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HTA and Managed Entry Practices inEurope
Industry Perspective
Dr Mercia PagePIPERSKA WORKSHOP,
GLASGOW 9th July 2009
OUTLINE
• Research and Innovation• Healthcare environment• HTA principles in practice
– Horizon scanning– Added therapeutic value– QALYs– Patient access schemes
• Conclusions
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Research and innovation
• Innovation– Bringing new/ improved technologies to
market that enhance the health of patientsand thereby bring value to patients, carers,families healthcare professionals and widersociety
• How to value innovation?
Innovation
• Extent of unmet need• Disease prevalence• Condition severity• Condition resolution vs stabilisation• Duration of benefit• Availability of alternative treatments• Patient convenience/ compliance
1960
1980
2000
Clofibrate
Carvedilol
1970
1990
Esmolol
Atenolol
Pindolol
Nadolol
Doxazosin
Terazosin
Prazosin
Phentolamine
Propranolol
Metoprolol
Sotalol
Labetalol
Timolol
Verapamil
Captopril
Nifedipine
Colestipol
Pronethanol
Losartan
Irbesartan Eprosartan
Acetalozamine
ChlorthiazidesFurosemide
Triamterene
Chlorthalidone Amiloride
Enalapril Lisinopril
BFGPeptides
Gemfibrizol
Lovastatin
QuinaprilRamipril
Benzapril
Perindopril
Pravastatin
Simvastatin
Atorvastatin
Diltiazem
AmlodipineNicardipine
Felodipine
Nimodipine
Isradipine
RosuvastatinMajor classes of innovative medicines introduced for CV disease
Source: The Impact of Therapeutic Reference Pricing on Innovation in Cardiovascular Medicine, Desmond Sheridan& Jim Attridge, 2006, Pharmacoeconomics, 24 Suppl.2, 40
““Vicious CircleVicious Circle””
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Health careresources are limited
Reimbursement ofinnovativetechnologies is achallenge in eachhealth care system
Without reimbursementpatients cannot getaccess to these life-saving technologies
Return on R&Dinvestment isreduced, innovativetherapies are moreexpensive
Source: Dr. Zoltán Kaló, Director, Health Economics Research Centre (HERC)Eötvös Loránd University, and President, Hungarian Health Economics Association &ISPOR Hungary Chapter, from presentation made 14 October 2008
Continually evolving context• Unprecedented economic downturn in addition to ageing, rising
expectations, greater incidence and prevalence of chronicconditions etc
• Impacts of economic downturn likely to be felt in a number of waysin the health care sector:– Unemployment on the rise and evidence that unemployed have higher
health needs than employed– Increase in ill health in the population as even employed become
worried– Delay of improvements in lifestyle behaviours (eg putting off quitting
smoking) and perhaps more poor lifestyle behaviours– Potential for ‘real’ budget cuts for health– Unclear extent or focus of cuts but perhaps prevention and other ‘soft’
targets such as medicine budgets
Together these all suggest even greater need for appropriate ways toinform inherently difficult resource allocation decisions
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Guiding principles for HTA
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Structure of HTAprogrammes Methods of HTA Processes for
conduct of HTAUse of HTA in
decision making
1. The Goal and Scope ofthe HTA Should BeExplicit and Relevant to ItsUse2. HTA Should Be anUnbiased andTransparent Exercise
3. HTA Should Include AllRelevant Technologies
4. A Clear System forSetting Priorities for HTAShould Exist
5. HTA Should IncorporateAppropriate Methods forAssessing Costs andBenefits
6. HTAs Should Considera Wide Range ofEvidence and Outcomes
7. A Full SocietalPerspective Should BeConsidered WhenUndertaking HTAs
8. HTAs Should ExplicitlyCharacterize UncertaintySurrounding Estimates
9. HTAs Should Considerand Address Issues ofGeneralizability andTransferability
10. Those ConductingHTAs Should ActivelyEngage All KeyStakeholder Groups
11. Those UndertakingHTAs Should Actively SeekAll Available Data
12. The Implementation ofHTA Findings Needs to BeMonitored
13. HTA Should Be Timely
14. HTA Findings Need toBeCommunicatedAppropriately to DifferentDecision Makers15. The Link Between HTAFindings and Decision-Making Processes Needs toBe Transparent and ClearlyDefined
Source: International Group for HTA Advancement (also called Drummond et al 2008), Key principles for the improved conduct of health technologyassessments for resource allocation decisions, International Journal of Technology Assessment in Health Care, 24:3 (2008), 1–15
Managed entry in the UK … more than HTA… full lifecycleNational……Regional……..Local
National Influence
Horizon scanningNHSC (National Horizon Scanning Centre)UKMI (UK Medicines Information)NPC (National Prescribing Centre)
HTA centresNICE (National Institute for Health andClinical Excellence)SMC (Scottish Medicines Consortium)AWMSG (All Wales Medicines Strategy Group)
Post-launch guidanceUKMI (UK Medicines Information)NPC (National Prescribing Centre)
Regional Influence
LNDG - London New Drugs Group LCNDG – London Cancer New Drugs Group MTRAC – Midlands Therapeutic Review and
Advisory Committee Wolfson Unit – Northern and Yorkshire
regional drug and therapeutics centre Berkshire Priorities Committee South Thames Regional MI Group – Guys,
NeLM Wessex drug and medicines information
centre SHAs Regional Specialised Commissioning Groups
(SCGs) Managed Clinical Networks – Scotland RMSC (Regional Medical Services
Consortium) – NI
Local Influence
APCsD&TCsPCOs – formularies/guidelines/incentivesPBCsPractices – practiceformulariesCancer Networks andother clinical networks
4. A Clear System forSetting Priorities for HTAShould Exist
National Horizon Scanning begins
NICE topic selection starts
Other Horizon Scanning Bodies start
Formulary Notification
Updates to additional databases groups
Early engagement with NICE
Primary/secondary carefinancial planninganalysis
Overview of horizon scanning
-3 yrs -2.5 yrs -2 yrs -1.5 yrs -1 yrs -0.5 yrs launch
Electronic Systems Access
HTA submissions start
Dialogue start with SMC/AWMSG plus keyarea Rxing committees
4. A Clear System forSetting Priorities for HTAShould Exist
Joint Work on UK HorizonScanning
• Commitment in 2009 PPRS for:
– “a single, unified horizon scanning process to identify newtechnologies in development by the industry. This process will bedeveloped in co-operation with the National Institute for Healthand Clinical Excellence (NICE), the Scottish MedicinesConsortium (SMC), the All Wales Medicines Strategy Group(AWMSG), the National Prescribing Centre (NPC), UKMedicines Information (UKMi) and the National HorizonScanning Centre (NHSC)”
• This coherent UK approach seems to be fit for purpose
• European level work via EIFFEL by EUnetHTA
11Source: DH, 2009 PPRS, http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/DH_091825
4. A Clear System forSetting Priorities for HTAShould Exist
Biologics and biosimiliars:We need to think carefully about interchangeability
• A biologic is medicinal product made from living organisms• Non-identical nature of a biosimilar to originator product can lead to
variations in bioactivity & immunogenicity• Clinical trials should be required to demonstrate safety, efficacy & lack of
deleterious immunogenicity of a biosimilar• Impact of interchangeability cannot be feasibly assessed due to required
size of clinical trial• All biologics should have unique names for distinguishing in prescribing,
dispensing, and for pharmacovigilance purposes• Do support an accelerated pathway for development• Do support standards to appropriately characterize molecule including the
conduct of clinical trials• Do not support interchangeability• Do support protecting incentives for innovations• Do support use of unique naming for Biosimilars12
Added Therapeutic Value: SomeApproaches
Swedish TLV explicitlycharged with ‘stimulatinginnovation’ though’ usingcost effectiveness from a‘societal perspective’.
Italian reimbursementcriteria make transparentdeterminations on thedegree of innovation
France – Amelioration duService Medical Rendu (ASMR)“Improvement in the MedicalService” (ASMR) criterionrelates to a medicine’s degree ofinnovation relative to the existingsituation/available treatments.
I. Major: ‘Major therapeutic progress’ II. Important: ‘Important improvement’ III. Modest: ‘Modest improvement’ IV. Minor: ‘Minor improvement’V. No improvement
Other codified criteria include: Severity & prevalence of disease Availability of existing treatments ‘Size’ of the therapeutic effect
Innovation scored on aScale of 1-5
Decision making based on three criteria: Human value principle Need and solidarity principle Cost-effectiveness principle
Added Therapeutic Value and JointAdvice• Emerging trend of greater interest by regulatory
agencies and HTA agencies• Opportunities to learn from this work:
– EMEA is currently looking at the potential for a risk –benefit ranking system which could summarise therelative benefits of products
– Early Scientific Advice in England - NICE– Joint Scientific Advice in UK planned – MHRA and
NICE– Joint Scientific Advice in Sweden - TLV and MPA
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QALYS
• Issues remain over the use of the QALY as themeasure of benefit– Different methods of underpinning the QALY result in
different answers, and not as yet consensus onappropriate method (EQ 5D, HUI3 etc)
– Bias towards life saving technologies– QALYs can discriminate against the old (less life
years left to live) and other groups– Ignores wider benefits, for example carers’ health
status may be improved if dependents’ health statusimproves
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5. HTA Should IncorporateAppropriate Methods forAssessing Costs andBenefits
Thresholds• Range of thresholds for cost/QALY used across Europe• No empirical underpinning• Much debate over appropriate scale of the threshold
(£20-£30,000k range currently used by NICE but othershave suggested it should be lower)
• Needs consideration of both:– Willingness to pay for health outcomes– Opportunity costs (what will be displaced by using a
particular technology)• And other factors which could be used to alter the
threshold (eg severity of disease as a modifier to thethreshold) as used in some countries (eg Sweden, beingexplored in Netherlands)
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Flexibility• There is considerable uncertainty over a products value at launch• Modelling and appropriate sensitivity analysis within economic
evaluation component of HTA can explore this• However, uncertainty will still remain in what the full value is and
when it will become evident....• Suggests flexibility is required within HTA and it’s resulting
recommendations• New guidance to NICE Appraisal Committees to take into
consideration when the following criteria are met:– The treatment is indicated for patients with a short life expectancy, normally less
than 24 months and;– There is sufficient evidence to indicate that the treatment offers an extension to
life, normally of at least an additional 3 months, compared to current NHStreatment, and;
– No alternative treatment with comparable benefits is available through the NHS,and;
– The treatment is licensed or otherwise indicated, for small patient populations.
• Too early to determine the impact of this change18
8. HTAs Should ExplicitlyCharacterize UncertaintySurrounding Estimates
Source, NICE, Dec 2008, http://www.nice.org.uk/media/88A/F2/SupplementaryAdviceTACEoL.pdf
Surrogate markers
• Need to recognise that there will always be risksand uncertainties at a given point in time
• May not be able to measure final outcome givenpractical constraints (may require large trial popn
and long follow up)• Surrogate markers (eg CD4 counts in HIV)
provide an opportunity to measure meaningfuloutcome(s) as a predictor for final outcome
• Area where there needs to be further work todetermine when and which surrogate outcomesare appropriate in HTA19
8. HTAs Should ExplicitlyCharacterize UncertaintySurrounding Estimates
Releasing funds for innovation• Reduces waste or increasing efficiency could
release funds for innovation• But again, this is hard….• Needs refocused efforts on the part of HTA
agencies to consider technologies and otheractivities in the system which do not bring benefitsand are of limited value
• HTA can identify what to do less of…but otheragencies may need to influence and implementchanges to release funds
• Suggests joint working across the system bydifferent agencies
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3. HTA Should Include AllRelevant Technologies
Patient access schemes
• UK has seen a number of patient accessschemes
• Still relatively early to assess their success inachieving access at acceptable costeffectiveness
• Likely other countries will find the principlesjointly developed between ABPI and the DHuseful
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15. The Link Between HTAFindings and Decision-MakingProcesses Needs to Be Transparentand Clearly Defined
UK NHS agreed to a payer-rebate schemewith J&J for Velcade to treat Multiple Myeloma in 2007
Company: J&JLocation: UKYear: 2007Product: VelcadeDA: Multiple Myeloma
Benefits
• Patients receive effective treatment for lifethreatening disease with few alternatives
• Unique working arrangement with NHSindicated willingness of J&J to engage ininnovative pricing
• May lead to closer working relationshipswith NHS
• Additional sales in UK and reducedPR concerns
Challenges
• Clinical outcomes are not always measurable• Complex issues regarding partial response;
patients who reach 48% reduction non-reimbursable but do have benefit
• May encourage over-use as non responderswill be reimbursed
Payer Rebate
Outcomes
Market access
Takeaways
• Definition of appropriate clinical endpoints iscritical to effective outcomes risk sharing
• May be challenging to implement without post-marketing study of actual (non-trial) use inapproved markets
• Approach predicated upon existing clinical data(observed effectiveness inother countries)
High
Medium
LowMarginal
Incremental
Novel
Other
Acute
Chronic
Patient
Physician
Hospital
Non-reimbursed
Restricted
Unrestricted
Generic
Comparable
Novel
Low
Significant
High
Cash pay
Private
Single payerKey info
Background• No consensus treatment for Multiple Myeloma• Velcade clinically effective in 38% of patients; approved in US in 2003, EU 2004• Cost of one cycle of Velcade is approximately £3,000; results in base-case analysis of
approximately £38,000 per QALY
Structure• Treatment continued for patients with complete or partial response (reduction in serum M
protein of 50% or more)• Response is measured using serum M protein after a maximum of four cycles
of treatment• Rebate for full cost of Velcade after a maximum of four cycles of treatment if patients has
less than a partial response
Outcome• Agreement covered England and Wales — still no coverage in
Scotland as of Oct 2008
Method
Lessons
TreatmentcostInnovation
Diseasetype AdministerPayer
Reimbur-sement
Compe-titionUnmet need
Biogen, Schering,Teva/Aventis, Serono MS Risk SharingScheme for Beta Interferons and Glatiramer Acetate in UK in
2002 and ongoingCompany: Biogen, Schering,
Teva/Aventis, andSerono
Location: UKYear: 2002–ongoingProduct: Avonex, Betaferon,
Copaxone, RebifDA: Muttiple Sclerosis
Background• Annual cost per patient of the beta interferons in the UK in 2002 was £7,259 (Betaferon),
£9,061 (Avonex) or £9,088/£12,068 (lower dose/higher dose Rebif ) and glatiramer acetatewas £6,650
• Significant variation in estimates of cost per QALY; £10,000 per QALY (an estimate derivedfrom commercial-in-confidence data) to over $3 million per QALY (an American researchgroup’s findings)
• Significant uncertainty in clinical benefits in the long termStructure• Target of £36,000 per QALY• 5,000 patients monitored on Expanded Disability Status Scale• Future price reductions could be asked for if fail to achieve this target• Compared against historical Canadian cohort of patients• Specialist nurses funded by manufacturers
Outcome• Widespread patient access to what was then the only treatment
options available• Only report on outcome to date concludes: demonstrates practical,
but highlights political tensions• No data available on cost per QALY estimates and/or if price
reductions have occurred
Benefits
• Patient access• Increased number of specialist nurses
Challenges
• Lack of infrastructure hindered implementation• Conflicts on ownership of data and intellectual
property led to change of contractor tocomplete analysis
• Questions raised about whether a longer termRCT would have been more appropriate
• Change in epidemiology of disease sincescheme set up
Budget
Takeaways
• First example of patient access scheme in UK• Schemes require investment in governance
arrangements
High
Medium
LowMarginal
Incremental
Novel
Other
Acute
Chronic
Patient
Physician
Hospital
Cash pay
Single payer
Non-reimbursed
Restricted
Unrestricted
Generic
Comparable
Novel
Low
Significant
HighKey info
Method
Lessons
Sources: http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_4012214.pdfhttp://www.mstrust.org.uk/research/risksharingscheme/http://www.mstrust.org.uk/downloads/rss.pdfhttp://www.bmj.com/cgi/content/extract/326/7385/388http://www.pharmj.com/Editorial/20020803/news/news_ms.htmlhttp://www.msrc.co.uk/index.cfm?fuseaction=show&pageid=1893&CFID=7878852&CFTOKEN=40510486http://pn.bmjjournals.com/cgi/reprint/3/4/194.pdfhttp://www.parliament.uk/post/pn168.pdfhttp://www.nice.org.uk/guidance/index.jsp?action=byID&o=11441http://www.biomedcentral.com/content/pdf/1471-2377-9-1.pdf
TreatmentcostInnovation
Diseasetype AdministerPayer
Reimbur-sement
Compe-titionUnmet need
Pricing by indication
Maintain market
Private
Patient access schemes: DH and ABPI Principles(1)
• Arrangements must respect the role of NICE in providing the NHS with an independentassessment and appraisal of the evidence on an intervention.
• Schemes are to be discussed first and agreed in principle by the Department and the company.NICE’s principal role is to assess the impact of such proposals on cost-effectiveness taking intoaccount the details of the proposed scheme.
• The full costs to the NHS of any such arrangements should be included in the costs consideredby the Appraisal Committee.
• Schemes should be clinically robust, clinically plausible, appropriate and monitorable (e.g. if it is aresponder scheme, there must be a relatively straightforward way to measure a patient’s clinicalresponse).
• Any scheme should be operationally manageable for the NHS without unduly complex monitoring,disproportionate additional costs and bureaucracy. Any burden for the NHS should beproportionate to the benefits of the scheme for the NHS and patients. Clarity is also required onthe exact duration of any agreement and the circumstances in which it might be terminated.
• It is important that the cumulative administrative burden of such schemes remains manageablefor all parties involved in their operation, including front-line NHS staff. It is reasonable for theDepartment to take this issue into account when considering the viability of individual schemes.Priority is likely to be given to schemes that deliver the greatest benefits to patients, for examplein enabling the NHS to address a previously unmet need.
24Source: DH, 2009 PPRS, http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/DH_091825
• Schemes should be consistent with existing financial flows in the NHS and with localcommissioning (e.g. payers must be able to calculate the effective price for theirpatient population, so the costs and savings accrue to those local services makingcommissioning and treatment decisions).
• The NHS in England and Wales must be consulted on patient access schemes, inparticular where these involve additional data collection beyond that associated withthe conventional purchase of medicines – for example in relation to patient numbers,or the monitoring and recording of a patient’s condition over and above that for thenormal management of a patient. The Department will set out in more detail thenature of that consultation.
• The more systematic use of such schemes will need to be reviewed in light ofexperience. The timing of such a review will be jointly agreed but will be initiated notlater than two years after the commencement of this agreement.
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Patient access schemes: DH and ABPI Principles(2)
Source: DH, 2009 PPRS, http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/DH_091825
HTA and the broader system• Useful to remind stakeholders of how HTA fits in the broader system• Can we ever expect HTA to deal with all the factors that influence
medicines expenditure?• Will always need a suite of tools to enable the system to deliver
optimal value from all inputs• Must also recognise HTA is continually evolving:• “Health technology assessment will have to evolve from an
expression of rationalism in the form of establishing normativebehaviours (e.g., how practitioners should use a given technology)to a means of providing information that will contribute toelucidating preferences. The next phase in its evolution willrequire a major shift from simple, linear dissemination to the morecomplex interactive communication of information with a view toassisting people in making decisions.” (1)
• Much to learn from other countries and networks involved in HTA
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15. The Link Between HTAFindings and Decision-MakingProcesses Needs to Be Transparentand Clearly Defined
(1) Battista, RN and Hodge, MJ The evolving paradigm of health technology assessment: reflections for the millennium JAMC 1999; 160 (10):1464-67
HTA as a Continuum in Informing Decisions
• Decisions are taken at a number of levels in the system:– Patient level– Provider level (eg Hospital)– Regional level (eg County Councils in Sweden, PCTs in England)– National level
• There can be tensions if the decisions are made on a differentbasis
• HTA can be a aid to consistency in theory (although questionsremain over how far HTA can and has delivered consistency inpractice)
• Must recognise always need for flexibility to fit the local context
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15. The Link Between HTAFindings and Decision-MakingProcesses Needs to Be Transparentand Clearly Defined
Conclusions
• Pharmaceutical R&D is costly, risky and takesconsiderable time
• Health care systems and wider economic environmentcontinually changing
• Current economic downturn places even greater focuson difficult resource allocation decisions
• HTA can inform these decisions, and should be guidedby principles for ‘good’ HTA
• Flexibility is useful in structures, methods, processes,and use of HTA in decision making, whilst respectingprinciples for HTA
• HTA links to patient access schemes directly but theytoo need flexibility and to be guided by principles for‘good’ schemes
• Still much work to be done, but increasingly networkedworld of HTA with expertise to draw on across the globe
• Ongoing dialogue will be required28