Towards a coordinated approach for managing accelerated patient access to potentially beneficial medicines: reporting the perspectives of a multi-stakeholder, international workshop.

Accelerated and conditional regulatory pathways for drug approvals are intended to enable earlier patient access to potentially life-saving treatments, or treatments that provide benefits in addressing a significant unmet need. However, there are questions about how well such pathways work, how appropriately they are applied, and how the work of regulators can be better coordinated with that of health technology assessment (HTA) and payer bodies, providers and health systems, and other stakeholders. In June 2023, a multi-stakeholder, international workshop was convened in Adelaide, Australia, to deliberate the challenges, goals, and opportunities to improve accelerated access pathways. Workshop attendees included representatives from patient organizations, regulators, HTA/payer bodies, universities (ethicists, health economists), and companies developing and marketing new medicines from Australia, Asia, Europe, and North America. We reviewed the contents of this workshop to identify areas of agreement and disagreement, report the key themes of the discussion, and delineate next steps for improving accelerated access pathways. We found that there was general agreement among workshop attendees that accelerated access could be improved significantly by strengthening processes for stakeholder coordination, and that coordinated efforts will be required to implement meaningful change moving forward.

Challenges in valuing and paying for combination regimens in oncology: reporting the perspectives of a multi-stakeholder, international workshop.

BACKGROUND: It is increasingly common for two or more treatments for cancer to be combined as a single regimen. Determining value and appropriate payment for such regimens can be challenging. This study discusses these challenges, and possible solutions. METHODS: Stakeholders from around the world attended a 2-day workshop, supported by a background paper. This study captures key outcomes from the discussion, but is not a consensus statement. RESULTS: Workshop attendees agreed that combining on-patent treatments can result in affordability and value for money challenges that delay or deny patient access to clinically effective treatments in many health systems. Options for addressing these challenges include: (i) Increasing the value of combination therapies through improved clinical development; (ii) Willingness to pay more for combinations than for single drugs offering similar benefit, or; (iii) Aligning the cost of constituent therapies with their value within a regimen. Workshop attendees felt that (i) and (iii) merited further discussion, whereas (ii) was unlikely to be justifiable. Views differed on the feasibility of (i). Key to (iii) would be systems allowing different prices to apply to different uses of a drug. CONCLUSIONS: Common ground was identified on immediate actions to improve access to combination regimens. These include an exploration of the legal challenges associated with price negotiations, and ensuring that pricing systems can support implementation of negotiated prices for specific uses. Improvements to clinical development and trial design should be pursued in the medium and longer term.

Cornerstones of 'fair' drug coverage: appropriate cost sharing and utilization management policies for pharmaceuticals.

At the heart of all health insurance programs lies ethical tension between maximizing the freedom of patients and clinicians to tailor care for the individual and the need to make healthcare affordable. Nowhere is this tension more fiercely debated than in benefit design and coverage policy for pharmaceuticals. This paper focuses on three areas over which there is the most controversy about how to judge whether drug coverage is appropriate: cost-sharing provisions, clinical eligibility criteria, and economic-step therapy and required switching. In each of these domains we present 'ethical goals for access' followed by a series of 'fair design criteria' that can be used by stakeholders to drive more transparent and accountable drug coverage.

Policy perspectives on alternative models for pharmaceutical rebates: a report from the Institute for Clinical and Economic Review Policy Summit.

Alternative approaches to the current rebate system are being considered by policymakers and stakeholders in the private insurance market. This paper presents an analysis of three alternative options to the current rebate model: retaining retroactive rebates but requiring 100% pass-through of rebates and fees to plan sponsors; retaining retroactive rebates but requiring that patients share in rebates at the point of sale; and eliminating retroactive rebates and replacing the current structure with upfront discounts. Each alternative approach presents a balance of potential advantages and disadvantages. Policymakers should not assume that switching to an alternative rebate model will deliver unalloyed benefits for patients and the health system.

Real-world evidence for coverage decisions: opportunities and challenges.

AIM: To explore current uses of real-world evidence (RWE) in the US healthcare system, summarize key concerns and highlight various opportunities that could be realized through best use of RWE. Materials & methods: Information was gathered via a literature review and interviews to generate a background paper for the 2017 Institute for Clinical and Economic Review Policy Summit meeting. RESULTS: RWE is currently being utilized in drug development decisions, regulatory approval decisions, post-approval monitoring, payer coverage decisions (initial decisions and reassessments) and for outcomes-based contracting. Solutions to key challenges and opportunities for future development are presented. CONCLUSION: Exciting opportunities for the use of RWE exist, yet important reservations remain. Solutions are within reach if effective partnerships between stakeholders can be nurtured.

A framework to guide the optimal development and use of real-world evidence for drug coverage and formulary decisions.

AIM: To provide a framework for optimizing the development and use of real-world evidence (RWE) in drug coverage decisions. Materials & methods: The Institute for Clinical and Economic Review convened a Policy Summit with representatives from 23 payer and life science companies that compose the Institute for Clinical and Economic Review membership. RESULTS: Summit participants helped refine a new conceptual framework that emphasizes the central role of contextual considerations and the evidentiary argument that the RWE is intended to support in designing the process for the development and interpretation of RWE. CONCLUSION: This framework may provide a structured way for pharmaceutical manufacturers and payers to develop a shared understanding of the best way to develop RWE that will ultimately be useful in informing coverage and formulary decisions.

Gene therapy: evidence, value and affordability in the US health care system.

AIMS: To explore the challenges presented by gene therapies, discuss potential solutions, and present policy recommendations. METHODS: A review of the literature and series of expert interviews were conducted and discussed at a Policy Forum convened by The Institute for Clinical and Economic Review (ICER). The Policy Forum was attended by independent experts and senior representatives from 20 payer organizations and life sciences companies. RESULTS: Three categories of challenges are identified: evidence generation, assessing value and affordability. Possible solutions and policy recommendations are presented for each of the three main categories of challenges. CONCLUSIONS: Gene therapies present exciting opportunities, but also pose major challenges. Dialogue between manufacturers and payers around the issues and possible solutions is crucial.

Indication-specific pricing of pharmaceuticals in the US healthcare system.

AIM: To explore the potential of indication-specific pricing (ISP) of pharmaceuticals and to discuss prospects for implementation in the US healthcare system. MATERIALS & METHODS: The Institute for Clinical and Economic Review convened a policy forum with 44 healthcare leaders from 22 payer and life sciences companies. Models of ISP were discussed. RESULTS: Payers and drug manufacturers saw the potential benefits of an ISP system that balances affordability for payers, sustainability for manufacturers and access for patients. The US healthcare system presents many challenges to implementation, including potential conflicts with existing pricing policies (Medicaid Best Price, average sales price and 340B) and insufficient data systems and analytic capabilities. CONCLUSION: Possible solutions and policy recommendations for payers and manufacturers are provided.

ASSESSING VALUE, BUDGET IMPACT, AND AFFORDABILITY IN ASIA.

OBJECTIVES: The aim of this study was to explore definitions of value and the use of budget impact and affordability considerations in health technology assessment (HTA) in the Asia region, particularly in relation to high cost technologies. METHODS: Issues were debated by senior representatives from HTA and payer systems in Asian countries, delegates from industry, and invited experts at the 2016 meeting of the HTAi Asia Policy Forum (HAPF). A premeeting survey was used to gather data on how value is assessed and budget impact calculations are used within current processes, as well as current approaches to managing affordability. RESULTS: All systems consider health benefit to be the key component of value. There is little consensus around "wider" elements of value that should be included. All systems use budget impact in decision making, although meeting attendees noted the challenges in making accurate estimates. The most common strategies used to address affordability concerns to date have been: restricting coverage, for example, to patients who are likely to get the highest value; discounts; and revenue caps. It was noted that these "solutions" may have unintended consequences of creating inequitable access to therapies and failing to provide adequate rewards for innovation. CONCLUSIONS: Decision makers, HTA agencies, and industry need to continue to work together to find mutually agreeable solutions to ensure that patients continue to get equitable access to effective therapies at costs that can be afforded throughout the Asia region.

CHANGING HEALTH TECHNOLOGY ASSESSMENT PARADIGMS?

OBJECTIVES: Health technology assessment (HTA) has to innovate to best support changing health system environments and to help provide access to valuable innovation under fiscal constraint. METHODS: Issues associated with changing HTA paradigms were identified through scoping and explored through deliberation at a meeting of industry and HTA leaders. RESULTS: Five broad areas of change (engagement, scientific dialogue, research prioritization, adaptive approaches, and real world data) were identified. The meeting focused on two themes derived from these: re-thinking scientific dialogue and multi-stakeholder engagement, and re-thinking value, affordability, and access. Earlier and ongoing engagement to steer the innovation process and help achieve appropriate use across the technology lifecycle was perceived as important but would be resource intensive and would require priority setting. Patients need to be involved throughout, and particularly at the early stages. Further discussion is needed on the type of body best suited to convening the dialogue required. There was agreement that HTA must continue to assess value, but views differed on the role that HTA should play in assessing affordability and on appropriate responses to challenges around affordability. Enhanced horizon scanning could play an important role in preparing for significant future investments. CONCLUSIONS: Early and ongoing multi-stakeholder engagement and revisiting approaches to valuing innovation are required. Questions remain as to the most appropriate role for HTA bodies. Changing HTA paradigms extend HTA's traditional remit of being responsive to decision-makers demands to being more proactive and considering whole system value.

TREATMENT SWITCHING: STATISTICAL AND DECISION-MAKING CHALLENGES AND APPROACHES.

OBJECTIVES: Treatment switching refers to the situation in a randomized controlled trial where patients switch from their randomly assigned treatment onto an alternative. Often, switching is from the control group onto the experimental treatment. In this instance, a standard intention-to-treat analysis does not identify the true comparative effectiveness of the treatments under investigation. We aim to describe statistical methods for adjusting for treatment switching in a comprehensible way for nonstatisticians, and to summarize views on these methods expressed by stakeholders at the 2014 Adelaide International Workshop on Treatment Switching in Clinical Trials. METHODS: We describe three statistical methods used to adjust for treatment switching: marginal structural models, two-stage adjustment, and rank preserving structural failure time models. We draw upon discussion heard at the Adelaide International Workshop to explore the views of stakeholders on the acceptability of these methods. RESULTS: Stakeholders noted that adjustment methods are based on assumptions, the validity of which may often be questionable. There was disagreement on the acceptability of adjustment methods, but consensus that when these are used, they should be justified rigorously. The utility of adjustment methods depends upon the decision being made and the processes used by the decision-maker. CONCLUSIONS: Treatment switching makes estimating the true comparative effect of a new treatment challenging. However, many decision-makers have reservations with adjustment methods. These, and how they affect the utility of adjustment methods, require further exploration. Further technical work is required to develop adjustment methods to meet real world needs, to enhance their acceptability to decision-makers.

TREATMENT SWITCHING IN CANCER TRIALS: ISSUES AND PROPOSALS.

OBJECTIVES: Treatment switching occurs when patients in a randomized clinical trial switch from the treatment initially assigned to them to another treatment, typically from the control to experimental treatment. This study discusses the issues this raises and possible approaches to addressing them in trials of cancer drugs. METHODS: Stakeholders from around the world were invited to a 1.5-day Workshop in Adelaide, Australia. This study attempts to capture the key points from the discussion and the perspectives of the various stakeholder groups, but is not a formal consensus statement. RESULTS: Treatment switching raises challenging ethical issues with arguments for and against allowing it. It is increasingly common in cancer drug trials and presents challenges for the interpretation of results by regulators, clinicians, patients, and payers. Proposals are offered for good practice in the design, management, and analysis of trials and wider development programs for cancer drugs in which treatment switching has occurred or is likely to. Recommendations are also offered for further action to improve understanding of the importance and challenges of treatment switching and to promote agreement between key stakeholders on guidelines and other steps to address these challenges. CONCLUSIONS: The handling of treatment switching in trials is of concern to all stakeholders. On the basis of the discussions at the Adelaide International Workshop, there would appear to be common ground on approaches to addressing treatment switching in cancer trials and scope for the development of formal guidelines to inform the work of regulators, payers, industry, trial designers and other stakeholders.

Targeting improved patient outcomes using innovative product listing agreements: a survey of Canadian and international key opinion leaders.

OBJECTIVES: To address the uncertainty associated with procuring pharmaceutical products, product listing agreements (PLAs) are increasingly being used to support responsible funding decisions in Canada and elsewhere. These agreements typically involve financial-based rebating initiatives or, less frequently, outcome-based contracts. A qualitative survey was conducted to improve the understanding of outcome-based and more innovative PLAs (IPLAs) based on input from Canadian and international key opinion leaders in the areas of drug manufacturing and reimbursement. METHODS: Results from a structured literature review were used to inform survey development. Potential participants were invited via email to partake in the survey, which was conducted over phone or in person. Responses were compiled anonymously for review and reporting. RESULTS: Twenty-one individuals participated in the survey, including health technology assessment (HTA) key opinion leaders (38%), pharmaceutical industry chief executive officers/vice presidents (29%), ex-payers (19%), and current payers/drug plan managers/HTA (14%). The participants suggested that ~80%-95% of Canadian PLAs are financial-based rather than outcomes-based. They indicated that IPLAs offer important benefits to patients, payers, and manufacturers; however, several challenges limit their use (eg, administrative burden, lack of agreed-upon endpoint). They noted that IPLAs are useful in rapidly evolving therapeutic areas and those associated with high unmet need, a quantifiable endpoint, and/or robust data systems. The Canadian Agency for Drugs and Technologies in Health, the pan-Canadian Pharmaceutical Alliance, and other arms-length organizations could play important roles in identifying uncertainty and endpoints and brokering pan-Canadian PLAs. Industry should work collaboratively with payers to identify uncertainty and develop innovative mechanisms to address it. CONCLUSION: The survey results indicated that while challenging, use of IPLAs may be associated with various benefits. Collaboration among stakeholders remains key: Canadian agencies could play an important role in the success of these agreements, while industry should be proactive in offering solutions that will help improve outcomes across the entire health care system.

Public participation in decision-making on the coverage of new antivirals for hepatitis C.

Purpose - New hepatitis C medicines such as sofosbuvir underline the need to balance considerations of innovation, clinical evidence, budget impact and equity in health priority-setting. The purpose of this paper is to examine the role of public participation in addressing these considerations. Design/methodology/approach - The paper employs a comparative case study approach. It explores the experience of four countries - Brazil, England, South Korea and the USA - in making coverage decisions about the antiviral sofosbuvir and involving the public and patients in these decision-making processes. Findings - Issues emerging from public participation ac tivities include the role of the universal right to health in Brazil, the balance between innovation and budget impact in England, the effect of unethical medical practices on public perception in South Korea and the legitimacy of priority-setting processes in the USA. Providing policymakers are receptive to these issues, public participation activities may be re-conceptualized as processes that illuminate policy problems relevant to a particular context, thereby promoting an agenda-setting role for the public. Originality/value - The paper offers an empirical analysis of public involvement in the case of sofosbuvir, where the relevant considerations that bear on priority-setting decisions have been particularly stark. The perspectives that emerge suggest that public participation contributes to raising attention to issues that need to be addressed by policymakers. Public participation activities can thus contribute to setting policy agendas, even if that is not their explicit purpose. However, the actualization of this contribution is contingent on the receptiveness of policymakers.

CHANGING HEALTH TECHNOLOGY ASSESSMENT PARADIGMS?-ERRATUM.

In Husereau et al., the affiliation for Laura Sampietro-Colom was listed as "Hospital Clinic". It should have instead been listed as, "Hospital Clinic, Barcelona, Spain".

IMPROVING THE EFFECTIVENESS AND EFFICIENCY OF EVIDENCE PRODUCTION FOR HEALTH TECHNOLOGY ASSESSMENT.

OBJECTIVES: Health Technology Assessment (HTA) needs to address the challenges posed by high cost, effective technologies, expedited regulatory approaches, and the opportunities provided by collaborative real-world evaluation of technologies. The Health Technology Assessment International (HTAi) Policy Forum met to consider these issues and the implications for evidence production to inform HTA. This paper shares their discussion to stimulate further debate. METHODS: A background paper, presentations, group discussions, and stakeholder role play at the 2015 HTAi Policy Forum meeting informed this paper. RESULTS: HTA has an important role to play in helping improve evidence production and ensuring that the health service is ready to adopt effective technologies. It needs to move from simply informing health system decisions to also working actively to align stakeholder expectations about realistic evidence requirements. Processes to support dialogue over the health technology life cycle need to be developed that are mindful of limited resources, operate across jurisdictions and learn from past processes. Collaborations between health technology developers and health systems in different countries should be encouraged to develop evidence that will inform decision making. New analytical techniques emerging for real-world data should be harnessed to support modeling for HTA. CONCLUSIONS: A paradigm shift (to "Health Innovation System 2.0") is suggested where HTA adopts a more central, proactive role to support alignment within and amongst stakeholders over the whole life cycle of the technology. This could help ensure that evidence production is better aligned with patient and health system needs and so is more effective and efficient.

TOWARD A SHIFTING HEALTH TECHNOLOGY ASSESSMENT PARADIGM: REACTIONS TO POLICY FORUM DISCUSSIONS.

Are we in a period of significant change? Is health technology assessment (HTA) undergoing a fundamental transformation? Or should it be? Are we in the middle of a paradigm shift? These are some of the questions the paper by Facey et al in this journal (1) raises about the future of HTA, based on discussions at the HTAi Policy Forum in February 2015. To further share the deliberations of the Forum and with a view to opening this debate among the wider HTA community, a panel within the HTAi 2015 Annual Meeting in Oslo was organized. Presentations at the panel included a summary of the HTAi Policy Forum deliberations and perspectives from a patient, a clinician, and representatives of an HTA organization, industry, and a health system. This letter presents issues and thoughts raised in the panel session.

How long does biomedical research take? Studying the time taken between biomedical and health research and its translation into products, policy, and practice.

BACKGROUND: The time taken, or 'time lags', between biomedical/health research and its translation into health improvements is receiving growing attention. Reducing time lags should increase rates of return to such research. However, ways to measure time lags are under-developed, with little attention on where time lags arise within overall timelines. The process marker model has been proposed as a better way forward than the current focus on an increasingly complex series of translation 'gaps'. Starting from that model, we aimed to develop better methods to measure and understand time lags and develop ways to identify policy options and produce recommendations for future studies. METHODS: Following reviews of the literature on time lags and of relevant policy documents, we developed a new approach to conduct case studies of time lags. We built on the process marker model, including developing a matrix with a series of overlapping tracks to allow us to present and measure elements within any overall time lag. We identified a reduced number of key markers or calibration points and tested our new approach in seven case studies of research leading to interventions in cardiovascular disease and mental health. Finally, we analysed the data to address our study's key aims. RESULTS: The literature review illustrated the lack of agreement on starting points for measuring time lags. We mapped points from policy documents onto our matrix and thus highlighted key areas of concern, for example around delays before new therapies become widely available. Our seven completed case studies demonstrate we have made considerable progress in developing methods to measure and understand time lags. The matrix of overlapping tracks of activity in the research and implementation processes facilitated analysis of time lags along each track, and at the cross-over points where the next track started. We identified some factors that speed up translation through the actions of companies, researchers, funders, policymakers, and regulators. Recommendations for further work are built on progress made, limitations identified and revised terminology. CONCLUSIONS: Our advances identify complexities, provide a firm basis for further methodological work along and between tracks, and begin to indicate potential ways of reducing lags.

Adaptive approaches to licensing, health technology assessment, and introduction of drugs and devices.

BACKGROUND: Adaptive approaches to the introduction of drugs and medical devices involve the use of an evolving evidence base rather than conventional single-point-in-time evaluations as a proposed means to promote patient access to innovation, reduce clinical uncertainty, ensure effectiveness, and improve the health technology development process. METHODS: This report summarizes a Health Technology Assessment International (HTAi) Policy Forum discussion, drawing on presentations from invited experts, discussions among attendees about real-world case examples, and background paper. RESULTS: For adaptive approaches to be understood, accepted, and implemented, the Forum identified several key issues that must be addressed. These include the need to define the goals of and to set priorities for adaptive approaches; to examine evidence collection approaches; to clarify the roles and responsibilities of stakeholders; to understand the implications of adaptive approaches on current legal and ethical standards; to determine costs of such approaches and how they will be met; and to identify differences in applying adaptive approaches to drugs versus medical devices. The Forum also explored the different implications of adaptive approaches for various stakeholders, including patients, regulators, HTA/coverage bodies, health systems, clinicians, and industry. CONCLUSIONS: A key outcome of the meeting was a clearer understanding of the opportunities and challenges adaptive approaches present. Furthermore, the Forum brought to light the critical importance of recognizing and including a full range of stakeholders as contributors to a shared decision-making model implicit in adaptive pathways in future discussions on, and implementation of, adaptive approaches.