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Positive listsand similar regulations:

Evaluating the (comparative) benefit of pharmaceuticals

Reinhard Busse, Prof. Dr. med. MPH FFPH,

Department Health Care Management,Technische Universität Berlin & Charité – Universitätsmedizin

European Observatory on Health Systems and Policies

Pharmaceutical regulation in industrialised countries

Positive List Australia Austria Canada FranceThe Netherlands Norway New Zealand Sweden Switzerland

Negative List Austria Germany Sweden United KingdomReference Pricing Australia Belgium Denmark Germany France

New Zealand The Netherlands Norway Spain Sweden

Public Price Setting Australia Belgium Canada Denmark Finland g gGreece Italy LuxembourgThe Netherlands Portugal Spain Sweden Switzerland

Public Price Negotiation Austria France Ireland New ZealandPublic Profit Control United Kingdom

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Rationale behind post-licensing evaluation 1: too many new drugs

without added benefit25

10

15

20

Truly innovative substances

Therapeutically relevant substances

Mee-too preparations

Data for Germany

0

5

Source: Schwabe and Paffrath 2004

Rationale behind post-licensing evaluation 2: market authorisation

doesn´t require added benefitS f t• Safety

• Pharmaceutical quality• Efficacy

Usually no comparison with already available treatment options

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Post-licensing evaluation =Health Technology Assessment (HTA) for drugs

[ ] Th l f HTA i[...] The goal of HTA is to provide input to decision making in policy and practice. (Henshall et al. 1997)

H T A R E P O R TD e fin itio n o f th e P o licy Q u e s tio n (s)

B ac k g ro u n d in fo rm a tio n / D e te rm in a tio n o f th e s ta tu s o f th e te ch n o lo g y

H T A P ro to c o l

D e fin itio n o f th e re sea rch q u estio n s

S a fe ty

S o u rces o f d a ta

A p p ra isa l o fev id en ce

S y n th es is o f

E ffic a cyE ffe c tiv en ess

S o u rce s o f d a ta

A p p ra isa l o fev id en ce

S y n th es is o f

P sy c h o lo g ic a lS o c ia l

E th ic a lS o u rce s o f d a ta

A p p ra isa l o fev id en ce

S y n th es is o f

O r g a n isa tio nP r o fe ss io n a l

S o u rce s o f d a ta

A p p ra isa l o fev id en ce

S y n th es is o f

E co n o m ic a l

S o u rces o f d a ta

A p p ra isa l o fev id en ce

S y n th es is o fyev id en ce

S y n th es is o fev id en ce

S y n th es is o fev id en ce

S y n th es is o fev id en ce

yev id en ce

C o n c lu s io n s / R ec o m m e n d a tio n sF IN A L H T A R E P O R T

D ra ft e lab o ra tio n

E x te rn a l R ev iew

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Who is in charge for post-licensing evaluation of drugs in

industrialised countries?industrialised countries?

National drug evaluating institutions

and their advisory bodies

Austria (AT) Federation of Austrian Social Insurance Institutions/Drug Evaluation Commitee

(Hauptverband der Österreichischen Sozialversicherungsträger/Heilmittel-Evaluierungs-Kommission)

Australia (AU) Pharmaceutical Benefits Advisory Committee/Economic Sub-Committee

Belgium (BE) National Institute for Sickness and Invalidity Insurance/Commission for Reimbursement of Medicines

(Institut national de l’assurance maladie-invalidité/Commission de réimboursement des médicaments)

Canada (CA) PMPRB - Patented Medicine Prices Review Board/Human and Veterinary Drug Advisory Panels

CDR - Canadian Expert Drug Advisory Committee/Common Drug Review-Directorate at Canadian

Coordinating Office for Health Technology Assessment

Finland (FI) Pharmaceuticals Pricing Board (Lääkkeiden hintalautakunta)

France (FR) Economic Committee for Health Products/Transparency Commission

(Comité économique des produits de santé/Commission de Transparence)

Germany (DE) Federal Joint Committee/Institute for Quality and Efficienty in Health Care

(Gemeinsamer Bundesausschuss/Institut für Wirtschaftlichkeit und Qualität im Gesundheitswesen)

The Netherlands (NL) Health Care Insurance Board/Committee for Pharmaceutical Aid

(College voor zorgverzekeringen/Commissie Farmaceutische Hulp)( g g g p)

Norway (NO) Norwegian Medicines Agency (Statens Legemiddelverk)

New Zealand (NZ) Pharmaceutical Management Agency/Pharmacology and Therapeutic Advisory Committee

Sweden (SE) Pharmaceutical Benefits Board (Läkemedelsförmånsämnden)

Switzerland (CH) Swiss Federal Office of Public Health/Confederal Drug Commission

(Bundesamt für Gesundheit/Eidgenössische Arzneimittelkommission)

United Kingdom (UK) National Institute for Clinical Excellence

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Drug Review Bodies:Role and Structure

AT AU BE

advisory-typebodies

regulatory type

AT AU BE CH DE NL

NO UK

CAFR

• Physicians• Health economists• Pharmacists, clinical pharmacologists• Epidemiologists• Government/insurance f d t tiregulatory-type

bodies FI NZSE

fund representatives• Consumers (AU, SE, UK)• Industry (UK)

Establishing comparativepost-licensing evaluation

2003 2004

IQWiGHEKPBAC

CEDAC

1987

PMPRB

1994

EAK

PPB

19991996

CFH

2002

NoMA

2000

PHARMAC

PBBNICE

CT

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Which pharmaceuticals are subject to evaluation?

• all newly licensed (AT, AU, NL)

th ith h i l b t (CA [CDR])• those with new chemical substances (CA [CDR])

• all patented (CA [PMPRB])

• all newly licensed for outpatient care (FI)

• newly licensed prescription drugs for outpatientcare (FR)care (FR)

• new and “old” prescription drugs (SE)

• specific products according to priority setting (UK)

Process of pharmaceuticalProcess of pharmaceutical evaluation in industrialised

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The pathway of a new drug

in Australia

Stakeholders may comment the ACD during a 4-wek period; individualy may access the ACD during the

final 3 weeks and may send comments directly to the Institute

(English) Department of Health and Welsh Govern-ment refer set of topics (“wave“) for appraisal to NICE

NICE appoints and contacts stakeholders to be

Appraisal

Evaluation process at NICE

Appraisal Committee discusses the comments received and issues the final recommendations:

Final Appraisal Document (FAD)

Stakeholders have the opportunity to appeal against the FAD

No appeal: An appeal is submitted:

2. Appraisal Committee is

NICE appoints and contacts stakeholders to be included in the process (patients´, nurses´

organisations, medical associartions, industry)

NICE commissions an independent institute (“assessment group“) to conduct the assessment and

NICE formulates “scope" of appraisal;this defines the relevant questions and outcomes (e.g. patient populations, outcome parameters)

FAD serves as basis for the Techno-logy

Appraisal Document

(TAG)

1. NICE changes the

TAG according to a

decision by the Appeal Panel (AP)

asked to review

evidence and conclusions and to take into account

the AP´s comments

Assessment group receives data, evidence and/or comments for potential inclusion in evaluation report

( g p )to write the assessment report

Appraisal Committee decides on preliminary recom-mendations: Appraisal Consultation Document (ACD)

TAG (Technical Appraisal Guidance) is published and formally submitted to the NHS in England und Wales

Assessment

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Sweden: Evaluation process at PBB

YELLOW BOX

EU-Ø

Price

Volume control through SHI association

Evaluation through DEC

Austria

YELLOW BOX

REDBOX Price band: Products

without an added benefit

Price band: Productswith an added benefit

Product after patentexpiry; pricewith generic = -30%

second generic

timet

without an added benefit

GREEN BOX

X months

(price = -25.7%)

Negotiations

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Who provides and analyses the data?

AU, NO, NL: Review bodies check and validate data provided by i d M f i d b i h iindustry. Manufacturers are required to submit a comprehensive summary of the drug’s effectiveness and cost-effectiveness data that is based on a systematic search and synthesis of published and unpublished evidence.

CA (CDR), NZ, SE, UK: Review bodies themselves perform systematic review of clinical and economic evidence independently of studies and data provided by companies.

AT, CA (PMPRB), CH, FI, FR: Assessments are mainly based on a definite number of clinical or economic studies which are submitted by pharmaceutical companies. Systematic reviews are preferred but not required.

Re-evaluation• in fixed or variable intervals (FI, FR, UK)• new characteristics of pharmaceutical

(e.g. new/broader indication)• if new/better clinical/economic evidence

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Methods for pharmaceutical evaluation in industrialised countries

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Criteria for Assessment and Decision-Making

Criteria AT

AU

BE

CA

CH

DE

FI

FR

NL

NO

NZ

SE

UK

Therapeutic benefit X X X X X X X X X X X X xTherapeutic benefit X X X X X X X X X X X X xPatient benefit X X X X X X X X X X X X XCost-effectiveness X X X X X X X X X XBudget impact X X X X X X X X XPharmacological/innovative characteristics X X X X X XAvailability of therapeutic alternatives X X X X X XEquity considerations X X X X XCommunity need X XPublic health impact X XR&D X XGovernment priorities X

In most countries drug is compared to• “common practice” (i.e. most frequently prescribed

medicine or most prevalent non pharmaceutical

Choice of Comparator

medicine or most prevalent non-pharmaceutical treatment) and/or

• the best available treatment (e.g. FI, NO, NZ, UK) or • least expensive therapeutic alternative (e.g. CA, FR,

NZ)Evaluation mostly for all licensed indication but in AUva uat o ost y o a ce sed d cat o but U

and FR only for main indication; CA also evaluates for off-label use.

Choice of comparator is crucial for result of assessment! Methological guidelines require close adherance

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Study designs• preferably “head-to-head” randomized

controlled trials (direct comparisons)• majority favours final outcome parameters

(change in mortality, morbidity, quality of life) and studies in “natural” and country specific setting

ili l f l• cost-utility analyses are most frequently recommended, required in AU, NZ, UK; quality-adjusted life years (QALYs) required as outcome in 4 countries

Final outcomes versus surrogate

parameters

source:PBAC

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Efficacy• explanatory trials

Effectivenessti t i l

Efficacy versus effectiveness

• explanatory trials• highly selected populations• comparator: placebo

• outcomes: clinical, morbidity,

• pragmatic trials• few exclusions• comparator: ‘current

(best) practice’• outcomes: patient-

mortality, adverse effects

• ‘what it says on the packet’

focused, down-stream resources

• ‘the real life effect’

Efficacy• explanatory trials

Effectivenessti t i l

Efficacy versus effectiveness

• explanatory trials• highly selected populations• comparator: placebo

• outcomes: clinical, morbidity,

• pragmatic trials• few exclusions• comparator: ‘current

(best) practice’• outcomes: patient-

mortality, adverse effects

• ‘what it says on the packet’

focused, down-stream resources

• ‘the real life effect’Evidence GapEvidence Gap

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Methodology: DetailsMethodologies further differ on:

sub-group analysis, time horizon, preferred outcome parameter (clinical patient benefitoutcome parameter (clinical, patient benefit, combined), use of „community effectiveness“ data (mostly preferred), indirect comparisons (mostly no), instruments to measure quality of life, perspective of economic analysis, costs included in analysis calculation of drug costsincluded in analysis, calculation of drug costs, incremental analysis, discounting (0%-15%), use of modelling techniques, sensitivity analysis, dealing with missing and unreliable data …

Methodological approaches to missing and incomplete data

• inclusion of various study designs and expert opinion (RCT is not a dogma)

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Classifying benefit(or benefit vs. harm)

France: Price negotiations according to Amélioration du Service Médical

Rendu-Classification (ASMR)ASMR I major therapeutic progress

ASMR II great improvement in terms of efficacy and/or reduction of side effects

ASMR III modest improvement

ASMR IV minor improvement

ASMR V no improvement but lower treatment costs

ASMR VI no improvement: no inclusion of the product on the positive list

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newsubstance

oldprinciple

drugtreatmentpossible

for first time

treatmentpossible

for first timeGrade of

innovation

newsubstance

newprinciple

Comparativebenefit no same/

similar

additional (patient

subgroup)

significantly additional(patient

subgroup)

none(i.e. generic)

newdosage

newcombination

new formof application

additional(majority of patients)

significantlyadditional

(majority ofpatients)

Efficiency

Price oforiginal

Price ofgeneric

44-48%below original/suffi-

ciently below existing generics?

therapeutic costs comparedto cheapest respective product in GREEN BOX

a bit

appropriatelyhigher?

economicallyappropriate and justifiable

without control?no

noyes

yes

no

no Austria-30%for first generc,

again ↓ with third generc?

No reimbursement GREEN BOXReimbursement without volume control

YELLOW BOXReimbursement

with volume control

sufficientlylower?

a bithigher?no yes

yes

yes

yes

no

no

Austria

New pharmaceuticals/ pharmaceuticals with new or broader indication(s)

Medical/th ti

Therapeutic Cost savingscompared to

No therapeuticadvantage and

Not appropriatefor Socialtherapeutic

break-through

padvantage compared to

other drugsadvantage andno cost savings

for SocialHealth Insurance

Switzerland

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Australia (PBAC): benefit (effectiveness) versus harm (toxicity)

e f f e c t i v e n e s s

more alike less

less ?

alike

toxic cost-

i i i ti

more

ity

minimisation-analysis

Decision-making: restrictions for use of pharmaceutical to…

• specific indications,• type and severity of diseases or conditions• type and severity of diseases or conditions,• populations (e.g. by age, sex),• therapeutic strategies (e.g. first/ second line,

salvage),• treatment settings (e.g. inpatient/ outpatient care,

general/specialist care),• prescribers (e.g. only specialists; FI, NZ) or • pre-authorisation through sickness fund (AT, BE)

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Decision-making: restrictions for use of pharmaceutical to…

• specific indications,• type and severity of diseases or conditionsnecessitates subgroup analyses – but • type and severity of diseases or conditions,• populations (e.g. by age, sex),• therapeutic strategies (e.g. first/ second line,

salvage),• treatment settings (e.g. inpatient/ outpatient care, attempt to target limited resources to

populations that are likely to benefit most

most RCTs are powered only for statistical significance of complete group

general/specialist care),• prescribers (e.g. only specialists; FI, NZ) or • pre-authorisation through sickness fund (AT, BE)

populations that are likely to benefit most (or to those for whom evidence is available)

Recommendations of NICEAll tech-nologies

Only drugs

% %

A Recommended 90.4 95.7

- for all indications 27.4 38.3

- Only for specific indications and/or populations

63.0 57.4

B Recommended only within clinical trials 6.9 4.3B Recommended only within clinical trials 6.9 4.3

C Not recommended 2.7 0.0

All decisions 100 100

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Linking degree of added benefit and/or innovation

to reimbursemento e bu se e

New pharmaceuticals/ pharmaceuticals with new or broader indication(s)

Medical/th ti

Therapeutic Cost savingscompared to

No therapeuticadvantage and

Not appropriatefor Social

Price = price ofcomparative drug

therapeuticbreak-through

padvantage compared to

other drugsadvantage andno cost savings

for SocialHealth Insurance

Price = price ofcomparative drug plus innovation mark-up of

10 to 20 %

Switzerland

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newsubstance

oldprinciple

drugtreatmentpossible

for first time

treatmentpossible

for first timeGrade of

innovation

newsubstance

newprinciple

Comparativebenefit no same/

similar

additional (patient

subgroup)

significantly additional(patient

subgroup)

none(i.e. generic)

newdosage

newcombination

new formof application

additional(majority of patients)

significantlyadditional

(majority ofpatients)

Efficiency

Price oforiginal

Price ofgeneric

44-48%below original/suffi-

ciently below existing generics?

therapeutic costs comparedto cheapest respective product in GREEN BOX

a bit

appropriatelyhigher?

economicallyappropriate and justifiable

without control?no

noyes

yes

no

no Austria-30%for first generc,

again ↓ with third generc?

No reimbursement GREEN BOXReimbursement without volume control

YELLOW BOXReimbursement

with volume control

sufficientlylower?

a bithigher?no yes

yes

yes

yes

no

no

Austria

Conclusion I:Criteria and Process

Post-licensing evaluation of drugs is a valuable policy tool

... it follows a systematic, evidence-based, comparative approach (which is not yet standardised),

IF...

... it is independently performed and supplemented by other criteria in the decision-making process

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Conclusion II:Methodological ChallengesPost-licensing evaluation of drugs is a valuable policy tool

... decision-makers are aware of its methological strenghts and limitations,... it is repeated once new evidence is

IF...

... it is repeated once new evidence is available.

Conclusion III:Policy Challenges

Post-licensing evaluation of drugs is a valuable policy tool

... it has reliable impact on rewarding manufacturers in terms of full reimbursement and/or free or premium pricing,

IF...

... potential for international collaboration to increase transparency and acceptability is increasingly used.

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500

600

AustriaBelgium

Pharmaceutical expenditure, PPP$ per capita

Does post-licencingevaluation save expenditure?Not necessarily …

200

300

400 DenmarkFinlandFranceGermanyGreeceIrelandItalyNetherlandsNorwayPortugalSpainSwedenSwitzerlandUnited Kingdom

0

100

1980 1985 1990 1995 2000 2005

This presentation and more material can be found on the following

websites:

http://mig.tu-berlin.de

www.observatory.dkhtt

p://m

ig.tu-

berlin

.de