Early Scientific Advice for Health Technology Assessment: Progressing Towards a Framework in Saudi Arabia

Early Scientific Advice for Health Technology Assessment: Progressing Towards a Framework in Saudi Arabia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Early Scientific Advice for Health Technology Assessment: Progressing Towards a Framework in Saudi Arabia Ahmed Al Jedai, Hajer AlMudaiheem, Naif AlOtaibi, Lamia Al Zubaidi, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8907697/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Background Early Scientific Advice (ESA) is an independent, non-binding process that gives patient-centred scientific guidance to manufacturers in the pre-market stage of product development. Unlike advisory boards, ESA provides objective advice from Health Technology Assessment (HTA) bodies or regulatory authorities, aiming to support the development of healthcare technologies in line with regulatory and health policy goals. This study examines global ESA practices and suggests a framework for implementing ESA in Saudi Arabia. Methods A literature review was conducted to examine established ESA systems, focusing on processes, workflows, timings, challenges, and lessons learned. Additionally, a roundtable discussion with experts from regulatory bodies, healthcare providers, and industry was held to identify the key pillars of the Saudi ESA framework. Several related topics were covered, including governance, patient involvement, types of products, review timing, the distinction between ESA and advisory boards, horizon scanning, and the use of ESA for technical quality assessments. Results The roundtable discussion revealed that the ESA framework in Saudi Arabia should focus on pharmaceuticals as well as medical devices. The panel proposed considering ESA before drug registration in late-stage clinical development and for phase 2 and 3 trials of drugs for diseases with local relevance (e.g., rare diseases). For medical devices, the ESA process should occur post-marketing authorization. It was agreed that the ESA process should be governed by the HTA body. Experts also recommended patient involvement during ESA review using targeted questionnaires to ensure a comprehensive review. Conclusion ESA in Saudi Arabia can enhance stakeholder engagement in the approval and reimbursement processes for pharmaceuticals, diagnostics, and medical devices. Implementing ESA within Saudi Arabia's advanced healthcare system is essential to support manufacturers, optimize outcomes, and improve access to these interventions. Early Scientific Advice Health Technology Assessment Pharmaceuticals Saudi Arabia Figures Figure 1 Figure 2 1. Background The approval and reimbursement of medical interventions depend on the availability of robust and comprehensive evidence that meets the expectations of regulatory bodies and Health Technology Assessment (HTA) agencies. Seeking scientific advice at an early point in the drug development process helps developers focus on generating relevant evidence through appropriate clinical program development and other studies, thereby reducing the risk of substantial objections during the evaluation of the marketing authorization application and for a future formulary review. 1 Early Scientific Advice (ESA) is a structured and formal process enabling manufacturers to obtain confidential, nonbinding feedback from HTA or regulatory bodies during the early stages of product or device development. 2 While ESA was initially associated primarily with regulatory bodies, authorities have recently begun offering a parallel ESA to address both regulatory and HTA-related queries. 3 ESA can be pursued through one of three approaches: (a) regulatory or HTA advice from a single country, (b) parallel (regulatory and HTA simultaneous) advice, and (c) multi-country advice, such as the National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH) parallel Scientific Advice (SA), US Food and Drug Administration (FDA), European Medicines Agency (EMA) parallel SA, among others. 3 – 5 The primary objective of ESA is to align clinical development plans with HTA expectations, thereby increasing the likelihood of positive evaluations and reimbursement decisions. ESA involves proactive engagement with regulators and payers, enabling manufacturers to develop an evidence package that satisfies the requirements of key stakeholders. This process allows manufacturers to seek guidance on the suitability of their clinical trial design, evidence-generation strategies, and Real-World Evidence (RWE) activities to support both marketing authorization and reimbursement. While regulatory and market access perspectives often differ, particularly regarding population coverage, comparators, and real-world outcomes. HTA agencies and payers across markets also employ varying evaluation criteria and methodologies to assess clinical and economic value based on their specific healthcare system needs. ESA may help reconcile these gaps and provide uniform guidance to achieve alignment on these aspects prior to the drug registration process. 1 , 6 , 7 ESA facilitates insights from authorities and helps identify efficient pathways into the healthcare system through appropriate channels. 8 , 9 ESA is particularly valuable for manufacturers developing innovative interventions when relevant details are unavailable or insufficient in existing guidelines, guidance documents, pharmacopoeia monographs, or draft documents. ESA is also beneficial when addressing emerging pathogens with unmet medical needs and no available guidance, or when manufacturers deviate from established guidelines or have limited knowledge of applicable regulations and requirements. 1 While ESA can help identify appropriate regulatory and HTA processes, it does not guarantee positive outcomes from the advising agency. 4 However, ESA offers significant potential benefits for all stakeholders in the drug approval and reimbursement process. 7 As drug development increasingly focuses on innovation, biotechnology, and orphan diseases, identifying suitable data for regulators and payers to make effective approval and reimbursement decisions has become more challenging. A pre-defined evidence generation plan can support the timely approval and reimbursement of innovative drugs and technologies. 10 ESA interactions align development and evidence-generation plans with the specific context of the country where the advice is sought. 11 , 12 Finally, as the end users of medicines, patients involved in the scientific advice get an early opportunity to present perspectives different from those of the medical and scientific experts and raise issues that had not previously been considered, boosting the utility of the intervention in real-world settings later. 13 A study of applications with negative reimbursement decisions from the United Kingdom’s (UK) NICE revealed that 49% of these applications, where ESA was not sought, could have potentially benefited from ESA, possibly leading to different reimbursement outcomes. 9 The healthcare system in Saudi Arabia is advanced, with universal healthcare funded by the government. 14 In 2016, Saudi Arabia announced Vision 2030, aiming to make public spending more efficient, use resources more effectively, and limit waste. 15 The population in Saudi Arabia is gradually increasing and aging, with Vision 2030 aiming to raise the average life expectancy to 80 years. At the same time, the country faces an increasing prevalence of non-communicable diseases, along with a heightened risk of communicable diseases. The Health Sector Transformation Program, launched in 2021 as part of Vision 2030, aims to restructure the healthcare system into a comprehensive, effective, and integrated model. This program focuses on transforming the healthcare sector into a value-based system, ensuring transparency and financial sustainability by prioritizing public health and disease prevention. Its specific goals include improving access to and the quality of healthcare services through optimal coverage and ensuring a comprehensive, equitable geographical distribution. This system focuses on the health of individuals and society, encompassing citizens, residents, and visitors. 16 , 17 To achieve this mission, the HTA process was introduced in Saudi Arabia to allocate healthcare resources more efficiently and provide evidence-based recommendations for decisions regarding the approval and reimbursement of interventions. 18 Given the purpose of ESA to enable the development of focused evidence for these decisions, it is important to establish a framework for the ESA process in Saudi Arabia. To achieve this goal, we invited a group of experts and key stakeholders from various ministries in Saudi Arabia to discuss and propose a framework for introducing ESA. This article discusses current global trends in ESA practice and proposes a framework for establishing the ESA process in Saudi Arabia. 1.1 Early Scientific Advice In 2009, the UK's NICE was the first agency to introduce an HTA-only single-country SA procedure. 7 Advice from a single HTA agency is usually sought to understand the national requirements to support jurisdictional access. Parallel regulatory plus HTA advice helps identify any discrepancies and/or gaps between regulatory and HTA requirements and the company’s development plan, helping to achieve alignment between the two. Simultaneous advice meetings with multiple HTA agencies provide a streamlined approach and may also present an opportunity to reconcile divergences between different agencies and confirm a single approach that may help satisfy the requirements of both agencies. The multi-country ESA process can also help optimize the allocation of development resources. 3 – 5 In 2010, EMA and several European HTA agencies launched a pilot program to provide parallel advice. This program was further refined through the European Network for Health Technology Assessment (EUnetHTA) and was formalized as EMA-EUnetHTA parallel consultation in 2017. 3 , 5 , 7 , 19 1.2. Global ESA practices The ESA framework is built upon several key pillars, including the scope of services, the ESA process, the type of evidence, the nature of the technology, product eligibility, the involvement of experts and patients, and concerns related to confidentiality and conflict of interest. Further, the pillars for adopting ESA include stakeholder collaboration, clear regulatory pathways, robust data strategies, and adaptive planning. Enablers for successful adoption of ESA include transparency, flexibility, and iterative feedback loops to optimize drug development and align health technology assessment. A typical ESA process encompasses the following stages: defining objectives, preparing data, presenting to regulators, discussing findings, receiving feedback, and subsequently refining strategies based on the feedback. 1.3. Process of ESA Initially, an application for an ESA is submitted to the relevant authority. Once the application is accepted and timelines are established, a briefing book is submitted to the authority. The manufacturer prepares a document that outlines the disease background, current treatment options, product details, and the proposed study design. Additionally, this document defines the specific questions the manufacturer seeks to address and the scope of engagement. The materials for the briefing book are often required to be submitted in the local language. After the briefing book is submitted, clarifications from the authority are addressed, and the briefing book is finalized. Following the finalization, a scientific advice meeting is conducted. The meeting may last between one and three hours and is attended by internal and external experts, ESA officials, and company representatives. After the meeting, the ESA authority shares a detailed written summary of the advice. 1 , 2 , 7 , 20 The entire process from application to finalization of ESA takes approximately 18 weeks; however, it may take as long as 6 to 8 months. 12 ESA can be incorporated into the planning process of the pivotal trial design. Although if pursued too early, there may be internal disagreements on major trial design aspects. Typically, the window of opportunity to seek ESA occurs after the conclusion of phase 2 trials, but before the initiation of phase 3 trials. This timing ensures sufficient data is available to address key uncertainties while allowing for necessary adjustments to the clinical development plan ahead of pivotal trials. ESA sought at the phase 2 trial stage allows for refinement of the clinical development plan. In contrast, ESA sought to align the clinical development plan with the market access requirements at the phase 3/pivotal trial stage. Finally, ESA sought that the post-marketing authorisation phase may help refine the RWE plan. 1 , 6 , 7 Although some agencies offer abbreviated processes, the typical ESA process lasts 6 to 8 months. 2 (Refer to Fig. 1 for Global ESA Process Overview) 2. Methods 2.1. Literature search We conducted a literature review to identify the processes, workflows, timings, challenges, and lessons learned from established ESA systems. The search was performed using the websites of regulatory authorities that provide ESA services, the PubMed database to access associated literature, and Google for supplementary information on challenges, gaps, and the applicability of the ESA process. The search was not restricted by time or population, and information published in English was accessed and included. 2.2. Roundtable meeting An in-person roundtable discussion meeting was conducted on October 17, 2024, in Riyadh, Saudi Arabia. Senior government officials (who routinely contribute to shaping health policy in Saudi Arabia) from the Saudi Arabian Ministry of Health, the Local Content and Government Procurement Authority, the National Guard Health Affairs, the Council of Health Insurance, the National Unified Procurement Company, and clinical experts were invited to a roundtable discussion to discuss the global ESA system benchmark and to agree on an initial framework for ESA in Saudi Arabia. 3. Results and Discussion 3.1. Roadmap for Saudi Arabia The discussion in the roundtable meeting revolved around four major pillars: products for consideration, timing of ESA, governance of ESA, and the role and extent of patient involvement in ESA. (Refer to Fig. 2 for Key Components of Saudi Arabia ESA Framework) 3.2. Products for Consideration Under ESA While most agencies provide ESA for pharmaceutical products, NICE, the French Haute Autorité de Santé (HAS), and EUnetHTA-EMA offer scientific advice on both pharmaceutical products and MedTech devices. NICE also offers ESA for non-device technologies such as digital health interventions. Additionally, NICE provides advice for products related to topics from the Priority Lists. The Welsh HTA agency focuses on non-medical technologies such as medical devices, diagnostics, or procedures for providing ESA. 6 , 7 , 12 , 21 For the proposed Saudi Arabia’s ESA system, the initial suggestion was to include only pharmaceutical products. However, eventually, both pharmaceutical agents and medical devices (including diagnostics) were agreed to be included. 3.3. Timing of ESA NICE suggests that the best time to seek advice varies with the manufacturer and the intervention under development. Most manufacturers avail themselves of the ESA service before phase 3 or pivotal clinical trials; however, the service is available at any point during the development cycle. NICE also directs companies with technologies in the late stages of development to aim to finalize the scientific advice project no later than 38 weeks before the expected NICE Technology Appraisal committee meeting, so that the timing can be aligned with the opinion of other regulatory authorities, such as the Committee of Human Medicinal Products of EMA. 7 CADTH, on the other hand, offers ESA from pre-pivotal trials before the finalization of the protocol and extends to those products that have received a “do not reimburse” recommendation due to shortcomings in clinical or real-world data surrounding the intervention. 6 EMA offers ESA during the initial development of a pharmaceutical product before the submission of a marketing authorization application. EMA also provides SA during the post-authorization phase. 1 Although the current clinical trials framework in Saudi Arabia may not be optimal for certain products at Phases 2 and 3, conducting ESA in therapeutic areas such as Sickle Cell Disease (SCD) and Rare Diseases (RD) is justified given their relevance to the local population. Some stakeholders emphasized the benefits of prioritizing post-authorization processes given the stability provided by the Saudi Food and Drug Authority (SFDA). However, with the establishment of the breakthrough committee for innovative medications, the ESA's role in shaping the committee's agenda before treatment registration was deemed significant. The panel recommended the following timelines for ESA in Saudi Arabia: Saudi ESA can be positioned before drug registration during the late stages of clinical development. The Saudi ESA can be offered for phase 2 and phase 3 trials of drugs for specific specialty diseases with relevance to the local population, such as rare diseases. For medical devices, the proposed timing for ESA is post-marketing authorization. The typical duration of the ESA procedure is approximately 4 months. The timeline for the EMA ESA process is 100 days from initial submission, whereas for CADTH it is 18 to 20 weeks. For NICE, the process lasts between 12 and 18 weeks. The actual ESA meeting typically lasts 3 hours. 1 , 6 , 7 In the Saudi Arabian framework, the proposed timeline/duration is not yet defined. Timing is crucial to ensuring a successful advisory process, as the ESA process itself is lengthy. Identifying the optimal timing for the ESA process can help manufacturers ensure sufficient alignment in the clinical development plan, while still allowing enough time to act on the advice before the product launch in cases of divergence between the proposed plan and the ESA. Furthermore, every HTA agency has eligibility criteria, mostly dependent on the stage of development, and specific data is expected to be presented at that stage. Incorrect timing for seeking ESA, such as too early, can result in suboptimal outcomes from the ESA process, which is typically lengthy. 2 Further deliberation on the timeline/duration of the process in the Saudi Arabian framework is required. 3.4. Governance for ESA In the Saudi Arabian ESA framework, the discussion regarding the authority for ESA highlighted that, although the ESA will be non-binding and not mandatory for registration or formulary inclusion, it is primarily expected to be adopted by the HTA body. Suggestions for oversight included establishing an independent body under the Ministry of Health (MoH), with other proposals for the Saudi Health Holding Company or the Saudi Health Council to take responsibility for the ESA committee. Concerns were raised about potential conflicts of interest if the MoH conducted assessments, which could compromise confidentiality. Involving experts from various sectors can enhance the effectiveness of the ESA process and decision-making. Nonetheless, the government has proposed a decree establishing the HTA body under the Ministry of Health (MoH). The final consensus was that the ESA should fall under the HTA body. 3.5. Patient Involvement Patient involvement is a key aspect of ESA, as patients' contributions have been shown to have a tangible impact on the recommendations provided to manufacturers. Involving patients at early stages of development may lead to further discussions on relevant patient perspectives, thereby improving outcomes. Agencies such as NICE and HAS include patients as and when required, while EMA also has mechanisms in place to invite patients for ESA. Patient input is sought by identifying eligible patients or patient groups, carers, or consumers. Input is collected through tools such as surveys and questionnaires, in accordance with confidentiality procedures. 12,13 In Saudi Arabia’s framework, experts proposed collecting input through a questionnaire targeting eligible patients. To achieve this, it is essential to establish eligibility criteria for participating patients and the questionnaire components. For instance, the questionnaire may include questions on out-of-pocket expenses, cost implications, and adverse events. The questionnaire should focus on short, closed-ended questions to facilitate clear responses. However, further deliberation is required to finalize the methodology for seeking patient input. 3.6. Further Deliberation for Saudi ESA Framework A. Difference between ESA and Advisory Board Meetings The ESA process differs from the advisory board (Ad-board) meetings often held around the launch of a pharmaceutical product. Ad boards are company-sponsored meetings where key opinion leaders (KOLs) provide insights on a product's clinical value for future marketing and sales purposes, and for treatment positioning within the guidelines, with a focus on commercial strategy. The participating experts must be specialists in the field and provide full disclosure of their involvement in these activities. 22 In contrast, ESA is an independent process led by HTA bodies and/or regulators, offering scientific advice either requested by companies or initiated by HTA following horizon scanning. ESA is patient-focused, adheres to regulatory standards, does not compensate advisors, and operates on a fee-for-service basis. B. Horizon Scanning Organizations worldwide face the challenge of keeping pace with the rapid emergence of high-impact innovations. To address this, a systematic, comprehensive, and sustainable approach is being employed to identify future innovations and trends. This enables policymakers and stakeholders to respond effectively, facilitating the smooth market entry of innovations while minimizing developmental, procurement, legal, regulatory, and process barriers. Horizon scanning has emerged as a valuable and practical strategy to accelerate the realization of this goal. 23 Horizon scanning involves systematically reviewing information sources to identify early indicators of significant developments. This approach primarily focuses on the early lifecycle stages of a technology, during the initial adoption phase, before it enters the market. Still, it can also encompass broader trends, challenges, and opportunities. The service provides a comprehensive summary of the available evidence on technologies that are not yet widely adopted. These include technologies that are not yet licensed, approved, or marketed for use, as well as those that are not yet widely available or integrated into routine clinical practice. 23 The horizon scanning service is designed to assist decision-makers in planning and prioritization by enhancing their awareness of new and emerging health technologies. The service typically follows a structured signal-detection process, drawing on diverse sources such as scientific literature, clinical trials, patents, and industry pipelines. Detected signals are then filtered and prioritized using predefined criteria, and their relevance to healthcare objectives is assessed. Based on insights from horizon scanning, agencies can engage manufacturers to deliver well-informed, timely early scientific advice. This approach helps streamline the development of emerging technologies while strategically addressing regulatory and medical requirements at an early stage. 23,24 C. Fees for ESA Service The fees for these services vary widely. While certain countries, such as France and Norway, do not charge ESA fees, agency fees may vary widely (Spain: €4,400; the UK: £91,000). 6,7,12 The specific details of the exact fees to be charged to the manufacturers were not discussed. The notion that ESA fees contribute to economic participation by facilitating local clinical trial requests and promoting local research and development was dismissed as a fundamental misunderstanding of the ESA’s purpose and process. The ESA is requested for inclusion in the formulary. The ESA aims to provide companies with guidance on what is needed to succeed in HTA appraisals. Moreover, while local clinical trials might drive economic contribution, ESA remains strictly a fee-for-service model, similar to the fees paid to the SFDA for product registration. Nonetheless, ESA fees could be considered an innovative source of funding for capacity-building efforts within the regulatory system. D. Utilizing ESA for Technical Quality Assessment The potential use of ESA to guide technical quality assessments for products before filing or registration, particularly for Market Authorization Holders (MAH) located outside the territory or for biosimilars, was also explored. This approach could involve conducting trials to validate product quality before submitting to the Saudi Food and Drug Authority (SFDA) and ensuring the accuracy of documentation before forming local partnerships. While ESA typically does not provide technical or regulatory advice, the need for technical evaluations within the Saudi ESA may warrant assessment. E. Inquiry Regarding Patient Experience The panel discussion sought to define patient experience, drawing on insights from both clinical trials and RWE. Patients contribute their perspectives through tools such as Patient-Reported Outcomes (PROs), which are essential for evaluating treatment effectiveness, particularly in terms of Quality of Life (QOL). QOL can be assessed during clinical trials through PRO questionnaires or measured post-marketing using RWE data. 4. Conclusion ESA provides significant benefits to all stakeholders involved in the approval and reimbursement processes for pharmaceutical interventions, diagnostics, or medical devices. For an advanced healthcare system such as Saudi Arabia's, it is important to provide ESA services to manufacturers to achieve optimal outcomes and improve access to these interventions. The discussion at the roundtable meeting revolved around four important pillars: products under consideration, timing of ESA, governance of ESA, and patient involvement. The panel proposed offering ESA for pharmaceuticals and medical devices (including diagnostics). Further, the panel suggested that ESA be considered before drug registration during the late stages of clinical development, and for phase 2 and phase 3 trials of drugs for specific specialty diseases relevant to the local population, such as rare diseases. For medical devices, the panel recommended the ESA process to be conducted post-marketing authorisation. The panel recommended that the HTA body in Saudi Arabia should be the governing body for ESA. Finally, the panel recommended seeking patient input through questionnaires administered to eligible patients and patient groups. Beyond these pillars, further deliberation on the operational timelines for the ESA process and the service fee is required. Declarations Contributors Ahmed Al Jedai contributed to study conception and design, overall scientific leadership, critical intellectual oversight, interpretation of findings, critical revision of the manuscript, and final approval of the version to be published. Hajer AlMudaiheem, Hind Hajj, and Nancy Sayed Awad led the drafting of the original manuscript, contributed to data interpretation, and participated in manuscript review, revision, and final approval. Mohamed Khedr contributed to study conceptualization, framing of the research objectives, interpretation of findings, critical review of the manuscript for intellectual content, and final approval. Nancy Sayed Awad and Hind Hajj additionally contributed to the study methodology, coordination and conduct of the work, and synthesis of evidence supporting the proposed framework. Naif AlOtaibi, Lamia Al Zubaidi, Mohamed Al Shennawi, Wejdan Aburas, Hana Alabdulkarim, Afaf Al Shamri, Bandar Al Harbi, Ashraf Al Grain, Ibtissam Al Harbi, and Nawaf Al Bali contributed equally to the study through input into study design and scope, interpretation of results within their respective institutional and policy contexts, critical review and revision of the manuscript, and final approval of the submitted version. All authors made substantial contributions to the conception and/or design of the work, or the acquisition, analysis, or interpretation of data; drafting the work or revising it critically for important intellectual content; approving the final version to be published; and agreeing to be accountable for all aspects of the work. Data sharing statement Not applicable Ethics Declaration Not applicable Consent for publication: All authors consent to the publication. Funding: Not applicable Author Contribution A.A. contributed to study conception and design, overall scientific leadership, critical intellectual oversight, interpretation of findings, critical revision of the manuscript, and final approval of the version to be published. H.A., H.H., and N.S.A. led the drafting of the original manuscript, contributed to data interpretation, and participated in manuscript review, revision, and final approval. M.K. contributed to study conceptualization, framing of the research objectives, interpretation of findings, critical review of the manuscript for intellectual content, and final approval. N.S.A. and H.H. additionally contributed to the study methodology, coordination and conduct of the work, and synthesis of evidence supporting the proposed framework. N.A., L.A., M.A., W.A., H.A., A.A., B.A., A.A., I.A., and N.A. contributed equally to the study through input into study design and scope, interpretation of results within their respective institutional and policy contexts, critical review and revision of the manuscript, and final approval of the submitted version.All authors made substantial contributions to the conception and/or design of the work, or the acquisition, analysis, or interpretation of data; drafting the work or revising it critically for important intellectual content; approving the final version to be published; and agreeing to be accountable for all aspects of the work. Acknowledgement: None Availability of data and materials: All materials are available by contacting the corresponding author. References Scientific advice and protocol assistance. European Medicines Agency website. https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-advice-protocol-assistance . Updated 2023. 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Accessed November 11, 2024. Advisory boards: words of advice and a 10-point checklist. the Map. March 10. 2020. https://www.ismpp-newsletter.com/2020/03/10/advisory-boards-words-of-advice-and-a-10-point-checklist/ . Accessed November 13, 2024. O’Neill J, Tabish H, Welch V, et al. Applying an equity lens to interventions: using PROGRESS ensures consideration of socially stratifying factors to illuminate inequities in health. J Clin Epidemiol. 2014;67(1):56–64. 10.1016/j.jclinepi.2013.08.005 . Horizon scan. CDA-AMC website. https://www.cda-amc.ca/horizon-scan . Accessed November 22, 2024. Additional Declarations No competing interests reported. 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Jedai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIie2RsWrDMBCGzwjU5VqvLg3NK5wRGEpp8yxCL5ApS8GVMChLwGuGPoyNoVlCshq6RHuGTCVDClXSKYuasVB9kyT+j/8OAUQifxKmCThg6g87IIAb/5aFleRHudWJmR8VfolyilFzVOACJZ22erybPA/EojV6Py6HHFj7gQElW0qdz1cKi6U0ZkZdboGrx5ACjdTi2jIsGjndoB/PAhZ3IWW4dlp82VcUtTPmQOXIQvoZVKj3LYntkDJpKiQmfQsPKnnvdD5bLTDrnakG1CnLuHh4Cyj3a/VO+8nLKK1Va7aH8qm+qly/Da3vP4LO7ywcP0U2v2cikUjkX/MNIHxM4kObEHcAAAAASUVORK5CYII=","orcid":"","institution":"King Faisal University","correspondingAuthor":true,"prefix":"","firstName":"Ahmed","middleName":"Al","lastName":"Jedai","suffix":""},{"id":595068666,"identity":"6ef73a98-42cf-4bed-af2c-56b279cdeac2","order_by":1,"name":"Hajer AlMudaiheem","email":"","orcid":"","institution":"Saudi Society of Clinical Pharmacy","correspondingAuthor":false,"prefix":"","firstName":"Hajer","middleName":"","lastName":"AlMudaiheem","suffix":""},{"id":595068667,"identity":"9d7e2ea4-c7a9-47c5-81d7-27d550aaf472","order_by":2,"name":"Naif AlOtaibi","email":"","orcid":"","institution":"University of Paris-Sud","correspondingAuthor":false,"prefix":"","firstName":"Naif","middleName":"","lastName":"AlOtaibi","suffix":""},{"id":595068668,"identity":"4dd1fb13-d62b-4d97-b0fb-bf156c5cee43","order_by":3,"name":"Lamia Al Zubaidi","email":"","orcid":"","institution":"Adaa Health Center, MOH – Diabetes Clinical Leader · Riyadh","correspondingAuthor":false,"prefix":"","firstName":"Lamia","middleName":"Al","lastName":"Zubaidi","suffix":""},{"id":595068669,"identity":"2720bedc-c401-41e8-950f-af93bbf006fd","order_by":4,"name":"Mohamed Al Shennawi","email":"","orcid":"","institution":"Ministry of Health","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"Al","lastName":"Shennawi","suffix":""},{"id":595068671,"identity":"eb9f59e5-f1d5-4321-9f07-6787fc2f75ef","order_by":5,"name":"Nawaf Al Bali","email":"","orcid":"","institution":"King Faisal University","correspondingAuthor":false,"prefix":"","firstName":"Nawaf","middleName":"Al","lastName":"Bali","suffix":""},{"id":595068673,"identity":"e1d70133-832a-4f29-9088-e0c986fe24cf","order_by":6,"name":"Wejdan Aburas","email":"","orcid":"","institution":"Ministry of Health","correspondingAuthor":false,"prefix":"","firstName":"Wejdan","middleName":"","lastName":"Aburas","suffix":""},{"id":595068676,"identity":"152e2438-be42-4912-9034-052d54bcbcdc","order_by":7,"name":"Hana Alabdulkarim","email":"","orcid":"","institution":"National Guard Health Affairs","correspondingAuthor":false,"prefix":"","firstName":"Hana","middleName":"","lastName":"Alabdulkarim","suffix":""},{"id":595068678,"identity":"8ea8edb0-f79d-4c6a-a2eb-71cd9b55d697","order_by":8,"name":"Afaf Al Shamri","email":"","orcid":"","institution":"King Abdulaziz Medical City, Ministry of National Guard-Health Affairs","correspondingAuthor":false,"prefix":"","firstName":"Afaf","middleName":"Al","lastName":"Shamri","suffix":""},{"id":595068682,"identity":"5bfbce23-acfe-441b-be0f-94b895fd54d7","order_by":9,"name":"Bandar Al Harbi","email":"","orcid":"","institution":"Prince Sultan Military Medical City","correspondingAuthor":false,"prefix":"","firstName":"Bandar","middleName":"Al","lastName":"Harbi","suffix":""},{"id":595068683,"identity":"8ad032b3-be8b-49f6-8644-0d658c7b1032","order_by":10,"name":"Ashraf Al Grain","email":"","orcid":"","institution":"Local Content and Government Procurement Authority","correspondingAuthor":false,"prefix":"","firstName":"Ashraf","middleName":"Al","lastName":"Grain","suffix":""},{"id":595068684,"identity":"02797f49-23ee-45e3-8b06-368418caca1b","order_by":11,"name":"Ibtissam Al Harbi","email":"","orcid":"","institution":"King Fahd Armed Forces Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ibtissam","middleName":"Al","lastName":"Harbi","suffix":""},{"id":595068685,"identity":"1e15cc65-3afb-42a8-9860-537511e3e65d","order_by":12,"name":"Mohamed Khedr","email":"","orcid":"","institution":"Medical Affairs, GSK","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"","lastName":"Khedr","suffix":""},{"id":595068686,"identity":"dc82d574-fdae-4cbc-bc81-5584d4383535","order_by":13,"name":"Hind Hajj","email":"","orcid":"","institution":"Masdar Al Hekmah, Saudi Arabia","correspondingAuthor":false,"prefix":"","firstName":"Hind","middleName":"","lastName":"Hajj","suffix":""},{"id":595068687,"identity":"b78f776e-6161-445a-8279-759d2ecaf3e9","order_by":14,"name":"Nancy Sayed Awad","email":"","orcid":"","institution":"Masdar Al Hekmah, Saudi Arabia","correspondingAuthor":false,"prefix":"","firstName":"Nancy","middleName":"Sayed","lastName":"Awad","suffix":""}],"badges":[],"createdAt":"2026-02-18 09:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8907697/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8907697/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103505928,"identity":"96b8958e-484d-480d-905a-73179f0e1a28","added_by":"auto","created_at":"2026-02-26 13:33:33","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":53141,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEarly Scientific Advice Process Overview\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"groupimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8907697/v1/5fc4fec737c547121af58bc0.jpeg"},{"id":103346523,"identity":"92097d69-849a-458f-acbe-ccf2ef4fb8eb","added_by":"auto","created_at":"2026-02-24 16:22:39","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":410345,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKey Components of the Saudi Arabia ESA Framework\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8907697/v1/dabca0f9af8d96f3b6b5ceb0.jpeg"},{"id":103509691,"identity":"ff37ebf1-77f0-4fe6-9359-91bb11419a38","added_by":"auto","created_at":"2026-02-26 14:00:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1206466,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8907697/v1/45b2678c-4c17-4841-8fb5-6fac2e15b89a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Early Scientific Advice for Health Technology Assessment: Progressing Towards a Framework in Saudi Arabia","fulltext":[{"header":"1. Background","content":"\u003cp\u003eThe approval and reimbursement of medical interventions depend on the availability of robust and comprehensive evidence that meets the expectations of regulatory bodies and Health Technology Assessment (HTA) agencies. Seeking scientific advice at an early point in the drug development process helps developers focus on generating relevant evidence through appropriate clinical program development and other studies, thereby reducing the risk of substantial objections during the evaluation of the marketing authorization application and for a future formulary review.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eEarly Scientific Advice (ESA) is a structured and formal process enabling manufacturers to obtain confidential, nonbinding feedback from HTA or regulatory bodies during the early stages of product or device development.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e While ESA was initially associated primarily with regulatory bodies, authorities have recently begun offering a parallel ESA to address both regulatory and HTA-related queries.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e ESA can be pursued through one of three approaches: (a) regulatory or HTA advice from a single country, (b) parallel (regulatory and HTA simultaneous) advice, and (c) multi-country advice, such as the National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH) parallel Scientific Advice (SA), US Food and Drug Administration (FDA), European Medicines Agency (EMA) parallel SA, among others.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe primary objective of ESA is to align clinical development plans with HTA expectations, thereby increasing the likelihood of positive evaluations and reimbursement decisions. ESA involves proactive engagement with regulators and payers, enabling manufacturers to develop an evidence package that satisfies the requirements of key stakeholders. This process allows manufacturers to seek guidance on the suitability of their clinical trial design, evidence-generation strategies, and Real-World Evidence (RWE) activities to support both marketing authorization and reimbursement. While regulatory and market access perspectives often differ, particularly regarding population coverage, comparators, and real-world outcomes. HTA agencies and payers across markets also employ varying evaluation criteria and methodologies to assess clinical and economic value based on their specific healthcare system needs. ESA may help reconcile these gaps and provide uniform guidance to achieve alignment on these aspects prior to the drug registration process.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e ESA facilitates insights from authorities and helps identify efficient pathways into the healthcare system through appropriate channels.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eESA is particularly valuable for manufacturers developing innovative interventions when relevant details are unavailable or insufficient in existing guidelines, guidance documents, pharmacopoeia monographs, or draft documents. ESA is also beneficial when addressing emerging pathogens with unmet medical needs and no available guidance, or when manufacturers deviate from established guidelines or have limited knowledge of applicable regulations and requirements.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e While ESA can help identify appropriate regulatory and HTA processes, it does not guarantee positive outcomes from the advising agency.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e However, ESA offers significant potential benefits for all stakeholders in the drug approval and reimbursement process.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAs drug development increasingly focuses on innovation, biotechnology, and orphan diseases, identifying suitable data for regulators and payers to make effective approval and reimbursement decisions has become more challenging. A pre-defined evidence generation plan can support the timely approval and reimbursement of innovative drugs and technologies.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e ESA interactions align development and evidence-generation plans with the specific context of the country where the advice is sought.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Finally, as the end users of medicines, patients involved in the scientific advice get an early opportunity to present perspectives different from those of the medical and scientific experts and raise issues that had not previously been considered, boosting the utility of the intervention in real-world settings later.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e A study of applications with negative reimbursement decisions from the United Kingdom\u0026rsquo;s (UK) NICE revealed that 49% of these applications, where ESA was not sought, could have potentially benefited from ESA, possibly leading to different reimbursement outcomes.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe healthcare system in Saudi Arabia is advanced, with universal healthcare funded by the government.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e In 2016, Saudi Arabia announced Vision 2030, aiming to make public spending more efficient, use resources more effectively, and limit waste.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e The population in Saudi Arabia is gradually increasing and aging, with Vision 2030 aiming to raise the average life expectancy to 80 years. At the same time, the country faces an increasing prevalence of non-communicable diseases, along with a heightened risk of communicable diseases. The Health Sector Transformation Program, launched in 2021 as part of Vision 2030, aims to restructure the healthcare system into a comprehensive, effective, and integrated model. This program focuses on transforming the healthcare sector into a value-based system, ensuring transparency and financial sustainability by prioritizing public health and disease prevention. Its specific goals include improving access to and the quality of healthcare services through optimal coverage and ensuring a comprehensive, equitable geographical distribution. This system focuses on the health of individuals and society, encompassing citizens, residents, and visitors.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e To achieve this mission, the HTA process was introduced in Saudi Arabia to allocate healthcare resources more efficiently and provide evidence-based recommendations for decisions regarding the approval and reimbursement of interventions.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Given the purpose of ESA to enable the development of focused evidence for these decisions, it is important to establish a framework for the ESA process in Saudi Arabia.\u003c/p\u003e \u003cp\u003eTo achieve this goal, we invited a group of experts and key stakeholders from various ministries in Saudi Arabia to discuss and propose a framework for introducing ESA. This article discusses current global trends in ESA practice and proposes a framework for establishing the ESA process in Saudi Arabia.\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003e1.1 Early Scientific Advice\u003c/h2\u003e \u003cp\u003eIn 2009, the UK's NICE was the first agency to introduce an HTA-only single-country SA procedure.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Advice from a single HTA agency is usually sought to understand the national requirements to support jurisdictional access. Parallel regulatory plus HTA advice helps identify any discrepancies and/or gaps between regulatory and HTA requirements and the company\u0026rsquo;s development plan, helping to achieve alignment between the two. Simultaneous advice meetings with multiple HTA agencies provide a streamlined approach and may also present an opportunity to reconcile divergences between different agencies and confirm a single approach that may help satisfy the requirements of both agencies. The multi-country ESA process can also help optimize the allocation of development resources.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn 2010, EMA and several European HTA agencies launched a pilot program to provide parallel advice. This program was further refined through the European Network for Health Technology Assessment (EUnetHTA) and was formalized as EMA-EUnetHTA parallel consultation in 2017.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.2. Global ESA practices\u003c/h2\u003e \u003cp\u003eThe ESA framework is built upon several key pillars, including the scope of services, the ESA process, the type of evidence, the nature of the technology, product eligibility, the involvement of experts and patients, and concerns related to confidentiality and conflict of interest. Further, the pillars for adopting ESA include stakeholder collaboration, clear regulatory pathways, robust data strategies, and adaptive planning. Enablers for successful adoption of ESA include transparency, flexibility, and iterative feedback loops to optimize drug development and align health technology assessment. A typical ESA process encompasses the following stages: defining objectives, preparing data, presenting to regulators, discussing findings, receiving feedback, and subsequently refining strategies based on the feedback.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.3. Process of ESA\u003c/h2\u003e \u003cp\u003eInitially, an application for an ESA is submitted to the relevant authority. Once the application is accepted and timelines are established, a briefing book is submitted to the authority. The manufacturer prepares a document that outlines the disease background, current treatment options, product details, and the proposed study design. Additionally, this document defines the specific questions the manufacturer seeks to address and the scope of engagement.\u003c/p\u003e \u003cp\u003eThe materials for the briefing book are often required to be submitted in the local language. After the briefing book is submitted, clarifications from the authority are addressed, and the briefing book is finalized. Following the finalization, a scientific advice meeting is conducted. The meeting may last between one and three hours and is attended by internal and external experts, ESA officials, and company representatives. After the meeting, the ESA authority shares a detailed written summary of the advice.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e The entire process from application to finalization of ESA takes approximately 18 weeks; however, it may take as long as 6 to 8 months.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eESA can be incorporated into the planning process of the pivotal trial design. Although if pursued too early, there may be internal disagreements on major trial design aspects. Typically, the window of opportunity to seek ESA occurs after the conclusion of phase 2 trials, but before the initiation of phase 3 trials. This timing ensures sufficient data is available to address key uncertainties while allowing for necessary adjustments to the clinical development plan ahead of pivotal trials. ESA sought at the phase 2 trial stage allows for refinement of the clinical development plan. In contrast, ESA sought to align the clinical development plan with the market access requirements at the phase 3/pivotal trial stage. Finally, ESA sought that the post-marketing authorisation phase may help refine the RWE plan.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough some agencies offer abbreviated processes, the typical ESA process lasts 6 to 8 months.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e (Refer to Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for Global ESA Process Overview)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Literature search\u003c/h2\u003e \u003cp\u003eWe conducted a literature review to identify the processes, workflows, timings, challenges, and lessons learned from established ESA systems. The search was performed using the websites of regulatory authorities that provide ESA services, the PubMed database to access associated literature, and Google for supplementary information on challenges, gaps, and the applicability of the ESA process. The search was not restricted by time or population, and information published in English was accessed and included.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Roundtable meeting\u003c/h2\u003e \u003cp\u003eAn in-person roundtable discussion meeting was conducted on October 17, 2024, in Riyadh, Saudi Arabia. Senior government officials (who routinely contribute to shaping health policy in Saudi Arabia) from the Saudi Arabian Ministry of Health, the Local Content and Government Procurement Authority, the National Guard Health Affairs, the Council of Health Insurance, the National Unified Procurement Company, and clinical experts were invited to a roundtable discussion to discuss the global ESA system benchmark and to agree on an initial framework for ESA in Saudi Arabia.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results and Discussion","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Roadmap for Saudi Arabia\u003c/h2\u003e \u003cp\u003eThe discussion in the roundtable meeting revolved around four major pillars: products for consideration, timing of ESA, governance of ESA, and the role and extent of patient involvement in ESA. (Refer to Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e for Key Components of Saudi Arabia ESA Framework)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Products for Consideration Under ESA\u003c/h2\u003e \u003cp\u003eWhile most agencies provide ESA for pharmaceutical products, NICE, the French Haute Autorit\u0026eacute; de Sant\u0026eacute; (HAS), and EUnetHTA-EMA offer scientific advice on both pharmaceutical products and MedTech devices. NICE also offers ESA for non-device technologies such as digital health interventions. Additionally, NICE provides advice for products related to topics from the Priority Lists. The Welsh HTA agency focuses on non-medical technologies such as medical devices, diagnostics, or procedures for providing ESA.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFor the proposed Saudi Arabia\u0026rsquo;s ESA system, the initial suggestion was to include only pharmaceutical products. However, eventually, both pharmaceutical agents and medical devices (including diagnostics) were agreed to be included.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Timing of ESA\u003c/h2\u003e \u003cp\u003eNICE suggests that the best time to seek advice varies with the manufacturer and the intervention under development. Most manufacturers avail themselves of the ESA service before phase 3 or pivotal clinical trials; however, the service is available at any point during the development cycle. NICE also directs companies with technologies in the late stages of development to aim to finalize the scientific advice project no later than 38 weeks before the expected NICE Technology Appraisal committee meeting, so that the timing can be aligned with the opinion of other regulatory authorities, such as the Committee of Human Medicinal Products of EMA.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCADTH, on the other hand, offers ESA from pre-pivotal trials before the finalization of the protocol and extends to those products that have received a \u0026ldquo;do not reimburse\u0026rdquo; recommendation due to shortcomings in clinical or real-world data surrounding the intervention.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eEMA offers ESA during the initial development of a pharmaceutical product before the submission of a marketing authorization application. EMA also provides SA during the post-authorization phase.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough the current clinical trials framework in Saudi Arabia may not be optimal for certain products at Phases 2 and 3, conducting ESA in therapeutic areas such as Sickle Cell Disease (SCD) and Rare Diseases (RD) is justified given their relevance to the local population.\u003c/p\u003e \u003cp\u003eSome stakeholders emphasized the benefits of prioritizing post-authorization processes given the stability provided by the Saudi Food and Drug Authority (SFDA).\u003c/p\u003e \u003cp\u003eHowever, with the establishment of the breakthrough committee for innovative medications, the ESA's role in shaping the committee's agenda before treatment registration was deemed significant.\u003c/p\u003e \u003cp\u003eThe panel recommended the following timelines for ESA in Saudi Arabia:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eSaudi ESA can be positioned before drug registration during the late stages of clinical development.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe Saudi ESA can be offered for phase 2 and phase 3 trials of drugs for specific specialty diseases with relevance to the local population, such as rare diseases.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFor medical devices, the proposed timing for ESA is post-marketing authorization.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe typical duration of the ESA procedure is approximately 4 months. The timeline for the EMA ESA process is 100 days from initial submission, whereas for CADTH it is 18 to 20 weeks. For NICE, the process lasts between 12 and 18 weeks. The actual ESA meeting typically lasts 3 hours.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e In the Saudi Arabian framework, the proposed timeline/duration is not yet defined. Timing is crucial to ensuring a successful advisory process, as the ESA process itself is lengthy. Identifying the optimal timing for the ESA process can help manufacturers ensure sufficient alignment in the clinical development plan, while still allowing enough time to act on the advice before the product launch in cases of divergence between the proposed plan and the ESA. Furthermore, every HTA agency has eligibility criteria, mostly dependent on the stage of development, and specific data is expected to be presented at that stage. Incorrect timing for seeking ESA, such as too early, can result in suboptimal outcomes from the ESA process, which is typically lengthy.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eFurther deliberation on the timeline/duration of the process in the Saudi Arabian framework is required.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Governance for ESA\u003c/h2\u003e \u003cp\u003eIn the Saudi Arabian ESA framework, the discussion regarding the authority for ESA highlighted that, although the ESA will be non-binding and not mandatory for registration or formulary inclusion, it is primarily expected to be adopted by the HTA body.\u003c/p\u003e \u003cp\u003eSuggestions for oversight included establishing an independent body under the Ministry of Health (MoH), with other proposals for the Saudi Health Holding Company or the Saudi Health Council to take responsibility for the ESA committee. Concerns were raised about potential conflicts of interest if the MoH conducted assessments, which could compromise confidentiality.\u003c/p\u003e \u003cp\u003eInvolving experts from various sectors can enhance the effectiveness of the ESA process and decision-making. Nonetheless, the government has proposed a decree establishing the HTA body under the Ministry of Health (MoH). The final consensus was that the ESA should fall under the HTA body.\u003c/p\u003e \u003c/div\u003e\u003cp\u003e \u003cstrong\u003e3.5. \u0026nbsp;Patient Involvement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient involvement is a key aspect of ESA, as patients\u0026apos; contributions have been shown to have a tangible impact on the recommendations provided to manufacturers. Involving patients at early stages of development may lead to further discussions on relevant patient perspectives, thereby improving outcomes. Agencies such as NICE and HAS include patients as and when required, while EMA also has mechanisms in place to invite patients for ESA. Patient input is sought by identifying eligible patients or patient groups, carers, or consumers. Input is collected through tools such as surveys and questionnaires, in accordance with confidentiality procedures.\u003csup\u003e12,13\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn Saudi Arabia\u0026rsquo;s framework, experts proposed collecting input through a questionnaire targeting eligible patients. To achieve this, it is essential to establish eligibility criteria for participating patients and the questionnaire components. For instance, the questionnaire may include questions on out-of-pocket expenses, cost implications, and adverse events. The questionnaire should focus on short, closed-ended questions to facilitate clear responses. However, further deliberation is required to finalize the methodology for seeking patient input.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6. \u0026nbsp; \u0026nbsp;Further Deliberation for Saudi ESA Framework\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA. Difference between ESA and Advisory Board Meetings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ESA process differs from the advisory board (Ad-board) meetings often held around the launch of a pharmaceutical product. Ad boards are company-sponsored meetings where key opinion leaders (KOLs) provide insights on a product\u0026apos;s clinical value for future marketing\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eand sales purposes, and for treatment positioning within the guidelines, with a focus on commercial strategy. The participating experts must be specialists in the field and provide full disclosure of their involvement in these activities.\u003csup\u003e22\u003c/sup\u003e In contrast, ESA is an independent process led by HTA bodies and/or regulators, offering scientific advice either requested by companies or initiated by HTA following horizon scanning. ESA is patient-focused, adheres to regulatory standards, does not compensate advisors, and operates on a fee-for-service basis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB. Horizon Scanning\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOrganizations worldwide face the challenge of keeping pace with the rapid emergence of high-impact innovations. To address this, a systematic, comprehensive, and sustainable approach is being employed to identify future innovations and trends. This enables policymakers and stakeholders to respond effectively, facilitating the smooth market entry of innovations while minimizing developmental, procurement, legal, regulatory, and process barriers. Horizon scanning has emerged as a valuable and practical strategy to accelerate the realization of this goal.\u003csup\u003e23\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHorizon scanning involves systematically reviewing information sources to identify early indicators of significant developments. This approach primarily focuses on the early lifecycle stages of a technology, during the initial adoption phase, before it enters the market. Still, it can also encompass broader trends, challenges, and opportunities. The service provides a comprehensive summary of the available evidence on technologies that are not yet widely adopted. These include technologies that are not yet licensed, approved, or marketed for use, as well as those that are not yet widely available or integrated into routine clinical practice.\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe horizon scanning service is designed to assist decision-makers in planning and prioritization by enhancing their awareness of new and emerging health technologies. The service typically follows a structured signal-detection process, drawing on diverse sources such as scientific literature, clinical trials, patents, and industry pipelines. Detected signals are then filtered and prioritized using predefined criteria, and their relevance to healthcare objectives is assessed. Based on insights from horizon scanning, agencies can engage manufacturers to deliver well-informed, timely early scientific advice. This approach helps streamline the development of emerging technologies while strategically addressing regulatory and medical requirements at an early stage.\u003csup\u003e23,24\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC. Fees for ESA Service\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe fees for these services vary widely. While certain countries, such as France and Norway, do not charge ESA fees, agency fees may vary widely (Spain: \u0026euro;4,400; the UK: \u0026pound;91,000).\u003csup\u003e6,7,12\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe specific details of the exact fees to be charged to the manufacturers were not discussed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe notion that ESA fees contribute to economic participation by facilitating local clinical trial requests and promoting local research and development was dismissed as a fundamental misunderstanding of the ESA\u0026rsquo;s purpose and process. The ESA is requested for inclusion in the formulary. The ESA aims to provide companies with guidance on what is needed to succeed in HTA appraisals.\u003c/p\u003e\n\u003cp\u003eMoreover, while local clinical trials might drive economic contribution, ESA remains strictly a fee-for-service model, similar to the fees paid to the SFDA for product registration. Nonetheless, ESA fees could be considered an innovative source of funding for capacity-building efforts within the regulatory system.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD. Utilizing ESA for Technical Quality Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe potential use of ESA to guide technical quality assessments for products before filing or registration, particularly for Market Authorization Holders (MAH) located outside the territory or for biosimilars, was also explored. This approach could involve conducting trials to validate product quality before submitting to the Saudi Food and Drug Authority (SFDA) and ensuring the accuracy of documentation before forming local partnerships. While ESA typically does not provide technical or regulatory advice, the need for technical evaluations within the Saudi ESA may warrant assessment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE. Inquiry Regarding Patient Experience\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe panel discussion sought to define patient experience, drawing on insights from both clinical trials and RWE. Patients contribute their perspectives through tools such as Patient-Reported Outcomes (PROs), which are essential for evaluating treatment effectiveness, particularly in terms of Quality of Life (QOL). QOL can be assessed during clinical trials through PRO questionnaires or measured post-marketing using RWE data.\u003c/p\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eESA provides significant benefits to all stakeholders involved in the approval and reimbursement processes for pharmaceutical interventions, diagnostics, or medical devices. For an advanced healthcare system such as Saudi Arabia's, it is important to provide ESA services to manufacturers to achieve optimal outcomes and improve access to these interventions. The discussion at the roundtable meeting revolved around four important pillars: products under consideration, timing of ESA, governance of ESA, and patient involvement. The panel proposed offering ESA for pharmaceuticals and medical devices (including diagnostics). Further, the panel suggested that ESA be considered before drug registration during the late stages of clinical development, and for phase 2 and phase 3 trials of drugs for specific specialty diseases relevant to the local population, such as rare diseases. For medical devices, the panel recommended the ESA process to be conducted post-marketing authorisation. The panel recommended that the HTA body in Saudi Arabia should be the governing body for ESA. Finally, the panel recommended seeking patient input through questionnaires administered to eligible patients and patient groups. Beyond these pillars, further deliberation on the operational timelines for the ESA process and the service fee is required.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eContributors\u003c/strong\u003e \u003cp\u003eAhmed Al Jedai contributed to study conception and design, overall scientific leadership, critical intellectual oversight, interpretation of findings, critical revision of the manuscript, and final approval of the version to be published. Hajer AlMudaiheem, Hind Hajj, and Nancy Sayed Awad led the drafting of the original manuscript, contributed to data interpretation, and participated in manuscript review, revision, and final approval. Mohamed Khedr contributed to study conceptualization, framing of the research objectives, interpretation of findings, critical review of the manuscript for intellectual content, and final approval. Nancy Sayed Awad and Hind Hajj additionally contributed to the study methodology, coordination and conduct of the work, and synthesis of evidence supporting the proposed framework. Naif AlOtaibi, Lamia Al Zubaidi, Mohamed Al Shennawi, Wejdan Aburas, Hana Alabdulkarim, Afaf Al Shamri, Bandar Al Harbi, Ashraf Al Grain, Ibtissam Al Harbi, and Nawaf Al Bali contributed equally to the study through input into study design and scope, interpretation of results within their respective institutional and policy contexts, critical review and revision of the manuscript, and final approval of the submitted version.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eAll authors made substantial contributions to the conception and/or design of the work, or the acquisition, analysis, or interpretation of data; drafting the work or revising it critically for important intellectual content; approving the final version to be published; and agreeing to be accountable for all aspects of the work.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eData sharing statement\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics Declaration\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e \u003ch2\u003eConsent for publication:\u003c/h2\u003e \u003cp\u003eAll authors consent to the publication.\u003c/p\u003e \u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.A. contributed to study conception and design, overall scientific leadership, critical intellectual oversight, interpretation of findings, critical revision of the manuscript, and final approval of the version to be published. H.A., H.H., and N.S.A. led the drafting of the original manuscript, contributed to data interpretation, and participated in manuscript review, revision, and final approval. M.K. contributed to study conceptualization, framing of the research objectives, interpretation of findings, critical review of the manuscript for intellectual content, and final approval. N.S.A. and H.H. additionally contributed to the study methodology, coordination and conduct of the work, and synthesis of evidence supporting the proposed framework. N.A., L.A., M.A., W.A., H.A., A.A., B.A., A.A., I.A., and N.A. contributed equally to the study through input into study design and scope, interpretation of results within their respective institutional and policy contexts, critical review and revision of the manuscript, and final approval of the submitted version.All authors made substantial contributions to the conception and/or design of the work, or the acquisition, analysis, or interpretation of data; drafting the work or revising it critically for important intellectual content; approving the final version to be published; and agreeing to be accountable for all aspects of the work.\u003c/p\u003e\u003ch2\u003eAcknowledgement:\u003c/h2\u003e \u003cp\u003eNone\u003c/p\u003e\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e \u003cp\u003eAll materials are available by contacting the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eScientific advice and protocol assistance. 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Accessed November 22, 2024.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cost-effectiveness-and-resource-allocation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cera","sideBox":"Learn more about [Cost Effectiveness and Resource Allocation](http://resource-allocation.biomedcentral.com)","snPcode":"12962","submissionUrl":"https://submission.nature.com/new-submission/12962/3","title":"Cost Effectiveness and Resource Allocation","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Early Scientific Advice, Health Technology Assessment, Pharmaceuticals, Saudi Arabia","lastPublishedDoi":"10.21203/rs.3.rs-8907697/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8907697/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEarly Scientific Advice (ESA) is an independent, non-binding process that gives patient-centred scientific guidance to manufacturers in the pre-market stage of product development. Unlike advisory boards, ESA provides objective advice from Health Technology Assessment (HTA) bodies or regulatory authorities, aiming to support the development of healthcare technologies in line with regulatory and health policy goals. This study examines global ESA practices and suggests a framework for implementing ESA in Saudi Arabia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA literature review was conducted to examine established ESA systems, focusing on processes, workflows, timings, challenges, and lessons learned. Additionally, a roundtable discussion with experts from regulatory bodies, healthcare providers, and industry was held to identify the key pillars of the Saudi ESA framework. Several related topics were covered, including governance, patient involvement, types of products, review timing, the distinction between ESA and advisory boards, horizon scanning, and the use of ESA for technical quality assessments.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe roundtable discussion revealed that the ESA framework in Saudi Arabia should focus on pharmaceuticals as well as medical devices. The panel proposed considering ESA before drug registration in late-stage clinical development and for phase 2 and 3 trials of drugs for diseases with local relevance (e.g., rare diseases). For medical devices, the ESA process should occur post-marketing authorization. It was agreed that the ESA process should be governed by the HTA body. Experts also recommended patient involvement during ESA review using targeted questionnaires to ensure a comprehensive review.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eESA in Saudi Arabia can enhance stakeholder engagement in the approval and reimbursement processes for pharmaceuticals, diagnostics, and medical devices. Implementing ESA within Saudi Arabia's advanced healthcare system is essential to support manufacturers, optimize outcomes, and improve access to these interventions.\u003c/p\u003e","manuscriptTitle":"Early Scientific Advice for Health Technology Assessment: Progressing Towards a Framework in Saudi Arabia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-24 16:22:31","doi":"10.21203/rs.3.rs-8907697/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-22T22:42:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-05T08:51:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-01T10:20:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"89388661022198086476027084045917454249","date":"2026-02-21T08:57:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"75345102682944593602861628120588590397","date":"2026-02-19T12:54:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-19T10:33:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-19T09:54:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-19T09:53:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cost Effectiveness and Resource Allocation","date":"2026-02-18T09:06:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cost-effectiveness-and-resource-allocation","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cera","sideBox":"Learn more about [Cost Effectiveness and Resource Allocation](http://resource-allocation.biomedcentral.com)","snPcode":"12962","submissionUrl":"https://submission.nature.com/new-submission/12962/3","title":"Cost Effectiveness and Resource Allocation","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"086514b9-e70a-4735-89a6-a2ee900c4f23","owner":[],"postedDate":"February 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-22T22:53:45+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-24 16:22:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8907697","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8907697","identity":"rs-8907697","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}