The Increasing Need to Harmonize Evidence Demands of Regulators, Payers, and Health Technology Assessment Bodies in Europe – Opportunities and Challenges
Assessing the value of new and existing health technologies carries an overall level of uncertainty demanding at least a shared understanding of the differing needs between regulatory bodies, health technology assessment (HTA) agencies, and payers; if not closer collabo-ration. Given their different roles, regulators, payers, and HTA agencies across Europe have created an array of requirements for evidence from manufacturers. These demands can be expensive, time-consuming, and sometimes conflicting and consequently stakeholders are beginning to explore ways of collaborating that acknowledges the needed benefit/risk balance, the market access issues, and the reimbursement considerations, whilst not forgetting the industry’s need for transparent and reasonable evidentiary standards to fully prepare for different market access environments across Europe.
Changing Landscape of Market
Access in Europe
The market access landscape is quickly evolving as payers continue to gain decision-making power across Europe. With the changing political environment, questions around the affordability of new technologies are becoming increasingly relevant. As costs of health technologies continue to increase, and health care sectors come under increased pressure to contain costs, policy makers question whether the rising level of investment in health technologies is an appropriate use of limited resources.
Health technology regulation is a multi-tiered process involving many stakeholders with differing roles and responsibilities. The role of the regulatory body – which, in the case of Europe is the European Medicines Agency (EMA) – is pivotal. Manufacturers in Europe are not allowed to market their products prior to receiving licensing approval from the EMA. After a manufacturer applies for marketing approval from the EMA, the assessment and approval process by the regulatory body operates with an emphasis on the scientific advice given by the Committee for Human Medicinal Products. Following marketing approval, manufacturers seek reimbursement from country-level third-party assessors and payers such as the HAS (Haute Autorité de Santé) in France. Decisions made by payers are primarily shaped by national or regional HTA bodies, which provide supporting evidence for or against coverage and reimbursement decisions. Both tiers of decision making – at the regulatory and payer levels – are crucial and influence the number of available health technology options clinicians and patients can choose from, for a given condition.
Figure 1. Decision makers on the road to market access 
For manufacturers, both time-to-marketing authorisation and time-to-reimbursement approval are equally relevant to gain market access. Most technologies now need to obtain a positive reimbursement or coverage decision from payers that commonly include an economic evaluation of the new product by assessing the costs of paying for one intervention against the forgone opportunity to pay for another. This is often operationalized by evaluating the acceptability of the incremental cost-effectiveness of the new product to establish whether the technology represents an efficient use of limited resources. The role of cost effectiveness in coverage and reimbursement decisions varies across Europe: although cost-effectiveness is a formal requirement in the UK, this is not the case in other large markets such as Germany, France, Italy and Spain.
Evidence Demands – Evolving
Together or Apart
Regulatory agencies, payers, and HTA agencies have different information needs according to their roles and functions. Whilst there is no inherent conflict concerning acceptable evidence by different players (creating one type of evidence does not preclude the creation of another), regulators focus on whether the drug does more good than harm in a defined group of patients and hence conduct benefit-risk assessments. EMA’s legal mandate implies that each new drug should be evaluated on its own merit, and without requiring the new drug to be assessed against other available treatments. By contrast, payers address the question of the health and cost consequences associated with the new technology - in other words, “what additional benefits does the technology offer over current approaches; and at what additional cost?” In many European jurisdictions, HTA agencies are responsible for reviewing and synthesizing the evidence base to support payers’ decision making. Defined formally, HTAs in Europe comprise a multidisciplinary process that summarizes information about the medical, social, economic, and ethical issues related to the use of a health technology in a systematic, transparent, unbiased, and robust manner.
Multidimensional Role of HTAs
Building on the level of information available to regulators at the time of marketing approval, HTA bodies aim to establish the wider context of the new technology in routine clinical practice. One dimension of the HTA process is the assessment of effectiveness. A technology is considered effective when there is evidence of benefit to patients when administered by physicians in routine clinical practice settings as opposed to the selective clinical trial environment.
Given this role, the issue of value comes into sharp focus; economic evaluations need to demonstrate that the economic benefits outweigh any perceived clinical harms and economic costs, since the resources consumed will need to be accommodated within the budgeted available resources.
Decisions by regulators and payers are increasingly conducted concurrently and are therefore, based on similar clinical data and information on new products . Because of the current limited communication between regulatory and ‘after approval’ systems in Europe, however, there are some inevitable inefficiencies and possible delays. Ensuring that the clinical evidence demands of regulators and payers are harmonized is important to create effective and efficient regulatory and ‘after approval’ decision-making processes.
In view of different levels of emphasis on the questions of “does it work?”, “does it work better?” and “is it worth it?” regulators and payers may arrive at decisions on the same technology that at first may appear conflicting. For example, a drug approved by a regulatory agency based on its safety and efficacy, may subsequently be deemed not reimbursable by payers. Differences also arise between the HTA agencies and payers of the separate European markets where there are different political priorities, different health care systems, different clinical pathways resulting in different comparators, as well as diverse definitions of clinical outcomes, methodological hurdles, and timings. Where possible, however, there is a need to mitigate potential delays to patient access caused by duplicating demands for providing locally-mandated evidence. Within this context, harmonization is put forward as a way to improve the efficiency in assessment of health technologies in Europe.
What to Harmonize? – Relative Effectiveness as an Emerging Interface
Given the recognised differences, it may not be possible to harmonise all data requirements (Fig. 3). In particular, economic evaluations that inform coverage and reimbursement decisions are inherently location-specific and cannot be standardized across European countries. There are, however, opportunities.
The most important emerging issue at the
regulatory-payer-HTA interface is the assessment of relative effectiveness . Over several years, there has been growing interest in the greater use of relative technology assessments to meet the evolving needs of regulators, payers, and other stakeholders.
There are two forces driving this change. On the regulatory side, researchers have argued that the ultimate goal of developing new medicines should be to improve treatment – that is, new medicines should provide additional clinical benefit to patients compared with those currently available . On the HTA/payer end of the spectrum, reimbursement decisions are increasingly dependent on relative measures of clinical value, which then feed into assessments of relative economic value. Further, clinicians and patients also require information on the extent to which a technology compares with existing products for the same indication. Such comparative evidence is also used to develop treatment guidelines. As a result, HTAs usually require an assessment of comparative clinical and sometimes cost-effectiveness data of similar health technologies. In this context, relative effectiveness is driving the interaction between regulators, payers, HTAs, and manufacturers, and may stimulate some rethinking across the different approval systems regarding methodological tools, and greater transparency and consistency of decision-making processes.
From a methodological standpoint, it is (in principle) possible to standardize the means by which relative effectiveness of technologies is determined; but determining what type of study design should be considered and accepted as ‘fit-for-purpose’ when generating relative effectiveness evidence is a hotly contested topic [3,4]. Different study designs have their advantages and disadvantages, and some of the alternative designs such as indirect comparisons and observational studies may not be well accepted due to perceived methodological issues – many of which are quite different from the ‘gold-standard’ of head-to-head randomized controlled trials.
Early scientific collaboration among all stakeholders (regulators, payers, HTAs, and industry) would be expected to contribute usefully towards early identification of data requirements. This partly relies, however, on judgments influenced by patterns of health care and service delivery as well as societal and political priorities which may well differ across the EU. The benefits expected from earlier data collection through studies have to be balanced against the risk of having to reconsider the study design when additional information becomes available.
Demonstration of clinical and economic ‘value’ also poses a significant challenge. In terms of relative effectiveness, contextual, i.e. Member State specific, information will be needed (for instance the definition of the ‘relevant comparator’ and ‘actual practice’ may differ considerably across settings). This is particularly an issue when considering economic value of health technologies because economic analysis is context specific by definition.
Different objectives of HTA bodies across Europe may require additional efforts. The methodological collaboration between the authorities in France (HAS), Germany (IQWIG), and the UK (NICE) has clarified that HTA processes in Europe are in different positions on the decision path of health technologies. In France, first listings by HAS occur before reimbursement decisions and before price fixing. Reassessments occur after reimbursement and price decisions that include economic analyses. In the UK, NICE conducts assessments before delivery by NHS but with prior knowledge of price. In Germany, however, IQWIG conducts assessments only after marketing approval for a known price of the candidate technology and advises on the maximum acceptable price for reimbursement, given the added therapeutic value of the technology. But the policy environment in Germany is now changing as IQWIG provides input into an assessment of added therapeutic value of health technologies, which then forms the basis of price determination. For early scientific advice, this diversity and constant change in responsi-bilities will continue to be a challenge.
There is also a danger of creating unrealistically high evidence standards that could have an impact on patient access because of delayed approval or even because drug development targets are no longer considered achievable. Sponsor companies might prematurely terminate development programs for potentially viable drugs. Do complex approval processes themselves help clinicians, patients, payers, or policy makers to make informed choices or guide clinical decision making when treating a patient? These challenges have been made exponentially more complex with the addition of cost as another vital dimension to consider in making therapeutic choices.
What is Happening?
Critical discussion is underway to find ways to harmonize relative effectiveness assessments at the EU level. Regulatory and HTA bodies have formally expressed willingness to improve communication, transparency, and openness, and more importantly, understand boundaries as well as venues for potential synergies. Moving towards common solutions will hinge upon a mutual understanding of the common aspects of processes across Europe.
Based on the understanding that EU Member States need identical comparative data that are context free, the suggested strengthening of relative effectiveness analysis at the EMA level should contribute towards reducing replication of efforts. Current developments are focused on an exchange of information between regulators and HTAs interested in developing consensus on the nature of data to use and the methods that need to be employed.
One significant example is the EMA and EUnetHTA Joint Action on European Public Assessment Report (EPAR) . This new collaboration has already proven to be an excellent platform for the transfer and translation of information, which would help build bridges between regulators and HTAs. The effort stems from the recognition that relative effectiveness assessments help policy makers identify the most valuable health technologies. It was initiated as a follow-up to one of the recommendations made by the EU High Level Pharmaceutical Forum for improving the availability and best use of data relevant to relative effectiveness assessment.
Manufacturers are taking an active role in these developments. AstraZeneca, GlaxoSmithKline, and Johnson & Johnson are funding and participating in a new initiative in collaboration with clinicians, HTAs, patient representatives, payers, regulators from France, Germany, Italy, the Netherlands, Sweden, the UK, and the EMA . The pilot programme arose from the efforts of the European Healthcare Innovation Leadership Network and aims to harmonize the types of evidence needed to demonstrate safety, efficacy, and value. These efforts reflect the reality that further collaboration is a priority for all stakeholders involved.
There is an increasing need to communicate about role boundaries between regulators and HTAs/ payers. Acknowledging that inherent differences exist across European health care systems with varying coverage and reimbursement policies, it is not possible to harmonize the economic aspects of health technology appraisals. Rather, relative effectiveness is emerging as an interface between various stakeholders. From a methodology perspective, all stakeholders need to agree on and apply common terminology and research standards for alternative study designs (e.g., indirect comparisons, observational studies). Regulators need to more clearly define criteria about relative effectiveness studies and openly converse with payers to agree on the validity, applicability, and acceptability of available method-ological approaches. This may in turn result in an increased collaboration between manufacturers and HTA agencies/payers to conduct not only prospective studies but also post-marketing studies to demonstrate relative efficacy and effectiveness of new and existing health technologies.
The industry will be under mounting pressure to adapt to the quickly changing landscape. In this environment, manufacturers are urged to act early and understand the importance of different forms of evidence for different audiences and collaborate with all stakeholders.
This paper was developed based on an Issue Panel, chaired by Lisbet Coulton, at the ISPOR 13th Annual European Congress in Prague, Czech Republic in November 2010. Panelists were: Hans-Georg Eichler of the European Medicines Agency (UK), Carole Longson of the National Institute for Health and Clinical Excellence (UK), Lise Rochaix of Haute Autorité de Santé (France), and Ansgar Hebborn of Roche (Switzerland).
Authors were full-time employees of the United BioSource Corporation (UK) while developing this manuscript. Authors thank Rob Thwaites and Jyoti Nandi, both of the United BioSource Corporation, for their editorial assistance with earlier versions of this paper.
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