1. C. Bernie Good MD MPH Department of Veterans Affairs University of Pittsburgh CADTH 2016 April 12, 2016

2.  Chair Medical Advisory Panel for Pharmacy Benefits Management, U.S. Department of Veterans Affairs  Co-Director VA Center for Medication Safety  FDA Drug Safety Oversight Board Member  No COI with industry

3.  Comprehensive health care system ◦ Direct provider of care ◦ Physicians are employees ◦ Prescription drug benefit is integrated  2014 Statistics ◦ 6.3 M veterans treated, 4.8M pharmacy users ◦ 271 million outpatient Rxes (30-day Eqv)

4.  EMR ◦ Clinical data ◦ Pharmacy data ◦ Adverse drug events  VA Center for Medication Safety ◦ Dedicated group of pharmacists, data analysts, programmers, and statisticians to support VA PBM  Routinely do data monitoring, rapid cycle analyses, and full studies as indicated  Work closely with FDA and other U.S. Federal Agencies

5. Drug/Drug Class IssuePotential Impact Real World VA Data Outcome or Action TZDsRosiglitazone CV Safety? 166,000 pts on TZD (2006) VA Data: Rosi > Pio for MI Rosi removed as preferred Zoster VaccineInc SAE’s in Clinical Trial ~ half VA patients >65 yo No inc in SAEs in VA patients Relaxed criteria VareniclineInc Neuropsych ADE, suicide comp NRT 24% VA smoke (17% U.S. > 18 yrs) No sig signalRelaxed criteria DOACsSafety, effectiveness v. warfarin in VA 307,000 VA pts with AF Safety, effectiveness ~ clinical trials 3 DOACs on VA formulary Hepatitis CComp. Eff; safety of meds 170,000 VA pts with HCV Real world < Clin Trials Use info for contracting EmpagliflozinComp Eff; Safety > 1M VA pts on DM Rx To Be Determined Reassess Recs

6.  Hep C Registry: Every VA patient with HCV ◦ Genotype, viral load, prior treatment, advanced liver disease (ALD) ◦ Treatment response, adverse events, discontinuation, etc  Weekly reports for new starts, by drug ◦ National, Regional, and site facility level ◦ Track new starts also by presence/absence of ALD ◦ Feedback to facilities for ALD starts, drug choice, with benchmarking  Hep C data is used for contracting, CER among agents, and feedback to facilities to manage appropriateness

7. > 50,000 VA Pts treated with DAA

9.  Post-marketing surveillance ◦ FDA warnings for neuropsychiatric adverse events, and suicide  VA had reports of Varenicline related suicide  As a result, VA developed criteria for use that restricted use of Varenicline as a third line treatment, with many safety measures  Use of Varenicline dropped dramatically in VA  Risk <<<< Benefit??

11.  Propensity-matched study in the era *prior to FDA warnings*  NRT vs. Varenicline ◦ Primary Outcome: Psychiatric adverse events  Subgroups: Patients with and without psychiatric diagnoses ◦ Inpatient admissions, outpatient visits ◦ Suicide  Results (pending publication) ◦ No significant increased adverse outcomes with Varenicline  VA has changed criteria for use- significantly relaxed ◦ Education efforts to increase use in appropriate patients

12.  DOACs- Clinical Trials: Better outcomes  outcomes strongly associated with INR control in the warfarin comparison patients- for both safety and efficacy  Greater patient convenience  Far more expensive than warfarin  VA Utilizes Pharmacy-based Anticoagulation Clinics  TTR’s in VA excellent  3 DOACs on VA Formulary- does comparative effectiveness warrant significantly greater cost?

13.  New user cohort, propensity matched cohort for non- valvular AF  VA has done similar study, for dabigatran, rivaroxaban, and apixaban. Results show benefit >> warfarin * Graham et al, Circulation 2014 OutcomeHR (95% CI) Ischemic Stroke0.80 (0.67-0.96) Intracranial Hemorrhage0.34 (0.26-0.46) Gastrointestinal Bleed1.28 (1.14-1.44) Acute Myocardial Infarction0.92 (0.78-1.08) Death0.86 (0.77-0.96)

14.  Real world data can inform clinical decisions ◦ Provide justification for increased expenditures based on improved clinically relevant outcomes ◦ Provide information that suggests utilization in VA should increase, based on safety and or effectiveness ◦ Provide information that drugs should be de-emphasized or removed from formulary status based on safety concerns

15.  Clinical guidance  Drug Monographs  Criteria for use  Clinical documents

18.  > 1 million pts with DM get medications from VA  Have emphasized metformin, de-emphasized other newer oral agents without proven benefit  Recent empagliflozin study indicates clinical benefit ◦ VA has added drug to our formulary with criteria for use ◦ Concerns regarding whether safety and effectiveness will be similar to clinical trial data ◦ Will monitor use of drug carefully, and track ADE, and later assess benefits