ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSIONENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSIONENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Building Health Technology Assessment into Your Regulatory Strategy

Adaptive pathwaysAdaptive pathways and pricing

Francois MAIGNEN, Head of Operations Research and Data Analytics, Office of Health Economics. 9-10 November 2017.

Introduction: validity of clinical trials, the path from development to reimbursement

What are adaptive pathways and what’s the rationale

Real world evidence

Products likely to benefit from adaptive pathways: transformative medicines

Regulatory framework for adaptive pathways

HTA and pricing

Learning Outcomes

Two conflicting properties of clinical trials which need to be balanced:

Clinical trials: validity

Internal validity(Regulatory, HTA)

External validity(HTA)

Internal validity of clinical trials

Prerequisite

● The degree to which the results of a study are likely to approximate the 'truth' (true effect) for the participants recruited in a study. It refers to the integrity of the study design and is a prerequisite for applicability (external validity) of a study's findings.

Threats to internal validity

● Biases: recruitment, allocation, assessment, etc.

● Absence of direct comparison, external and historical comparisons.

Methods used to ensure the internal validity of a trial

● Randomisation.

● Blinding.

● Patient selection and comorbidities.

Source: NICE Methods Guide to Technology Appraisals, 2013.

External validity of clinical trials

Generalisability

● The degree to which the results of an observation, study or review are likely to hold true in a population or clinical practice setting outside of the study population/setting.

Threats to external validity

● Restrictive eligibility criteria, homogeneity of study population.

● Study environment (protocol, monitoring, compliance, etc.) and trial medical practice and standard of care.

Methods used to improve the external validity

● Eligibility criteria which will recruit a representative population (patients with comorbidities, special populations).

● Standard of care and standard practice.

● Conduct of trials which reflect the medical reality (e.g. pragmatic trials).

Source: NICE Methods Guide to Technology Appraisals, 2013.

Earlier access to transformative medicines The clinical development, authorisation, HTA evaluation and reimbursement decisions is a sequential process

● This process usually takes several years: better integration of the regulatory and HTA processes and requirements.

● One step is usually conditional on the previous ones (and authorisation is the limiting one).

● However, companies have to integrate both regulatory and HTA requirements in their clinical development. In particular, companies have to conduct studies which can be generalised to all the countries in which the medicine is planning to be reimbursed without compromising the internal validity.

● This means that medicines which have the potential to fulfil important medical unmet needs and change the prognosis of life-threatening or long term serious conditions (called transformative medicines e.g. orphan or anticancer medicines) are often accessible to patients several months or years after the completion of clinical development.

Adaptive pathways

The primary objectives of the adaptive pathway is to provide:

● Earlier access to transformative medicines to patients.

● While using additional evidence to improve the external validity of clinical studies and support HTA evaluations.

Implementing the adaptive pathways concept

● Focus on areas of high unmet medical need.

● Identify small populations with severe disease where benefit-risk balance may be favourable.

● Identify in advance areas where real world evidence will be appropriate to support clinical trial data.

● Involve stakeholders, such as HTA bodies, early in the development process.

● Maintain highest standards of benefit-risk assessment.

Source: Adaptive Pathways Workshop Report, EMA 2017.

Adaptive pathways

Adaptive pathways are not:

● An earlier access to new medicines based on incomplete or early (pharmacodynamics or PK/PD) clinical studies.

● A lowering of the regulatory or HTA standards of evaluation.

● A new procedure which will be applicable to any new medicines upon request of the sponsor / company.

Adaptive pathways will be based on existing regulatory and HTA procedures and standards:

● Accelerated assessment and conditional approval (provided that the requirements in the legislation and legal obligations are met).

● Involve early dialogues (scientific advice) between companies, regulatory authorities and HTA bodies.

● The use of RWE will have to comply with the scientific (e.g. NICE methods guide and DSU guidance), legal (data protection) and regulatory (e.g. GCP) standards applied to regulatory and HTA procedures.

What is Real World Evidence? And why?There are numerous and (very) different definitions of “real world evidence” (RWE).

● RWE consists of health data (patients demographics, diseases, treatments and clinical outcomes) usually not collected in clinical trials for registration which reflect the routine medical practice of the country or structure in which the data are collected.

● RWE is used in the development and approval process to “bridge the gap” between the regulatory and health technology assessment (HTA) requirements (Galson and Simon 2016).

● The clinical development of medicines will be supplemented by RWE which will provide evidence to demonstrate the clinical effectiveness of new technologies in addition to the demonstration of a positive risk/benefit ratio (i.e. based on evidence of efficacy).

● RWE might be used to understand the standard of care, decrease uncertainty, support any modelling assumptions, define the relationship between surrogate and long-term clinical outcomes.

Source: Adapted from Adaptive Pathways Workshop Report, EMA 2017. IMI GetReal and NICE DSU TSD 17.

Examples of RWE

Sources of Real World Evidence include:

Data from interventional studies (usually prospective):

● Supplementary to traditional RCTs: patient reported outcomes (PRO), health related quality of life, resource use and cost data.

● Pragmatic clinical trials.

Observational studies or health data (prospective or retrospective):

● Registry studies which are prospective, observational cohort studies of patients.

● Claims databases/administrative data and insurance systems (Choudhry, 2017).

● Health surveys to collect descriptions of health status and wellbeing, health care utilisation, treatment patterns, and health care expenditures from patients, providers, or individuals in the general population.

● Electronic health records (EHR) e.g. Clinical Practice Research Datalink (CPRD) (UK) (Garrison et al, 2007; IMI GetReal).

Other definitions of RWE

Non randomised evidence: misnomer

● RWE is sometimes associated to “non-randomised evidence” (NICE DSU TSD 17).

● Randomisation is a method to minimise selection bias and imbalances in interventional clinical studies: not related to medical practice in the real world.

● Some sources of RWE can be obtained from randomised studies: Pragmatic clinical trials.

● Not all interventional trials are subject to a randomisation procedure; e.g. non comparative studies / single-arm trials.

● Some “non-randomised” trials can have a poor external validity: single-arm interventional trials.

RWE: opportunities and pitfalls

Possible advantages

● Possibility to capture the medical practices in the different countries in which HTA evaluations are performed.

● Obtain some information on variables which are not traditionally collected in clinical studies: resources, costs.

Pitfalls

● Risk of biases (selection, recollection, assessment, change in medical practice, incomplete or erroneous information …).

● Imbalance and non-comparability of the treatment arms (treatment group and external control – matching techniques are not as powerful as randomisation to minimise the influence of possible biases).

● Historical comparisons always tend to favour the new technology.

Adaptive pathways and HTA

Specific issues:

● Product authorised in small populations under a conditional approval: increased uncertainty (populations, effect size, long term clinical outcomes, e.g. survival and quality of life).

● Methods to integrate and analyse RWE will have to be developed and implemented.

● Early dialogues: scientific advice and dedicated patient access schemes.

● The target population of patients will be subsequently broadened and the ongoing collection of RWE might result in successive appraisals.

● Identification of the candidates and definition of transformative medicines.

● Schemes working on a very similar concept have been implemented: Cancer Drugs Fund (England).

● Initiatives: IMI GetReal, ADAPT-SMART, IMI Harmony, EMA pilot.

Source: Bouvy et al. 2016 doi:10.1002/cpt.448

Adaptive pathways and pricing

Pricing of technologies developed according to an adaptive pathway:

● Pricing and reimbursement procedures will likely be different from the procedures currently in place for early access schemes.

● New technologies may be reimbursed or commissioned by healthcare systems under specific schemes and conditions (collection of RWE).

● Adaptive pathways will probably open the door to new pricing strategies (e.g. pricing which depends on the indication, multi-indication pricing).

Adaptive pathways and pricing

Adaptive pathways is a regulatory and HTA framework which is aimed at providing earlier access to transformative medicines.

Adaptive pathways will build on existing regulatory procedures: accelerated assessment and conditional approval (provided that the conditions laid down in the legislation are met).

Real world evidence (health data) collected retrospectively or prospectively will be used to supplement the evidence from clinical development (pivotal efficacy study).

The main risk associated with the use of RWE is a risk of bias. A product developed under adaptive pathways will have to adhere to current evidence standards.

Reimbursement and pricing strategies will take into consideration the uncertainties associated with this approach to the development of new technologies.

Learning Outcomes: Recap

Contacts

To enquire about additional information, please contact Francois Maignen at fmaignen@ohe.org

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