Peer-Reviewed Article

Coverage With Evidence Development: An Environmental Scan of Funding Programs Leveraging Real-World Evidence to Support Funding Decisions

Authors: Caroline Muñoz, Jessica Arias, Alayna Brown, Mitali Garg, Scott Gavura

Abstract

Background: New cancer drugs with increasing costs and uncertainties in clinical trial evidence are being approved and funded faster. Coverage with evidence development (CED), using real-world evidence (RWE), has the potential to help manage drug costs and address uncertainties in evidence. A national CED program in Canada may facilitate patient access to new drugs while assessing clinical performance and value for money to support final funding decisions. Descriptions of Canadian and international CED policies using RWE to support final funding decisions are limited.

Objectives: This Environmental Scan aimed to identify the use of CED for drug funding in Canadian and international jurisdictions, describe the components of various CED programs in which RWE is generated to support decision-making, and report on the limitations of CED.

Methods: To complete the Environmental Scan, we identified CED programs where RWE was used to support decision-making. We searched Embase and various health-related websites, from 2007 to 2024. Search terms related to CED, funding, decision-making, and RWE were applied. Data were extracted on article information, jurisdiction, CED policies, RWD collection, and RWE generation. We reported on which jurisdictions have applied CED, the processes for drug funding and RWE generation during the CED period, and the limitations of CED experiences.

Results: We identified the use of CED agreements in 13 jurisdictions. Variation in the CED components and processes were observed between jurisdictions with limited transparency in the details of CED agreements. Performance-based or outcome-based agreements and/or financial agreements are used as part of CED agreements to support risk-sharing between payers and manufacturers. Limitations of CED include a lack of defined outcomes to support final funding decision-making, entry and exit criteria, project timelines, and feasibility of data collection and evidence generation to address uncertainties.

Conclusion: This Environmental Scan highlights the variation in how CEDs are applied between jurisdictions as well as the limitations of using RWE to inform drug funding decisions. CED supports risk-sharing and evidence development, but challenges related to implementation, transparency, and decision-making criteria have been documented. Lessons learned from international experiences can be leveraged to explore the development of a robust Canadian CED model.

Background

Health technology assessment (HTA) committees play an important role in helping payers manage access to expensive new drugs, particularly when evidence of clinical effectiveness and cost-effectiveness is minimal and the pressure to accelerate funding is high. In Canada, provincial drug coverage and reimbursement policies are established following HTAs by the Institut national d'excellence en santé et en services sociaux (INESSS) in Quebec and Canada’s Drug Agency (CDA-AMC) in the remaining provinces and territories.^1,2 During HTAs, a drug’s clinical effectiveness and cost-effectiveness are assessed based on a review of the submitted evidence, which is summarized to support informed decision-making by policy-makers.³ In cases where the clinical evidence or cost-effectiveness is uncertain, CDA-AMC may issue a recommendation to reimburse with conditions (e.g., price reduction required to make the therapy cost-effective).

Reimbursement recommendations with conditions are common across many jurisdictions and are similarly based on uncertainties in the clinical effectiveness and cost-effectiveness data submitted. Uncertainties in clinical trial data can be a consequence of suboptimal trial design, limited follow-up time for clinical and cost-effectiveness outcomes, and the inclusion of patients that are not comparable to real-world populations.³ Public funding agencies have sought to facilitate patient access to these drugs by funding them through managed entry agreements (MEAs).^4,5

“MEA” is an umbrella term that encompasses a variety of agreements between manufacturers and payers aimed at increasing and accelerating patient access to novel therapies while meeting conditions specific to each agreement.⁵ MEAs can be financial agreements or performance-based agreements.^4,5 Financial agreements, such as rebates, price caps, and price-volume agreements, aim to address uncertainties around the financial impact of a drug by reducing its cost.^4,5 Performance-based agreements aim to address uncertainties around the performance or clinical benefit of a drug and can include outcomes-based agreements (OBAs), coverage with evidence development (CED), and payment by result. Payers agree to reimburse the cost of a drug when evidence is submitted demonstrating the drug has achieved clinical end points set out in the terms of the agreement.^4,5 Performance-based agreements often include a financial agreement component to support risk-sharing of high drug costs between manufacturers and payers.^4,5

In the case of CED, an interim funding period is the set time during which a drug receives temporary public funding, allowing patients to access the drug while clinical effectiveness and/or cost-effectiveness data are collected on patients receiving the drug.^4,5 Data collected during the interim funding period are used to generate clinical trial evidence or real-world evidence (RWE) to support assessments of the drug’s performance at a later date. RWE, generated with real-world data (RWD), may be described as “evidence generated from multiple types of data, collected from multiple sources, aggregated, shared, and often reaggregated in multiple sectors of the health care system.”^6,7

In recent years, Canada has made advancements in accelerating access to cancer drugs through various initiatives. Most relevant to CED is the introduction of CDA-AMC’s Time-Limited Recommendations and the pan-Canadian Pharmaceutical Alliance (pCPA)’s Temporary Access Process (pTAP).^8,9 These programs launched in 2023 to expedite the listing of drugs, fulfilling an unmet need. In these cases of CED, the manufacturer is expected to submit updated phase III trial data to CDA-AMC to obtain a final funding recommendation. Both programs are meant to be evaluated with the potential to expand this recommendation category and negotiation process to additional drugs, potentially where phase III data will not be available or where phase III data still have uncertainties. Additionally, bilateral agreements between the federal and provincial governments in Canada are facilitating access to drugs for rare diseases (DRD) with the expectation that RWE is used to support further decision-making about DRD.^10,11

Developing a national approach could be strengthened by examining existing CED programs both within Canada and in countries around the world where RWE is used to support funding decisions. There is limited literature describing jurisdictional CED polices and the use of RWE to support final funding decisions. Consequently, the objectives of this Environmental Scan were to identify the use of CED for drug funding in Canadian and international jurisdictions, describe the components of various CED programs in which RWE is generated to support decision-making, and report on the limitations of CED.

Methods

An Environmental Scan was conducted to identify and describe CED programs implemented in Canada and in international jurisdictions. To ensure a comprehensive search was undertaken, multiple evidence sources were searched. Table 1 presents a list of all evidence sources and key websites.

In consultation with a research librarian, a database-specific search strategy was designed for Embase using a combination of the following terms with the Boolean operators (“and” and “or”): evidence building, evidence development, coverage with evidence, managed entry, managed access, agreement, and outcome. Searches were limited to the English language and to results published within the past 17 years (from 2007 to November 2024). The scan started in 2022, and a 15-year look-back period for sources was established based on expert input. The scan was updated in November 2024, resulting in a period of 2007 to November 2024 to capture relevant sources. The database search was not limited to any specific jurisdiction but was limited to articles in English. To ensure a comprehensive search strategy was developed, the inclusion of terms related to RWE, drug funding, and decision-making concepts was too restrictive, and thus these concepts were omitted from the final search strategy. The Embase search strategy is presented in Appendix 1.

To locate grey literature and white papers, we also conducted a web-based search using the Google search engine and reviewed key organizational websites (e.g., for the National Institute for Health and Care Excellence [NICE]) for potentially relevant literature. Google searches and organizational website searches were conducted using a combination of the key search terms presented in Table 2 and the jurisdictions of interest. Seven jurisdictions of interest were selected through consultation with HTA experts. RWE, drug funding, and decision-making concept terms were included in the grey literature searches as they increased the accuracy of the searches.

Study Selection

Articles were identified using a 2-phase screening approach: phase 1 for title and abstract screening, and phase 2 for full-text screening. All articles identified from the electronic database search were imported into Microsoft Excel for the removal of duplicate articles and screening.

Title and abstract screening was conducted by 3 reviewers: CM, AB, and MG. Articles were classified as potentially relevant based on the study selection criteria outlined in Table 3. All 3 reviewers independently reviewed the same randomly selected 12 abstracts to ensure accuracy and transparency in the selection of relevant abstracts. Discussions were held to achieve consensus on the 12 trial abstracts, and the final inclusion decision was documented in the Excel abstract screening document.

A full-text review of the articles selected for inclusion from title and abstract screening was conducted by CM. CM reviewed the reference lists of articles to identify additional potentially relevant articles for inclusion.

CM reviewed the first 5 pages of the Web-based search results from Google and key organization websites for relevant grey literature. The search terms used to identify relevant grey literature were documented in a Microsoft Excel spreadsheet. Grey literature was included if it met the study selection criteria outlined in Table 3.

Data Extraction

A single reviewer extracted data from included studies with respect to general study information, program characteristics, and program structures and operations. Appendix 2 presents a sample data extraction form for articles, reports, and web pages included in the scan.

Data Synthesis

Extracted data were summarized by jurisdiction to provide a description of the structure and operations of jurisdictional CED programs. The results presented are organized by CED program structural and operational themes. The intent with this organization is to demonstrate high-level trends and variation in CED program structures and operations among jurisdictions.

Results

This scan identified 70 articles describing the structure and operations of CED programs in 12 countries (13 jurisdictions), including Australia, Belgium, Canada (2 jurisdictions: Alberta and Ontario), France, Germany, Ireland, Italy, the Netherlands, Scotland, Sweden, the UK, and the US (Figure 1). The search strategy in Embase produced 852 relevant abstracts, of which 121 articles (14%) underwent full-text review, and data were extracted from 37 articles (4%). The grey literature scan resulted in full-text review for 105 articles and data extraction for 33 (31%) of 105 articles.

Figure 1: Study Selection Process (PRISMA Diagram)

PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

CED Common Terms

The MEA nomenclature varies between jurisdictions. Literature on agreements from Belgium, Canadian jurisdictions, France, Germany, the Netherlands, Scotland, Sweden, the UK, and the US refer specifically to CED or evidence-building agreements.^12-38 Literature on agreements from Australia, Ireland, and Italy use the term MEAs while describing CED agreements as funding agreements with conditions to provide additional evidence to support final funding statuses.^{12,17,19,39-43}

CED Objectives

The objective for CEDs is common across all jurisdictions: enable patient access to new drugs and indications while generating clinical and/or cost-effectiveness evidence to address uncertainties and support final funding recommendations.^{4,12-15,19,20,22-24,26,31,44-52} In Belgium, France, and Italy, an additional objective of CED agreements is to improve forecasting and limit the budget impact of high-cost drugs.^4,31,49

CED Framework

Across jurisdictions, there appears to be a common framework for funding drugs with CED agreements. Common elements within the framework include having processes for health system partner engagement, drug selection, RWD collection, RWE generation, establishing financial terms and duration of interim funding, and making a final funding decision. (Figure 2). Each jurisdiction may approach these aspects differently. The various approaches are discussed in further detail in the next sections. Table 4 details CED characteristics and frameworks by jurisdiction.

Figure 2: CED Framework

CED = coverage with evidence development; HTA = health technology assessment; RWD = real-world data; RWE = real-world evidence.

Drug Selection

Funding agreements with CED components are most common when a drug receives a conditional funding recommendation by regional or national HTA agencies and/or ministries of health (Figure 2). Uncertainties in initial evidence identified through HTAs can be addressed with additional data collection and evidence generation. Such evidence generation can be completed during interim funding periods as part of a CED agreement.^{12,14,17-27,31,32,34-37,40,41,43,44,46,49,51,53-57}

A drug with a conditional funding recommendation requiring additional evidence generation has to meet defined inclusion criteria to be considered for CED in most jurisdictions. Common themes of criteria include uncertainties in clinical-effectiveness and/or cost-effectiveness evidence; addressing a disease with high, unmet clinical need; feasibility of collecting additional data; and ability of collected data to generate evidence to address uncertainties during a prespecified period.^{4,15,21,49,58,59} In Ontario (Canada), France, Germany, and Sweden, 1 CED program inclusion criterion is the use of RWD collection during interim funding to generate additional evidence.^{15,18-21,31,49,53,60} CED agreements have been established for oncology drugs,^46,52 CAR T-cell therapies,^12,17,19 orphan drugs,^12,43 and DRD.^4,18 In the UK, separate CED programs have been established: the Cancer Drug Fund (CDF) for oncology drugs and the Innovative Medicines Funds (IMF) for non-oncology drugs.^23,37,61 Drugs considered for funding with CED agreements must meet medical technology designations including “innovative status” in Italy, “ultra orphan drug” in Scotland, or “reasonable and necessary” in the US.^{12,17-19,26,27,43}

Drug Funding

We identified national and regional governments that are responsible for paying for drugs funded with CED agreements. In Australia, Ontario (Canada), Ireland, Italy, Scotland, and the UK, national departments or ministries of health provide funding to national or regional drug funding programs that are responsible for organizing and providing reimbursements of drug costs to hospitals that administer treatments.^{12,15,17-21,13,26,28,31,32,34-37,39-41,43-45,48,54,56,57,62-65} Countries including Belgium, France, the Netherlands, and Sweden have statutory national health insurance programs that receive funding from national health service departments and are responsible for organizing and distributing drug cost reimbursements to hospitals.^{4,13,18,21,28,48,59} In Germany and the US, health insurance organizations determine which drugs will be funded with CED agreements. Only patients with health insurance organized by these organizations are eligible to receive CED-funded drugs.^{18,21,40,50,60} In the US, these health insurance organizations include the Centers for Medicare & Medicaid Services (CMS) and private insurance companies.^40,50,66,67

RWD Collection for RWE Generation

Processes for and funding related to RWD collection and RWE generation for CED programs vary across jurisdictions and may differ across drugs and indications. When it comes to RWD, the 2 primary sources appear to be prospective data and health care administrative databases. Prospective data collection starts when a patient is approved to receive a funded drug, and it can continue throughout the interim funding period.⁴⁹ Registries and observational studies were the most frequently identified tools for prospective data collection.^40,58 Web-based registries can be created specifically for CED-funded drugs, as is the case with Italy’s Italian Medicine Agency (Agenzia Italiana del Farmaco [AIFA]) registries.^12,18,21,43 Alternatively, existing registries collecting data on the patient population of interest may be used, as is the case with the UK’s Systemic Anti-Cancer Therapy (SACT) datasets. SACT datasets capture data on patients with a particular disease or receiving a specific therapy and are organized and maintained by the National Cancer Registry Analysis Service at Public Health England.^{4,12,17-19,21,38,40,54,68,69} Administrative health databases are another source for RWD and can be the sole source for data or combined with prospective data collection. In Ontario (Canada), data from administrative databases are combined with prospective data collection to generate supporting evidence.¹⁵ CMS guidance notes that RWD can come from patients enrolled in prospective clinical studies or through disease registries that can be linked with claims data.^67,69-71

In France, new clinical trial data must be accompanied by RWD from disease registries, electronic medical records, or claims databases.^4,12,20,59 Germany’s Federal Joint Committee (Gemeinsamer Bundesausschuss [G-BA]), requires that data be collected to produce comparative evidence resubmitted at the end of interim funding.^18,21 In Ontario (Canada), the Netherlands, and the UK, CED programs set out the source and method of data collection to generate additional evidence.^{4,15,23,25,32,54} The UK’s CDF and IMF programs require data collection agreements and commercial access agreements. The data collection agreement details the end points that must be reported to address identified uncertainties in clinical effectiveness and/or cost-effectiveness, and the commercial access agreement details the cost of drugs and any risk-sharing conditions.^{26-30,68,72,73} In the UK, drugs funded through the CDF must demonstrate whether data collected in the SACT datasets can be used for evidence generation.^{4,32,54,56,61,68} Data for evidence generation may also come from Blueteq data, Public Health England data, established disease registries, market share data, or chart review.^{4,12,17,19,35,37,38,54,57,72}

Across jurisdictions, it is common for the manufacturer to be responsible for setting up and carrying out the data collection methods.^{4,12,18,19,21,22,25,28,30,40,44,53,58,60,63,67} In Australia, France, Germany, Italy, the Netherlands, Scotland, and Sweden, the manufacturer is responsible for funding data collection through real-world studies. In Belgium, the UK, and the US, the funding source and organization of data collection vary by each funded drug and may be the responsibility of the manufacturer, the payer, or both partners.^{4,12,13,18,21,28,35-37,40,48,56} In Italy, manufacturers are responsible for providing financial support for AIFA registry data collection with help from the Italian Ministry of Health and National Health Service.^{12,18,20,21,43,45,46} In Belgium, the manufacturer provides funding for data analysis processes.¹² Ontario (Canada) was the only jurisdiction identified where RWD collection through the Ontario Health Provincial Drug Reimbursement Programs, is consistently paid for by the payer (i.e., Ontario Ministry of Health).¹⁵

Financial Agreements

Following the announcement of a conditional funding agreement with a CED requirement, the manufacturer, market authorization holder, funder, and payers will typically collaborate to develop the funding agreement. Risk-sharing may be used in addition to the CED requirements, as identified in Australia, Belgium, France, Ireland, Italy, the UK, and the US.^{12,13,19-21,28,30,35,37,40-43,45,46} We identified common requirements as part of agreement schemes across jurisdictions. For example, Australia, Belgium, France, Italy, and the US require manufacturers to provide full or partial refunds for patients who do not achieve outcomes specified before funding, regardless of approval for long-term funding at the end of interim funding.^{4,13,23,28,39,45,49,58,59}

During interim funding periods, CED agreements may have a set price per volume or maximum budgetary amount, both of which can be reviewed at the end of interim funding. After final HTA review, the long-term price or budget cap can be altered along with the eligibility criteria of the drug, depending on the generated evidence. We identified price alterations in Australia, France, Germany, Italy, and the UK.^{18,20,21,40,46,49,58,59,63} In Germany, the manufacturer can be penalized with a price reduction for not generating agreed-upon evidence by the end of the set interim funding period.^19,21,48 In Italy, drug payments are provided at set intervals, with the final interval payment being withheld until the manufacturer provides the additionally generated evidence.^4,21,45,48

Final Funding Status

At the end of the interim funding period, the generated RWE is usually reviewed by the HTA agency and funder to determine if the uncertainties identified in the initial HTA are addressed and whether the terms of the CED agreement are met.^18,19,21 The manufacturer is typically the group required to submit evidence generated to address clinical and cost-effectiveness uncertainties identified by the HTA agency during the initial funding review.^{15,17,25,32,35,37,49,50,53,54,58,62} In Belgium, preliminary evidence reviews are conducted 6 months before the end of the interim funding period to determine whether the CED agreement should be terminated or prolonged for a maximum of 1 year.^13,31 In the US, the CMS requires evidence generated during CED to be publicly available in peer-reviewed journals or in online registries of clinical studies as part of their final review for funding.^67,71,74 Based on the outcome of the HTA reassessment, the drug may be recommended for long-term drug funding through standard reimbursement processes or an end to funding altogether, with the final funding decision determined by the national or regional ministry or department of health.^{4,12,15,17,18,20,21,23,25,31,37,41,45,48,49,53,54,59,71,75} Long-term funding for the drug may not be agreed upon if the terms of the CED agreement have not been met or if the generated evidence does not address clinical and/or cost-effectiveness uncertainties.

System Partners Involvement

Parties involved in CED agreements include the manufacturer, payer, funder, HTA advisory committees, clinicians, pharmacists, patients, patient organizations, health professionals, health economists, and consumer representatives. HTA advisory committees responsible for reviewing and summarizing clinical and cost-effectiveness evidence at initial assessments and reassessments may consist of clinicians, health professionals, pharmacists, and health economists.^18,58 Advisory committees of clinicians with expertise on rare diseases are involved in evidence review during HTAs of highly specialized technologies in the Netherlands and the UK.¹⁸ In France, Germany, Sweden, and the UK, patients and patient organizations are involved during CED negotiation and final decision-making.^{12,17-19,21,23,31,32,34-37,41,42,51,54,56,57,60,76} Representatives — including clinicians, nurses, pharmacists, hospitals, universities, and disease registry organizations — may be involved in the CED agreement, depending on data collection processes.^19,35,39,58

In the UK, CED agreement oversight committees include NICE employees, NHS England employees, clinicians, patient organization representatives, manufacturer company representatives, and NHS data custodian representatives.^35,72 Oversight committees and task forces have the following responsibilities: to support determination of appropriate outcome measurements for evidence generation during initial CED negotiations; during interim funding periods, to regularly review submitted evidence to ensure the data collection is progressing on track; and to support issues related to analysis planning, access to treatment service issues, clinical assessment issues, and safety issues as signalled by patients and/or clinicians.^31,35,72

Interim Funding Period Duration

The length of interim drug funding periods varies between CEDs. We noted that most CED interim funding periods range from 1 to 5 years (Table 4).^{4,12,17-20,22,23,32,34,35,44,45,54,66,} Some jurisdictions set the same length of funding for all drugs or set drug-specific periods of funding based on the length of time needed to collect data and generate additional evidence. The length of interim funding to support sufficient data collection and evidence generation is estimated by the partners involved in arranging the CED agreement.^{12,15,20,21,40,46,49,71}

CED Limitations

Common limitations were identified among jurisdictions with experience conducting CED. CED programs lacked clearly defined entry and exit criteria, exit plans, deliverables, and project timelines. Such issues were noted to have an impact on programs’ abilities to successfully make decisions about funding by the end of interim funding periods, leading to overspending.^{4,22,23,25,29,66,70,76,77} We identified limited transparency in the details of CED agreements and the accompanying financial terms. Specifically, there was limited information available related to evidence-generation plans, how evidence was used at the end of interim funding to support a final funding decision, how drugs were priced in the interim, and drug eligibility criteria.^4,13,18,49

CED agreements that rely on RWD collection and RWE generation are faced with high resource demand to set up and maintain data collection platforms or access existing data. Where data are prospectively collected, health care providers must devote additional time and resources to RWD collection.^4,13 The use of RWD captured from administrative health data sources or registries may result in limited length of follow-up of patients, resulting in immature data that do not address uncertainties in clinical benefit and cost-effectiveness. The use of existing data sources and registries can limit the cohort identification, comparator populations, and study end points.^25,54 Additionally, RWE limitations of CED were identified as contributing to overspending and uncertainties persisting at the end of interim funding periods.^{4,13,18,21-23,49,51,58}

Discussion

This paper identified and described CED agreements applied in 13 jurisdictions that leverage RWE to address uncertainties in evidence submitted as part of HTAs. We reported on the processes of drug selection for CED agreements, RWD collection and RWE generation, financial agreements tied to CED, determination of final funding status, health system partner engagement, and limitations of these CED agreements. The findings of our scan demonstrate variation in the structure of CED agreements and limited transparency on the eventual outcomes of whether and how RWE supports a final funding decision.

CED Agreement Variation

Variation between CED agreements may be driven by several factors, including types of drugs selected, RWD availability, financial agreements, health care delivery structure, and information sharing. Drug selection results in a particular treatment population, and this can impact CED terms. Drugs targeting rare diseases with low annual patient volumes may require extended length of interim funding to allow for appropriate data collection and evidence-generation timelines. Patient population sizes can also impact RWE generation plans, including the end points that can be assessed and whether comparative evidence assessments can be conducted.

RWD availability and accessibility may also be a source of variation between CED agreements. Depending on the required data, prospective data collection and/or administrative health data sources may be leveraged. Where the use of RWD is not possible due to availability and accessibility limitations, CED agreements may have to rely on phase IV clinical trial data, which are out of scope for this Environmental Scan.

Variation in the type of financial agreements applied during CED was identified. We noted the use of refunds, interval payments, price alterations and reductions, price per volume agreements, and budget caps applied with CED agreements. However, the availability of agreement details in the literature and sources included in our scan were limited, likely due to the confidential nature of financial agreements.

Additional variability was identified among different health care system structures, and this impacted both the CED terms and financial agreements. For example, decentralized health care systems may require support from all regions to engage in CED and collaborate on RWD collection and RWE generation, whereas centralized systems may have more direct access to and consistency across data elements within jurisdictions. With regard to funding RWD collection and RWE generation, the responsibility may shift between the payer and drug manufacturer, depending on a jurisdiction’s health care system. Single-payer systems and universal health care payers may have more straightforward access to administrative health data, which could increase their involvement in data collection plans, funding, and RWE generation as compared to systems with private health care coverage options. Single-payer systems and universal health care payers should also have access to claims data for their entire jurisdiction’s population, increasing the generalizability of evidence generated with the data.

Finally, restricted availability of and access to information on how CED agreements are established and structured may lead to further variation. CED agreements may be similar between jurisdictions, but details on patient eligibility, RWD sources, clinical-effectiveness and cost-effectiveness end points, financial agreements, and CED outcomes are limited. This limits what other countries can learn about CED and how to apply it in their own jurisdictions.

CED Agreement Transparency

This Environmental Scan also revealed the extent of missing information related to the outcomes of CED agreements using RWE (i.e., the eventual funding decisions). This limits the ability to evaluate the benefit of CED and determine whether future applications of CED are appropriate. Kang et al. and Morel et al. conducted reviews of the UK’s CDF final appraisal documents and reported limited use of RWE to support final funding decisions.^48,54 RWE from SACT databases was reviewed as part of the final funding review for 15 CDF drugs, of which only 5 reviews used RWD for parametric purposes and 2 of the 5 reviews used RWD for primary end points.⁵⁴ The CDF program provides annual activity reports detailing the number of MEAs under the program and reappraisals following interim funding by NICE. As of January 2025, NICE had conducted reappraisals of 39 drugs funded through the CDF program, of which 34 received recommendations for long-term funding, 2 were not approved for long-term funding, 2 did not proceed due to lack of evidence submitted by the drug manufacturers, and 1 had a withdrawn product licence.⁷⁸ Reappraisal meeting documents for 1 of the 2 drugs not approved for long-term funding — pembrolizumab — are available online and describe the RWE included in the reassessment.⁷⁹ However, the details that went into these final funding recommendations remain limited. RWE to support CED may remain infrequently used for final decision-making if limited transparency into CED agreements and their outcomes persists. Knowledge-sharing among jurisdictions may increase the likelihood of using RWE for CED, as it can save time when selecting drugs, establishing financial terms, developing analysis plans, and evaluating evidence.

An exception to the noted transparency around CED agreements was the CMS in the US. The CMS makes several CED guidance documents, reviews of CMS processes, and final funding decisions following CED available, intended for use by all system partners. Further, the CMS website lists therapies funded with CED and includes details of clinical trials and RWE studies planned and under way to support final funding decisions. Final decisions are posted online with descriptions of evidence used to inform the final funding decisions.^67,71,74 The weight of RWE in contributing to a final funding decision remains unclear; however, the degree of transparency of the CMS’s CED processes and final reviews provides a fine example for other jurisdictions.

Overcoming Limitations

The high variation in and limited transparency of jurisdictional CED programs do not negate the potential benefits of CED and opportunities for using RWE to support accelerating access to drugs where there is a high unmet need and/or limited evidence. Still, criticisms of CED and strategies to address these criticisms must be discussed.

A drawback of CED from the payer perspective is its potential to encourage manufacturers to present preliminary evidence with uncertainties to HTA organizations, thereby securing interim funding, shifting the risk to payers and patients. A further criticism is that manufacturers may not feel committed to providing data for evidence generation that is required per the agreement if they are receiving funding upfront.^13,17,18 CED, however, may enable HTA agencies and payers to have more oversight into the quality and robustness of data collection and evidence generation.³⁰ For example, CED agreements can stipulate regular data review or evidence-sharing during interim funding periods, with interval payments paid to the manufacturer upon receipt of data or evidence.⁴ Outcome-based or performance-based agreements may help ensure continued evidence generation and promote risk-sharing if manufacturers are required to provide repayments or discounts for not achieving agreed-upon outcomes.^21,25

Another limitation of CEDs is the lack of clear entry and exit criteria, as was the case with the UK’s original MEA process, which led to its reorganization and introduction as the CDF in 2016.⁵⁴ Clearly defined entry criteria, deliverables, exit plans, reporting intervals, data sources, and project timelines should be set to ensure programs achieve their goals, maintain transparency, and avoid overspending.^{4,22,23,25,29,66,70,77} Research questions, objectives, and end points needed to address uncertainties must also be clearly identified to avoid resource wastage and meet evidence-generation goals.^{4,22,25,26,29,49,54}

A limitation of CED specific to countries with decentralized health care systems — such as Canada, Italy, and Spain — is the potential for inequitable access to drugs funded with CED agreements between regions, provinces, and/or territories. Maintaining national organization of drugs funded with CED agreements supports patients and clinicians by ensuring patients in all jurisdictions have equitable access to the same therapies.³⁴ National organization of funded drugs should include data collection plans that allow for data sharing and comparison across jurisdictions to increase the generalizability and potential validity of study outcomes. National disease registries have been implemented in Italy (AIFA registries) and Spain (Valtermed registries), despite their decentralized health care systems, to support MEAs. In Italy, AIFA registries have been established for a number of years to support OBAs and CED.^12,18,21,43 Spain’s Valtermed registries were more recently established (in 2019) and, to our knowledge, have only supported OBAs.^80,81 The existence of these registries not only allows for generated RWE to be more representative of patients across a country but for national funding decisions to be applied across all jurisdictions and to ensure equitable access to publicly funded drugs.

Early planning and partner engagement during the development of CED agreements can improve their success and mitigate the previously noted limitations. An appropriate mix of system partners — such as HTA representatives, clinicians, payers, patients, patient representatives, methodologists, and manufacturer representatives — should be included throughout the entire CED process. CED member roles should be clearly defined to ensure system partners achieve and are accountable for their responsibilities.^13,30,66,76

CED is often viewed as costly due to the resource use and population-level data collection processes.^4,13 The cost to set up and maintain data collection platforms and the time required to collect data, often by clinicians, may be barriers to implementing CED. Exploring the use of routinely collected data that can support CED may eliminate costly prospective data collection. While time- and resource-intensive, CED agreements to expand patient access to and confirm value of costly therapies is justified if the added resource demands can be minimized or well placed. System partners must collaborate to identify the specific circumstances in which CEDs may be cost-beneficial. For example, establishing drug-selection criteria and a clear mechanism to renegotiate or delist a drug can provide added assurances that the health system and patients may benefit. The cost may prove to be a worthwhile investment if generated evidence demonstrates clear clinical benefit; identifies safety concerns; leads to price renegotiations; or, in cases where clinical benefit is not identified, leads to delisting of drugs.

Opportunities for Canada

In the last several years, Canada has made advancements in accelerating access to cancer drugs through various initiatives. Health Canada joined Project Orbis in 2019, led the by FDA in the US, with the goal of accelerating access to promising new treatments through streamlining regulatory reviews.⁸² In 2025, the pCPA implemented the Early Negotiation Process (ENP) to support Canadian provinces and territories in expediting public listing of Project Orbis drugs after negotiation.⁸³ Ontario also implemented the Funding Accelerated for Specific Treatments (FAST) pilot program to expedite the listing of Project Orbis drugs.⁸⁴ Most relevant to CED was the establishment of the TLR pathway by CDA-AMC⁸ and pTAP by the pCPA.^8,9

Faster regulatory pathways may result in submissions that lack mature outcomes data or long-term evidence of a drug’s benefit and financial impact. The development of novel access pathways given evidence limitations provides an opportunity in Canada to incorporate RWE into drug funding decisions. Ontario (Canada) has already demonstrated success using RWE to facilitate CED through the Ontario Health (Cancer Care Ontario) Evidence Building Program. The Evidence Building Program has used RWD and RWE to support final funding decisions for 2 drugs. Cheung et al. explored the feasibility of using RWD from administrative health data sources in Alberta (Canada) to support OBAs for oncology drugs.⁸⁵ The findings demonstrated that it is feasible to leverage OBAs using Alberta (Canada) RWD with little additional data outside of what is available in administrative health data sources.⁸⁵ There is an opportunity to learn from current and past experiences with the goal of implementing a CED program that uses RWD and RWE to facilitate expedited access to promising new therapies.

Limitations

This Environmental Scan had limitations. The approach was pragmatic and, as such, relevant literature may have been missed and thus not included in this scan. Details about jurisdictional CED agreements may have been missed or not presented if jurisdictions limited the availability or accessibility of information about their CED agreements, or if information was not provided in English.

Conclusion

This Environmental Scan sought to identify CED programs globally, specifically where RWE is generated to support decision-making. Programs were identified in Canadian and international jurisdictions, and we described the various components and discussed the limitations of these CED programs. Many countries use CED agreements to fund drugs where there are uncertainties in submitted evidence. Variation exists in the CED components and processes between jurisdictions, and limited transparency into CED details has an impact on what can be learned from jurisdictions that have already applied CED. Increased CED policy-planning within jurisdictions and sharing between jurisdictions can contribute to improved efficiencies and sustainability in health care systems.

Jurisdictional experiences with and lessons learned from their CED programs can be leveraged to explore the development of a robust Canadian CED model. Given the increasing pressure to accelerate funding, CED may provide an opportunity to enable earlier patient access to promising, expensive therapies while assessing value and benefit to support long-term funding decisions.

Acknowledgements

The authors would like to acknowledge Sadaf Ullah, who provided support as a medical librarian for Ontario Health (Cancer Care Ontario) at the time that this scan was conducted and who is currently employed with Unity Health Toronto. The authors would also like to acknowledge Senior Research Associates Pam Takhar and Jaemin Kim, from Ontario Health’s Evidence Search and Review Synthesis team, for their support on this Environmental Scan and in the review of this manuscript. The authors would like to acknowledge Nany Guo, Gabriella Sgrignuoli, and Laureen Rance from the Ontario Ministry of Health for their review of this manuscript.

Author Information

Caroline Muñoz, Jessica Arias, Alayna Brown, Mitali Garg, Scott Gavura

Ontario Health, 525 University Avenue, Toronto, Ontario

Corresponding Author

Caroline Muñoz, MSc

Senior Analyst, Provincial Drug Reimbursement Programs, Acute and Hospital-Based Care, Ontario Health

525 University Avenue, Toronto, Ontario, Canada

Telephone: (647) 953-1618

caroline.munoz@ontariohealth.ca

Authorship confirmation: All authors certify that they meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship.

Funding or support: The authors received no financial support for this research.

References

1.Battista RN, Côté B, Hodge MJ, Husereau D. Health technology assessment in Canada. Int J Technol Assess Health Care. 2009;25(SUPPL.S1). doi:10.1017/S0266462309090424 PubMed

2.Quay T, Dulong C, Lachance CC, Topfer LA. Collaboration in Health Technology Assessment in Canada.; 2019. https://www.cadth.ca/sites/default/files/es/es0329-hta-collaboration.pdf

3.CADTH. Procedures for CADTH Reimbursement Reviews.; 2023. https://www.cadth.ca/sites/default/files/Drug_Review_Process/CADTH_Drug_Reimbursement_Review_Procedures.pdf

4.Wenzl M, Chapman S. Performance-based managed entry agreements for new medicines in OECD countries and EU member states: How they work and possible improvements going forward. OECD Heal Work Pap. 2019;(115):102. https://dx.doi.org/10.1787/6e5e4c0f-en

5.Pauwels K, Huys I, Vogler S, Casteels M, Simoens S. Managed entry agreements for oncology drugs: Lessons from the European experience to inform the future. Front Pharmacol. 2017;8(APR). doi:10.3389/fphar.2017.00171 PubMed

6.Malone DC, Brown M, Hurwitz JT, Peters L, Graff JS. Real-World Evidence: Useful in the Real World of US Payer Decision Making? How? When? And What Studies? Value Heal. 2018;21(3). doi:10.1016/j.jval.2017.08.3013 Medline PubMed

7.Hurwitz JT, Brown M, Graff JS, Peters L, Malone DC. Is real-world evidence used in P&T monographs and therapeutic class reviews? J Manag Care Spec Pharm. 2017;23(6). doi:10.18553/jmcp.2017.16368 Medline PubMed

8.Canada’s Drug Agency. Our Time-Limited Recommendation Category Aims to Support Earlier Access to Promising Drugs. 2023. Accessed January 15, 2025. https://www.cda-amc.ca/news/our-time-limited-recommendation-category-aims-support-earlier-access-promising-drugs

9.pan-Canadian Pharmaceutical Alliance. pCPA Temporary Access Process (pTAP). 2025. Accessed January 15, 2025. https://www.pcpacanada.ca/ptap

10.CADTH. Drugs for Rare Diseases: A Review of National and International Health Technology Assessment Agencies and Public Payers’ Decision-Making Processes.; 2021. https://www.cadth.ca/sites/default/files/es/es0355-drugs-for-rare-diseases-pw.pdf

11.Government of Canada. The National Strategy for Drugs for Rare Diseases. 2024. Accessed December 29, 2025. https://www.canada.ca/en/health-canada/services/health-care-systems/national-pharmacare/strategy-drugs-rare-diseases.html

12.Facey KM, Espin J, Kent E, et al. Implementing Outcomes-Based Managed Entry Agreements for Rare Disease Treatments: Nusinersen and Tisagenlecleucel. Pharmacoeconomics. 2021;39(9):1021-1044. doi:https://dx.doi.org/10.1007/s40273-021-01050-5 PubMed

13.Gerkens S, Neyt M, San Miguel L, Vinck I, Thiry N, Cleemput I. How to improve the Belgian process for managed entry agreements? An analysis of the Belgian and international experience. Heal Serv Res Brussels Belgian Heal Care Knowl Cent. 2017;KCE report:75. https://kce.fgov.be/sites/default/files/2021-11/KCE_288_Improve_Belgian_process_managed_entry_agreements_Report.pdf

14.Alberta Health. Alberta Health -Alberta Health Product Listing Agreement Policy.; 2022.

15.Cancer Care Ontario. Evidence Building Program (EBP). Accessed March 13, 2022. https://www.cancercareontario.ca/en/Funding/Evidence_Building_Program

16.Cancer Care Ontario. Provincial Drug Reimbursement Programs. https://www.cancercareontario.ca/en/cancer-care-ontario/programs/provincial-drug-reimbursement

17.Jørgensen J, Hanna E, Kefalas P. Outcomes-based reimbursement for gene therapies in practice: the experience of recently launched CAR-T cell therapies in major European countries. J Mark Access Heal Policy. 2020;8(1):1715536. doi:10.1080/20016689.2020.1715536 PubMed

18.Stafinski T, Glennie J, Young A, Menon D. HTA decision-making for drugs for rare diseases: comparison of processes across countries. Orphanet J Rare Dis. 2022;17(1):258. doi:https://dx.doi.org/10.1186/s13023-022-02397-4 PubMed

19.Jørgensen J, Kefalas P. The use of innovative payment mechanisms for gene therapies in Europe and the USA. Regen Med. 2021;16(4):405-421. doi:10.2217/rme-2020-0169 PubMed

20.Jarosawski S, Toumi M. Market Access Agreements for pharmaceuticals in Europe: Diversity of approaches and underlying concepts. BMC Health Serv Res. 2011;11. doi:10.1186/1472-6963-11-259 PubMed

21.Grubert N. Lessons Learned from Europe, the United States, Canada and Australia Pharmaceutical Managed Entry Agreements. 2018;(December).

22.Van Harten WH. Innovations that reach the patient: Early health technology assessment and improving the chances of coverage and implementation. Ecancermedicalscience. 2016;10:683. doi:https://dx.doi.org/10.3332/ecancer.2016.683 PubMed

23.Faulkner SD, Lee M, Qin D, et al. Pricing and reimbursement experiences and insights in the European Union and the United States: Lessons learned to approach adaptive payer pathways. Clin Pharmacol Ther. 2016;100(6). doi:10.1002/cpt.508 PubMed

24.Niezen M, de Bont A, Stolk E, Eyck A, Niessen L, Stoevelaar H. Conditional reimbursement within the Dutch drug policy. Health Policy (New York). 2007;84(1). doi:10.1016/j.healthpol.2006.11.005 PubMed

25.Makady A, van Veelen A, Hillege H, Klungel OH. Implementing managed entry agreements in practice: The Dutch reality check. Health Policy (New York). 2019;123(3):267-274. doi:https://dx.doi.org/10.1016/j.healthpol.2018.09.016 PubMed

26.Lewis JRR, Kerridge I. Coverage with evidence development and managed entry in the funding of personalized medicine: Practical and ethical challenges for oncology. J Clin Oncol. 2015;33(34):4112-4117. doi:https://dx.doi.org/10.1200/JCO.2015.61.2838 PubMed

27.Relyea-Chew A. Ethical considerations in CMS’s coverage with evidence development. J Am Coll Radiol. 2011;8(12):838-841. doi:https://dx.doi.org/10.1016/j.jacr.2011.08.011 PubMed

28.Stafinski T, McCabe C. Funding the unfundable: Mechanisms for managing uncertainty in decisions on the introduction of new and innovative technologies into healthcare systems. Pharmacoeconomics. 2010;28(2):113-142. doi:https://dx.doi.org/10.2165/11530820-000000000-00000 PubMed

29.Mohr PE. Access with evidence development: The US experience. Pharmacoeconomics. 2010;28(2):153-162. doi:https://dx.doi.org/10.2165/11531050-000000000-00000 PubMed

30.Trueman P, Grainger DL. Coverage with evidence development: Applications and issues. Int J Technol Assess Health Care. 2010;26(1):79-85. doi:https://dx.doi.org/10.1017/S0266462309990882 PubMed

31.Ferrario A. Dealing with uncertainty and high prices of new medicines: A comparative analysis of the use of managed entry agreements in Belgium, England, the Netherlands and Sweden. Soc Sci Med. 2015;124:39-47. doi:https://dx.doi.org/10.1016/j.socscimed.2014.11.003 PubMed

32.Shengnan D, Zixuan L, Na Z, Weikai Z, Yuanyuan Y, Jiasu L. Using 5 consecutive years of NICE guidance to describe the characteristics and influencing factors on the economic evaluation of orphan oncology drugs. Front public Heal. 2022;10:964040. doi:https://dx.doi.org/10.3389/fpubh.2022.964040 PubMed

33.Kang J, Cairns J. “Don’t Think Twice, It’s All Right”: Using Additional Data to Reduce Uncertainty Regarding Oncologic Drugs Provided Through Managed Access Agreements in England. PharmacoEconomics - Open. 2023;7(1). doi:10.1007/s41669-022-00369-9 PubMed

34.Mayor S. New “managed access” process for Cancer Drugs Fund to go ahead, NHS England confirms. BMJ. 2016;352. doi:10.1136/bmj.i1208 PubMed

35.NICE. Managed Access. 2023. https://www.nice.org.uk/about/what-we-do/our-programmes/managed-access

36.NHS England. Cancer Drugs Fund. https://www.england.nhs.uk/cancer/cdf/

37.NHS England. Innovative Medicines Fund. https://www.england.nhs.uk/medicines-2/innovative-medicines-fund/

38.Simoens S, De Groote K. Critical Reflections on Reimbursement and Access of Advanced Therapies. Front Pharmacol. 2022;13:771966. doi:https://dx.doi.org/10.3389/fphar.2022.771966 PubMed

39.Kim H, Comey S, Hausler K. A real world example of coverage with evidence development in Australia - ipilimumab for the treatment of metastatic melanoma. J Pharm Policy Pract. 2018;11(1):4. doi:https://dx.doi.org/10.1186/s40545-018-0131-4 PubMed

40.Lexchin J. Coverage with evidence development for pharmaceuticals: A policy in evolution? Int J Heal Serv. 2011;41(2):337-354. doi:https://dx.doi.org/10.2190/HS.41.2.h PubMed

41.Health Service Executive. Managed Access Protocols. 2023. https://www.hse.ie/eng/about/who/cspd/ncps/medicines-management/managed-access-protocols/

42.Gorry C, Daly M, Barrett R, et al. Utilising Health Technology Assessment to Develop Managed Access Protocols to Facilitate Drug Reimbursement in Ireland. Appl Health Econ Health Policy. Published online November 1, 2024. doi:10.1007/s40258-024-00904-1 PubMed

43.Xoxi E, Facey KM, Cicchetti A. The Evolution of AIFA Registries to Support Managed Entry Agreements for Orphan Medicinal Products in Italy. Front Pharmacol. 2021;12. doi:10.3389/fphar.2021.699466 PubMed

44.Australian Government Department of Health and Aged Care. Framework for the introduction of a Managed Entry Scheme for submissions to the Pharmaceutical Benefits Advisory Committee. 2011. https://www.pbs.gov.au/info/publication/factsheets/shared/framework-for-introduction-of-managed-entry-scheme-for-PBAC-submissions

45.Montilla S, Xoxi E, Russo P, Cicchetti A, Pani L. Monitoring registries at Italian medicines agency: Fostering access, guaranteeing sustainability. Int J Technol Assess Health Care. 2015;31(4). doi:10.1017/S0266462315000446 PubMed

46.Adamski J, Godman B, Ofierska-Sujkowska G, et al. Risk sharing arrangements for pharmaceuticals: Potential considerations and recommendations for European payers. BMC Health Serv Res. 2010;10. doi:10.1186/1472-6963-10-153 PubMed

47.Mohseninejad L, Van Gils C, Uyl-De Groot CA, Buskens E. Evaluation of patient registries supporting reimbursement decisions: The case of oxaliplatin for treatment of stage III colon cancer. Value Heal. 2015;18(1):84-90. doi:https://dx.doi.org/10.1016/j.jval.2014.10.008 PubMed

48.Morel T, Arickx F, Befrits G, et al. Reconciling uncertainty of costs and outcomes with the need for access to orphan medicinal products: A comparative study of managed entry agreements across seven European countries. Orphanet J Rare Dis. 2013;8(1). doi:10.1186/1750-1172-8-198 PubMed

49.Ferrario A, Kanavos P, Dabbous O, et al. Managed entry agreements for pharmaceuticals: the European experience. Ecancermedicalscience. 2013;12(2):1-151. https://doi.org/10.1016/j.jval.2018.11.010%0Ahttp://www.oecd.org/health/health-systems/Pharmaceutical-Innovation-and-Access-to-Medicines-Executive-Summary-ENGLISH.pdf%0Ahttps://www.duo.uio.no/bitstream/handle/10852/58667/Peters_Marjolein_Master_Thesis_EuH

50.CMS. Guidance for the Public, Industry, and CMS Staff National Coverage Determinations with Data Collection as a Condition of Coverage: Coverage with Evidence Development. 2006;(410). http://www.cms.hhs.gov/center/coverage.asp%5Cnhttp://www.cms.hhs.gov/InfoExchange/06_contactus.asp#TopOfPage.

51.World Health Organization Regional Office for Europe. Access to New Medicines in Europe: Technical Review of Policy Initiatives and Opportunities for Collaboration and Research.; 2015. https://ppri.goeg.at/sites/ppri.goeg.at/files/inline-files/WHO_AccessNewMedicines_Report_FINAL2015_1.pdf

52.Cancer Care Ontario. Evidence Building Program Policy. 2011;(October). https://www.cancercareontario.ca/sites/ccocancercare/files/assets/CCOEvidenceBuildingPolicy.pdf

53.Willis M, Persson U, Zoellner Y. Reducing uncertainty in value-based pricing using evidence development agreements: The case of continuous intraduodenal infusion of levodopacarbidopa (Duodopa) in Sweden. Appl Health Econ Health Policy. 2010;8(6):377-386. doi:https://dx.doi.org/10.2165/11531160-000000000-00000 PubMed

54.Kang J, Cairns J. “Don’t Think Twice, It’s All Right”: Using Additional Data to Reduce Uncertainty Regarding Oncologic Drugs Provided Through Managed Access Agreements in England. PharmacoEconomics - Open. 2023;7(1). doi:https://dx.doi.org/10.1007/s41669-022-00369-9 PubMed

55.Pouwels X, Grutters J, J. B, Ramaekers B. Uncertainty and Coverage With Evidence Development: Does Practice Meet Theory? Value Heal. 2019;22(7):799-807. doi:https://dx.doi.org/10.1016/j.jval.2018.11.010 PubMed

56.Lee J, Trevor N, Adedokun L, Lilley C. Optimizing Managed Access: Lessons From the Cancer Drugs Fund. ISPOR. 2021;7(2).

57.National Audit Office C and AG. Investigation into the Cancer Drugs Fund.; 2015. https://www.nao.org.uk/wp-content/uploads/2015/09/Investigation-into-the-Cancer-Drugs-Fund1.pdf

58.Tuffaha HW, Scuffham PA. The Australian Managed Entry Scheme: Are We Getting it Right? Pharmacoeconomics. 2018;36(5). doi:10.1007/s40273-018-0633-6 PubMed

59.HAS. Innovative medicines assessment action plan. 2020;(January):1-6. https://www.has-sante.fr/upload/docs/application/pdf/2020-03/innovative_medicine_action_plan_27.01.20.pdf

60.IGES Institute. Reimbursement of Pharmaceuticals in Germany 2020/2021 - Finding Your Way into the German Pharmaceutical Market. Published online 2021. https://www.iges.com/e15094/e15095/e15096/e17469/IGES_Reimbursement_Pharmaceuticals_Germany_2020_2021_WEB_ger.pdf

61.NHS England. NHS commercial framework for new medicines.

62.Robinson MF. Characteristics of managed access agreements for medicines in Australia. Value Heal. 2017;20(5):A65. https://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=emed18&NEWS=N&AN=617600325

63.Vitry A. Managed entry agreements for pharmaceuticals in Australia. Health Policy (New York). 2014;117(3):345-352. doi:https://dx.doi.org/10.1016/j.healthpol.2014.05.005 PubMed

64.Australian Government Department of Health and Aged Care. PBAC Minutes for the Managed Access Program Framework - March 2015. 2015. https://www.pbs.gov.au/info/news/2015/07/pbac-minutes-for-the-managed-access-program-framework

65.Wonder M, Backhouse ME, Sullivan SD. Australian Managed Entry Scheme: A New Manageable Process for the Reimbursement of New Medicines? Value Heal. 2012;15(3):586-590. doi:10.1016/j.jval.2012.02.004 PubMed

66.Zeitler EP, Gilstrap LG, Coylewright M, Slotwiner DJ, Colla CH. Coverage with Evidence Development: Where Are We Now? Am J Manag Care. 2022;28(8):382-389. doi:https://dx.doi.org/10.37765/ajmc.2022.88870 PubMed

67.Centers for Medicare & Medicaid Services. Coverage with Evidence Development.; 2024. https://www.cms.gov/files/document/ced-guidance2024pdf.pdf

68.Farmer C, Barnish MS, Trigg LA, et al. An evaluation of managed access agreements in England based on stakeholder experience. Int J Technol Assess Health Care. 2023;39(1). doi:10.1017/S0266462323000478 PubMed

69.McPhail M, Bubela T. Can Managed Access Agreements Mitigate Evidentiary, Economic and Ethical Issues with Access to Expensive Drugs for Rare Diseases in the Canadian Context? Healthc Pap. 2023;21(1). doi:10.12927/hcpap.2023.26994 PubMed

70.Lakdawalla D, Tunis S, Neumann P, Whicher D, Zeitler E, Liden B. A Roadmap for Improving Medicare’s Application of Coverage With Evidence Development. Value Heal. 2024;27(9):1191-1195. doi:10.1016/j.jval.2024.05.008 PubMed

71.Centers for Medicare & Medicaid Services. Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development. 2014. https://www.cms.gov/medicare-coverage-database/view/medicare-coverage-document.aspx?MCDId=27

72.National Institute for Health and Care Excellence. Data collection agreement. 2024. https://www.nice.org.uk/what-nice-does/our-guidance/about-technology-appraisal-guidance/data-collection-agreement

73.Trigg LA, Barnish MS, Hayward S, et al. An Analysis of Uncertainties and Data Collection Agreements in the Cancer Drugs Fund. PharmacoEconomics - Open. 2024;8(2). doi:10.1007/s41669-023-00460-9 PubMed

74.Segal J, Levy J, DiStefano M, et al. Analysis of Requirements for Coverage With Evidence Development (CED) – Topic Refinement.; 2022. https://www.cms.gov/files/document/id110ta.pdf

75.Medicines Australia. Finding common ground for accelerating access. 2023. https://www.health.gov.au/sites/default/files/2023-12/attachment_a_-_meeting_26_medicine_australia_slides_deep_dive_accelerated_access.pdf

76.Bishop D. Politics and its intersection with coverage with evidence development: a qualitative analysis from expert interviews. BMC Health Serv Res. 2013;13:88. doi:https://dx.doi.org/10.1186/1472-6963-13-88 PubMed

77.Hutton J, Trueman P, Henshall C. Coverage with evidence development: an examination of conceptual and policy issues. Int J Technol Assess Heal Care. 2007;23(4):452-32. doi:10.1017/S0266462307070651 PubMed

78.NHS England. Cancer Drugs Fund activity update Q2 2024-25. 2025. Accessed December 29, 2025. https://www.england.nhs.uk/long-read/cancer-drugs-fund-activity-update-q2-2024-25/

79.National Institute for Health and Care Excellence. Pembrolizumab for untreated PD-L1-positive, locally advanced or metastatic urothelial cancer when cisplatin is unsuitable (terminated appraisal). 2021. Accessed December 29, 2025. https://www.nice.org.uk/guidance/ta674

80.Tomassy J, Caban A, Hammes F. PNS225 CURRENT STATUS OF OUTCOMES-BASED AGREEMENTS IN SELECTED EUROPEAN COUNTRIES AND CANADA. Value Heal. 2019;22(Supplement 3):S799. doi:https://dx.doi.org/10.1016/j.jval.2019.09.2125

81.Angulo-Pueyo E, Bernal-Delgado E. A new information system to assess the therapeutic value of drugs in real practice. European Observatory on Health Systems and Policies. 2019. Accessed December 27, 2025. https://eurohealthobservatory.who.int/monitors/health-systems-monitor/updates/hspm/spain-2018/a-new-information-system-to-assess-the-therapeutic-value-of-drugs-in-real-practice

82.Government of Canada. Project Orbis. 2022. Accessed January 15, 2025. https://www.canada.ca/en/health-canada/services/drugs-health-products/international-activities/project-orbis.html

83.pan-Canadian Pharmaceutical Alliance. Early Negotiation Process (ENP). 2025. Accessed November 29, 2025. https://www.pcpacanada.ca/enp-pathway

84.Government of Ontario. Funding Accelerated for Specific Treatments (FAST) pilot program. 2025. Accessed December 29, 2025. https://www.ontario.ca/page/funding-accelerated-specific-treatments-fast-pilot-program

85.Cheung WY, Cameron C, Mitha A, Wills A. Building infrastructure for outcomes-based agreements in Canada: can administrative health data be used to support an outcomes-based agreement in oncology? Support Care Cancer. 2023;31(1). doi:10.1007/s00520-022-07486-5 PubMed

86.Haute Autorité de Santé. Real-World Studies for the Assessment of Medicinal Products and Medical Devices.; 2021. https://www.has-sante.fr/upload/docs/application/pdf/2021-06/real-world_studies_for_the_assessment_of_medicinal_products_and_medical_devices.pdf

87.Dabbous M, Chachoua L, Caban A. Managed Entry Agreements: Policy Analysis From the European Perspective. Value Heal. 2020;23(4):425-433. doi:https://dx.doi.org/10.1016/j.jval.2019.12.008 PubMed

88.Koleva-Kolarova R, Buchanan J, Vellekoop H, et al. Financing and Reimbursement Models for Personalised Medicine: A Systematic Review to Identify Current Models and Future Options. Appl Health Econ Health Policy. 2022;20(4):501-524. doi:https://dx.doi.org/10.1007/s40258-021-00714-9 PubMed

89.Phillips KA. CMS Coverage with Evidence Development - Challenges and Opportunities for Improvement. JAMA Heal Forum. 2022;3(9). doi:10.1001/jamahealthforum.2022.3061

Appendix 1: Tables

Please note that this appendix has not been copy-edited.

Table 1: Sources of Research Evidence

Table 2: Web-Based Concepts and Search Terms, and Jurisdictions of Interest

Note: Singular and plural forms of terms searched.

Table 3: Study Selection Criteria

CED = coverage with evidence development. RWE = real-world evidence.

Table 4: Jurisdictional CED Agreement Characteristics and Processes

AIFA = Agenzia Italiana del Farmaco; CAA = commercial access agreement; CAR = chimeric antigen receptor; CED = coverage with evidence development; CEPS = Comité Economique Des Produits De Santé; CDF = Cancer Drug Fund; CTG/CGM = Commission for Reimbursement of Medicines; CMS = Centers for Medicare & Medicaid Services; DAC = Drug Advisory Committee; DCA = data collection agreement; EBP = evidence building program; G-BA = Gemeinsamer Bundesausschuss; GKV = Gesetzliche Krankenversicherung; HAS = Haute Autorité de santé; HSE = Health Service Executive; HTA = health technology assessment; IMF = Innovative Medicines Fund; INAMI = National Institute for Health and Disability Insurance; IQWiG = Institute for Quality and Efficiency in Health Care; MAP = managed access program; NHS = National Health Service; NICE = National Institute for Health and Care Excellence; NZa = Nederlandse Zorgautoriteit; PBAC = Pharmaceutical Benefits Advisory Committee; PBS = Pharmaceutical Benefits Scheme; PKV = Private Krankenversicherung; RFPLA = Request for Product Listing Agreement; RWD = real-world data; RWE = real-world evidence; SACT = systemic anti-cancer therapy; SMC = Scottish Medicines Consortium; TLV = Tandvårds-och Läkemedelsförmånsverket; ZIN = Zorginstituut Nederland.

Appendix 2: Search Strategy — Embase, 2007 to November 6, 2024

Please note that this appendix has not been copy-edited.

1. ((coverage adj3 evidence adj3 (development or building)).ti,ab,kw.

2. ((coverage or access) adj3 evidence adj3 (development or building)).ti,ab,kw.

3. (managed adj1 access).ti,ab,kw.

4. (managed adj3 entry adj3 (access or agreement)).ti,ab,kw.

5. ((evidence or outcome*) adj3 based adj3 agreement)).ti,ab,kw.

6. 1 or 2 or 3 or 4 or 5

7. Limit 6 to (English language and yr=”2007-Current”)

Appendix 3: Sample Data Extraction Form

Please note that this appendix has not been copy-edited.

Table 5: Sample Data Extraction Form

HTA = health technology assessment; RWD = real-world data; RWE = real-world evidence.

Appendix 4: Supplemental Material

Please note that this appendix has not been copy-edited.

Table 6: Sources Included in Environmental Scan, Identified Through Web-Based Searches and Embase Database

AIFA = Agenzia Italiana del Farmaco; CAR = chimeric antigen receptor; CED = coverage with evidence development; CMS = Centers for Medicare & Medicaid Services; EU = Europe; HTA = health technology assessment; HSE = Health Service Executive; ISPOR = International Society for Pharmacoeconomics and Outcomes Research; NHS = National Health Service; NICE = National Institute for Health and Care Excellence; OCED = Organization for Economic Co-operation and Development.

Note: References to the term “stakeholder” are included from original sources.