Developing a Framework for the Health Technology Assessment of Histology-independent Precision Oncology Therapies.

Scientists have been looking at the role the immune system may play in fighting cancer for decades, but it is only recently that this knowledge has been translated into immuno-oncology therapies that provide the promise of long-term quality survival to patients [1–3]. Agents are now available to patients with advanced melanoma [1] and castration resistant prostate cancer, [3] and many more agents are expected to become available in the next few years, including in some of most common (e.g. breast and lung) and most difficult-to-treat cancers [1–5]. What makes these new therapies unique is that they confer long-lasting memory to the immune system, enabling it to adapt itself to fight against cancer cells even after remission. Side-effects also tend to be manageable compared to many other cancer therapies. But as with all new treatments, providing fast access to immuno-oncology therapies to appropriate patients will be increasingly challenging in our resource-constrained health care systems. In addition, the science of immuno-oncology is rapidly evolving, and we are still learning how to use these agents to achieve the best possible response in patients [4]. We still lack a clear understanding of what biological factors make a given immuno-oncology therapy work in a particular patient [6]. Also, the clinical development pathways traditionally used in oncology were typically developed for conventional cytotoxic therapies and may be poorly suited to reflect the effects seen with immunooncology therapies [7]. With these challenges in mind, the European Expert Group on Immuno-Oncology was established in early 2014 as an independent network of patients, oncology healthcare professionals, scientists, industry and politicians to help improve overall understanding of what immuno-oncology therapies are and what they may mean for cancer patients. A first goal of the Expert Group was to help policymakers identify what policy adaptations were needed to enable rapid access to immunooncology therapies in appropriate patients across Europe. The resulting Policy Action Framework [8] was launched at the European Parliament in November 2014 along with a guide for patients on immuno-oncology [9]. The Action Framework proposes five priority areas, as shown in Figure 1. Figure 1. Key recommendations for policymakers on immuno-oncology [8]. Promoting a greater understanding of immuno-oncology among policymakers, regulatory and Health Technology Assessment (HTA) agencies, health professionals and patients is key. Informed policymakers are more likely to integrate new therapies into cancer plans and policies, and ensure that appropriate resources and funding are put in place to deliver on these plans at the local level. Professional training across the entire care team is essential for treatments to be used as appropriately as possible in patients who are most likely to benefit, and to monitor the long-term effects, including toxicity, of this new group of agents. And patients need continuous information and support in order to engage fully in treatment decisions. Long-term quality survival is the ultimate goal of cancer therapy [10], however obtaining this evidence may take several years. Therefore, it is important to identify validated intermediary endpoints that are predictive of long-term survival [11]. Integrating appropriate measures of quality of life into clinical trials and clinical practice is also critical to assess the impact of new therapies on patients both during and after treatment. Also, HTA agencies and subsequent funding decisions should be based on what matters most to patients and their families, and take account of the full societal benefits of new therapies, for example individuals’ ability to return to work and lead a ‘normal’ life with long-term survival. Greater flexibility is also needed in existing regulatory frameworks to allow for an appropriate balance between the need for safety and efficacy data and rapid access to promising therapies [12]. For example, the European Medicines Agency is currently exploring more flexible frameworks which allow regulatory decisions to be based on an evolving set of data for selected therapies [13, 14] Early collaboration between drug developers, patient organisations, regulatory agencies and HTA agencies is instrumental for the success of such schemes, as they need to agree to a comprehensive development and licensing plan early on, matched with adaptive frameworks for reimbursement and HTA decisions as well. Collaborative, multidisciplinary research platforms in the form of public-private partnerships (PPPs) also have a huge role to play in immuno-oncology. For example, the Innovative Medicines Initiative is Europe’s largest PPP aimed at speeding up the development of, and patient access to, innovative medicines, particularly in areas where there is high unmet patient need [15]. PPPs may also help provide access to immuno-oncology therapies in poorer-resourced countries as part of compassionate use programmes. Collaborations between the research community and pharmaceutical companies may also allow the creation of large databases that combine data from several clinical trials. These data may help identify which patient characteristics make individuals more likely to respond to different immuno-oncology therapies and develop suitable biomarkers and other patient selection tools as a result. Finally, mechanisms need to be put in place to make sure that the most effective new therapies are included in local care pathways and supported by appropriate funding streams, particularly in heavily decentralised health care systems. For example, the Melanoma Taskforce in the UK developed a national toolkit for local commissioners responsible for funding care to ensure equitable, timely and appropriate access to the full range of approved treatments for people with advanced melanoma across all localities. Long-term alternative financing mechanisms that address payer concerns and maximize and accelerate patient access will also be critical.

IntroductionOver the past decade there have been increasing interactions between health technology assessment (HTA) agencies through international networks at the policy level and European joint actions at the product level. A pilot project is underway to explore collaboration beyond Europe between HTA agencies in Australia, Canada, and the UK. This study the compared HTA recommendations of new active substances (NAS) appraised by Australia’s Pharmaceutical Benefits Advisory Committee (PBAC), Canada’s CADTH, and England’s National Institute for Health and Care Excellence (NICE).MethodsUsing publicly available data and established benchmarking methodology, we examined 45 NAS appraised by PBAC, CADTH, and NICE between 2017 and 2021. Analysis was performed to assess rollout time from regulatory to HTA recommendation, and to the first HTA recommendation.ResultsMost products were submitted to the Europe Medicine Agency first (89%). However, 71 percent of NAS in Australia and 69 percent in Canada were submitted to HTA in parallel with regulatory review, which shortened overall rollout time. The median HTA submission gap among the three agencies was 140 days in Australia, 102 days in Canada, and 8 days in England. PBAC had the highest number of negative recommendations (51%), followed by CADTH (18%), and NICE (5%). The congruence of HTA decisions was highest between CADTH and NICE (56%), compared with PBAC and CADTH (11%), and PBAC and NICE (20%)ConclusionsTo achieve a more collaborative HTA process it is necessary to understand the rollout time in these jurisdictions. This study identified submission gaps among the regulatory agencies, but there may be more synergy in the future as regulators in the three jurisdictions work collaboratively through the Access Consortium. Currently, the submission gap for the three HTA agencies was mostly within six months, making collaboration on joint assessment possible. We observed divergences in HTA recommendations due to the methodology and decision criteria applied by each agency. Therefore, collaboration on assessment should build on the clinical aspects, although HTA decisions should be grounded in the local context.

Background despite advances in precision medicine, the translation of genetic and genomic technologies into routine practice is hampered by a heterogeneous and limited evidence base and the absence of standardized evaluation methodologies. Health Technology Assessment (HTA) plays a critical role in bridging this gap, yet assessment approaches and comprehensiveness vary widely. This systematic review aims to map the landscape of the assessment reports on genetic and genomics applications, analyze their methodological aspects and identify emerged gaps. Methods PubMed, Scopus, Web of Science, and the international HTA database, were searched for assessment reports of genetic/genomic technologies. Information on reports general characteristics, assessment domains and their components, consulted sources of evidence and reported gaps was extracted. Findings were synthesized narratively. This study is supported by the EC and MUR under PNRR - M4C2-I1.3 Project PE_00000019 ‘HEAL ITALIA’. Results out of 27,331 screened records, 41 reports were included, predominantly from Canada, the United Kingdom, and Australia, mainly aimed at informing policy making for single or multiple gene tests for cancer patients. Most reports used a generic HTA methodology and assessment domains varied across reports. Key clinical aspects, such as clinical accuracy and safety, suffered from evidence gaps (39.0% and 22.0%), while personal and societal aspects were the least investigated assessment domain (48.8%-78.0%). Overall, lack of evidence and limited generalizability of findings were the most commonly reported gaps across multiple domains. Conclusions the review highlighted significant fragmentation in current evaluation methodologies of genetic and genomic applications, with underassessment of analytical/clinical accuracy, safety, and non-health outcomes, alongside evidence gaps and limited generalizability. Key messages • Issues emerged in multiple domains compromise both evaluation and decision-making process. • There is an urgent need for alternative study designs and standardized, comprehensive assessment frameworks to facilitate the successful implementation of emerging genetic and genomic technologies.

PBI66 ARE HTA AGENCIES BUYING INTO THE CAR-T HYPE?

Health Technology Assessment for Cardiovascular Digital Health Technologies and Artificial Intelligence: Why Is It Different?

PNS174 COMMON THREADS: REGULATORY AND HEALTH TECHNOLOGY ASSESSMENT (HTA) AGENCIES’ RECOMMENDATIONS ON REAL-WORLD EVIDENCE (RWE) USE IN DECISION-MAKING

The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company’s perspective, as market prospects are strongly influenced by third-party payers’ coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed.

The science of decision making has been established, but research is limited regarding the quality and transparency of the decision-making processes through which medicines become available. Indeed, it is not always clear what explicit processes pharmaceutical companies, regulatory authorities and health technology assessment (HTA) agencies are using to arrive at their decisions. Previous research resulted in the development of the ten Quality Decision-Making Practices (QDMPs), which are considered as the best practices in decision making in the lifecycle of medicines, as well the Quality of Decision-Making Orientation Scheme (QoDoS), which is a technique that can be used to measure the incorporation of these QDMPs in companies and agencies. The aim of this research, therefore, was to develop a roadmap for improving the quality of decision-making processes for key strategic decisions made by pharmaceutical companies, regulatory authorities and HTA agencies, by firstly evaluating current processes in place; secondly by assessing the ten QDMPs and thirdly by developing approaches for incorporating the ten QDMPs into organisational processes. In formalising the study design, various methodologies were appraised and it was rationalised that in order to fulfil the aim of the study, it would be appropriate to adopt a mixed method approach i.e. combination of self-administered questionnaires, focus groups as well as case studies. In addition, a systematic review of literature was conducted to identify the most robust and psychometrically sound technique for assessing the QDMPs. Results from four questionnaires developed for the purpose of this research demonstrated that companies and agencies do not always utilise frameworks for key decision-making processes, namely regulatory submission processes, regulatory approvals, HTA submissions and HTA appraisals. Moreover, the majority of organisations with established frameworks did not incorporate all ten QDMPs into their processes, although all these practices were considered relevant. The study also identified challenges in decision making as well as biases, where all the participants believed there was room for improvement and suggested a number of solutions, which included training and the use of structured processes. The results also uncovered that organisations do not generally have formal assessments in place to measure the quality of decision making. However, a systematic literature review of techniques for evaluating the QDMPs during the lifecycle of medicines revealed a paucity of available techniques, which could explain why such assessments are not taking place. The QoDoS was considered as the most promising technique out of the 13 identified in the review. A subsequent case study with QoDoS demonstrated its reliability and relevance in target audiences. Three additional QoDoS case studies, with a company, a regulatory authority and an HTA agency, demonstrated its practicality in assessing the consistency of favourable and unfavourable practices in…

IntroductionThe interactions between regulators, health technology assessment (HTA), and companies play a significant role in the process of getting medicine to patients. These have evolved at a product level as well as at a policy and cross-jurisdictional level; however, it is important these activities are adding value for stakeholders involved. A survey conducted in March 2021 assessed the current interactions from multi-stakeholders, and their perceptions on the added value these interactions bring to better decision-making.MethodsThree separate questionnaires containing nine questions were developed to assess the perceptions from pharmaceutical companies, regulators, and HTA agencies. The three questionnaires contained analogous questions where appropriate. The company questionnaire was sent to senior management at 19 international pharmaceutical companies, the agency survey was sent to 32 agencies (17 regulatory agencies and 15 HTA agencies) in Australia, Canada, Europe, and Asia.ResultsSeven regulators, seven HTA agencies, and nine companies responded to the survey. All regulators and HTAs indicated they have interactions with their peer agencies, as well as between regulators and HTA. The top areas of interactions for regulators were formal work-sharing between regulators during review (86% response) and regulatory strengthening (86%), whilst for HTAs, interactions between HTA on methodology/framework (83%) and HTA capacity building (67%). Regulatory-HTA interactions were seen to have fewer practical benefits, which may suggest areas for improvement. Both companies and agencies believed an effective engagement model should support evidence generation; agencies also viewed an aligned process and improved decision-making as important. Respondents believed that an ideal ecosystem for interactions should facilitate separate remits for stakeholders, converged requirements, aligned process and increased transparency and trust.ConclusionsThis survey provided a snapshot of the current landscape interactions between stakeholders during the life cycle of new medicines, identified the areas where value is added and improvement are needed. Suggested building blocks to improve future interactions included early scientific advice, alignment of evidence requirements, and a collaborative approach among all stakeholders.

Introduction:North America is facing a public health epidemic – the opioid crisis – part of which is attributed to the inappropriate use of opioids in pain management. As such, the 2017 Canadian Guideline for Opioids for Chronic Non-Cancer Pain recommends optimizing non-opioid pharmacotherapy or non-pharmacological therapy to treat chronic pain, before a trial of opioids. However, the Guideline itself is not designed to provide evidence on the effectiveness of these non-opioid alternatives, leaving a gap for those attempting to put the recommendation into practice.Methods:In collaboration with its partners, including clinicians and policymakers, the Canadian Agency for Drugs and Technologies (CADTH) identified the gaps in evidence, and developed an action plan to bridge the evidence gaps to support the optimization of non-opioid alternatives in pain management.Results:Since the release of the Guideline, CADTH produced over 20 Rapid Response reports that synthesize and appraise evidence on non-opioid alternatives in the management of a wide range of pain, both acute and chronic. Additionally, CADTH has also reviewed evidence on multidisciplinary pain treatment programs, and is developing environmental scan reports on the availability and access to non-pharmacological treatments for pain in Canada, and on drugs for emerging non-opioid pain. Further, CADTH developed knowledge mobilization tools based on the evidence reviews. The evidence reviews and tools are used as a resource by CADTH partners, including the Coalition of Safe and Effective Pain Management and McMaster University National Pain Center.Conclusions:This presentation will discuss the role of HTA and CADTH to fill the gaps in evidence for a crucial clinical practice guideline recommendation in a time of public health crisis, and help put the evidence into action. It will present the evidence synthesized by CADTH on various non-opioid alternatives for pain management, while highlighting the remaining gaps in evidence. Understanding the evidence on non-opioid alternatives will inform clinical and policy decisions and potentially reduce inappropriate use of opioids in pain management.

The primary objective of the study was to analyse the proposed clinical development and economic evaluation plans for investigational medicinal products for which pharmaceutical companies have sought health technology assessment (HTA) scientific advice (SA). We have selected and analysed all the scientific advice procedures undertaken by National Institute for Health and Care Excellence (NICE) SA between 1 January 2009 and 3 December 2015 for investigational medicinal products. We have mapped the questions asked by the companies and the areas of advice highlighted in the advice reports to the sections of the NICE methods guide to the technology appraisals (2013). An overwhelming proportion of SA procedures have addressed questions related to the clinical development and specifically the main pivotal efficacy studies. Approximately a quarter of the questions relate to the approaches to economic evaluation. Questions raised in European Medicines Agency-HTA procedures generally focus on clinical efficacy issues whereas cost-effectiveness ones tend to dominate in NICE-only procedures. Our analysis shows that the issues mostly discussed in the HTA SA are the choice of comparator, the generalisability of the clinical trial evidence to the NHS practice and the impact of the clinical trial outcomes on quality of life and survival. Less disagreement with the developers' plans was seen in the choice of clinical endpoints, population definition, position of the technology in the treatment pathway and study design. Scientific advice is designed to improve the quality of evidence and approaches to evidence generation for future regulatory approval and HTA evaluation. Our experience to date suggests that payer requirements are inconsistently integrated in the clinical development programmes. More efforts should be dedicated to demonstrating the clinical value of new medicinal products to patients and key decision-makers.

Health technology assessment (HTA) can be used to make healthcare systems more equitable and efficient. Advances in precision oncology are challenging conventional thinking about HTA. Precision oncology advances are rapid, involve small patient groups, and are frequently evaluated without a randomized comparison group. In light of these challenges, mechanisms to manage precision oncology uncertainties are critical. We propose a life-cycle HTA framework and outline supporting criteria to manage uncertainties based on real world data collected from learning healthcare systems. If appropriately designed, we argue that life-cycle HTA is the driver of real world evidence generation and furthers our understanding of comparative effectiveness and value. We conclude that life-cycle HTA deliberation processes must be embedded into healthcare systems for an agile response to the constantly changing landscape of precision oncology innovation. We encourage further research outlining the core requirements, infrastructure, and checklists needed to achieve the goal of learning healthcare supporting life-cycle HTA.

Due to limited clinical data, high uncertainty, and outcome variability, assessing therapies for paediatric and rare disease populations poses specific challenges, often requiring adjustments to standard health technology assessment (HTA) frameworks. This study examines how national HTA guidelines and recommendations across Europe reflect these demands, identifying methodological adaptations and country-specific disparities. HTA organisations across the 27 EU Member States and the UK were identified via INAHTA, EUnetHTA, and ISPOR reference listings. Publicly available documents were screened, and 29 relevant national guidelines were selected. A structured document analysis was performed using a predefined coding framework. Key terms were systematically searched, and content was categorised into thematic domains. Among the 29 guidelines, 16 included references to rare disease populations, and 12 to paediatric populations. For paediatric populations, most references focused on quality-of-life measurement and proxy assessments. Adaptations for rare diseases recognised flexible cost-effectiveness thresholds (e.g. adjusted incremental cost-effectiveness ratios [ICERs] or gross domestic product [GDP]-based modifiers), tailored economic modelling, and acceptance of alternative data sources. However, significant variability was observed across countries, with no consistent pattern. While several HTA bodies have introduced adjustments for paediatric and rare disease populations, guidance oftenremains limited and heterogeneous. The findings indicate that HTA guidelines and recommendations require further collaboration to properly define and account for the specific needs of these patients. Methodological shortcomings are mainly due to the nature of these diseases, where the limited data available are primarily from clinical practiceand often lack comparative effectivenessevidence.

Real-world evidence (RWE), derived from real-world data (RWD), is already used, to some extent, for health technology assessment (HTA) purposes. With the increased availability of RWD, there is potential for more widespread use but also challenges ensuring reliable RWE for HTA. Opportunities to overcome key challenges, identified at a scoping meeting, were discussed during the 2019 HTA international (HTAi) Global Policy Forum (GPF). Reflection of discussions using Design Thinking (an interactive process aimed to solve complex problems) between seventy-three representatives from not-for-profit, for-profit organizations, and HTAi leadership. The discussions were informed by a background paper, and presentations from three invited keynote speakers and eleven GPF members. Several options were listed for addressing the identified key challenges: quality and acceptability, governance and accountability, transferability, and informing decision making. The GPF emphasized that the HTA community should first understand what questions could be answered with RWE. Additionally, more clarity on methods, standards, streamlining RWD collection, data sharing across jurisdictions, replication of RWD, and expert analysis were mentioned as important priorities. The HTA community is currently standing at a cross-road as it is not yet fully equipped to address these key challenges. It is, therefore, time for action. The community should start aligning on what is the best source of evidence according to purpose and how the data should be collected to create reliable evidence. It should also initiate the development of actions and guidance to properly develop and manage RWD/RWE to inform decision making across the technology lifecycle.

Pharmacogenomics: challenges and opportunities in therapeutic implementationEdited by Yui-Wing FrancisLam and LarisaCavallari. 2013. 510 pp. Hardcover, price £60.99. ISBN 978--0-12-391918-2