Publication Plan: Dabigatran

January 19

2003This is a mock publication plan for dabigatran (Pradaxa, manufactured by Boehringer Ingelheim). The true date of preparation: 4/19/2013. Prepared for BW780 (Special Topics) – Medical Publication Planning for the Biopharmaceutical Industry – Spring 2013

Kimberly Koon, Pharm D

Kimberly Koon

Page 1 of 16

Table of Contents

Dabigatran Data Dissemination Plan Overview ....................................................................... 2

Tactical/Implementation Plan ................................................................................................... 7

Prevention of Embolic and Thrombotic Events (PETRO) .................................................... 7

Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) ........................... 9

Cost-effectiveness of Dabigatran for Stroke Prophylaxis in Atrial Fibrillation.................. 12

References ............................................................................................................................... 16

Kimberly Koon

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Dabigatran Data Dissemination Plan Overview

Dabigatran (Pradaxa, manufactured by Boehringer Ingelheim) will be the second oral direct-

thrombin inhibitor to be marketed for outpatient anticoagulation therapy. The first, ximelagatran

(Exanta, manufactured by AstraZeneca) is expected to be removed from the market due to liver

toxicity.1 The current first-line oral anticoagulation therapy, warfarin, is high risk for a large

portion of patients unable to manage the careful dose, diet, and lab monitoring required.2-5

These

patients are the primary target population for dabigatran therapy. In the outpatient setting,

warfarin is used long-term in patients with atrial fibrillation to prevent stroke, and it is used in

otherwise healthy patients to treat and prevent venous thrombosis. Dabigatran will make large

contributions to the safety and cost management of anticoagulation with simple dosing, fewer

adverse events, and it will obviate specialty monitoring clinics.

The ongoing phase II clinical trial involving dabigatran, Prevention of Embolic and Thrombotic

Events (PETRO), is set to find a safe and effective dose in patients with atrial fibrillation

requiring stroke prevention. Future phase III trials, Randomized Evaluation of Long Term

Anticoagulant Therapy (RE-LY) and Efficacy and Safety of Dabigatran Compared to Warfarin

for 6 month Treatment of Acute Symptomatic Venous Thromboembolism (RE-COVER) will

demonstrate dabigatran’s equivalence and superiority to warfarin in thrombosis prophylaxis

secondary to atrial fibrillation and venous thrombosis; and treatment of venous thrombosis.

Publication plans for dabigatran are broad and aim to educate clinicians in the fields of

cardiology, geriatrics, emergency medicine, hospital, internal medicine, nursing, physician

Kimberly Koon

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assistance and pharmacy. The broad spectrum of clinicians expected to utilize dabigatran

necessitates presentation at large general cardiology conferences and publication in top-tier

clinical journals, as well as targeted journals. The results of PETRO are to be presented at the

largest gathering of pharmacists in the United States followed by publication in a high-volume

journal for clinicians interested in stroke treatment and prevention. To keep information flowing

about dabigatran, a rationale and methods publication covering the RE-LY trial design is planned

during the interim after PETRO publication and during the phase III trials. The publication plan

makes use of open access publishing for the rationale and methods publication, this enables

dabigatran information to reach practitioners with no access to top-tier medical journals. The

phase III trial, RE-LY, is scheduled to be presented at the largest cardiovascular conference in

the world followed by publication in a top-tier medical journal. The planned economic

evaluation of the RE-LY trial will be presented at the largest stroke congress in the world,

followed by publication in the top journal for formulary decision makers. The phase III trial, RE-

COVER is to be presented at the largest cardiovascular conference in the United States followed

by publication in a top-tier medical journal.

Limitations of the publication plan include the lack of named second journals in the instance of

rejection by the first journal, and tight deadlines from the date of data maturation to congress

submission deadlines. The publication team should make use of late-breaking abstract

submissions, offered by the three non-pharmacy congresses, if these deadlines are too narrow.

Dates for late-breaking congress submissions are listed in the appendix.

Kimberly Koon

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Table 1. Publication Plan Overview

Target Clinician United States Demographicsa Numbers

Physician Cardiovascular 227 000

Emergency Medicine 317 000

Family Practice 854 000

General Practice 96 000

Internal Medicine 1 061 000

Neurology 152 000

Physician

Assistant

Emergency Medicine 8 890

Primary Care 25 930

Internal Medicine: Cardiology 2 445

Internal Medicine: Neurology 620

Pharmacists 249 381

Total 2 994 266

Study Statements Presentation

/Publication

Target

Clinician

Numbers

PETRO Dabigatran is a safe and effective,

oral twice daily medication for

prevention of thrombosis in

patients with atrial fibrillation.

Dabigatran is not associated with

liver toxicity.

ASHP

Midyear

Clinical

Meeting,

Healthcare

Administrators

Pharmacists,

11 480

Stroke; A

Journal of

Cerebral

Circulation

neurologists

cardiologists

vascular

surgeons

internists

neurosurgeons

17 900

RE-LY Dabigatran is as effective as

warfarin in the prevention of

stroke and systemic embolism in

patients with atrial fibrillation.

Patients on dabigatran therapy for

stroke prevention secondary to

atrial fibrillation have similar rates

of mortality compared to patients

on warfarin for the same

indication.

BMC

Medicine

Online

Journal

researchers

clinicians

authors

peer reviewers

open access to

all

1 500 000

European

Society of

Cardiology

Congress

Cardiologists

Nurses

General

Practitioners

Surgeons

Technicians

Public Health

27 080

Kimberly Koon

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Journal of

the American

Medical

Association

Internal Med

CV disease

General

Practice

Emergency

Med

Neurology

Geriatrics

Critical Care

Preventive

Medicine

300 000

RE-LY

Economic

Study

Dabigatran is more cost effective

for patients requiring antithrombic

therapy due to atrial fibrillation

and have no access to high quality

warfarin management.

Due to the costs of adverse events

and resulting effects on quality of

life, dabigatran is more cost

effective than aspirin alone or

aspirin with clopidogrel for stroke

prevention secondary to atrial

fibrillation.

International

Stroke

Conference

Administrator

Pharmacist

Nurses

CRNP

Physician

Emergency

Medicine

Family

Practice

Hematology

Internal

Medicine

Neurology

Vascular Med

Cardiology

Administrator

General

Cardiology

Heart Failure

Imaging

Interventional

Prevention

4 192

Journal of

Managed

Care

Pharmacy

Senior Execs,

VP, Director,

Manager

HMO, MCO,

PBM, Mail

order

pharmacy

P&T Members

15,000

RE-COVER Dabigatran is an oral thrombin

inhibitor effective for treatment

and prevention of VTE with no

frequent monitoring required.

Dabigatran is more effective and

American

Heart

Association

Scientific

Sessions

Physician

Physician

Assistant

Pharmacist

Other Health

19 192

Kimberly Koon

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has fewer adverse effects than

warfarin for the treatment and

prevention of VTE.

Care

Professional

Administrator

RN/CRNA

EMT/Paramedi

c

Journal of

the American

Medical

Association

Internal Med

CV disease

General

Practice

Emergency

Med

Neurology

Geriatrics

Critical Care

Preventive

Medicine

300 000

Number of

target

audience

reached

through

presentations

and

publications

2 194 844

a. Data from US Bureau Stastical Abstract of the United States: 2011 Health and Nutrition,6 Physician

Assistant Census Report,7 2009 National Pharmacist Workforce Survey. Midwest Pharmacy Workforce

Research Consortium.8

Kimberly Koon

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Tactical/Implementation Plan

Prevention of Embolic and Thrombotic Events (PETRO)

Key Objectives

Determine safe and effective dose of dabigatran in patients with atrial fibrillation

Assess for liver toxicity due to dabigatran

Start Date: October 2003

End Date: November 2004

Scientific Statements

Dabigatran is a safe and effective, oral twice daily medication for prevention of

thrombosis in patients with atrial fibrillation.

Dabigatran is not associated with liver toxicity.

Proposed Congress: American Society of Health-System Pharmacists, Midyear Clinical

Meeting, December 2005

Proposed Journal: Stroke; A Journal of Cerebral Circulation, December 2005

Kimberly Koon

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Table 2. PETRO Trial

Publication Timeline

Action Items

Responsible

Parties Oct

2003

Ap

r 2004

Oct

2004

Nov 2

004

May 2

005

Ju

ne

2005

Oct

2005

Nov 2

005

Dec

2005

Register ClinicalTrials.gov Sponsor Co.

Form publication team Sponsor Co. x

Authors named Study Leads x

Guarantor named Study Leads x

Sponsor named Study Leads x

Corresponding author

named

Study Leads x

Conflict of interest

disclosures to all authors

Legal x

PETRO Starts x

Acknowledgement

permission form distributed

Pub. Team x

Form steering committee Pub. Team x

Review/revise publication

plan

Steering

Committee

x x x x x

Start drafting abstract &

manuscript

Steering

Committee

x

PETRO End Date x

PETRO Data Available x

Pre-submission inquiry

written & submitted to

Stroke

Pub. Agency,

Corresponding

Author

x

Abstract written Pub. Agency x

Poster submission to ASHP

Midyear Clinical Meeting

Pub. Agency x

Congress presenter named Steering

Committee

x

Manuscript submission to

Stroke

Corresponding

Author

x

Synopsis to

ClinicalTrials.gov

Steering

Committee

x

Manuscript review, revision

or re-submission

Steering

Committee,

Corresponding

Author

x x

ASHP Midyear Clin. Mtg. Congress

Presenter x

PETRO Published: Stroke x ASHP: American Society of Health-Systems Pharmacists

Kimberly Koon

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Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY)

Comparing the efficacy and safety of two blinded doses of dabigatran etexilate with open label

warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial

fibrillation: prospective, multi-centre, parallel-group, non-inferiority trial.

Key Objectives

Demonstrate efficacy and safety of dabigatran etexilate in patients with non-valvular

atrial fibrillation for the prevention of stroke and systemic embolism

Establish non-inferior status for dabigatran in comparison to warfarin

Start Date: November 2005

End Date: April 2009

Scientific Statements

Dabigatran is as effective as warfarin in the prevention of stroke and systemic embolism

in patients with atrial fibrillation.

Patients on dabigatran therapy for stroke prevention secondary to atrial fibrillation have

similar rates of mortality compared to patients on warfarin for the same indication.

Proposed Congress for Abstract: European Society of Cardiology, February 2010

Proposed Journal for Publication: Journal of the American Medical Association, February

2010

Kimberly Koon

Page 10 of 16

Table 3. RE-LY

Timeline

Action Items Responsible

Parties Nov 2

005

May 2

006

Nov 2

006

May 2

007

Sep

2007

Nov 2

007

May 2

008

Nov 2

008

Ap

r 2009

Jan

2010

Feb

2010

Ju

n 2

010

Ju

l 2010

Sep

2010

Oct

2010

Register at Clinical

Trials.gov

Sponsor Co. x

Form publication team Sponsor Co. x Authors named Study Leads x Guarantor name Study Leads x Sponsor named Study Leads x Corresponding author

named

Study Leads x

Conflict of interest

disclosures to authors

Legal x

RE-LY Starts x Acknowledgement

permission form

delivered

Pub. Team x

Form Steering

Committee

Pub. Team x

Review/revise

publication plan

Steering

Committee x x x x x x x x x x

Draft RE-LY Rationale

& Methods manuscript

Pub. Team x

Submit RE-LY

Rationale & Methods

Manuscript: BMC

Medicine

Corresp.

Author x

RE-LY Rationale &

Methods Published:

BMC Medicine

x

Start drafting abstract &

manuscript

Steering

Committee x

RE-LY End Date x RE-LY Data Ready x Congress presenter

named

Steering

Committee x

Abstract written Pub. Agency x Congress abstract

submitted to ECS

12/09-2/10

Pub. Agency x

Send synopsis to

ClinicalTrials.gov

Steering

Committee x

Pre-submission inquiry

written & Submitted to

JAMA

Pub. Agency,

Corresp.

Author

x

Manuscript Submission:

JAMA

Corresp.

Author x

Manuscript review/

revision/re-submission

Steering

Committee,

Corresp.Auth.

x

Kimberly Koon

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ESC Presentation Congress

Presenter x

RE-LY Published:

JAMA

x

BMC Med: BioMed Central Medicine; ECS: European Cardiovascular Society; JAMA: Journal of the American Medical

Association

Kimberly Koon

Page 12 of 16

Cost-effectiveness of Dabigatran for Stroke Prophylaxis in Atrial

Fibrillation.

Key Objectives

Compare costs of dabigatran therapy to that of warfarin, aspirin, aspirin with clopidogrel

or nothing for stroke prevention in patients with atrial fibrillation.

Correlate adverse event rates and quality of life effects with the costs of antithrombic

therapy for stroke prevention in patients with atrial fibrillation.

Start date: not given

End date: not given

Scientific Statements

Dabigatran is more cost effective for patients requiring antithrombic therapy due to atrial

fibrillation and have no access to high quality warfarin management.

Due to the costs of adverse events and resulting effects on quality of life, dabigatran is

more cost effective than aspirin alone or aspirin with clopidogrel for stroke prevention

secondary to atrial fibrillation.

Proposed congress for abstract: International Stroke Conference, February 2010

Proposed Journal for publication: Journal of Managed Care Pharmacy, February 2010

Kimberly Koon

Page 13 of 16

Table 4. Cost

Effectiveness Study

Timeline

Action Items

Responsible

Parties

Nov 2

005

May 2

006

Nov 2

006

May 2

007

Nov 2

007

May 2

008

Nov 2

008

Ap

r 2009

May 2

009

Au

g 2

009

Sep

2009

Nov 2

009

Feb

2010

Form publication team Sponsor Co. x

Authors named Study Leads x

Guarantor named Study Leads x

Sponsor named Study Leads x

Corresponding author

named

Study Leads x

Conflict of interest

disclosures to authors

Legal x

RE-LY Starts x

Acknowledgement

permission form sent

Pub. Team x

Form Steering

Committee

Pub. Team x

Review/revise

publication plan

Steering

Committee

x x x x x x x x x x

Start drafting abstract

& manuscript

Steering

Committee

x

RE-LY end date x

RE-LY data ready,

begin economic study

x

Congress presenter

named

Steering

Committee

x

Abstract written Pub. Agency x

Congress abstract

submission to ISC

Pub. Agency x

Pre-submission inquiry

written & submitted to

JMCP

Pub. Agency,

Corresp.

Author

x

Manuscript submission:

JMCP

Corresp.

Author

x

Manuscript review/

revision/re-submission

Steering

Committee,

Corresp.Auth.

x

ISC Presentation Congress

Presenter

x

RE-LY Economic

Study Published:

JMCP

x

ISC: International Stroke Conference; JMCP: Journal of Managed Care Pharmacy

Kimberly Koon

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Efficacy and Safety of Dabigatran Compared to Warfarin for 6 month

Treatment of Acute Symptomatic Venous Thromboembolism (RE-COVER)

A Phase III, Randomised, Double Blind, Parallel-group Study of the Efficacy and Safety of Oral

Dabigatran Etexilate 150 mg Twice Daily Compared to Warfarin (INR 2.0-3.0) for 6 Month

Treatment of Acute Symptomatic Venous Thromboembolism (VTE), Following Initial

Treatment (5-10 Days) With a Parenteral Anticoagulant Approved for This Indication. (RE-

COVER)

Key Objectives

Demonstrate efficacy of dabigatran for treatment and prevention of symptomatic venous

thromboembolism (VTE)

Compare safety and efficacy of dabigatran to that of warfarin for treatment and

prevention of symptomatic VTE

Highlight areas where dabigatran is superior to warfarin for treatment and prevention of

symptomatic VTE

Start date: February 2006

End date: May 2009

Scientific Statements

Dabigatran is an oral thrombin inhibitor effective for treatment and prevention of VTE

with no frequent monitoring required.

Dabigatran is more effective and has fewer adverse effects than warfarin for the treatment

and prevention of VTE.

Kimberly Koon

Page 15 of 16

Proposed congress for abstract: American Heart Association, Scientific Sessions, November

2010

Proposed Journal for Publication: Journal of the American Medical Association, November

2010

Table 5. RE-COVER

Publication Timeline

Action Items

Responsible

Parties

Feb

2006

Au

g 2

006

Feb

2007

Au

g 2

007

Feb

2008

Au

g 2

008

Feb

2009

May 2

009

Au

g 2

009

Feb

2010

May 2

010

Ju

ne

2010

Ju

ly 2

010

Au

g 2

010

Nov 2

010

Register at ClinicalTrials.gov Sponsor Company x

Form publication team Sponsor Company x

Authors named Study Leads x

Guarantor named Study Leads x

Sponsors named Study Leads x

Corresponding author named Study Leads x

Conflict of interest

disclosures to authors

Legal x

RE-COVER Start Date x

Acknowledgement naming

authorizations sent

Publication Team x

Form steering committee Publication Team x

Publication plan review &

revise

Steering

Committee

x x x x x x x x x x x x

RE-COVER End Date x

RE-COVER Data Ready x

Congress presenter named Study Leads x

Abstract written Publication

Agency

x

Synopsis to

ClinicalTrials.gov

Steering

Committee

x

Congress abstract submission

to AHA Scientific Sessions

4/09-6/09

Publication

Agency

x

Pre-submission inquiry

submitted to JAMA

Publication

Agency

x

Manuscript submission to

JAMA

Corresponding

Author

x

Manuscript review, revision

& re- submission

Pub. Agency,

Steering

Committee,

Corresp. Author

x

AHA Scientific Sessions

Congress

Congress

Presenter x

RE-COVER Publication:

JAMA

x

AHA: American Heart Association, JAMA: Journal of the American Medical Association

Kimberly Koon

Page 16 of 16

References

1. Gomberg-Maitland M, Wenger NK, Feyzi J, et al. Anticoagulation in women with non-

valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor

(SPORTIF) trials. Eur Heart J. 2006;27(16):1947-1953. doi: 10.1093/eurheartj/ehl103.

2. Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL.

National surveillance of emergency department visits for outpatient adverse drug events.

JAMA. 2006;296(15):1858-1866. doi: 10.1001/jama.296.15.1858.

3. Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency

department visits for adverse drug events in older adults. Ann Intern Med.

2007;147(11)755-765. http://annals.org.db.usip.edu/article.aspx?articleid=737751.

Accessed February 25, 2013.

4. Nieuwlaat R, Capucci A, Lip GY, et al; Euro Heart Survey Investigators. Antithrombotic

treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on

Atrial Fibrillation. Euro Heart J. 2006(24):3018-3026. doi: 10.1093/eurheartj/ehl015.

5. Poli D, Antonucci E, Grifoni E, Abbate R, Gensini GF, Prisco D. Bleeding risk during

oral anticoagulation in atrial fibrillation patients older than 80 years. J Am Coll Cardiol.

2009;54(11):999-1002. doi: 10.1016/j.jacc.2009.05.046.

6. US Bureau Stastical Abstract of the United States: 2011 Health and Nutrition,

Washington DC: US Census Bureau; 2013.

7. American Academy of Physician Assistants. Physician Assistant Census Report: Results

from the 2010 AAPA Census AAPA Research and Statistics.

8. 2009 National Pharmacist Workforce Survey. Midwest Pharmacy Workforce Research

Consortium.