Convergence of HTA assessments in Europe

ACCESSPOINT • VOLUME 5 • ISSUE 10 PAGE 45
The author
Natalia balko, mbA
is Engagement Manager, RWE Solutions, IMS Health
Nbalko@imshealth.com
Convergence of HTA assessments
in Europe – reality or aspiration?
Health policy developments across Europe continue to focus
on the dual ambition of controlling costs while improving
access to innovative drugs. Health Technology Assessments
(HTA) are a key lever for appraising the value of medicines to
manage pharmaceutical expenditure. With their inﬂuence and
number growing in the region there have been moves towards
harmonization but, as analysis of recent launches shows, many
complex and countervailing forces make this a challenging goal.

IMS HEALTH REAL-WORLD EVIDENCE SOLUTIONS
HTA trends in Europe
HTA agencies have been playing a
meaningful role in pharmaceutical pricing and
reimbursement in Europe for a number of
years and will continue to do so. However,
their impact can vary due to differences in
assessment approach and implementation.
Assessment approach
Since they were first established, the various European HTA
bodies have continued to evolve their criteria and
methodologies for assessment. These typically include:
measures of clinical effectiveness and safety; quality of life;
cost (including cost-effectiveness or budget impact); and
country-specific values (eg, equity). Further, individual
countries may have their own specific requirements. In
Germany, for example, appropriate comparators are defined
by the G-BA (Federal Joint Committee); failure to use an
appropriate comparator results in a ‘no additional benefit’
decision from the HTA process.
Given the differences in assessment criteria, methodologies
and requirements, HTA decisions among countries can
differ substantially for a given product. This becomes
challenging for manufacturers in planning development
and launch strategies if the same evidence package can be
evaluated in different ways, with varying results.
Implementation
Typically, HTA agencies influence access; many also affect
reimbursed price. Exceptions are France and Germany,
where HTA solely impacts reimbursed price (Figure 1).
Some countries have had a proliferation of regional HTA
bodies (eg, Italy) or agencies focused on a subset of
therapeutic classes (eg, Denmark for high-cost therapies).
With different scopes of influence, the impact of an HTA
decision on price, access and ultimately uptake will vary
based on the specific system. As implementation of HTA is
primarily defined by the pricing and reimbursement
structure, there will necessarily be differences by country
or region.
Given that implementation will vary from market to market
by definition, addressing differences in assessment
approach has become the focus of efforts for convergence
by policymakers, pharmaceutical manufacturers, HTA
agencies and associations, with the goal of achieving
greater 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
ImpactonReimbursedPrice
Impact on Access
NO YES
NOYES
Convergence of HTA assessments
in Europe – reality or aspiration?
INSIGHTS COMMERCIAL & MARKET ACCESS

continued on next page
The push towards HTA convergence
As countries evolve their HTA systems, there is a natural
tendency towards divergence in their evaluations. However,
several counterbalancing forces are tempering this:
• Formal and informal referencing. Increasingly,
countries have been referencing the HTA decisions of
other markets; in particular, the UK, Sweden, France and
Germany are often referenced by neighboring markets or
countries with similar value systems. A recent IMS
Health analysis found evidence of formal referencing in
10 EU markets and informal referencing in 16 markets.
Three markets showed evidence of both formal and
informal referencing depending on the timing of reviews,
specific topics (eg, cost-effectiveness) and case-by-case
needs. Most countries that do not reference today are
expected to begin referencing informally in the future. In
considering the evaluations of other countries, HTA
agencies effectively reduce some of the differences in
reviews and methods. Potentially, this also leads to a
more consistent evaluation of evidence.
• European collaboration. Progress is being made towards
greater collaboration in assessments among EU markets,
with the goal of developing common approaches. In
particular, the establishment of EUnetHTA has been
instrumental in facilitating this collaboration, in part
through the development of methodologies, guidelines
and tools.
• Reassessments. Conditional reimbursement and
requirements for RWE are becoming increasingly
common. As an example, Zytiga (abiraterone) gained
access in Sweden conditional on an agreement to study
real-world use and performance. France recently re-
evaluated the ‘new oral anticoagulants’, lowering the
therapeutic (SMR) value of Pradaxa (dabigatran) and
raising that of Eliquis (apixaban) given evidence from
real-world practice and the level of value perceived.
RWE generated to support these reassessments increases
the evidence base that can be evaluated on an ongoing
basis and can address some of the uncertainties that led
to different initial decisions.
These forces can be expected to moderate divergence but
not fully correct for it; some criteria considered by HTA
agencies, such as cost or local guidelines, will vary by
market and limit the potential for total convergence.
However, greater consistency in evidence evaluation,
particularly around the perceived level of benefit
improvement, would help to reduce inefficiencies and risks
for pharmaceutical manufacturers and, potentially, barriers
to access and uptake.
Drivers of convergence and divergence in
HTA evaluations
To assess the extent of convergence among HTA
evaluations, IMS Health analyzed results for 12 recent
launches in four therapeutic areas (TA): type 2 diabetes;
multiple sclerosis; prostate cancer; and hepatitis C. As a
proxy for convergence, the analysis considered the
heterogeneity of HTA evaluations between countries and
within a country for products in a TA. Convergence in the
market would be seen if:
• Views of the evidence submission were similar among
countries
• Products were evaluated similarly across markets
• Products in the same class or TA were evaluated using a
consistent set of criteria
The TAs were selected to represent characteristics that can
differentially affect HTA decisions:
• Type of TA (traditional vs. specialty)
• Budget impact
• Payer perceived unmet need
• Level of genericization
Source: IMS Health
Dimension
Nature of
Therapeutic
Area
Critical
Endpoints
Trial
Design
Divergence
High cost Low unmet
need, limited
differentiation
Epidemiology High unmet need,
strong product
differentiation
Patient-reported
outcomes
Surrogate endpoints Hard endpoints
Several
plausible
comparators
Superiority
vs. inferiority
Subgroup
definition
Clear
comparator
Convergence
Figure 2: Dimensions affecting HTA convergence

IMS HEALTH REAL-WORLD EVIDENCE SOLUTIONS
INSIGHTS COMMERCIAL & MARKET ACCESS
HTA evaluations were compared in France, Germany, Sweden
and the UK (England and Scotland) due to the importance of
these markets in influencing other EU countries and the
perceived differences between the HTA approaches.
The analysis identified three primary dimensions that
influence the extent of convergence that can be expected for
HTA evaluations across markets (Figure 2).
Overall, HTA agencies had greatest alignment for TAs that
are more ‘simple’ – that is, they have well-accepted
benchmarks (eg, overall survival primary endpoint for
prostate cancer), clear subpopulations, and well-accepted
treatment paradigms and guidelines.
HTA agencies were least aligned for more ‘complex’ TAs and
situations where there is the greatest room for
interpretation around the level of improvement. This
suggests that there is some implicit convergence in HTA
decisions but an opportunity for greater alignment in areas
where there is a fundamental difference in the
understanding and evaluation of the evidence.
Nature of the TA
Inherent characteristics of a TA can affect the extent to
which HTA assessments are likely to diverge. While many of
these factors are largely beyond the influence of
manufacturers, they provide context for the environment in
which the product will be assessed.
• High unmet need, strong product differentiation.
HTA assessments tended to converge on the benchmarks
used to evaluate the product and the overall level of
clinical benefit afforded. In the case of hepatitis C, for
example, HTA agencies were in general agreement that
Sovaldi (sofosbuvir) was differentiated, addressed unmet
needs and offered clinical benefit.
• Epidemiology. Country-level differences in disease
epidemiology can influence the perceived need within a
disease or specific subgroups and therefore the value that
a therapy can bring. In hepatitis C, agencies evaluated
genotypes differently which can be attributed in part to
prevalence differences in individual countries.
• Low unmet need, limited differentiation. Products are
more likely to have divergent HTA evaluations between
markets. In type 2 diabetes, for example, the ultimate
result of evaluations for the SGLT-2 class varied
substantially between markets even though agencies
were relatively consistent in their evaluation of products
within the class. The differences may be attributed to a
number of factors, including different thresholds for the
level of benefit expected.
• High cost. With HTA agencies varying in their
consideration of cost measures, high-cost therapies are
inherently subject to divergence as these bodies look to
manage cost or budget impact exposure.
While many of these intrinsic TA characteristics cannot be
changed by manufacturers, they nevertheless should be
considered in designing the trial and evidence submission to
understand where divergence is likely and anticipate
evidence needs to address underlying differences.
Critical endpoints
Choice of trial endpoints has a substantial impact on
efficacy evaluations. HTA agencies varied significantly in
their assessment of ‘soft’ endpoints, including the extent to
which they afforded a benefit and the weight these
endpoints played in decision making. In many cases
agencies expressed uncertainty in this assessment, which
suggests a role for manufacturers in working with HTA
bodies to develop understanding around these endpoints
early in development to maximize impact.
• Hard endpoints. Hard endpoints, such as overall survival
in prostate cancer, were evaluated with greatest
consistency among countries and products. As these
endpoints are well understood and tend to have
established benchmarks, agencies generally agree in
their evaluations.
• Surrogate endpoints. Agencies tend to view surrogate
endpoints differently across markets, in part because
their impact on overall outcomes may not be well
defined. This is especially true for surrogate endpoints
that are relatively new within a given TA, such as blood
pressure and weight for the SGLT-2 inhibitor class. Given
the often lack of general agreement over evaluation of
these endpoints, interpretation can vary by market.
• Patient-reported outcomes (PROs). Similar to surrogate
endpoints, PROs can be interpreted differently by market
depending on acceptance and perception of their value.
Different views are compounded because agencies vary in
the weight they place on these endpoints (eg, quality of
life) and whether they expressly take them into account
as a part of the evaluation. Sweden, for example, tended
to consider the impact of new prostate cancer therapies
on pain more explicitly than other countries.
In many cases, choice of endpoint is dictated by the TA.
Nevertheless, manufacturers should anticipate that
agencies are likely to have divergent views on surrogate
endpoints and PROs, and work with them to improve
understanding of these endpoints, which can lead to more
consistent evaluation.
Intrinsic therapy area characteristics should be considered in designing
the trial and evidence submission to understand where divergence is
likely and anticipate evidence needs.
“
”

Efforts to align stakeholders should increase shared understanding of
endpoints, benchmarks and trial design elements, such that a piece of
evidence is evaluated similarly across countries.
“
”
Trial design
Elements of trial design, such as comparator, subgroup
definition and powering of the trial (superiority vs. non-
inferiority) can be a deciding factor in HTA evaluations. This
is particularly true in markets like Germany, where use of
the ‘wrong’ comparator can result in ‘no additional benefit’
being granted. More complex TAs (many comparators, lack
of appropriate standard of care, complicated subgroups) can
be subject to divergent assessments because each agency can
define its benchmarks and important criteria differently.
• Comparator selection. Having a clear comparator
supports convergence across markets. However, in TAs
with multiple plausible comparators, selecting the
‘right’ comparator is critical. In Germany, for example, it
is critical to include an appropriate comparator as
defined by the G-BA. Failing to do so will create
divergence, especially if other markets accept the
specific comparator. Choice of comparator influences
place within the treatment paradigm so it is important
that the comparators selected adequately account for
market differences.
• Sub-group definition. Subgroups can support positive
HTA evaluations by narrowing the population to one that
shows greater effectiveness, relative benefit or cost-
effectiveness. However, unless relevant subpopulations
have robust and statistically significant clinical
endpoints, agencies can interpret the benefit in these
populations differently. In the case of subpopulations
that are not clearly defined, this segmentation can be
detrimental to the evaluation.
• Trial powering (superiority vs. non-inferiority).
Superiority trials are typically thought to be demanded by
payers. However, they appear to hold greater weight in
certain markets, such as France. For example, lack of
superiority data for Tecfidera (dimethyl fumarate) was
cited as a key reason for its ASMR V rating (no
therapeutic benefit); however, it had more positive
evaluations in Sweden and the UK, reflecting a lack of
HTA convergence in multiple sclerosis overall.
Each HTA agency has requirements or preferences for trial
design elements; failure to follow these principles can lead to a
negative evaluation but also divergence of evaluations across
markets, due to different standards. However, trial design
presents an opportunity for pharmaceutical manufacturers to
align with agencies during drug development to ensure that
trial plans meet stakeholder needs. Further, this is an area
where EU collaborative efforts and closer alignment with
regulators can increase the potential for convergence through
clear methods and standards.
Implications
Convergence in HTA assessments has begun but is far from
being widespread. A greater degree of convergence is
observed in more straightforward situations where
benchmarks are well understood, such as clear hard
endpoints, high unmet need and strong differentiation, and
clear comparators and subgroups. On the other hand,
divergence continues in more complex situations which
would stand to benefit from greater convergence.
There are several principles that manufacturers should
consider during development and pre-launch to increase the
likelihood of more consistent evaluations across markets:
• Carefully select appropriate comparators
• Focus on hard endpoints where possible
• Ensure that subpopulations are clearly defined with
robust analyses
Efforts to align stakeholders should increase shared
understanding of endpoints, benchmarks and trial design
elements, such that a piece of evidence is evaluated
similarly across countries. However, full convergence is
unlikely as countries will still have fundamental differences,
for example on the importance of cost or the weight placed
on PROs.
Manufacturers should consider how TA and product-specific
factors are likely to be evaluated differently by each HTA
agency to inform trial and launch planning as well as
preparations for post-launch RWE generation. It may be
possible to influence greater convergence by creating shared
understanding of different endpoints and trial design
elements. In doing so, manufacturers can reduce risks and
inefficiencies associated with divergent evaluations.

Convergence of HTA assessments in Europe

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