Is There a Role For Pharmacokinetic/Pharmacodynamics Guided Dosing For Novel Anticoagulants?

Thursday, December 3, 2015

Final agenda and links to presentations:

8:00am-8:10amIntroduction and goals of the Think Tank– Philip Sager, M.D. (Stanford University)

8:10am-10:40amSession I: What does the current information tell us about NOAC dosing? What evidence is there that there of the variable clinical responses to PK parameters? What conclusions can we draw from these data?
Moderator: Philip Sager, M.D. (Stanford University)
Lead Discussant: Norman Stockbridge, M.D., Ph.D. (FDA)

Setting the Stage: What is the problem we are trying to address regarding NOAC dosing? Christopher Granger, M.D. (Duke University) (20min)

Summary from the EMA/CHMP Workshop on the role of PK and PD in the use of direct oral anticoagulants – Jens Heisterberg, M.D. (CHMP) (10min)

For whom are the current dosages optimal? Who might benefit from alternative dosing strategies? Noel Chan, M.D. (Monash University/McMaster University) (10min)

What evidence is there that variable clinical responses to PK parameters exist for NOACs? What conclusions can we draw from these data?
(Which PK/PD factors associated with bleeding and thrombotic events? What patient factors are associated with stroke/thrombotic events? What is the extent of Intra-individual PK variability? Can PK/PD be used as a guide for dosing?)

Review of Data from

Dabigatran- Paul Reilly, Ph.D. (Boehringer Ingelheim Pharmaceuticals) (10min)
Rivaroxaban- Dagmar Kubitza, M.D. (Bayer) (10min)
Apixaban- Jack Lawrence, M.D. (Bristol-Myers Squibb) (10min)
Edoxaban- Michele Mercuri, M.D.,Ph.D (Daiichi Sankyo) (10min)

FDA Interpretation- Jeffry Florian, Ph.D. (FDA) (10min)

Discussion: What are the problems with the current NOAC dosing strategy? How big they; what groups or patients are most effected? If there are issues, what data will we need moving forward?

10:40-10:55:- Break

10:55am-1:00pmSession II: Is it possible that with better precision dosing we can do better in avoiding strokes and bleeds? What types of clinical evidence would be necessary to support PK/PD dosing? How do we ensure we are not hurting anyone?
Moderator: Jonathan Seltzer, M.D., M.B.A. (ACI Clinical)
Lead Discussant: Michele Mercuri, M.D., Ph.D. (Daiichi Sankyo)

Point/Counterpoint: PK-based dosing strategy should be recommended for certain patient populations to improve public health vs. PK based dosing strategy is impractical and may will not add value. Pro-Robert Temple, M.D. (FDA) (15min); Con-Scott Berkowitz, M.D. (Bayer Healthcare) (15min)

Initial PK measurement—should we do it?
Is there a rationale for monitoring?
Is it possible to measure and/or monitor?

What are the potential regulatory pathways for labeling PK based approaches? Since it is impractical to think that large trials would be undertaken to prove the benefit of PK driven dosing in already approved NOACS, what can or should be done? Do we need more evidence and what level of evidence? Is it necessary to do new clinical trial(s)? What outcomes or other endpoints would be necessary? What sort of evidence, if any, are needed to show that testing makes a difference?

Regulatory Speaker- Martin Rose, M.D. (FDA) (10min)
Academic/Industry Speaker- John Eikelboom, M.D., M.B.B.S. (McMaster University) (10min)

Discussion: What are reasonable goals to pursue for regulatory approval? What types of evidence are necessary for new labeling indications? What types of evidence will be required for new diagnostic tests? What are the pathways available? What are the obstacles?


2:00pm-4:00pmSession III: Additional key issues impacting potential implementation
Moderator: Scott Berkowitz, M.D. (Bayer Healthcare);
Lead Discussant: Paul Reilly, Ph.D (Boehringer Ingelheim)

What is the pathway for approval of point of care test or companion diagnostic? What would the study look like? Lea Carrington, M.S., M.B.A. (FDA) (10min)

What is the pathway for approval of tests for measuring the specific anticoagulant activity of NOAC? Francois Depasse,PharmD (Stago)(10min)

Physician/Patient Issues

What are the current measurement technologies/assays? What might be needed? Which tests might be appropriate? Thomas Ortel, M.D., Ph.D. (Duke University) (10min)
How are doctors actually going to do this, i.e. adjust PK with patient bleeding risk – what are patient risk factor (biologic, cultural, con meds) What are the challenges and potential solutions to support PK/PD dosing? Peter Kowey, M.D. (Lankenau) (10min)

System Issues

Would payers (e.g. Medicare) be willing to support additional cost in order to enhance NOAC dosing? What type of evidence would be needed? James Rollins, M.D., Ph.D, (CMS) (10min)


4:00pm-4:30pm-Wrap-Up, Next Steps