The Challenge of Formulary Management in the DoD – UF 101

Promoting high quality, cost effective drug therapy throughout the Military Health System

The Challenge of Formulary Management in the DoD – UF 101

Dr. Dave Bretzke, Dr. Angela Allerman, and Major Wade Tiller Dr. Dave Bretzke, Dr. Angela Allerman, and Major Wade Tiller PEC Conference 2007PEC Conference 2007

2

Objectives

• Describe the UF decision making process

• Differentiate the roles and responsibilities of the DoD PEC and the DoD P&T

• Explain why UF decisions apply across both the direct care and purchased care points of service

• Discuss the key elements that must be considered in all Uniform Formulary decisions

3

Uniform Formulary

• Intended to provide ‘uniform’ availability across DoD dispensing venues

• Legislated and published regulation– Must do

– How to do it

• Introduce 3rd tier (pay for preference)

• Copays governed by law– Limits ability to increase spread

– Difficult to change

4

Uniform Formulary

• Decisions apply across dispensing venues

• Defined role of DoD P&T Committee

• Types of decisions– Formulary status

– PA, QL, MN

• Moved decision from DoD P&T Committee to TMA Executive Director (Dr. Winkenwerder)

• Introduced visibility through Beneficiary Advisory Panel (BAP)

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Uniform Formulary

• Must review all drug classes– Implement one at a time

– New drugs

• P&T defines class – complete freedom

• Class set as BCF or ECF

• Within every class, at least one agent must be BCF / ECF

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Loading the hopper

• Mandate to review every drug class

• Identify drug class candidates– DoD high spend, high use

– Competition

– New drugs / generics

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Loading the hopper (con’t)

• Feasibility– Current situation

– Likely constituents

– Likely outcomes

– Cover BCF/ECF requirement

• Determine priority

• Staff workload

• Industry considerations

• Put on calendar

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Uniform Formulary Decision Cycle

• Preliminary review (T-180 270)

• P&T Committee meets (T-90 180)

– Defines class, BCF or ECF

• Request for Pricing Info (T-75 100)

• Price Quotes Received (T-20 30)

• P&T Committee meets (T)

– Final review, recommendations

• BAP meets (T+45)

– Comments to TMA

• TMA Director reviews & signs minutes (T+60)

• Implementation of decisions (no later than T+240)

PEC Completes

Clinical and

Economic Analysis

Implement Date

Beneficiary Advisory

Panel Meeting

DOD P&T Meeting

Director TMA Decision

90-Day Decision Cycle

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Everything Happens at Once…

PEC Completes

Clinical and

Economic Analysis

Implement Date

Beneficiary Advisory

Panel Meeting

DOD P&T Meeting

Director TMA Decision

May 062 Classes

Feb 053 Classes

Nov 054 Classes

Aug 063 Classes

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Why review Statin Class now?

• Statin contract set to expire

• Simvastatin available in a generic version– Exclusivity?

• #1 MHS drug class– 1M users

– $550M / year (9% of MHS total)

• How would you define the class?

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Antilipidemic I ClassGeneric name Brand name Generic availability?

Statins

Atorvastatin Lipitor No

Fluvastatin Lescol

Lescol XL

No

No

Lovastatin IR

Lovastatin ER

Mevacor

Altoprev (previously Altocor)

Yes

No

Pravastatin Pravachol Yes except Pravachol 80mg

Rosuvastatin Crestor No

Simvastatin Zocor Yes

Statin Combinations

Atorvastatin/Amlodipine Caduet No

Pravastatin/Aspirin Pravigard PAC Discontinued May 13, 2005

Lovastatin/Niacin Advicor No

Simvastatin/Ezetimibe Vytorin No

Add-on therapies

Niacin Niaspan, Niacin IR No, yes

Ezetimibe Zetia No

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Antilipidemics-I Evaluation Strategy

• Developed by the PEC

• Factors considered– Clinical needs of the DoD population

– Generic availability

– Market competition within the therapeutic class

• Approved by DoD P&T Committee

• Develop bidding scenarios

• Put it on the street

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PEC Process for Determining Relative Clinical Effectiveness

• UF Rule: DoD P&T Committee considers information regarding safety, effectiveness, and clinical outcomes when comparing drugs in the class

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Relative Clinical Effectiveness ProcessAntilipidemic I agents

• Team approach

• Developed key questions to answer– Class divided into intensive LDL lowering (>45% in LDL) and

low to moderate LDL lowering (<45% in LDL) drugs

– Efficacy differences• Surrogate outcomes (LDL , HDL )• Clinical outcomes (myocardial infarction, acute coronary

syndromes, mortality, revascularization, stroke)

– Safety / Tolerability differences• Common adverse effects

• Serious: elevated liver enzymes, proteinuria, myopathy, rhabdomyolysis

• Drug interactions, special populations (pediatric, pregnancy)

– Other Factors (pleiotropic effects, dosing initiation schedules)

• Initial assessment of DoD population needs

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Intensive vs. low to moderate % LDL lowering

HMG CoA Reductase Inhibitors (Statins)Statin LDL reduction

Lovastatin (Mevacor)

Lovastatin (Altoprev)

Pravastatin (Pravachol)

Simvastatin (Zocor)

Fluvastatin (Lescol, Lescol XL)

Atorvastatin

(Lipitor)

Rosuvastatin

(Crestor)

25-30% 20mg 20mg 20mg 10mg 40mg

30-40% 40-80mg 40mg 40mg 20mg 80mg XL 10mg

40-45% 80mg

(40mg X 2)

60mg 80mg 40mg or Vytorin 10/10

20mg 5mg

45-50% Note: Ezetimibe or Niacin generally decreases LDL up to an additional 15%

80mg or Vytorin 10/20

40mg 10mg

50-55% Vytorin 10/40

80mg 20mg

>55% Vytorin 10/80

40mg

Combination agents follow their parent statin

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0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%1 4 7

10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64

Percent LDL-C Reduction

Per

cen

t o

f P

op

ula

tio

n E

xpec

ted

to

Rea

ch G

oal

Atorvastatin 40mgRosuvastatin 10mgSimvastatin 80mgVytorin 10/20mg

Atorvastatin 80mgRosuvastatin 20mg

Vytorin 10/40mg

Rosuvastatin 40mg

Vytorin 10/80mg

(NHANES3 Data Modeling by DoD PEC)

Estimated Percent of Population Expected to Reach ATP-III LDL Goals with Increasing LDL Reduction

85% of the population

45%

LD

L R

edu

ctio

n

85% of the patients

Will use simvastatin

< 40mg/day

Majority of DoD population can meet LDL goals with simvastatin

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Relative Clinical Effectiveness ProcessAntilipidemic I agents

• Define search strategy for evidence– FDA website

– MEDline search for approved and off-label uses

– Evidence Based Medicine (EBM) sites searched

– Existing guidelines (ACC, AHA, NCEP ATP III, VA/DoD)

– Database, retrospective cohort studies (safety)

• Solicit provider opinion– Survey development

– SG Consultants teleconference

– Survey to providers and pharmacists

• Invited pharmaceutical manufacturer presentations

• Ongoing discussion with cost-effectiveness expert

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Relative Clinical Effectiveness ProcessAntilipidemic I agents

• Evidence Based Medicine (EBM)– Integrating best research evidence with needs of

patient/population

• EBM principles– Helps to assess the quality of clinical evidence

• rigorous study design• appropriate statistical tests• inclusion of patients similar to DoD• appropriate inclusion and exclusion criteria• appropriate objective clinical endpoints• appropriate definition of adverse events• valid conclusions based on studied outcomes and statistical

tests– Goal for relative clinical effectiveness section is to use the

best quality evidence when determining the differences between the class members

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Relative Clinical Effectiveness ProcessAntilipidemic I agents

• Systematic process to identify best evidence available• Hierarchy of levels of evidence

– Systematic reviews• Condense the results of several trials (10s-100s) into an

understandable format• Can help determine differences in efficacy, safety between drugs• Sources: Cochrane, UK, Canada, Oregon• Some limitations: different patient populations, different

background medications– Randomized, double-blind, controlled trials

• Head-to-head trials• Placebo controlled trials

– Non-randomized trials: unequal allocation of drug treatment– Cohort studies, case control studies: no intervention given– Case reports, anecdotal reports: lowest level of evidence;

small numbers of patients

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Relative Clinical Effectiveness Process Sections of class review

• Efficacy– Discuss key issues in efficacy differences between class

members or limitations in the available evidence

• Safety– How likely will each drug in the class cause harm?

– Often need evaluation of sources other than clinical trials• Well-designed retrospective health claims database study

• Published FDA data available

– Required lab monitoring

– Tolerability assessment: How likely will patients take the drug?• Drug discontinuations due to adverse effects

• Other Factors: anything else we can think of

• Overall clinical effectiveness conclusion

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Antilipidemics I: Clinical Evidence SummaryCHD

Stroke1o Prevention

2o PreventionMixed 1o & 2o Prevention   General

Acute Coronary Syndrome

 Atherosclerotic Progression

AtorvaASCOTCARDS

TNT*IDEAL*

GREACE

MIRACL

PROVE-IT*REVERSAL

ASAP4D

ASCOTCARDS

TNT*SPARCL

Fluva LIPS FLORIDA Riegger et al ALERT

Lova AFCAPS Knatterud et al   MARS

Prava WOSCOPSLIPIDCARE

PROVE-IT*PACT

REVERSALREGRESS

L-CAD

ALLHATPROSPER

CARELIPID

Simva HPS4S

IDEAL*A to (Z)* MAAS

ASAPHPS

4SHPS

Rosuva ASTERIOD  * = Active control trial

• Most studies compared a statin to placebo• Update to ATP III NCEP guidelines primarily based on 5 major clinical trials: ALLHAT-LLT,

ASCOT-LLA, HPS, PROSPER, and PROVE-IT

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= statistically significant RRR; X = available trials, but no statistically significant difference shown

Atorva Fluva Lova Prava Simva Rosuva

1o CHD 10 mg 20-40 mg 40 mg 40 mg

2o CHD

General pop 10-80 mg 80 mg(after PTCA)

40 mg 20-40 mg

ACS 80 mg X X X

Revasc 80 mg 80 mg(after PTCA)

40-80 mg(after CABG)

40 mg 20-40 mg

Stroke 10-80 mg 40 mg 20-40 mg

Antilipidemic I agents: Efficacy Conclusion

• No head-to-head trials of equivalent doses of different statins for reducing coronary events or mortality

• Meta-analysis (Zhou et al): In low to moderate doses of atorva = prava = simva in long-term cardiovascular prevention using adjusted indirect comparison

• Evidence summary:

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Relative Clinical Effectiveness ProcessAntilipidemic I agents

• First draft of written class review

• Assess military readiness issues if applicable

• Gather additional clinical information

• Evaluate feasibility of classifying one or more drugs as non-formulary under the UF– Requires input from PEC management, clinical staff,

economic experts, and procurement experts

• Initial consideration of medical necessity criteria

• Final written draft completed, edited by PEC staff

• Revisions completed, slides developed for meeting

• Ongoing process; steps are not necessarily sequential

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Challenges of Relative Clinical EffectivenessAntilipidemic I agents

• Lack of comparative head-to-head trials overall, or problems when available– Is the comparison drug inferior?

– Comparison of non-equivalent doses of statins• PROVE-IT trial compared 80 mg atorvastatin with 40 mg

pravastatin in ACS patients

• What to do in absence of head-to-head trials– Calculate NNT

– Compare hazard ratios, odds ratios, confidence intervals

– Similar point estimates? Overlapping confidence intervals

• Efficacy vs. Effectiveness– Strict study conditions may not reflect use of drug in “real

world”

– Co-morbid conditions not represented in RCTs

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Challenges of Relative Clinical EffectivenessAntilipidemic I agents

• Safety– Safety data for new market entry is often incomplete and

based on 1,000s of patients, rather than 1,000,000s of patients

– Length of time on the market and provider experience can determine provider confidence in a drug’s safety profile

• Provider opinion– Past experiences and perceptions play a role

• Degree of therapeutic interchangeability within the drug class– Difficult to conclusively determine that “Drug A is better than

Drug B”

– Can usually say “Drug A is no worse than Drug B

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Introduction Relative Cost-Effectiveness

• The UF final rule states– “If a pharmaceutical agent in a therapeutic class is

not cost-effective relative to other pharmaceutical agents in that therapeutic class, it may be classified as a non-formulary agent” (Federal Register / Vol. 69, No. 63 / Thursday, April 1, 2004 / Rules and Regulations)

• Applies to– Therapeutic class reviews

– New agents in classes already reviewed

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Relative Cost-effectiveness Process

• PEC performs two different types of economic analyses

– Pharmacoeconomic Analysis• “Identifies, measures, and compares the costs (i.e., resources

consumed) and consequences (clinical, economic, and humanistic) of pharmaceutical products and services” (Bootman, et al., Principles of Pharmacoeconomics 2nd Ed., New York, St. Martin’s Press,1996)

– Budget Impact Analysis• By definition, a BIA estimates the impact on annual healthcare

use and cost for the first, second and subsequent years after the introduction of the new product for a national or health plan population (Mauskopf, JA et al.)

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Pharmacoeconomic AnalysisProcess

– What type or types of analyses performed?• Clinical team provides insight as to how the agents differ in

terms of relative clinical effectiveness and to identify significant clinical outcomes– The type of pharmacoeconomic analysis performed is dependent

upon the how the outcomes are measured and the extent that these outcomes differ between the agents within a therapeutic class

• Scour the literature for every pharmacoeconomic analysis that has ever been performed on the agents within the class

• Industry for any published or unpublished pharmacoeconomic models they use to support their respective agents

– Synthesize the information and develop pharmacoeconomic models to critically evaluate the cost-effectiveness of the agents within the class.

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Pharmacoeconomic Analysis ProcessAntilipidemic I Agents

– Strong intermediate outcome evidence• Mean % LDL reduction by drug and strength

• Total cholesterol/HDL ratios

• Head-to-head RCT

– Long-term clinical outcomes evidence• There are no head-to-head trials comparing equivalent

doses of statins that evaluate clinical outcomes for reducing mortality or other clinical outcomes (e.g., myocardial infarction, stroke, need for revascularization)

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Pharmacoeconomic AnalysisModels

• The Annual Cost per 1% LDL Decrease decision analytic model.

• The Annual Cost per Patient Treated to Goal Monte Carlo simulation model

• The Medical Cost Offset Model (industry) – Compared the cost-effectiveness of these agents based on

their predicted outcomes and total predicted health care expenditures for CHD and CHD risk-equivalent patients.

• The Cost per Event-Free Patient decision analytic model

– Based on the results of the IDEAL Trial, compared the cost-effectiveness of the agents included in that trial—high-dose (80mg) atorvastatin (Lipitor) vs. low-dose (20-40 mg) simvastatin (Zocor, generics)

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Pharmacoeconomic AnalysisResults

• Results of the first three cost-effectiveness analyses showed ezetimibe/simvastatin (Vytorin) to be the most cost effective high % LDL lowering agent.

• Results of the fourth analysis revealed that high-dose (80 mg) atorvastatin (Lipitor) was more effective but considerably more costly compared to low dose (20-40mg) simvastatin (Zocor, generics).

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Budget Impact AnalysisAffordability

SafetyEfficacy

Quality

Cost-Effectiveness

Affordability

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Budget Impact Analysis Overview

• Models the MHS budget impact dynamics of a UF decision

• Factors included in the model– Market growth

– Market share migration• Change in utilization among therapeutic class agents as beneficiaries

migrate from NF to UF agents

– Point of Service Migration• Change in utilization among POS

– Costs associated with migration from NF to UF agents• Medical necessity processing fees

• Provider costs associated with switching patients from NF to UF agents

• Lab costs

– Cost reduction associated with NF $22.00 copay

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Budget Impact AnalysisMethodology Overview

• Dynamic Markov Model– Differs from static model in that it incorporates the

element of time

– Migration transitions from NF to UF occur gradually overtime…no longer assumes instantaneous migration

– Open not closed…beneficiaries enter and exit model over time…allows for market growth

– Allows for providers/beneficiaries to change agents over time (migrate back and forth between Markov states)

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Budget Impact Analysis Results

• Interesting– All scenarios that included Lipitor on the UF were

more favorable compared to scenarios without Lipitor on the UF

• Ultimately– The Uniform Formulary scenario that included

atorvastatin (Lipitor), ezetimibe/simvastatin (Vytorin), and simvastatin (Zocor, generics) 80 mg as the high % LDL lowering agents on the UF was the most cost effective UF scenario.

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P&T Committee DecisionFactors Considered

• Relative Clinical Effectiveness

• Relative Cost Effectiveness– Pharmacoeconomic Analysis

• Vytorin the most cost-effective agent intensive dose statin

• No economic benefit to exclude any of the low to moderate % LDL lowering agents from the UF

– Budget Impact Analysis• The UF scenario that included Vytorin, Lipitor, and Simvastatin

80mg along with the low to moderate % LDL lowering agents was the most cost-effective UF scenario

• Market Conditions

• Potential Impact/Disruption to Beneficiaries

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Distribution of Unique Users (UUs) by Agent and POS

0

100000

200000

300000

400000

500000

600000

Lipito

r

Vytorin

Crest

or

Simva

statin

Prava

statin

Altopre

v

Lovasta

tin

Lescol

Zetia

Niacin

ER

Advico

r

Caduet

Mail

Retail

MTF

UUs

Source: Utilization Data - PDTS; BPA - Manufacturers; Current – MTF (Prime Vendor), Retail & TMOP from PDTS; FSS - VAPBM

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After the P&T Meeting

• BAP meeting

• Minutes from DoD P&T & BAP meetings presented to TMA Executive Director and signed

• Minutes posted– MTF formulary management (pushout) documents

– Medical Necessity criteria

– Finalize forms and submit to ESI / post

• Real work begins – implementation!

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MTF Implementation

• Review decisions

• Develop implementation plan– Provider education

– New vs. existing patients

– Confirm prices loaded

– Follow-up MUE / DUE

• Execute

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PEC Monitoring

• Develop monitoring plan– Ongoing

– Specific targets

• Monthly trend analysis– Combined

– By Point of Service

• Monthly cost per ???? tracking– Rx, 30-day Eq Rxs, Treatment day, Tab/cap

• Prime Vendor availability

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PEC Monitoring

• Field alerts

• Add to PACER

• Return and Report– DoD P&T Committee

– BAP

– Dr. Winkenwerder

– Conferences

– ??????

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PEC Monitoring - Example

• Statins– Ongoing analysis

• Trend by drug by month

• Cost per day by month

– Specific targets• Simvastatin cannibalization

– Equipotent doses (e.g. Lipitor 10 & 20mg)

• Up prescribing– Brand over-marketing (e.g. Lipitor + Vytorin vs. class)

• Cost effective – High Potency Use (Crestor vs. Lipitor 40 & 80mg vs. Vytorin)

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Summary - Statins

• Extremely important drug class for DoD

• Use Vytorin in patients who need > 45% reduction in LDL

• “Our efforts to sustain…the TRICARE Rx benefit require that MTF prescribers continue using simvastatin…”

• “I strongly encourage MTF commanders, doctors and pharmacists to maximize the use of simvastatin”

Dr. Winkenwerder, ASD-HA

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Summary - Overall

• The UF process and drug class reviews are comprehensive and (sometimes painfully) thorough

• Best real world application of EBM reviews and pharmacoeconomic analyses

• MTF input is extremely valuable

• Strives to find the best balance of access vs. costs

• Future offers depend on today’s performance

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Contact Info

• Major Wade Tiller, RPh, MHA, PhDBiomedical Sciences CorpDeputy Director, DoD Pharmacoeconomic Centerkevin.tiller@amedd.army.mil

• David R. Bretzke, PharmDProcurement / Informatics PharmacistDoD Pharmacoeconomic Centerdavid.bretzke@amedd.army.mil

• Angela Allerman, PharmD, BCPSClinical Pharmacy SpecialistDoD Pharmacoeconomic Centerangela.allerman@amedd.army.mil