even from multiple centers, including non-audited Registries: Supportive evidence

Prospective studies, open trials performed with standardization: Convincing evidence

Randomized Controlled Trials: comparative clinical research: Forms evidence base

Limitations to case reports and follow-up studies

Retrospective reviews are limited to medical record data

Series are usually surgeon- or site-specific

Outcome-specific information is usually quite limited, focusing on deaths and major complications

There are no “control” patients or groups

Treasure, Eur J Cardiothorac Surg 2009; 35:474-78

Randomized clinical trialsin surgery

Goal of any trial is to generate rigorous scientific evidence of safety and efficacy

RCTs aim to eliminate selection biasDistribute confounding factors among study groups to mitigate potential biasing influences on interpretation of outcomes

Class III

Risk = BenefitNo additional studies needed

Procedure/Treatment should NOT be performed/administeredSINCE IT IS NOT HELPFUL AND MAY BE HARMFUL

Class IIb

Benefit = RiskAdditional studies with broad objectives needed; Additional registry data would be helpful

Procedure/Treatment MAY BE CONSIDERED

Class IIa

Benefit >> RiskAdditional studies with focused objectives needed

IT IS REASONABLE to perform procedure/administer treatment

Class I

Benefit >>> Risk

Procedure/ Treatment SHOULD be performed/ administered

Level C: Only consensus of experts opinion, case studies, or standard of care

Very limited populations evaluated

Level B: Data derived from a single randomized trial or nonrandomized studies Limited populations evaluated

Level A: Data derived from multiple randomized clinical trials or meta-analyses

Multiple populations evaluated;

Applying Classification of Recommendations and Level of Evidence

Level of Evidence:

Requirements for Developing a Clinical Research Program

Motivated surgeon-leader with Division and Department support (dedicated time and initial funding assistance)

Dedicated research team with committed research coordinator

Supportive and facilitating academic and clinical environment

Clinical collaborators (cardiologists, oncologists, biostatisticians, etc.)

Usual Questions for Trial Design

Clear and relevant hypothesisPrimary and secondary endpointsAppropriate patient populationsWell defined comparatorsPower – sample sizeStatistical designSites and recruitment expectations

Ann Thorac Surg 2007; 83: 1934-9

Observational Report

Ann Thorac Surg 2008; 86: 1139-46

12,812 patients from 1997 – 2006, 44% OPCAB

Propensity matched between CPB- and OP-CABG

“OPCAB provides significant mortality & morbidity advantages, especially in women

Similar outcomes at 10 years

RCT, but small sample size

Single surgeon trial100 patients in each

armSimilar outcomes at

30 days and 1 yearReduced costs with

OPCABAdequate for non-

inferiority conclusion?

JAMA 2004: 291: 1841-49

RCT, with Level A evidence

2203 patients, 18 centers, qualified surgeonsComposite 30-day and 1-year clinical end pointsOPCAB patients had worse outcomes including graft

patency

N Engl J Med 2009; 361: 1827-37

Observational data, Registry-based

EACTS 2010 • Three-year Outcomes of the SYNTAX Trial • Kappetein • Slide 18

Optimal revascularization strategy in Optimal revascularization strategy in patients with three-vessel disease and/or patients with three-vessel disease and/or

left main diseaseleft main disease

The 3-year Outcomes of the SYNTAX TrialThe 3-year Outcomes of the SYNTAX Trial

Optimal revascularization strategy in Optimal revascularization strategy in patients with three-vessel disease and/or patients with three-vessel disease and/or

left main diseaseleft main disease

The 3-year Outcomes of the SYNTAX TrialThe 3-year Outcomes of the SYNTAX Trial

A. Pieter Kappetein, MD PhDA. Pieter Kappetein, MD PhDErasmus Medical Center, Erasmus Medical Center,

Rotterdam, The NetherlandsRotterdam, The NetherlandsOn behalf of the SYNTAX investigatorsOn behalf of the SYNTAX investigators

12 September 201012 September 2010Conflicts of Interest: NoneConflicts of Interest: None

EACTS 2010 • Three-year Outcomes of the SYNTAX Trial • Kappetein • Slide 19

The 3-year SYNTAX results suggest that CABG remains the standard of care for patients with complex disease (intermediate or high SYNTAX Scores); however, PCI may be an acceptable alternative revascularization method to CABG when treating patients with less complex (lower SYNTAX Score) disease.

The 3-year MACCE rates for the CABG and PCI registry were 16.4% and 38.0% respectively

SYNTAX patients will continue to be followed for 5 years.

Summary: II Summary: II

http://www.ctsurgerynet.org/

Evaluation of Outcomes Following Mitral Valve Repair/Replacement in Severe Chronic Ischemic Mitral Regurgitation

OBJECTIVES:

The objective of this study is to evaluate the safety and efficacy of mitral valve repair and mitral valve replacement for patients with severe ischemic mitral regurgitation (MR). Specifically, this study compares mitral valve repair with annuloplasty and a sub-valvular procedure for severe tethering to mitral valve replacement and complete preservation of the sub-valvular apparatus. o The primary aim of this trial is to evaluate the impact of these two surgical approaches on left ventricular

remodeling. o 250 subjects; 90% power to detect an absolute difference of 15 ml/m2 in LVESVI based on a 35%

(replacement) v. 20% (repair) reduction in LVESVI.o Secondary aims of this trial include assessment of the impact of these two surgical interventions on

cardiac performance, mortality, adverse events, quality of life, functional status, severity of MR, and health resource use.

Enrollment as of Feb 23, 2011 = 165/250 (66%)

22

Patients with Severe Ischemic MR (Per site echocardiographer)

Determination of Eligibility and Collection of Baseline Data

Random Assignment of Treatment

Mitral Ring Annuloplasty ± CABG

(subvalvular procedure for severe tethering)

Mitral Valve Replacement ± CABG

(complete subvalvular preservation)

Outcomes Measured at 1, 6, 12, and 24 months

Primary OutcomeLVESVI at 12 mos

Secondary OutcomesSurvival, Funct Status, QoL, Operative Measures, LOS,

Readmission, MR, Remodeling, LVEF, Revasc, AE’s Cost

Data Analysis

Note: Mitral valve replacement will include complete preservation of the subvalvar apparatus. The technique of preservation, choice of prosthetic valve, and technique of suture placement will be dependent on the surgeon’s preference. The prosthetic valve will be tested for paravalvular leaks using the left ventricular saline infusion test

Note: The annuloplasty ring will be chosen by the surgeon. The ring is sized to the anterior leaflet and intertrigonal distane. A semi-rigid or rigid annuloplasty ring will be used and. If tethering is present, a subvalvar procedure may be performed.

Patient enrollment issuesPatients are often uncomfortable when

there is uncertainty expressed by the surgeon about effectiveness of the proposed treatment

Referring physicians may expect their treatment preferences to be honored

“Doctor, you do what you think is best”Program marketing may confound the

patient enrollment challenges

Equipoise – mandatory concept for RCTs, but often lacking among

surgeonsUncertainty about comparative merits of 2 different diagnostic or treatment options

Ethically, the investigator should have no significant preference

For most RCTs, “clinical equipoise” refers to genuine uncertainty within the expert medical community about the treatment options

Freedman B, N Engl J Med 1987; 317: 141-5

Why should I develop or participate in a Clinical Research

Program?Supports and defines academic mission

Provides evidence-basis for surgical practice

Helps clarify best clinical practicesAssociated with surgical leadership