ACCESSPOINT • VOLUME 5 • ISSUE 10 PAGE 45

The author

Natalia balko, mbA is Engagement Manager, RWE Solutions, IMS HealthNbalko@imshealth.com

Convergence of HTA assessmentsin Europe – reality or aspiration?

Health policy developments across Europe continue to focuson the dual ambition of controlling costs while improvingaccess to innovative drugs. Health Technology Assessments(HTA) are a key lever for appraising the value of medicines tomanage pharmaceutical expenditure. With their influence andnumber growing in the region there have been moves towardsharmonization but, as analysis of recent launches shows, manycomplex and countervailing forces make this a challenging goal.

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HTA trends in EuropeHTA agencies have been playing ameaningful role in pharmaceutical pricing andreimbursement in Europe for a number ofyears and will continue to do so. However,their impact can vary due to differences inassessment approach and implementation.

Assessment approachSince they were first established, the various European HTAbodies have continued to evolve their criteria andmethodologies for assessment. These typically include:measures of clinical effectiveness and safety; quality of life;cost (including cost-effectiveness or budget impact); andcountry-specific values (eg, equity). Further, individualcountries may have their own specific requirements. InGermany, for example, appropriate comparators are definedby the G-BA (Federal Joint Committee); failure to use anappropriate comparator results in a ‘no additional benefit’decision from the HTA process.

Given the differences in assessment criteria, methodologiesand requirements, HTA decisions among countries candiffer substantially for a given product. This becomeschallenging for manufacturers in planning developmentand launch strategies if the same evidence package can beevaluated in different ways, with varying results.

ImplementationTypically, HTA agencies influence access; many also affectreimbursed price. Exceptions are France and Germany,where HTA solely impacts reimbursed price (Figure 1).

Some countries have had a proliferation of regional HTAbodies (eg, Italy) or agencies focused on a subset oftherapeutic classes (eg, Denmark for high-cost therapies).With different scopes of influence, the impact of an HTAdecision on price, access and ultimately uptake will varybased on the specific system. As implementation of HTA isprimarily defined by the pricing and reimbursementstructure, there will necessarily be differences by country or region.

Given that implementation will vary from market to marketby definition, addressing differences in assessmentapproach has become the focus of efforts for convergenceby policymakers, pharmaceutical manufacturers, HTAagencies and associations, with the goal of achievinggreater consistency in evaluation of the underlying evidence.

Figure 1: Scope and impact of HTA by market

Germany France

Austria Belgium Bulgaria Estonia

Italy Finland Lithuania Netherlands Norway

Poland Portugal Romania Sweden

Spain Croatia Cyprus Denmark

Ireland Hungary Latvia

Malta Slovak Republic UK Switzerland

Czech Republic Greece

Slovenia Turkey

Impa

ct o

n Re

imbu

rsed

Pric

e

Impact on Access

NO YES

NO

YES

Convergence of HTA assessmentsin Europe – reality or aspiration?

INSIGHTS COMMERCIAL & MARKET ACCESS

ACCESSPOINT • VOLUME 5 • ISSUE 10 PAGE 47

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The push towards HTA convergenceAs countries evolve their HTA systems, there is a naturaltendency towards divergence in their evaluations. However,several counterbalancing forces are tempering this:

• Formal and informal referencing. Increasingly,countries have been referencing the HTA decisions ofother markets; in particular, the UK, Sweden, France andGermany are often referenced by neighboring markets orcountries with similar value systems. A recent IMSHealth analysis found evidence of formal referencing in10 EU markets and informal referencing in 16 markets.Three markets showed evidence of both formal andinformal referencing depending on the timing of reviews,specific topics (eg, cost-effectiveness) and case-by-caseneeds. Most countries that do not reference today areexpected to begin referencing informally in the future. Inconsidering the evaluations of other countries, HTAagencies effectively reduce some of the differences inreviews and methods. Potentially, this also leads to amore consistent evaluation of evidence.

• European collaboration. Progress is being made towardsgreater collaboration in assessments among EU markets,with the goal of developing common approaches. Inparticular, the establishment of EUnetHTA has beeninstrumental in facilitating this collaboration, in partthrough the development of methodologies, guidelinesand tools.

• Reassessments. Conditional reimbursement andrequirements for RWE are becoming increasinglycommon. As an example, Zytiga (abiraterone) gainedaccess in Sweden conditional on an agreement to studyreal-world use and performance. France recently re-evaluated the ‘new oral anticoagulants’, lowering thetherapeutic (SMR) value of Pradaxa (dabigatran) andraising that of Eliquis (apixaban) given evidence fromreal-world practice and the level of value perceived.

RWE generated to support these reassessments increasesthe evidence base that can be evaluated on an ongoingbasis and can address some of the uncertainties that ledto different initial decisions.

These forces can be expected to moderate divergence butnot fully correct for it; some criteria considered by HTAagencies, such as cost or local guidelines, will vary bymarket and limit the potential for total convergence.However, greater consistency in evidence evaluation,particularly around the perceived level of benefitimprovement, would help to reduce inefficiencies and risksfor pharmaceutical manufacturers and, potentially, barriersto access and uptake.

Drivers of convergence and divergence in HTA evaluationsTo assess the extent of convergence among HTAevaluations, IMS Health analyzed results for 12 recentlaunches in four therapeutic areas (TA): type 2 diabetes;multiple sclerosis; prostate cancer; and hepatitis C. As aproxy for convergence, the analysis considered theheterogeneity of HTA evaluations between countries andwithin a country for products in a TA. Convergence in themarket would be seen if:

• Views of the evidence submission were similar amongcountries

• Products were evaluated similarly across markets

• Products in the same class or TA were evaluated using aconsistent set of criteria

The TAs were selected to represent characteristics that candifferentially affect HTA decisions:

• Type of TA (traditional vs. specialty)

• Budget impact

• Payer perceived unmet need

• Level of genericization

Source: IMS Health

Dimension

Nature ofTherapeutic

Area

Critic alEndpoints

TrialDesign

Divergence

High cost Low unmetneed, limiteddifferentiation

Epidemiology High unmet need,strong productdifferentiation

Patient-reportedoutcomes

Surrogate endpoints Hard endpoints

Severalplausible

comparators

Superiorityvs. inferiority

Subgroupdefinition

Clearcomparator

Convergence

Figure 2: Dimensions affecting HTA convergence

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INSIGHTS COMMERCIAL & MARKET ACCESS

HTA evaluations were compared in France, Germany, Swedenand the UK (England and Scotland) due to the importance ofthese markets in influencing other EU countries and theperceived differences between the HTA approaches.

The analysis identified three primary dimensions thatinfluence the extent of convergence that can be expected forHTA evaluations across markets (Figure 2).

Overall, HTA agencies had greatest alignment for TAs thatare more ‘simple’ – that is, they have well-acceptedbenchmarks (eg, overall survival primary endpoint forprostate cancer), clear subpopulations, and well-acceptedtreatment paradigms and guidelines.

HTA agencies were least aligned for more ‘complex’ TAs andsituations where there is the greatest room forinterpretation around the level of improvement. Thissuggests that there is some implicit convergence in HTAdecisions but an opportunity for greater alignment in areaswhere there is a fundamental difference in theunderstanding and evaluation of the evidence.

Nature of the TAInherent characteristics of a TA can affect the extent towhich HTA assessments are likely to diverge. While many ofthese factors are largely beyond the influence ofmanufacturers, they provide context for the environment inwhich the product will be assessed.

• High unmet need, strong product differentiation.HTA assessments tended to converge on the benchmarksused to evaluate the product and the overall level ofclinical benefit afforded. In the case of hepatitis C, forexample, HTA agencies were in general agreement thatSovaldi (sofosbuvir) was differentiated, addressed unmetneeds and offered clinical benefit.

• Epidemiology. Country-level differences in diseaseepidemiology can influence the perceived need within adisease or specific subgroups and therefore the value thata therapy can bring. In hepatitis C, agencies evaluatedgenotypes differently which can be attributed in part toprevalence differences in individual countries.

• Low unmet need, limited differentiation. Products aremore likely to have divergent HTA evaluations betweenmarkets. In type 2 diabetes, for example, the ultimateresult of evaluations for the SGLT-2 class variedsubstantially between markets even though agencieswere relatively consistent in their evaluation of productswithin the class. The differences may be attributed to anumber of factors, including different thresholds for thelevel of benefit expected.

• High cost.With HTA agencies varying in theirconsideration of cost measures, high-cost therapies areinherently subject to divergence as these bodies look tomanage cost or budget impact exposure.

While many of these intrinsic TA characteristics cannot bechanged by manufacturers, they nevertheless should beconsidered in designing the trial and evidence submission tounderstand where divergence is likely and anticipateevidence needs to address underlying differences.

Critical endpointsChoice of trial endpoints has a substantial impact onefficacy evaluations. HTA agencies varied significantly intheir assessment of ‘soft’ endpoints, including the extent towhich they afforded a benefit and the weight theseendpoints played in decision making. In many casesagencies expressed uncertainty in this assessment, whichsuggests a role for manufacturers in working with HTAbodies to develop understanding around these endpointsearly in development to maximize impact.

• Hard endpoints. Hard endpoints, such as overall survivalin prostate cancer, were evaluated with greatestconsistency among countries and products. As theseendpoints are well understood and tend to haveestablished benchmarks, agencies generally agree intheir evaluations.

• Surrogate endpoints. Agencies tend to view surrogateendpoints differently across markets, in part becausetheir impact on overall outcomes may not be welldefined. This is especially true for surrogate endpointsthat are relatively new within a given TA, such as bloodpressure and weight for the SGLT-2 inhibitor class. Giventhe often lack of general agreement over evaluation ofthese endpoints, interpretation can vary by market.

• Patient-reported outcomes (PROs). Similar to surrogateendpoints, PROs can be interpreted differently by marketdepending on acceptance and perception of their value.Different views are compounded because agencies vary inthe weight they place on these endpoints (eg, quality oflife) and whether they expressly take them into accountas a part of the evaluation. Sweden, for example, tendedto consider the impact of new prostate cancer therapieson pain more explicitly than other countries.

In many cases, choice of endpoint is dictated by the TA.Nevertheless, manufacturers should anticipate thatagencies are likely to have divergent views on surrogateendpoints and PROs, and work with them to improveunderstanding of these endpoints, which can lead to moreconsistent evaluation.

Intrinsic therapy area characteristics should be considered in designingthe trial and evidence submission to understand where divergence islikely and anticipate evidence needs.

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ACCESSPOINT • VOLUME 5 • ISSUE 10 PAGE 49

Efforts to align stakeholders should increase shared understanding ofendpoints, benchmarks and trial design elements, such that a piece ofevidence is evaluated similarly across countries.

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Trial designElements of trial design, such as comparator, subgroupdefinition and powering of the trial (superiority vs. non-inferiority) can be a deciding factor in HTA evaluations. Thisis particularly true in markets like Germany, where use ofthe ‘wrong’ comparator can result in ‘no additional benefit’being granted. More complex TAs (many comparators, lackof appropriate standard of care, complicated subgroups) canbe subject to divergent assessments because each agency candefine its benchmarks and important criteria differently.

• Comparator selection. Having a clear comparatorsupports convergence across markets. However, in TAswith multiple plausible comparators, selecting the‘right’ comparator is critical. In Germany, for example, itis critical to include an appropriate comparator asdefined by the G-BA. Failing to do so will createdivergence, especially if other markets accept thespecific comparator. Choice of comparator influencesplace within the treatment paradigm so it is importantthat the comparators selected adequately account formarket differences.

• Sub-group definition. Subgroups can support positiveHTA evaluations by narrowing the population to one thatshows greater effectiveness, relative benefit or cost-effectiveness. However, unless relevant subpopulationshave robust and statistically significant clinicalendpoints, agencies can interpret the benefit in thesepopulations differently. In the case of subpopulationsthat are not clearly defined, this segmentation can bedetrimental to the evaluation.

• Trial powering (superiority vs. non-inferiority).Superiority trials are typically thought to be demanded bypayers. However, they appear to hold greater weight incertain markets, such as France. For example, lack ofsuperiority data for Tecfidera (dimethyl fumarate) wascited as a key reason for its ASMR V rating (notherapeutic benefit); however, it had more positiveevaluations in Sweden and the UK, reflecting a lack ofHTA convergence in multiple sclerosis overall.

Each HTA agency has requirements or preferences for trialdesign elements; failure to follow these principles can lead to anegative evaluation but also divergence of evaluations acrossmarkets, due to different standards. However, trial designpresents an opportunity for pharmaceutical manufacturers toalign with agencies during drug development to ensure thattrial plans meet stakeholder needs. Further, this is an areawhere EU collaborative efforts and closer alignment withregulators can increase the potential for convergence throughclear methods and standards.

ImplicationsConvergence in HTA assessments has begun but is far frombeing widespread. A greater degree of convergence isobserved in more straightforward situations wherebenchmarks are well understood, such as clear hardendpoints, high unmet need and strong differentiation, andclear comparators and subgroups. On the other hand,divergence continues in more complex situations whichwould stand to benefit from greater convergence.

There are several principles that manufacturers shouldconsider during development and pre-launch to increase thelikelihood of more consistent evaluations across markets:

• Carefully select appropriate comparators

• Focus on hard endpoints where possible

• Ensure that subpopulations are clearly defined withrobust analyses

Efforts to align stakeholders should increase sharedunderstanding of endpoints, benchmarks and trial designelements, such that a piece of evidence is evaluatedsimilarly across countries. However, full convergence isunlikely as countries will still have fundamental differences,for example on the importance of cost or the weight placedon PROs.

Manufacturers should consider how TA and product-specificfactors are likely to be evaluated differently by each HTAagency to inform trial and launch planning as well aspreparations for post-launch RWE generation. It may bepossible to influence greater convergence by creating sharedunderstanding of different endpoints and trial designelements. In doing so, manufacturers can reduce risks andinefficiencies associated with divergent evaluations.