Since the late 1990s I have worked for and advised a variety of life science companies to develop and execute evidence development strategies to successfully meet the emerging requirements of health technology assessment (HTA) and reimbursement agencies.
Here are three key questions clients often ask me:
Q1: How do HTA agencies differ in their evidence requirements for new health technologies?
Formal HTA agencies linked to reimbursement of new health technologies (including pharmaceuticals) have emerged over the last 25 years to meet the needs of country healthcare systems which differ in their organization and characteristics. Their aims are broadly similar: to ‘inform policy and clinical decision making around the introduction and diffusion of health technologies’ HTA International 2013, however the scope, processes and methods used differ to fit each parent health system, and the specific decisions (the ‘decision problem’) informed by the technology appraisal process.
All HTA agencies require evidence on the burden of disease and unmet need, as well as the treatment pathway and positioning of the new therapy under consideration. They also require evidence of the efficacy, safety and effectiveness of the new intervention, although the specifics of this may differ. Most agencies require evidence of budget or financial impact of a new technology and an important subset also require evidence of cost-effectiveness. Other types of evidence may be required by specific agencies, such as the impact on health inequalities, or ethical, organizational, patient/social and legal aspects (set out in the EUnetHTA Core model).
To facilitate evidence development planning HTA systems with similar characteristics have been grouped into archetypes. Broadly these archetypes are:
Clinical differentiation: payers determine additional clinical benefit vs standard of care, which will inform reimbursement and price negotiation decisions (key countries: France, Germany).
Health economic: payers make decisions on reimbursement based on value for money vs standard of care in terms of cost-effectiveness or cost-utility (key countries: UK, Canada, Australia, Sweden).
Budget driven: decisions on reimbursement and pricing are primarily determined by budget impact at national or regional levels (key countries: Spain, Italy, Turkey).
Other: health care systems primarily driven by out-of-pocket payments and free-market competition mediated by private insurance (key countries: US, Brazil).
This classification simplifies a complex and dynamic picture: France and Germany will look at cost-effectiveness in certain cases. Different HTA processes and evidence requirements may be used for different types of intervention: the UK focuses on cost minimization and budget impact for medical devices. The US consists of a wide variety of healthcare providers and payers/insurers, many of which use some elements of HTA. Many countries in the APAC region are moving towards the health economic archetype.
Probably the most important and pervasive differences between HTA agencies is in their requirements for evidence of clinical efficacy and effectiveness. Although all are interested in understanding the totality of clinical trial evidence (safety and efficacy) relevant to a decision problem, they differ in their approaches to synthesizing such evidence (in meta-analysis) and methods used to adjust or combine evidence from different sources if the trial data are inadequate. This may occur when trial populations are not representative of the local population who might receive the new intervention, where trials compare against placebo or comparator therapies not those used as standard of care locally, or where only single arm trials are available. Such challenges may occur especially for interventions in rare diseases or in adaptive licensing (early access) situations. There may be different preferences for the use of patient-relevant endpoints, with agencies such as UK NICE requiring valuations of outcomes, typically as quality adjusted life-years (QALYs). There are differences in the relevant time-period over which health outcomes are considered relevant: the UK has adopted a lifetime ‘time horizon’, requiring the use of modelling to project study results over long periods. Finally agencies differ in how they incorporate uncertainty into their assessments.
Q2: How willing are HTA agencies to adopt new methods for analysing and synthesizing evidence?
HTA agencies and healthcare payers need comparative evidence of clinical and cost effectiveness. This is at a stage in the development of new medicines when there is limited direct evidence outside the clinical trial programme, which is directed primarily at regulatory agencies to obtain marketing authorisation. Over the past 20 years this has stimulated the development of a variety of new methods for analysing and synthesizing evidence:
Development and validation of new patient-focused outcomes, either traditional patient reported outcomes or (more recently) digital endpoints for use in clinical trials.
Methods for performing indirect comparisons, where no direct evidence exists comparing the new medicine with current best practice: most notably network meta-analysis and matched adjusted indirect comparisons.
Methods to adjust for potential confounding in comparative (non-randomised) ‘real world’ observational studies, in particular those based on propensity weightings.
Methods of economic modelling to undertake cost-effectiveness/utility analyses, especially survival analysis to project health outcomes over long durations, and valuation of health outcomes as quality adjusted life years - QALYs) for use in cost-utility analysis.
Various design modifications to traditional clinical trials have been developed to improve the recruitment of subjects and generalisability of results to routine practice: for example pragmatic, decentralised, platform, basket and cluster trials, trials within cohorts as well as adaptive trial designs.
HTA agencies generally take their lead from regulatory agencies such as EMA and FDA for acceptability of new trial designs. In other areas more specific to their assessments they differ somewhat in their acceptance of new methods. Larger, better resourced, agencies such as UK NICE have a greater bandwidth and access to technical expertise (both internally and externally) to make judgments about new methods: quite a lot of detail can be found in its methods guide (currently under revision). NICE also funds a Decision Support Unit at the University of Sheffield to review new methods. This unit has produced a series of excellent reports on different methodological topics. Smaller agencies may struggle to find technical expertise and will tend to rely more on well-accepted methods. All HTA agencies will be more willing to accept methods that have been well published and applied in previous technology assessments, especially those endorsed by reputable organisations such as ISPOR good practice guidelines or EUnetHTA methodology guidelines. All agencies will seek to understand the rationale for the use of new methods in a submission: why conventional methods were considered inadequate, and whether the decision for their use was post hoc (i.e. after reviewing pivotal trial results). They will also seek to understand the impact of using these methods on the uncertainty of the results (which can be quite high).
Some agencies, especially those such as Germany driven by clinical effectiveness have less interest methods specifically developed for economic evaluation. Germany also is generally more conservative about accepting new statistical methods for meta-analysing trial results. US and Canada tend to favour use of different instruments (HUI rather than EQ-5D) for valuing health outcomes and generating QALYs.
If new methods are being considered it is important to seek local advice about their acceptability (possibly through formal Scientific Advice process). A strong rationale for their use should be established, if possible including peer reviewed publications and case studies from their previous use.
Q3: When should I start planning for HTA and reimbursement success?
The simple answer is ‘earlier than you might expect’.
‘Early’ activities take place when the medicine is at the pre-clinical or early clinical (Phase 1) stage, when there may be a range of medicines under development with different characteristics and potential targets within a broad disease area. At this stage it is useful to generate evidence of the progression and burden of disease (costs, impact on quality of life) as well as current treatment patterns. Investment in data resources such as disease registries (deliver useful results at the time of launch) may be considered. If new patient reported outcomes or digital endpoints may better capture the value of the new medicine than existing instruments, development work needs to start so that validated instruments may be included in pivotal studies and potentially in product labelling. Likewise for new epidemiological studies to understand the course of the disease, which may be important for economic modelling.
‘Mid-development’ activities focus on refining the understanding of disease burden, disease progression and treatment patterns for the more specific populations that may be studied in pivotal trials and for which reimbursement may be sought. These may take the form of published studies to communicate the unmet need for such populations. Reviews of the existing evidence on efficacy, effectiveness and safety may be initiated, to be updated later. A preliminary economic model should be constructed to predict the economically justifiable price that will be associated with different product profiles that may be supported by results from pivotal (Phase 3) studies. An evidence development plan should be set up, to include the clinical trial programme itself and complementary studies and analyses required to meet the needs of HTA, payers and other stakeholders. Local affiliates or external experts can be consulted about specific country requirements. In recent years there has been increasing use of Scientific Advice consultations with HTA organisations (possibly in parallel consultation with regulatory agencies such as EMA). These can be laborious but useful exercises, not only to obtain feedback on key data sources, study designs and analytical methods, but also as a way of focusing the internal R&D teams on HTA/payer evidence needs. Medicines intended for rare diseases or where adaptive licensing (or accelerated approval) is anticipated may have different routes to reimbursement and specific challenges to address (with small amounts of data, non-comparative studies…).
‘Late’ activities (during Phase 3 and prior to launch) are generally more familiar. Trial results need to be summarised in a form suitable for HTA submissions, as will the results of other studies conducted in parallel, perhaps generating evidence of (local) resource use/cost, disease progression, and valuations of health outcomes (utilities). Economic models will need to be completed, validated and used to support cost-effectiveness/utility analyses. Systematic reviews of different types of evidence will be undertaken, and efficacy and safety results will be synthesized in meta-analyses. The totality of evidence will be collated in ‘value dossiers’ which can be used both to support local country submissions to HTA agencies and also market-focused communications to local payers and clinicians.
Bear in mind these key principles throughout the generation and delivery of evidence for HTA:
Quality Ensure that data sources, study designs and methods are fit for purpose.
Flexibility Trial results are unpredictable, and may direct focus towards different patient populations or different health outcomes. Be prepared to change course.
Patient focus HTAs seek input from clinicians and patients about the burden of disease, unmet need and potential impact of new therapies. Evidence of value for the new medicine should address their needs.
Commitment HTA and especially payers may be interested in comparative data after launch, for example when coverage with evidence development is granted. This will help confirm the results predicted at launch and optimise patient access to the new medicine.
The development of new medicines is uncertain, with the possibility of failure or significant course corrections needed at different phases. So the effort put in needs to build as the likelihood of success of reaching marketing authorisation increases.
About Mike Chambers
With degrees in mathematical philosophy, demography and health economics, I have worked in the UK NHS, academia (epidemiology and health services research), contract research (health economics) and for two major life science organisations. At Amersham Health (later GE Healthcare), I developed a health economics function focusing on diagnostic imaging technologies. Subsequently at GlaxoSmithKline I was director of health economics and led the respiratory area health outcomes team. I then became head of reimbursement and value demonstration in market access for Europe, where I advised on emerging evidence requirements for reimbursement and access to medicines and innovative methods to communicate the value of medicines to healthcare decision makers.
In 2016 I founded my own consulting practice to provide advice to developers of health technologies on:
Evidence requirements of healthcare payers
Strategies and plans to generate evidence of the value of new healthcare interventions
Successful execution and communication of payer focused studies and analyses.
My current focus and interest include:
Contributing to EU (Innovative Medicines Initiative) public private partnership projects in real world evidence and digital outcomes, for example GetReal, IDEA-FAST, RADAR-AD
Coordinating and delivering a remote learning training programme in Real World Evidence at the University of Utrecht, Netherlands
Serving as a member of the UK NICE technology appraisal committee
Providing strategic support directly to technology manufacturers for submissions to health technology assessment agencies
Collaborating with HEOR research agencies in providing strategic advice on HTA evidence requirements and economic evaluations.