With real world evidence (RWE) a topic of great interest to various key stakeholders in drug development, the meeting’s agenda encompassed current challenges, latest innovations and future trends in RWE. Day 1 saw speakers tackle important themes such as the need for cross-functional working within companies, the contribution of RWE to value-based outcomes for healthcare systems, and use of RWE earlier in the product lifecycle to increase the speed at which patients can access new medicines. The day’s talks are summarised below.
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Chair’s opening address
The morning of Day 1 saw delegates joined by attendees of the 3rd Annual Access Europe Summit 2017. The morning’s Chair, Reg Waldeck (Celldex), kicked off the meeting by welcoming delegates from this related field and highlighting that, as the world of RWE expands and evolves, cross-functional working between disciplines will be key to ensuring that the overarching aim of RWE research is achieved: getting the right drug to the right patient at the right time, with value in mind.
Work cross-functionally to unlock new insights throughout the lifecycle
In the first plenary session of the meeting, Michael Seewald (Novartis) delved further into the subject of cross-functional working. Michael began by reminding attendees of the potential for RWE to improve healthcare globally. He outlined the key advantage of RWE, which is locally-generated, patient-centric and derived from ‘real’ patients: it can help those involved in developing new medicines to better understand patients and their needs. He went on to describe RWE as the key to sustainable and value-based healthcare.
Michael also touched upon the challenges surrounding RWE-related terminology, with a current lack of unified definitions potentially hampering stakeholder understanding of the field. He offered the following definition of RWE itself: “evidence generated in routine medical practice [that is] used for decision making” and described a number of potential sources of RWE: laboratory values and biomarkers, mortality data, data from social media, data from pharmacies and hospitals, observational clinical trials, surveys, disease registries, electronic health records (EHRs), and claims databases.
Although a component of the drug development pathway for many years, RWE is being looked at anew by all stakeholders as value-based healthcare comes more sharply into focus globally. Evidence generation during the development of a novel product has traditionally followed a linear path, with RWE appearing at a late stage, often post launch. Michael argued that this linear model is no longer optimal. Instead, the focus must be on providing the right evidence at the right time, with real world data (RWD) generated earlier in the pathway in order to inform decision making during progression along the development pathway. Michael highlighted the various ways in which RWE can be of value in this setting including in: recruitment to randomised controlled trials (RCTs); clinical trial feasibility assessments; effectiveness predictions; outcomes agreement between companies, payers and regulators; post-launch negotiations; and value-based pricing. He concluded with a call to action: for pharmaceutical companies to recognise the value of RWE across the product lifecycle and to move from a “sprint to market access” to a “marathon of evidence generation throughout the product cycle”.
Insights, ecosystems and outcomes: using data to drive value-based, personalised healthcare
Picking up on the themes of value-based healthcare and the changing drug development landscape, Brett Davis and Sebastien Burnett (Deloitte) expanded upon the need for the pharmaceutical industry to move beyond providing data from RCTs to demonstrating value-based outcomes for healthcare systems. The speakers further outlined some of the challenges and changes currently faced by healthcare systems and the industry, including evolving reimbursement and payment models, advancing technology and data proliferation, higher patient expectations, and a changing regulatory landscape. They emphasised the potential for RWE to inform product strategy, design and patient care and to improve decision making across the product lifecycle.
Brett and Sebastien also reported findings of a recent Deloitte survey on RWE that found that 54% of respondents in life science companies felt that their current RWE capability did not meet their organisation’s needs, with lack of access to the right RWD cited as a limiting factor by 60% of respondents. Comparative effectiveness research was identified as a top priority, and the survey results suggested that companies currently identify the research and development (R&D) phase of drug development as a key focus for RWE resourcing.
A tale of two detectives: compiling the evidence
Barbara Jaszewski (Lundbeck) took a deeper look at some of the inherent challenges in cross-functional working, with a specific focus on the potential reasons for communication difficulties between R&D and commercial teams with respect to RWE. Likening these disciplines to detectives with widely differing approaches, she suggested that while commercial teams tend to use inductive reasoning (the “Sherlock Holmes” approach) to generate a conclusion (i.e. observing before constructing a hypothesis) R&D teams tend to favour deductive reasoning (the “Columbo” method), starting from a hypothesis and conducting research to confirm if it is correct. While both have their merits these differing perspectives can lead to challenges! Collaboration and an integrated approach are needed, with pre-phase II RWE potentially playing a vital role in aligning communication and expectations, enabling the development of a clear therapeutic product profile at this relatively early stage. Barbara also suggested that a truly cross-functional team guiding a product from concept to post-launch is optimal, rather than ‘passing the baton’ between teams at the clinical development stage-gate.
Panel discussion: emerging data sources – meet evolving data needs with the latest innovations
Chaired by Anne-Toni Rodgers (AstraZeneca), a panel of industry experts (Martin Price, Janssen; Patrick Hopkinson, BMS; Michael Seewald, Novartis) discussed key challenges and innovations within RWE in Europe today. Current challenges are not insignificant and include lack of infrastructure, stakeholder attitudes and a need for greater integration of RWE into the drug development pathway. However, the panel also highlighted exciting areas of innovation including mobile technology, use of social media to track and capture RWD in real time, and common data models for standardisation of data analysis.
The panel also discussed opportunities for sharing and comparing RWE across different countries. Although this is an important long-term goal, challenges exist due to differences in local healthcare systems, data collection infrastructure, confidentiality rules, and attitudes to RWD. For example, while in many Nordic countries public and healthcare professional (HCP) attitudes are very open to the collection of RWD, in other countries, such as the UK, concerns exist. However, such disparities are expected to dissipate as all healthcare systems focus more and more on value-based outcomes.
The discussion closed with panel members considering what they would change if they had one ‘wish’ for the development of RWE. One such ‘wish’ was for RWE to be collected more quickly than is currently possible. Due to the complexity of setting up and running RWE studies and collecting data in Europe (where large claims databases such as those seen in the USA are not available) studies can currently take 3–5 years. This can mean that RWE is not available in time to impact a medicine’s approval and instead becomes supportive, post-launch data. Another ‘wish’ was for increased data transparency between study collaborators, which could also speed up collection of RWE.
Increase product launch success with a cross-functional use of real world evidence
The practical application of cross-functional working in the generation of RWE was illustrated by Tra-Mi Phan (Novo Nordisk) using a real-life case study that now forms the basis of best practice within her company. The case study, describing the RWE plan for the launch of a novel basal insulin product, outlined key patient and payer unmet needs, as well as regulatory constraints surrounding phase III clinical trial design that meant that some unmet needs could not be fully explored via the traditional RCT approach. RWE was used to evaluate additional outcomes of interest to payers and to patients, including effectiveness and safety in target patient populations outside of the RCT population. The RWE plan incorporated retrospective and prospective studies, and considered the quality of data as well as the need for timely availability.
Tra-Mi concluded that RWE planning and data utilisation should begin 2–3 years before product launch in first wave countries, and continue throughout the product lifecycle via a systematic, cross-functional approach.
External collaboration with stakeholders to optimize patient access strategies “from clinical development to patient access”
Tay Salimullah (Novartis) and Pam Bacon (Celgene) demonstrated the collaboration that is possible between different stakeholders through the Innovative Medicines Initiative (IMI) programme, an EU and European Federation of Pharmaceutical Industries and Associations (EFPIA) initiative that delivers a range of public–private partnerships in drug development aimed at speeding up patient access to new medicines. The speakers described their involvement in one such project, ‘Healthcare Alliance for Resourceful Medicines Offensive against Neoplasms in hematologY’ (HARMONY), which sees a number of stakeholders partnering to use ‘big data’ to improve the care of patients with haematological cancers, as part of the IMI’s ‘big data for better outcomes’ programme. HARMONY aims to harmonise outcome measures in haematological cancers across Europe and between health technology assessment (HTA) bodies, regulators and payers, via the development of a big data platform focussed on patient-related outcomes. One innovative approach HARMONY is evaluating is the use of a virtual comparator RWE arm (obtained via RWE data collection or retrospective registry-based data collection) in RCTs. Starting in January this year, HARMONY will run until December 2021. Its goals for the first two years centre around shaping outcome definitions. Over the next five years, the project will look at moving to translating these into value for patients and identifying unmet medical needs, with longer-term goals aimed at increasing the speed at which patients can access innovative new medicines and improving the targeting of new medicines to patients.
Driving market access with RWE: rhetoric vs reality
The morning session of Day 1 was concluded by Anne-Toni Rodgers (AstraZeneca) who gave a lively overview of the ‘rhetoric vs the reality’ for RWE, as described to her by industry colleagues.
“RWE is driven by payers”
It is important for pharmaceutical companies to engage with payers in RWE methodology development
“RWE has regulators really excited”
Regulators’ attitudes to RWE is somewhat mixed
EU: implementing the adaptive pathways concept (in areas of unmet medical need, with appropriate benefit–risk balance in specific patient population)
However, as RWE and RWD collection enters clinical guidelines the impact on clinical care is likely to grow
Anne-Toni concluded that RWE should be a key part of the evidence planning strategy for new products in development, not just used at a later stage to ‘close gaps’. She also emphasised that RWE requires investment, alignment of internal resources, and cross-functional working within pharmaceutical companies, as well as external collaboration.
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Day 1’s afternoon sessions were chaired by Agathe Le Lay (Novo Nordisk).
Multi-presentation feature: see how IMI’s ‘GetReal’ project is increasing RWE’s practical application with earlier adoption into the lifecycle
Chris Chinn (Sanofi) and Rob Thwaites (Takeda) got the afternoon underway with a series of five ‘mini’ presentations outlining the lessons learnt from the IMI ‘GetReal’ project. This 3-year project aimed to develop a common understanding between healthcare systems and the pharmaceutical industry regarding the acceptability and utility of RWE to determine the effectiveness of new medicines. The project examined pre-launch RWE by evaluating learning from existing post-launch projects, looking at the gap that exists in predicting the value of a new medicine and that could be filled by using RWE earlier in development.
The project has resulted in a wide range of outputs and a growing list of publications. Among these are ‘PragMagic’, a decision support tool for pragmatic trial design (launch webinar June 2017), and ‘RWE Navigator’, an open access tool to help users work through potential issues and options during development of a RWE plan.
Chris and Rob also described key learnings from the GetReal project, confirming the importance of planning early, liaising with HTA bodies and regulators, and fully integrating evidence planning, both pre- and post-launch.
Lean clinical development – adding value with visual evidence
Professor Howard Stevens (bddpharma) presented an alternative perspective on RWE, guiding delegates through some of the ways in which the data variability seen in the ‘real world’ may not be reflected in the comparatively rigid environment of an RCT. He also highlighted that RCT data are usually averaged and therefore can overlook individual differences that could be the key to effectiveness in the real world. Using real world imaging data from individual clinical trial participants he illustrated challenges posed by standard RCT design (e.g. patient compliance, real world conditions versus regulator-stipulated experimental conditions) and demonstrated how such issues could be pre-empted via careful trial design informed by RWD.
Optimise your clinical trials using electronic health records
Mats Sundgren (AstraZeneca R&D) presented another IMI project: the Electronic Health Records for Clinical Research (EHR4CR) Champion Program. Mats began by giving delegates an overview of the growing importance of EHRs in pharmaceutical research. EHR use in clinical practice has expanded rapidly over the last 5–10 years and EHRs now form part of routine clinical care, accounting for up to 90% of all healthcare records in some countries. However, they are not generally optimised for research use and most hospitals use multiple systems, each for a different type of data. Currently, when such data are used in clinical trials they are often entered twice: once into a patient’s EHR and then again into an electronic clinical trials database, leading to redundancy in data entry, higher costs and increased potential for error.
The EHR4CR project aimed to provide a scalable platform for ‘trustworthy re-use’ of EHR data, thus unlocking RWD for improving clinical research. The project focussed on three key areas: 1) testing clinical trial protocols with RWD, 2) speeding up patient recruitment, and 3) facilitating EHR data extraction for use during clinical trials.
The InSite platform currently has eight commercial sponsors and contains data relating to patient demographics, diagnosis, procedures, medications and laboratory tests. While protecting patient confidentiality, the platform aims to provide researchers with information to speed up recruitment to clinical trials (via dynamically updated query data) and to assess protocol feasibility (via the generation of waterfall scores for eligibility criteria). The Champion Program is currently working to further validate and refine InSite. Plans for the future include developing the program so that it includes up to 30 hospitals from seven European countries, reaching out to the USA, and building technical partnerships.
The importance of an integrated medical plan
Alastair MacDonald (INC Research) vividly illustrated the challenges currently facing healthcare systems and the subsequent increasing need for RWE. Alastair highlighted that by 2020 the global cost of medicines is projected to exceed $1.4trillion USD, and over half the world’s population are projected to be taking at least one medicine per day. In the next five years, 225 new drugs will reach the market, with a third of these developed for patients with cancer. Such statistics point to the cost and capacity challenges faced by payers and the need for those developing new medicines to clearly demonstrate their value to healthcare systems.
Alastair went on to further highlight the potential value of RWE, citing the CVD-REAL study as a recent example. He also pointed to the potential costs of inaccurate sales projections. He informed delegates that two-thirds of drug launches fail to meet pre-launch sales expectations for their first year on the market, and presented a case study of a cardiovascular drug predicted to be a ‘blockbuster’ with peak year sales of $2.7billion USD, which actually only reached a peak value $671million USD. Alastair suggested that pre-launch RWE, as part of an integrated medical plan, could potentially have helped to predict this issue.
Alastair emphasised the importance of ‘beginning with the end in mind’ when generating an integrated medical plan. This can be achieved by establishing the unmet needs of key stakeholders (patients, HCPs, payers and regulators) and mapping these against evidence generation plans, from product concept to launch.
Why choosing RWD from the right league changes everything
Considering reasons for the sometimes negative stakeholder perceptions of RWE, Mattias Kyhlsedt (Synergus) argued that, for many, the concept of RWE is equated with ‘lower league’ EHR-based datasets, rather than the potentially higher quality or ‘higher league’ data available from large, global, patient registries.
Mattias made the case that a potential limitation of EHRs is that they have not been written with research in mind, possibly limiting data quality. Patient registries however are designed by a clinical specialist to monitor or optimise care; therefore, the quality of the data entered is generally high. Global registries exist for stroke and MS, yielding high quality data from large numbers of centres and countries.
Mattias concluded with a look at whether registry-based RCTs (R-RCTs) might represent a new clinical paradigm. With a number of R-RCTs completed or ongoing, such trials might offer an alternative to traditional RCTs and their associated limitations.
Real world data and real world evidence: turning the myriad of data sources into clinical practice evidence
Drawing Day 1 to a close, Enkeleida Nikai (Eli Lilly) summarised the key issues raised relating to the use of RWD and RWE.
Enkeleida began by considering why RWE is considered to be a ‘new’ trend in drug development. She outlined that advances in technology, coupled with higher expectations from stakeholders (payers, HCPs, patients and regulators) for evidence beyond that possible to obtain from RCTs, means that RWE is being used earlier and more broadly in the product lifecycle. RWE methodologies range from pragmatic studies and disease registries to the use of social media and big data.
She reminded delegates of some of the complexities and ambiguities relating to terminology discussed at the meeting’s outset, with a particular focus on the differentiation between RWD and RWE. Enkeleida described RWD as any “data on health interventions [and] observations of routine clinical practice…collected in the real world”, while describing RWE as an “umbrella term for evidence generated outside of RCTs”, or “testing a hypothesis using RWD and applying analysis”. She went on to emphasise the differentiation between primary and secondary RWD and RWD sources: primary data being collected for the purpose of clinical research (e.g. from prospective observational trials, patient registries, surveys and pragmatic clinical trials), and secondary data initially collected for another purpose (e.g. EHRs, claims databases, social media, smart devices/wearable technology). Each methodology presents differing levels of opportunities and risks; a thought-provoking insight for delegates to carry forwards into Day 2 of the meeting, in which speakers discussed a range of methodologies, studies and RWD sources.
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