Navigating the Post-COVID Landscape

Authored by BresMed, now part of Lumanity

We are going through a period of unpredictability, transformative change and accelerated innovation. The biopharma industry has been tasked with rapidly developing and launching new therapies to meet the needs of patients with COVID-19, all while navigating unprecedented levels of attention and scrutiny on reimbursement decisions, telemedicine, and the diversity of patient populations.

Not only has our industry drastically changed in response to this global pandemic, but it is evolving and innovating at a much faster pace than before. This brings to the fore questions of what impact will we see in the long term? And how can we act on these changes to improve how medical advances and life-changing treatments are brought to patients?

With respect to health technology assessment and reimbursement, we believe there are seven key trends that will have a significant impact on the appraisal, market access and commercial success of new treatments. Biopharma needs to not only be aware of these trends, but should carefully consider their impact, and adjust their market access and evidence generation plans accordingly.

In this paper we explore how each of these trends will likely affect manufacturers of new therapies and suggest actions to address them. Our discussion highlights several key themes and recommendations that are essential to consider when navigating our new market environment.

Key themes and actions for manufacturers

Plan ahead

Accelerating development and approval processes means biopharma needs to prepare earlier and faster.

• Keep up to date with changes to assessment processes
• Consider evidence needs and launch sequencing for each indication for the product
• Allow enough time for landscaping and evaluation of stakeholder needs
• Plan evidence development in advance to increase efficiency and ensure reimbursement needs are met

Explore new ideas

An awareness of individual market and patient needs allows for the development of specific solutions.

• Lead the way in collaborating with and challenging payers to assess new types of technologies and consider new payment methods
• Consider new types of data and research, including synthetic control arms, qualitative interviews and health data from digital technologies

Embrace innovation

Digital interventions, machine learning and real world evidence are becoming our new reality.

• Explore new methods for demonstrating the effectiveness of health technologies
• Use new technologies to effectively interact with stakeholders, patients and experts

Involve patients

Including the patient perspective at every step increases the likelihood of commercial success.

• Assess whether the clinical trial programme will provide evidence on the patient experience
• Understand the treatment pathway and when and how patients interact with the healthcare system
• Trial the use of digital tools to reach under-served and under-represented groups

We would like to hear from you. How are you navigating and managing change, and where might you need help? For more information, or to discuss how we can help you develop your own tailored approach, please contact us.

Increased scrutiny of the industry and new medicines

The global nature of the pandemic has served to highlight disparities in pricing, affordability and access to therapies across different markets. It has also elicited different responses from across ‘big pharma’; some manufacturers have condemned and refused to participate in the World Health Organization’s efforts to pool trial data and patent rights for COVID-19, while others have continued to price treatments to make a profit.^1-3 Examples of ‘profiteering and dysfunction’ have been called out by the Lown Institute⁴, and we can expect to see further criticism of such activities from patient associations and the media.

We are seeing a shift towards using health technology assessment (HTA) to inform payer decision-making as more countries consider adopting formal appraisal processes, including India⁵, China⁶ and the US. The start of the Biden administration has particularly energized discussions in the US around establishing a publicly funded HTA body and whether this would have decision-making and/or price-setting powers.^{7, 8}

Meanwhile, markets with established HTA agencies are increasingly mandating the inclusion of cost-effectiveness assessments (see the Chuikyo in Japan⁹ and AIFA in Italy¹⁰). The US-based Institute for Clinical and Economic Review (ICER), which uses cost-effectiveness analyses, has launched its ICER Analytics™ platform to allow payers and manufacturers to access ICER models and submit their own analyses.¹¹ Other HTA agencies can subscribe to this platform, with free access for those in low- and middle-income countries.

Key takeaways:

• Manufacturers should expect deeper investigation from payers into their evidence base and their proposed price
• They should also be prepared for changes in assessment processes, with increased consideration of innovation, cost effectiveness and comparison with pricing in other markets

Suggested actions:

• Conduct landscaping of reimbursement requirements in markets of interest to determine whether accelerated pathways are available and to inform the development of detailed market access plans
• Develop a clear value proposition for new medicines and a pre-launch publication plan to support reimbursement
• Prepare post-launch objection handlers to anticipate and respond to questions regarding the product’s value and price
• Consider inequalities and societal costs as part of early economic modelling and market access planning
• Publish articles comparing reimbursement requirements in different markets to review differences and recommend changes that will fairly support innovative, high-cost medicines

Acceleration of regulatory and reimbursement processes

Therapeutics developed and trialled for COVID-19 and vaccines have mostly received regulatory approval on accelerated timelines, on the condition that there will be rolling data collection to inform further review. This raises the question of non-COVID-19 priority medicines: will there be other indications or classes of treatment where new technologies can skip the queue?

Other ways we have seen approval (and therefore access) accelerated is through the use of histology-independent approvals, and the use of real world evidence (RWE) to expand indications for a particular treatment (for example, prescribing palbociclib for male breast cancer, and the ongoing nivolumab ATTRACTION-2 study).¹²

Regulatory agencies have also put in place further data collection measures to provide earlier access while managing uncertainty for new treatments. HTA and reimbursement agencies will need to adapt to follow this model; medicines will need to be assessed on less evidence from shorter trials and on a faster timeline to keep pace with regulatory approvals. It will be difficult (if not impossible) to do this while meeting the rigorous analysis standards in place in some markets. As part of its ongoing HTA methods and processes review, the National Institute for Health and Care Excellence (NICE) has already found that their current managed access process is too resource-intensive and that their process for exiting the managed access period is unclear.¹⁴ This is one example of where processes need to be updated to meet the needs of new biopharma developments; any such changes must be clearly communicated to manufacturers for this to be feasible.

We are starting to see some positive changes. The UK’s Innovative Licensing and Access Pathway, which launched at the start of 2021, aims to provide closer collaboration between regulators, HTA agencies and the NHS so that patients can access innovative medicines sooner.^{15, 16}

Key takeaways:

• HTA agencies are likely to request more information earlier in regulatory processes and add further review and reassessment stages for new drugs where manufacturers will need to provide more data
• Earlier data cuts from Phase I and II trials will be of increasing importance for reimbursement submissions, as will high-quality follow-up from later-stage trials
• Manufacturers will see more requests for data beyond those obtained from standard randomized controlled trials (RCTs), such as observational data for reassessments and RWE to support expanding the indications or treatment lines for a therapy

Suggested actions:

• Develop market access plans early to inform clinical trial development and data collection, and consider the potential future needs for managed entry agreements
• Build early economic models to understand the impact of different managed entry agreements on the desired product price and chances of reimbursement success
• For multi-indication products, plan launch sequences and pricing structures (by indication and market) to achieve the best possible price for the product while reducing the risk that one indication will affect the price or success of a later one. This can also lead to efficiencies in evidence generation and reimbursement dossier development
• Explore new development paradigms including synthetic control arms, long-term observational data for current practice, surrogate outcomes research and pragmatic trials to support the value proposition for your product
• Continue to collect robust key outcomes data, beyond the relevant data cut for licensing, to inform later reassessments
• Be involved in consultations with HTA agencies on methods and process development, and gather the knowledge for relevant products or indications to be able to push for consistency in assessments

Divergence in local market requirements

As HTA agencies come into maturity, there are increasing differences in requirements – both between markets and regionally within markets. It is therefore becoming more difficult to develop a global value dossier and economic model as a ‘one-size-fits-all’ approach that can be adapted to meet local needs.

While there are initiatives to align requirements and submissions across markets, such as the European Network for Health Technology Assessment (EUnetHTA¹⁷) and the Beneluxa Initiative¹⁸, these have not gained traction as an alternative route to reimbursement. This is likely  because they have not significantly reduced either the work required to develop a submission or the length of the reimbursement timeline, and they have yet to scale up to the volume of appraisals handled by individual markets.

Key takeaways:

• Market access is becoming increasingly expensive and complex – especially as it is now more common for HTA agencies to charge a fee for their assessment or advice

Suggested actions:

• Plan ahead to get an understanding of market requirements early in the process by engaging with local affiliates and/or seeking early scientific advice from reimbursement bodies
• Conduct landscaping to map out reimbursement needs and timelines in advance; the value proposition and market access plan should take these into account. Planning ahead is almost always easier and more cost efficient than retrofitting existing evidence for reimbursement needs
• Carefully consider the base case for global materials. Assign the base case for global materials based on the priority markets for launch and the level of analysis required by HTA agencies and payers in these areas, rather than using the company ‘default’ base case
• Consider developing regional (rather than global) core materials, grouped by markets with similar processes (such as Europe, Canada and Australia) with a separate dossier and model for the US

Shift away from simple discounting to innovative payment models

The advent of precision and ‘curative’ technologies, such as cell and gene therapies, has brought with it a wave of high-cost treatments that do not fit within traditional payment models, as the upfront cost – and therefore budget impact – is prohibitive to payers. Combination therapies are also an issue; the value of the products used in a combination therapy is not necessarily an additive function of the individual treatments, making it difficult to assign a ‘fair’ price. This can be further complicated by competition legislation in cases where the component therapies have different market authorization holders. Thus, novel payment mechanisms have been developed to deal with such complex cases and allow technologies to be reimbursed.

For instance, it can be argued that the use of standard payment models does not lead to the development of products that the market needs, such as antimicrobials. Individual governments are therefore looking for alternatives to incentivize the development in these areas of unmet need, such as the UK’s ‘subscription-style’ model for new antibiotics.¹⁹ Meanwhile in the US, payers have reported that manufacturers could facilitate negotiations for performance-based risk-sharing arrangements by providing transparent contract financial risk evaluation and modelling.²⁰

Feedback from early assessment of innovative payment models has indicated varying levels of success and payer acceptability. Criticisms and barriers for adoption include the high administrative burden for more complex mechanisms; the potential for indication bias; the availability of data necessary to implement agreements; and the challenge of making comparative assessments of therapies when pricing agreements are confidential.^{21, 22}

Key takeaways:

• Changes and innovation in payment models mean that later indications or lines of therapy for a product may require different approaches to those used for earlier ones, especially when there is a significant time period between launches
• It may be possible to attain earlier market access for a new therapy through negotiating managed entry agreements. However, this depends on both increased usage of RWE databases and the development of robust methodology for such usage to implement more complex therapies
• The resource and cost burden to develop market access plans and reimbursement dossiers will increase, as markets have different legislation and payer systems
• As payment models are still being developed to meet the needs of manufacturers, payers and the market, there is a gap in the manufacturer’s understanding of the options available and what is needed to achieve payer acceptance

Suggested actions:

• Work collaboratively with payers to increase the likelihood that payment mechanisms are accepted, to understand the possibilities and restrictions for use, and to develop a design that works for all stakeholders
• Develop an innovative pricing roadmap to scope payment mechanisms used in markets of interest and provide frameworks for products and indications under consideration. This roadmap should be updated regularly to accurately reflect payer requirements
• Integrate complex or novel mechanisms into early economic models to fully understand the benefits and risks of the different options
• Explore external tools such as ICER’s Interactive Modeler™ tool¹¹, which allows manufacturers to input data as they become available for price negotiation and run their own analyses using ICER’s model structure
• For managed entry agreements, anticipate the clinical trial or RWE study needed to generate the required evidence for initial assessment, implementation and monitoring of an agreement and any subsequent reassessment

Increasing inclusion of the patient voice in drug development and reimbursement

The COVID-19 crisis coupled with the wave of Black Lives Matter protests over the summer of 2020 highlighted the disproportionate number of deaths from coronavirus in some ethnic groups²³ and the lack of diversity in clinical trials.²⁴ Beyond the pandemic, as the number of available cell and gene therapies continues to grow and the biopharma industry increasingly focuses on precision medicines, the individuality of a patient and their treatment is becoming more important.

Therefore, there are two key issues for manufacturers – and the industry as a whole – to acknowledge and subsequently implement change:

1. The need to consider and include the patient perspective earlier in and throughout the entire drug development and commercialization process

2. The need to ensure that this perspective comes from a diverse range of voices, reflecting the heterogeneity of the patient population and varying levels of access to healthcare

Regulatory and HTA agencies are taking steps on these issues and adapting processes to put greater emphasis on considerations of equity, burden of illness and quality of life in their decision-making. Recently, the European Medicines Agency has co-sponsored an International Council for Harmonisation reflection paper on patient-focused drug development that identifies key areas where incorporation of the patient perspective could improve the quality, relevance, safety and efficiency of drug development and inform regulatory decision making.²⁵

In the UK, NICE has taken the patient voice into account in their HTA methods review, proposing that the ‘Summary of Information for Patients’ element of submission dossiers is transferred from a pilot programme to a standard part of the process.¹⁴ This is in addition to proposals to raise the profile and usage of qualitative evidence (from patients and other sources) in submission dossiers.²⁶

Meanwhile in the US, ICER has launched their Patient Engagement Program and appointed a dedicated Vice President.²⁷ This will, among other things, support patient organizations in preparing for ICER assessments, facilitate patient feedback at touchpoints throughout the assessment process, and enable patients to participate in public deliberations.²⁸

Key takeaways:

• Regulatory, reimbursement and access decisions are made within a limited societal scope due to a lack of diversity within clinical trial populations, patient advocates and associations, and decision-maker bodies. This leads to under-represented and under-served patient groups
• Product launches may potentially hit below commercial expectations due to a misunderstanding of patient needs, lack of value to patients, and inconvenient treatment or dosing²⁹
• Manufacturers risk falling out of favour with both the public and payers if they ignore calls for increased patient input, diversity in clinical trial enrolment, and analysis of ethnic and gender subgroups within heterogenous patient populations
• HTA submission dossiers that do not include quantitative analysis (or alternative evidence sources) of quality of life and burden of illness for patients risk a more challenging and longer appraisal process and are ultimately more likely to be unsuccessful

Suggested actions:

• Conduct a landscaping assessment early in the drug development process to understand the patient population and potential subgroups, and use this information to develop a representative clinical trial
• Carefully consider how to demonstrate impact on quality of life within the clinical trial design
  • One key consideration is whether there is a sufficient number of patients to show any positive trends, or whether the focus should be on demonstrating that the product will not have a detrimental impact. This is of particular concern within smaller patient populations where a difference between treatments is more difficult to demonstrate
  • Another is whether the included instruments demonstrate good validity within the relevant patient population, and ensuring that they will meet HTA requirements
  • A final key consideration is the frequency and duration of measurement; assessments should continue throughout extended follow-up where possible
• Assess whether the clinical trial programme will provide evidence on the patient experience or if additional evidence needs to be developed in parallel to support future reimbursement dossiers
  • Where such evidence is needed, explore using robust qualitative methods for eliciting the patient voice to support the development of the product’s value proposition and to provide appropriate context for decision-makers
• Involve patient advocates in planning for the product’s value proposition and health economic case
• Review and analyse the treatment pathway for the product and the points of interaction between patients and healthcare providers to find and address potential inequalities in access to treatment for different patient groups
• Measure and evaluate how actions to include the patient perspective (such as those listed above) have affected access to treatment and the commercial success of the product to determine whether there are still gaps to be addressed

Growth of the digital health sector

Digital health includes the use of digital interventions for preventative and therapeutic treatments, telehealth for patient–clinician contact, and the Internet of Things to improve monitoring and data sharing. The ongoing pandemic has increased both patient and provider uptake of telehealth options, including clinician appointments and remote data collection in clinical trials.^{30, 31}

As the pool of digital interventions widens to embrace new technologies – such as the first prescription video game approved by the US Food and Drug Administration³² – HTA and reimbursement agencies are racing to catch up and implement assessment processes that differentiate digital therapeutics from more traditional medical devices and diagnostics. NICE recently completed its digital health technologies evaluation pilot with conditional reimbursement of the Zio® XT service to detect abnormal heart rhythms.³³ ICER has also reviewed digital health therapeutics, in this instance to treat opioid use disorder, and provided several policy recommendations for demonstrating the value of these technologies, including advising manufacturers to provide evidence on the productivity impact, security and scalability of therapeutics and recommending the use of outcomes- or subscription-based payment models.³⁴

The digital health sector is expected to continue to grow. However, it is not without its challenges. It is difficult to design an RCT for a digital intervention that measures outcomes objectively or accounts for additional social factors absent in traditional clinical trials, such as consumer technology adoption. Other areas of concern include the cybersecurity of wearables, apps and other technologies³⁵, and the lack of standardization in implementation and reporting in studies on digital health and associated therapies.

Key takeaways:

• There is an expectation from patients and payers that biopharma companies will take a ‘digital-first’ approach in developing new therapies and clinical trial designs
• Changes and experiments in regulatory and HTA guidelines are anticipated in order to meet the needs of new digital technologies
• There is the potential to introduce cost-sharing payment models to manage the cybersecurity requirements for digital interventions

Suggested actions:

• Keep up to speed with the rapidly developing digital sector, including the methods adopted by different HTA agencies to assess them
• Focus on demonstrating the cost offsets that result from new digital technologies, given the challenge of robustly demonstrating superior clinical outcomes
• Follow value demonstration ‘best practice’ when preparing to launch a digital technology – but be aware of the individual needs for the product
• Consider the potential influence of emerging digital technologies on more standard product uptake and usage, and aim to provide a wrap-around service to support patients and clinicians with new tools
• Trial using digital tools to access traditionally ‘harder-to-reach’ populations to increase the diversity of clinical trial populations. Offer more support to patients from under-represented and under-served groups, and broaden the pool of patient advocates

Expansion of data collection, sharing and analysis methods

Technological developments and COVID-19 have contributed to changes in data collection and analysis to inform drug development, approvals and access. Though this has been an area of growth for many years, digital technologies (e.g. wearables, apps, the Internet of Things) along with the proliferation of databases for specific markets, payers and indications have increased the types and volume of available observational data.

Artificial intelligence (AI) has long been a buzzword in the biopharma sphere, even when it has resulted in limited amounts of success.³⁶ However, the development of machine learning methods to better analyse the available data combined with the shift in focus from standalone AI to augmented intelligence have led to improvements in the outputs and applicability of AI.

Challenges remain in this space to ensure that AI data inputs and subsequent outputs are representative of patient populations (such as including non-European genetic data) and therefore useful for healthcare decision-makers. There is also concern from the public on the use of their data to inform decisions on both public healthcare provision and commercial drug development.³⁷ To address some of the issues around infrastructure and governance, several organizations are now developing and using common data models to improve data quality, transparency and usefulness. One prominent example is the European Health Data and Evidence Network (EHDEN), which has recently partnered with NICE to provide another data source for evaluating unmet need and the effectiveness of new treatments.³⁸

For regulators, the use of real world data (RWD) and RWE to evaluate new treatments has been established for a couple of years.^{40, 41} Increased data availability and accelerated regulatory and reimbursement timelines are now leading HTA agencies to make similar commitments to use RWD and RWE to support their decision-making. In 2020, ICER announced that they will pilot using RWE as part of updating their assessments for drugs after 24 months in the market, and explore options for generating further RWE as part of updates to their methods and procedures.⁴² NICE has also published their intent to use broader sources of data, such as electronic health records and registries, and analytical methods to enhance their existing methods and processes.⁴³

However, there are still barriers to overcome. A significant problem is that, confusingly, the terms RWD and RWE are used interchangeably by both the scientific community and the public. Other issues include quality of data; acceptability of a broader spectrum of data (RWD, digital therapies, observational data); interoperability between payer systems and databases; data governance and security; and understanding of data types and analysis methods in the wider scientific community.⁴⁴ While the COVID-19 pandemic has brought unprecedented levels of data sharing within and between academia and industry to fuel the search for effective treatments, it remains to be seen whether this will continue post-pandemic – though there have already been calls from non-profits⁴⁵ and academia⁴⁶ for open access and collaboration to continue.

RWE is derived through analysis and interpretation of RWD⁴⁷

Key takeaways:

• Smaller study sizes and accelerated regulatory timelines mean that manufacturers, regulators and HTA agencies are relying less on traditional RCT evidence. Evidence from pivotal studies therefore needs to be supplemented with other data to inform the clinical and cost effectiveness value case for the product⁴⁸
• To meet this requirement, manufacturers will need to explore new drug development and evidence generation paradigms, including using simulation methods to optimize clinical trial design and using pragmatic trials to determine treatment effect. They will also need to apply RWE to identify optimal treatment pathways and algorithms, enable novel payment and managed access agreements and expand the approved indications for a product

Suggested actions:

• Assess the expected trial outcomes and safety requirements as part of early pipeline planning to decide whether an RCT or an RWD study would be most appropriate, and ensure that endpoints can be used to inform the health economic value case as well as gain regulatory approval
• Conduct landscaping of HTA agency requirements and acceptance of data sources to inform supplemental data analysis when developing the product reimbursement dossier
• Use the evidence from RWD databases to inform trial design and ensure the appropriate evidence is collected
• Consider carefully how and when to use RWE for regulatory and reimbursement purposes

If you would like to discuss any of the trends or suggestions mentioned here, please contact us.

Seven key trends

Increased scrutiny of the industry and new medicines

Acceleration of regulatory and reimbursement processes

Divergence in local market requirements

Shift away from simple discounting to innovative payment models

Increasing inclusion of the patient voice in drug development and reimbursement

Growth of the digital health sector

Expansion of data collection, sharing and analysis methods

Histology-independent treatment

Also known as tumour- or site-agnostic, treatments that are histology-independent will act on any solid (i.e. non-haematological) tumour with a specific genomic mutation regardless of its location of origin.¹³

Payment model terms

Managed entry (or access) agreement refers to a reimbursement agreement conditional upon additional evidence collection.

An innovative payment model is a form of reimbursement with payment based on outcomes, capping scheme, or other factors beyond a fixed price or discount.

Artificial intelligence

‘Computational methods used to produce systems that perform tasks which exhibit intelligent behavior that is indistinguishable from human behavior’³⁸

Augmented intelligence

‘A conceptualization of artificial intelligence that focuses on artificial intelligence’s assistive role, emphasizing that its design enhances human intelligence rather than replaces it’³⁸

Machine learning

A subset of artificial intelligence and computer science where algorithms are constructed to make accurate predictions about future outcomes by using pattern recognition and rule-based logic³⁹