The 30-Billion-Dollar Distribution Markups and Taxes of Pharmaceuticals in Latin American Countries: Impact, Options, and Trade-Offs.

OBJECTIVES: The World Health Organization provides 10 specific guidelines for managing the prices of pharmaceutical products. Many of those are widely known and used such as reference pricing, value-based pricing, price transparency, and tendering. Less attention and knowledge is concentrated in markup regulation across the pharmaceutical supply chain and distribution and in tax exemptions or reductions. This article quantifies the impact of these price components in the Latin American (LatAm) region and places the findings in the context of economic theory and international policy experiences. METHODS: 2020 retail pharmaceutical sales data from 8 major LatAm markets covered in the IQVIA database were decomposed into ex-factory, distributor markups, and taxes using price build up information and the Price Decipher Methodology developed by the Novartis Global Pricing Governance and Negotiation team. The findings were reviewed by an international panel representing academia, health policy, health economics, patient, and industry. RESULTS: The ex-factory market value of the analyzed markets was $49 billion. Distribution markups added $20 billion and taxes a further $10.5 billion. This represented a 63% increase over ex-factory prices, considered high if compared with 24% for an international benchmark of 35 ex-LatAm countries. Reducing markups for these LatAm countries to 24% would represent up to $19 billion in savings for payers and patients. CONCLUSIONS: There is potential for significant cost reductions associated with tax and distribution markup refinements in the LatAm retail pharmaceutical market. National policies should be informed by additional context-specific research for effective implementation.

A Systematic Review of Value Criteria for Next-Generation Sequencing/Comprehensive Genomic Profiling to Inform Value Framework Development.

OBJECTIVES: To comprehensively identify and map an exhaustive list of value criteria for the assessment of next-generation sequencing/comprehensive genomic profiling (NGS/CGP), to be used as an aid in decision making. METHODS: We conducted a systematic review to identify existing value frameworks (VFs) applicable to any type of healthcare technology. VFs and criteria were mapped to a previously published Latin American (LA) VF to harmonize definitions and identify additional criteria and or subcriteria. Based on this analysis, we extracted a comprehensive, evidence-based list of criteria and subcriteria to be considered in the design of a NGS/CGP VF. RESULTS: A total of 42 additional VFs were compared with the LA VF, 88% were developed in high-income countries, 30% targeted genomic testing, and 16% specifically targeted oncology. A total of 242 criteria and subcriteria were extracted; 227 (94%) were fully/partially included in the LA VF; and 15 (6%) were new. Clinical benefit and economic aspects were the most common criteria. VFs oriented to genomic testing showed significant overlap with other VFs. Considering all criteria and subcriteria, a total of 18 criteria and 36 individual subcriteria were identified. CONCLUSIONS: Our study provides an evidence-based set of criteria and subcriteria for healthcare decision making useful for NGS/CGP as well as other health technologies. The resulting list can be beneficial to inform decision making and will serve as a foundation to co-create a multistakeholder NGS/CGP VF that is aligned with the needs and values of health systems and could help to improve patient access to high-value technologies.

Assessing the Value of Provider-Facing Digital Health Technologies Used in Chronic Disease Management: Toward a Value Framework Based on Multistakeholder Perceptions.

OBJECTIVES: Hardly any value frameworks exist that are focused on provider-facing digital health technologies (DHTs) for managing chronic disease with diverse stakeholder participation in their creation. Our study aimed to 1) understanding different stakeholder opinions on where value lies in provider-facing technologies and 2) create a comprehensive value assessment framework for DHT assessment. METHODS: Mixed-methods comprising both primary and secondary evidence were used. A scoping review enabled a greater understanding of the evidence base and generated the initial indicators. Thirty-four indicators were proposed within 6 value domains: health inequalities (3), data rights and governance (6), technical and security characteristics (6), clinical characteristics (7), economic characteristics (9), and user preferences (3). Subsequently, a 3-round Web-Delphi was conducted to rate the indicators' importance in the context of technology assessment and determine whether there was consensus. RESULTS: The framework was adapted to 45 indicators based on participant contributions in round 1 and delivered 16 stable indicators with consensus after rounds 2 and 3. Twenty-nine indicators showed instability and/or dissensus, particularly the data rights domain, in which all 5 indicators were unstable, showcasing the novelty of the concept of data rights. Significant instability between important and very important ratings was present within stakeholder groups, particularly clinicians and policy experts, indicating they were unsure how different aspects should be valued. CONCLUSIONS: Our study provides a comprehensive value assessment framework for assessing provider-facing DHTs incorporating diverse stakeholder perspectives. Instability for specific indicators was expected due to the novelty of data and analytics integration in health technologies and their assessment. Further work is needed to ensure that, across all types of stakeholders, there is a clear understanding of the potential impacts of provider-facing DHTs. HIGHLIGHTS: Current health technology assessment (HTA) methods may not be well suited for evaluating digital health technologies (DHTs) because of their complexity and wide-ranging impact on the health system.This article adds to the literature by exploring a wide range of stakeholder opinions on the value of provider-facing DHTs, creating a holistic value framework for these technologies, and highlighting areas in which further discussions are needed to align stakeholders on DHTs' value attributes.A Web-based Delphi co-creation approach was used involving key stakeholders from throughout the digital health space to generate a widely applicable value framework for assessing provider-facing DHTs. The stakeholders include patients, health care professionals, supply-side actors, decision makers, and academia from the United States, United Kingdom, and Germany.High levels of instability among stakeholders and value domains are demonstrated, indicating the novelty of assessing provider-facing DHTs and their impact on the health system.

How can health technology assessment be improved to optimise access to medicines? Results from a Delphi study in Europe : Better access to medicines through HTA.

INTRODUCTION: Access to medicines is a shared goal across healthcare stakeholders. Since health technology assessment (HTA) informs funding decisions, it shapes access to medicines. Despite its wide implementation, significant access variations due to HTA are observed across Europe. This paper elicited the opinions of European stakeholders on how HTA can be improved to facilitate access. METHODS: A scoping review identified HTA features that influence access to medicines within markets and areas for improvement, while three access dimensions were identified (availability, affordability, timeliness). Using the Delphi method, we elicited the opinions of European stakeholders to validate the literature findings. RESULTS: Nineteen participants from 14 countries participated in the Delphi panel. Thirteen HTA features that could be improved to optimise access to medicines in Europe were identified. Of these, 11 recorded a positive impact on at least one of the three access dimensions. HTA features had mostly a positive impact on timeliness and a less clear impact on affordability. 'Early scientific advice' and 'clarity in evidentiary requirements' showed a positive impact on all access dimensions. 'Established ways to deal with uncertainty during HTA' could improve medicines' availability and timeliness, while more 'reliance on real-world evidence' could expedite time to market access. CONCLUSIONS: Our results reiterate that increased transparency during HTA and the decision-making processes is essential; the use of and reliance on new evidence generation such as real-world evidence can optimise the availability of medicines; and better collaborations between regulatory institutions within and between countries are paramount for better access to medicines.

Algorithms and heuristics of health technology assessments: A retrospective analysis of factors associated with HTA outcomes for new drugs across seven OECD countries.

CONTEXT: Positive health technology assessment (HTA) outcomes can have important implications for equity, efficiency and timely patient access to novel therapies. Several outcomes and dimensions of benefit beyond utility feed into HTA processes. OBJECTIVE: We analyse a proprietary dataset of HTA outcomes in 7 countries, to (a) test whether HTA decision-making is grounded in welfarist or extra-welfarist approaches; and (b) empirically determine the factors associated with positive HTA outcomes, the time to achieve these and establish the magnitude of inter-country differences in assessment processes. METHODS: Data were extracted from publicly available HTA reports on drugs that received marketing authorisation between 2009 and 2018 (N = 1415). The outcomes of interest were the probability of positive HTA outcomes and the time-to-HTA outcome; these were examined with respect to clinical, regulatory, product- and disease-related, evidence uncertainty and contextual variables. Econometric models utilising survival analysis and multinomial logistic regression were specified. FINDINGS: Positive HTA outcomes accounted for 87.3% of the sample (n = 1235), of which 71% (n = 1004) were restricted. Drugs with positive HTA outcomes were subject to clinical restrictions (n = 652, 46%), financial risk-sharing (n = 439, 31%) or had been rejected at least once (n = 282, 20%). Significant predictors of positive HTA outcomes were orphan drugs with cancer indications, high quality of evidence linked to clinical and economic evidence uncertainties which had been overcome, and contextual considerations, particularly innovativeness and unmet need. Comparative analyses revealed systematic differences between countries in their propensity to accept the same drugs, particularly oncology and orphan drugs. CONCLUSIONS: Our results are contextual and reinforce arguments in favour of explicitly accounting for social value judgements, establishing separate assessment frameworks for highly uncertain products, adopting risk mitigation strategies for novel therapies with early phase evidence, and sharing of HTA practices across settings. Lastly, HTA agencies have adopted an extra-welfarist approach to value assessment and resource allocation.

A Value Framework to Assess Patient-Facing Digital Health Technologies That Aim to Improve Chronic Disease Management: A Delphi Approach.

OBJECTIVES: Digital health technologies (DHTs) can optimise healthcare costs and improve quality and efficiency of care. However, the fast-paced rate of innovation and varying evidence standards can make it difficult for decision-makers to assess these technologies in an efficient and evidence-based manner. We sought to develop a comprehensive framework to assess the value of novel patient-facing DHTs used to manage chronic diseases by eliciting stakeholder value preferences. METHODS: Literature review and primary data collection from a three-round web-Delphi exercise was utilized. 79 participants from 5 stakeholder groups (patients, physicians, industry, decision makers, and influencers) and 3 countries (United States of America, United Kingdom, and Germany) took part. Likert scale data were statistically analyzed to determine intergroup differences in both country and stakeholder groups, stability of results, and overall consensus. RESULTS: The resulting co-created framework comprised 33 stable indicators with consensus from quantitative value judgments across domains: health inequalities, data rights and governance, technical and security, economic characteristics, clinical characteristics, and user preferences. Lack of stakeholder consensus was observed on the importance of value-based care models, optimizing resources for sustainable systems, and stakeholder involvement in DHT design, development, and implementation; however, this was because of high rates of neutrality and not negative judgments. Supply-side actors and academic experts were the most unstable stakeholder groups. CONCLUSION: Stakeholder value judgments revealed a need for a coordinated regulatory and health technology assessment policy response that updates laws to meet technological innovations, offers a pragmatic approach to evidence standards to assess DHTs, and involves stakeholders to understand and meet their needs.

The patient pathway in ATTR-CM in Greece and how to improve it: A multidisciplinary perspective.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed disease associated with high mortality rates and the patient journey is characterized by increased complexities. Accurate and timely diagnosis and prompt initiation of disease-modifying treatment constitute the contemporary unmet need in ATTR-CM. ATTR-CM diagnosis is characterized by considerable delays and high rates of misdiagnosis. The majority of patients present themselves to primary care physicians, internists, and cardiologists, and many have undergone repeated medical evaluations before an accurate diagnosis has been made. The disease is diagnosed mainly after the development of heart failure symptoms, reflecting a long course of missed opportunities before diagnosis and disease-modifying treatment initiation. Early referral to experienced centers ensures prompt diagnosis and therapy. Early diagnosis, better care coordination, acceleration of digital transformation and reference networks, encouragement of patient engagement, and implementation of rare disease registries are the key pillars to improve the ATTR-CM patient pathway and achieve important benefits in ATTR-CM outcomes.

Road traffic mortality and economic uncertainty: Evidence from the United States.

Previous studies have shown that financial turbulence is associated with a short-term increase in road traffic collisions, largely due to drivers' emotional state, distraction, sleep deprivation and alcohol consumption. In this paper we advance this debate by studying the association between economic uncertainty and road traffic mortality in the United States. We used a State-level uncertainty index and State fatalities for the period 2008-2017 and found that a one standard deviation increase in economic uncertainty is associated with an additional 0.013 monthly deaths per 100,000 people per State, on average (a 1.1% increase) - or 40 more monthly deaths in total nationwide. Results are robust to different model specifications. Our findings show that, similar to drink-driving, it is important to raise awareness about driving when distracted due to financial worries and during periods of economic uncertainty.

Do Reimbursement Recommendations by the Canadian Agency for Drugs and Technology in Health Translate Into Coverage Decisions for Orphan Drugs in the Canadian Province of Ontario?

OBJECTIVES: Unlike other high-income countries, Canada has no national policy for drugs treating rare diseases (orphan drugs). Nevertheless, in 2022, the Canadian government committed to creating a national strategy to make access to these drugs more consistent. Our aim was to study whether recommendations made by the Canadian Agency for Drugs and Technology in Health (CADTH) translated into coverage decisions for orphan drugs in Ontario, the largest Canadian province. This study is the first to look at this question for orphan drugs, which are at the center of policy attention. METHODS: We included 155 orphan drug-indication pairs approved and marketed in Canada between October 2002 and April 2022. Cohen's kappa was used to test the agreement across health technology assessment (HTA) recommendations and coverage decisions in Ontario. Logistic regression was used to test which factors, relevant to decision-makers, might be associated with funding in Ontario. RESULTS: We found only fair agreement between CADTH's recommendations and coverage decisions in Ontario. Although a positive and statistically significant association between favorable HTA recommendations and coverage was found, more than half of the drugs with a negative HTA recommendation were available in Ontario, predominately through specialized funds. Successful pan-Canadian pricing negotiations were a strong predictor of coverage in Ontario. CONCLUSIONS: Despite efforts to harmonize access to drugs across Canada, considerable room for improvement remains. Introducing a national strategy for orphan drugs could help increase transparency, consistency, promote collaborations, and make access to orphan drugs a national priority.

Healthcare Payer Perspectives on the Assessment and Pricing of Oncology Multi-Indication Products: Evidence from Nine OECD Countries.

BACKGROUND: New pharmaceuticals are increasingly being developed for use across multiple indications. Countries across Europe and North America have adopted a range of different approaches to capture differences in the value of individual indications. OBJECTIVE: The three aims of this study were (i) to review the price-setting practice over the past 5 years for multi-indication products across England, France, Italy, Spain, Belgium, Switzerland, Turkey, Canada and the USA; (ii) to assess the impact of current practices on launch strategy; and (iii) to identify issues in the implementation of indication-based pricing. METHODS: Ten current and former members of health insurance organisations, healthcare payer organisations or health technology assessment agencies with expertise on pharmaceutical purchasing were invited to participate in semi-structured interviews. Interview transcripts were imported into NVivo 12 for thematic analysis. RESULTS: The majority of countries studied require full assessments upon launch of a new indication. Five different approaches to pricing were identified: weighted pricing, differential discounting, mandatory discount, price anchoring and free pricing. Manufacturers show a tendency to launch first in niche indications with high unmet need to achieve a high price. Stakeholders from England, France, Italy, Belgium and Switzerland consider their current system fit for purpose, while other countries expressed concern over the administrative burden of monitoring products at indication level. CONCLUSIONS: Given the high administrative burden, it is questionable whether indication-based pricing would provide additional public benefit above and beyond current weighted dynamic single pricing and differential discounting practices for multi-indication products.

Launch sequencing of pharmaceuticals with multiple therapeutic indications: evidence from seven countries.

BACKGROUND: New medicines are increasingly being identified as efficacious across multiple indications. The impact of current pricing and reimbursement policies on launch decisions across these indications remains unclear. OBJECTIVE: This paper, first, maps marketing authorisation and HTA coverage recommendation sequences of multi-indication medicines across Germany, France, England, Scotland, Canada, Australia, and the USA, and, second, evaluates the clinical characteristics, clinical development time and coverage recommendation time of multi-indication medicines, drawing comparisons between the first and subsequent indications of an approved molecule. METHODS: Medicine approvals by the Food and Drug Administration between 2009-2019 were screened to identify multi-indication products with approved oncology indications. Data on clinical trial characteristics, clinical performance and HTA outcomes were extracted from publicly available regulatory approval and HTA reports. RESULTS: Relative to subsequent indications, first indications were more likely to receive conditional marketing authorisation, have an orphan designation, have a single arm phase II pivotal trial and lower MCBS score. Subsequent indications had faster HTA coverage recommendation times in England and Canada. While the majority of first indications received HTA coverage recommendations across all settings, the proportion of subsequent indications with HTA coverage recommendations was lower and uptake varied considerably across settings. CONCLUSIONS: Discordance in the value of first versus subsequent indications can pose major challenges in systems that define price based on the initial indication. Current pricing and reimbursement systems generate significant fragmentation in the approval and availability of multi-indication products across settings.

Value Insider Season 1 Episode 6: How Will Market Access and Value Demonstration Evolve? (Future Outlook) [Podcast].

How will market access and value demonstration evolve? In this episode of the Value Insider podcast, host Mike Chambers speaks with Ass. Prof. Panos Kanavos about the future of value assessments in healthcare. Dr Kanavos is Associate Professor of the International Health Policy in the Department of Health Policy at London School of Economics and Political Science as well as Deputy Director at LSE Health and Program Director of the Medical Technology Research Group (MTRG), and advisor to prominent organizations including the European Commission, the European Parliament, the World Bank, the WHO and OECD. Discussing key changes, Dr Kanavos outlines which opportunities and challenges will alter the way we value healthcare interventions.

How do HTA agencies perceive conditional approval of medicines? Evidence from England, Scotland, France and Canada.

There is a growing disconnect between regulatory agencies that are promoting expedited approval to medicines based on early phase clinical evidence and health technology assessment (HTA) agencies that require robust clinical evidence to inform coverage decisions. This paper provides an assessment of the evidence gap between regulatory and HTA agencies on medicines receiving conditional marketing authorisation (CMA) and examines how HTA agencies in France, England, Scotland, and Canada interpret and appraise evidence for these medicines. A mixed methods research design was used to identify the types and frequency of parameters raised in the context of HTA decision-making for all conditional approvals in Europe and Canada between 2010 and 2017. Significant heterogeneity was found across the HTA agencies in England, Scotland, France, and Canada in the assessment of medicines receiving CMA, with the highest likelihood of rejection present in Quebec (50%) and Scotland (25%). Rejected medicines were more likely to have unresolved uncertainties related to the magnitude of clinical benefit, study design, and issues in economic modelling. More systematic use of joint early dialogue and conditional reimbursement pathways would help clarify evidence requirements and avoid delays in patient access to innovative medicines.

Challenges for health systems seeking to embrace virtual health care for population health.

A gradual move to proactive illness prevention requires a strategic shift towards population health management by health care systems. Such a shift becomes necessary to improve outcomes, reduce inequalities and manage costs better, as life expectancy increases and chronic illness becomes more prevalent. Health system digitisation and greater focus on virtual health care (VHC) can contribute to active population health management. For that to happen, health systems need to address and overcome several challenges currently preventing the rapid introduction and scale up of VHC for population health; these include implementing changes in care models and focus on digitally enabled population health approaches; addressing culture and mindset barriers; resolving regulatory bottlenecks; overcoming technical limitations, inter-operability and data security issues; and, finally, aligning stakeholder incentives and expectations.

Impact of Managed Entry Agreements on availability of and timely access to medicines: an ex-post evaluation of agreements implemented for oncology therapies in four countries.

BACKGROUND: Despite the increased utilisation of Managed Entry Agreements (MEAs), empirical studies assessing their impact on achieving better access to medicines remains scarce. In this study we evaluated the role of MEAs on enhancing availability of and timely access to a sample of oncology medicines that had received at least one prior rejection from reimbursement. METHODS: Funding decisions and their respective timelines for all oncology medicines approved between 2009 and 2018 in Australia, England, Scotland and Sweden were studied. A number of binary logit models captured the probability (Odds ratio (OR)) of a previous coverage rejection being reversed to positive after resubmission with vs. without a MEA. Gamma generalised linear models were used to understand if there is any association between time to final funding decision and the presence of MEA, among other decision-making variables, and if so, the strength and direction of this association (Beta coefficient (B)). RESULTS: Of the 59 previously rejected medicine-indication pairs studied, 88.2% (n = 45) received a favourable decision after resubmission with MEA vs. 11.8% (n = 6) without. Average time from original submission to final funding decision was 404 (± 254) and 452 (± 364) days for submissions without vs. with MEA respectively. Resubmissions with a MEA had a higher likelihood of receiving a favourable funding decision compared to those without MEA (43.36 < OR < 202, p < 0.05), although approval specifically with an outcomes-based agreement was associated with an increase in the time to final funding decision (B = 0.89, p < 0.01). A statistically significant decrease in time to final funding decision was observed for resubmissions in Australia and Scotland compared to England and Sweden, and for resubmissions with a clinically relevant instead of a surrogate endpoint. CONCLUSIONS: MEAs can improve availability of medicines by increasing the likelihood of reimbursement for medicines that would have otherwise remained rejected from reimbursement due to their evidentiary uncertainties. Nevertheless, approval with a MEA can increase the time to final funding decision, while the true, added value for patients and healthcare systems of the interventions approved with MEAs in comparison to other available interventions remains unknown.

The future of oncology policy.

To ensure the previous progress seen in cancer survival rates continues as we move through the 21st Century it is important to determine future effective policy related to oncology healthcare delivery and funding. Recent successes with, for example, the COVID vaccine response, the decision-making agility exhibited by governments and healthcare systems and the effective use of telehealth and real-world evidence highlight the progress that can be made with pooled efforts and innovative thinking. This shared approach is the basis for the European Beating Cancer Plan which outlines action points for governments and health systems for the period 2021-2025. It focuses on a whole government approach, centred on patients, maximising the potential of new technologies and insights across policy areas including employment, education, transport and taxation, enabling the tackling of cancer drivers in schools, workplaces, research labs, towns and cities and rural communities. Despite the plan there are still concerns that oncology policy has not adequately responded to the pace of innovation and the unique challenges generated by innovative oncological technologies. There needs to be focus on: gaining consensus on the most appropriate methods to assess and price combination therapies and cell and gene therapies, developing effective outcome-based payment models for personalised medicine and developing consensus on the ideal approach for multiple indication pricing. Finally, future policy needs to ensure pharmaceutical companies and other research organisations are adequately rewarded for innovation to ensure continued R&D and the development of innovative oncological products.

A Proposal for Value-Based Managed Entry Agreements in an Environment of Technological Change and Economic Challenge for Publicly Funded Healthcare Systems.

Managed entry agreements (MEA) represent one of the main topics of discussion between the European National Payers Authorities. Several initiatives on the subject have been organized over the past few years and the scientific literature is full of publications on the subject. There is currently little international sharing of information between payers, mainly as a result of the confidentiality issues. There are potential benefits from the mutual sharing of information, both about the existence of MEAs and on the outcomes and results. The importance of involving all the players in the decision-making process on market access for a medicinal product (MP) is that it may help to make new therapies available to patients in a shorter time. The aim of this project is to propose a new pathway of value-based MEA (VBMEA), based on the analysis of the current Italian pricing and reimbursement framework. This requires elaboration of a transparent appraisal and MEA details with at least a 24-month contract. The price of the MP is therefore valued based on the analysis of the VBMEA registries of the Italian Medicines Agency. Although the proposal focuses on the Italian context, a similar approach could also be adapted in other nations, considering the particularities of the single health technology assessment (HTA)/payer system.

Value and Price of Multi-indication Cancer Drugs in the USA, Germany, France, England, Canada, Australia, and Scotland.

PURPOSE: Oncology drugs are often approved for multiple indications, for which their clinical benefit varies. Aligning a single price to this differing value remains a challenge. This study examines the clinical and economic value, price, and reimbursement of multi-indication cancer drugs across seven countries, representing different approaches to value assessment, pricing, and coverage decisions: the USA, Germany, France, England, Canada, Australia, and Scotland. METHODS: Twenty-five multi-indication cancer drugs across 100 indications were identified with US Food and Drug Administration (FDA) approval between 2009 and 2019. For each indication data on Health Technology Assessment (HTA) recommendations, disease prevalence, and drug prices were obtained. Quality-adjusted life years (QALYs) gained, disease prevalence, list prices, and HTA outcomes were then compared across indications and regions. RESULTS: First approved indications provide a higher clinical benefit whilst targeting a smaller patient group than indication extensions. Quality-adjusted life year gains were higher for first (0.99, 95% CI 0.05-3.25) compared to second (0.51, 95% CI 0.02-1.63, p < 0.001) and third (0.58, 95% CI 0.05-2.07, p < 0.01) approved indications. Disease prevalence per 100,000 inhabitants was 20.7 (95% CI 0.2-63.3) for first compared to 27.1 (95% CI 1.5-109.6, p = 0.907) for second and 128.3 (95% CI 3.1-720.1, p < 0.001) for third approved indications. With each approved indication drug prices declined in Germany and France, remained constant in the UK, Canada, and Australia, whilst they increased in the USA. Negative HTA outcomes, clinical restrictions, and managed entry agreements (MEAs) were more frequently observed for indication extensions. CONCLUSIONS: Results suggest that indication development is prioritised according to clinical value and disease prevalence. Countries employ different mechanisms to account for each indication's differential benefit, e.g., weighted-average prices (Germany, France, Australia), differential discounts (England, Scotland), clinical restrictions, and MEAs (England, Scotland, Australia, Canada). Value-based indication-specific pricing can help to align the benefit and price for multi-indication cancer drugs.

Initial and supplementary indication approval of new targeted cancer drugs by the FDA, EMA, Health Canada, and TGA.

BACKGROUND: Previous research focused on the clinical evidence supporting new cancer drugs' initial US Food and Drug Administration (FDA) approval. However, targeted drugs are increasingly approved for supplementary indications of unknown evidence and benefit. OBJECTIVES: To examine the clinical trial evidence supporting new targeted cancer drugs' initial and supplementary indication approval in the US, EU, Canada, and Australia. DATA AND METHODS: 25 cancer drugs across 100 indications were identified with FDA approval between 2009-2019. Data on regulatory approval and clinical trials were extracted from the FDA, European Medicines Agency (EMA), Health Canada (HC), Australian Therapeutic Goods Administration (TGA), and clinicaltrials.gov. Regional variations were compared with χ2-tests. Multivariate logistic regressions compared characteristics of initial and supplementary indication approvals, reporting adjusted odds ratios (AOR) with 95% confidence intervals (CI). RESULTS: Out of 100 considered cancer indications, the FDA approved 96, the EMA 92, HC 86, and the TGA 83 (83%, p < 0.05). The FDA more frequently granted priority review, conditional approval, and orphan designations than other agencies. Initial approvals were more likely to receive conditional / accelerated approval (AOR: 2.69, 95%CI [1.07-6.77], p < 0.05), an orphan designation (AOR: 3.32, 95%CI [1.38-8.00], p < 0.01), be under priority review (AOR: 2.60, 95%CI [1.17-5.78], p < 0.05), and be monotherapies (AOR: 5.91, 95%CI [1.14-30.65], p < 0.05) than supplementary indications. Initial indications' pivotal trials tended to be shorter (AOR per month: 0.96, 95%CI [0.93-0.99], p < 0.05), of lower phase design (AOR per clinical phase: 0.28, 95%CI [0.09-0.85], p < 0.05), and enroll more patients (AOR per 100 patients: 1.19, 95%CI [1.01-1.39], p < 0.05). CONCLUSIONS: Targeted cancer drugs are increasingly approved for multiple indications of varying clinical benefit. Drugs are first approved as monotherapies in rare diseases with a high unmet need. Whilst expedited regulatory review incentivizes this prioritization, indication-specific safety, efficacy, and pricing policies are necessary to reflect each indication's differential clinical and economic value.