Interactions between health regulation and Health Technology Assessment for coverage in health systems and comprehensive care

Ramos, Maíra Catharina; Oliveira, Margarete Martins de; Andrade, Aurélio Matos de; Silva, Erica Tatiane da; Elias, Flávia Tavares Silva

doi:10.1590/S0104-12902023220925en

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Original Articles • Saude soc. 32 (Suppl 1) • 2023 • https://doi.org/10.1590/S0104-12902023220925en copy

Interactions between health regulation and Health Technology Assessment for coverage in health systems and comprehensive care

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

This study analyzes the interactions between regulatory and health technology assessment (HTA) processes aimed at health systems coverage. A review was carried out in five databases to identify experiences of articulation between regulatory processes and HTA processes, and 19 publications were selected. Regarding the type of process, early dialogue, scientific advice and parallel advice stood out as forms of interaction between HTA and regulation. The studies addressed the interaction between HTA and health regulation for medicines coverage policies in health systems, with scant evidence in relation to other products. Furthermore, this interaction is basically described according to the entry of new technologies into health systems. The interaction between HTA and health regulation resulted in reduced deadlines for the commercialization and incorporation of the technology into health systems. The types of interaction processes identified can benefit the entire health system, increasing coverage and comprehensiveness of care. However, despite advances, some barriers to interaction between regulatory agencies and the management of coverage systems still persist.

Keywords:
Health Technology Assessment; Health Care Coordination and Monitoring, Review

Author (year)	Location	Institutions involved	Function in the regulation cycle	Type of interaction process
Balaisyte; Joos; Hiligsmann (2018BALAISYTE, L.; JOOS, A.; HILIGSMANN, M. Early dialogue in Europe: perspectives on value, challenges, and continuing evolution. International Journal of Technology Assessment in Health Care, Cambridge, v. 34, n. 5, p. 514-518, 2018. DOI: 10.1017/S0266462318000545 https://doi.org/10.1017/S026646231800054... )	European Union	EMA and HTA agencies	Reimbursement	Early dialogue
Battista et al (1999BATTISTA, R. N. Health technology assessment and the regulation of medical devices and procedures in Quebec. Synergy, collusion, or collision? International Journal of Technology Assessment in Health Care, Cambridge, v. 15, n. 3, p. 593-601, 1999.)	Canada	CETS and regulation	Incorporation	Not specified
Berntgen et al (2014)BERNTGEN, M. et al. Improving the contribution of regulatory assessment reports to health technology assessments: a collaboration between the European medicines agency and the European network for health technology assessment. Value in Health, Amsterdam, v. 17, p. 634-641. DOI: 10.1016/j.jval.2014.04.006 https://doi.org/10.1016/j.jval.2014.04.0...	European Union	EUnetHTA	Marketing authorizations	Early dialogue Scientific Advice
Henshall et al (2011HENSHALL, C. Interactions between health technology assessment, coverage, and regulatory processes: emerging issues, goals, and opportunities. International Journal of Technology Assessment in Health Care, Cambridge, v. 27, n. 3, p. 253-260, 2011. DOI: 10.1017/s0266462311000262 https://doi.org/10.1017/s026646231100026... )	European Union	Not shown	Regulatory approval and coverage	Early dialogue Scientific Advice Risk sharing or managed entry
Cuche et al (2014CUCHE, M. et al. Early dialogue with health technology assessment bodies: a european perspective. International Journal of Technology Assessment in Health Care, Cambridge, v. 30, n. 6, p. 571-578, 2014. https://doi.org/10.1017/s0266462314000713 https://doi.org/10.1017/s026646231400071... )	European Union	EUnetHTA	Pricing and reimbursement process	Early dialogue
Facey et al (2015FACEY, K.; HENSHALL, C.; SAMPIETRO-COLOM, L.; THOMAS, S. Improving the effectiveness and efficiency of evidence production for health technology assessment. International Journal of Technology Assessment in Health Care, Cambridge, v. 31, n. 4, p. 201-206, 2015. DOI: 10.1017/s0266462315000355 https://doi.org/10.1017/s026646231500035... )	Not shown	HTAi	Not shown	Early dialogue
Forrester et al (1997FORRESTER, J. S.; TOPOL, E. J.; ABELE, J. E.; HOLMES, D. R. J.; SKORTON, D. J. Task force 5: Assessment, approval, and regulation of new technology. Journal of the American College of Cardiology, Amsterdam, v. 29, n. 6, p. 1171-1179, 1997. DOI: 10.1016/s0735-1097(97)82752-0 https://doi.org/10.1016/s0735-1097(97)82... )	U.S.	FDA	Marketing authorizations and post-market monitoring	Early Dialogue
Frønsdal et al (2012FRØNSDAL, K. et al. Interaction initiatives between regulatory, health technology assessment and coverage bodies, and industry. International Journal of Technology Assessment in Health Care, Cambridge, v. 28, n. 4, p. 374-381, 2012. DOI: 10.1017/s0266462312000591 https://doi.org/10.1017/s026646231200059... )	Australia, Canada, European Union	HTAi and CIRS Policy Forum. Collaboration on EPAR content (EUnetHTA and EMA)	Regulatory approval and coverage	Scientific advice Parallel submissions Information sharing Parallel advice Parallel review of medical devices
Henshall et al (2014HENSHALL, C. et al. Understanding the role and evidence expectations of health technology assessment and coverage/payer bodies: what are they looking for, and how and why does this differ from what regulators require? Therapeutic Innovation & Regulatory Science, London, v. 48, n. 3, p. 341-346, 2014. DOI: 10.1177/2168479013512488 https://doi.org/10.1177/2168479013512488... )	UK	HTAi	Not shown	Early dialogue
Cox; de Pouvourville (2015COX, J. L.; POUVOURVILLE, G. Achieving access: addressing the needs of payors and health technology assessment agencies. European Heart Journal, Oxford, v. 17, supl. D, D15-20, 2015. DOI: 10.1093/eurheartj/suv041 https://doi.org/10.1093/eurheartj/suv041... )	European Union	EMA and HTA agencies	Reimbursement	Real world evidence Risk sharing or managed entry
Drummond (2015DRUMMOND, M. Health technology assessment and its interface with regulation, policy and management. In: LLANO-SEÑARÍS, J. C.; CAMPILLO-ARTERO, C. Health Technology Assessment and health policy today: a multifaceted view of their unstable crossroads. London: Springer International Publishing, 2015. p. 3-14.)	Sweden	EUNetHTA	Regulatory approval and coverage	Early dialogue Parallel advice
Maignen et al (2017MAIGNEN, F. Integrating health technology assessment requirements in the clinical development of medicines: the experience from NICE scientific advice. European Journal of Clinical Pharmacology, Berlin, v. 73, n. 3, p. 297-305, 2017. DOI: 10.1007/s00228-016-2174-2 https://doi.org/10.1007/s00228-016-2174-... )	European Union	NICE and EMA	Not shown	Parallel advice Scientific advice
McAuslane; Liberti; Connelly (2019)MCAUSLANE, N.; LIBERTI, L.; CONNELLY, P. The confluence of accelerated regulatory and Health Technology Assessment access pathways. Clinical Pharmacology & Therapeutics, Hoboken, v. 105, n. 4, p. 935-942, 2019. DOI: 10.1002/cpt.1315 https://doi.org/10.1002/cpt.1315...	U.S.	CIRS	Not shown	Flexible access and reimbursement pathways Early dialogue
Tafuri et al (2018TAFURI, G. et al. The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations. British Journal of Clinical Pharmacology, London, v. 84, n. 5, p. 1013-1019, 2018. DOI: 10.1111/bcp.13524 https://doi.org/10.1111/bcp.13524... )	European Union	EUnetHTA /EMA	Not shown	Scientific advice
Tafuri et al (2016TAFURI, G. et al. How aligned are the perspectives of EU regulators and HTA bodies? A comparative analysis of regulatory-HTA parallel scientific advice. British Journal of Clinical Pharmacology, London, v. 82, p. 965-973, 2016. DOI: 10.1111/bcp.13023 https://doi.org/10.1111/bcp.13023... )	European Union	EMA and HTA agencies	Not shown	Scientific advice
Tsoi (2013TSOI, B. et al. Harmonization of reimbursement and regulatory approval processes: a systematic review of international experiences. Expert Review of Pharmacoeconomics & Outcomes Research, London, v. 13 n. 4, p. 497-511, 2013. DOI: 10.1586/14737167.2013.814962 https://doi.org/10.1586/14737167.2013.81... )	Canada	CADTH, HQO, INESSS, Alberta Health and Wellness	Regulatory approval and coverage	Harmonization of HTA-reimbursement and regulatory activities
Vella Bonanno et al (2019)VELLA BONANNO, P. et al. Proposal for a regulation on health technology assessment in Europe - opinions of policy makers, payers and academics from the field of HTA. Expert Review of Pharmacoeconomics & Outcomes Research, London, v. 19, n. 3, p. 251-261, 2019. DOI: 10.1080/14737167.2019.1575730 https://doi.org/10.1080/14737167.2019.15...	European Union	EUnetHTA	Pricing and reimbursement process	Real world evidence Scientific advice
Wang et al (2018WANG, T. Building synergy between regulatory and hta agencies beyond processes and procedures-can we effectively align the evidentiary requirements? A survey of stakeholder perceptions., Amsterdam, v. 21, n. 6, p. 707-714, 2018. DOI: 10.1016/j.jval.2017.11.003 https://doi.org/10.1016/j.jval.2017.11.0... )	European Union	TLV, NICE, OSTEBA, EMA, IMB, MEB and MPA	Pricing and reimbursement process	Scientific advice Information sharing
Wonder et al (2013WONDER, M.; BACKHOUSE, M. E.; HORNBY, E. Early scientific advice obtained simultaneously from regulators and payers: findings from a pilot study in Australia. Value in Health, Amsterdam, v. 16, n. 6, p. 1067-1073, 2013. DOI: https://doi.org/10.1016/j.jval.2013.07.007 https://doi.org/10.1016/j.jval.2013.07.0... )	Australia	TGA and PBAC	Pricing and reimbursement process	Early dialogue

Type of process	Definition
Early dialogue	Early dialogue is characterized as an initial dialogue between the industry and HTA and health regulatory agencies. It occurs in the pre-clinical phase, more specifically between phases II and III. It can facilitate the development of new technologies by clarifying the needs, expectations, and requirements for specific patient populations, comparators, and endpoints, as well as raising discussions about unmet needs in clinical practice, products in progress, expected indications, potential market size, benefits envisaged, regulatory approach and forms of evidence that are likely to be required (Balaisyte; Joos; Hiligsmann, 2018BALAISYTE, L.; JOOS, A.; HILIGSMANN, M. Early dialogue in Europe: perspectives on value, challenges, and continuing evolution. International Journal of Technology Assessment in Health Care, Cambridge, v. 34, n. 5, p. 514-518, 2018. DOI: 10.1017/S0266462318000545 https://doi.org/10.1017/S026646231800054... ; Facey et al., 2015FACEY, K.; HENSHALL, C.; SAMPIETRO-COLOM, L.; THOMAS, S. Improving the effectiveness and efficiency of evidence production for health technology assessment. International Journal of Technology Assessment in Health Care, Cambridge, v. 31, n. 4, p. 201-206, 2015. DOI: 10.1017/s0266462315000355 https://doi.org/10.1017/s026646231500035... ). Technology developers often present their proposed clinical trial designs to regulators in order to obtain recommendations and receive suggestions for improvement (Drummond, 2015DRUMMOND, M. Health technology assessment and its interface with regulation, policy and management. In: LLANO-SEÑARÍS, J. C.; CAMPILLO-ARTERO, C. Health Technology Assessment and health policy today: a multifaceted view of their unstable crossroads. London: Springer International Publishing, 2015. p. 3-14.).
Scientific advice	Scientific advice is a voluntary and early dialogue, in which companies request advice from a regulatory body and/or HTA on their clinical development plans (population and comparison used and expected results) and economic models (Maignen, et al., 2017MAIGNEN, F. Integrating health technology assessment requirements in the clinical development of medicines: the experience from NICE scientific advice. European Journal of Clinical Pharmacology, Berlin, v. 73, n. 3, p. 297-305, 2017. DOI: 10.1007/s00228-016-2174-2 https://doi.org/10.1007/s00228-016-2174-... ). The aim is to answer questions from the pharmaceutical industry, as well as improve interactions and understanding of methodologies between the two agencies (Frønsdal et al., 2012FRØNSDAL, K. et al. Interaction initiatives between regulatory, health technology assessment and coverage bodies, and industry. International Journal of Technology Assessment in Health Care, Cambridge, v. 28, n. 4, p. 374-381, 2012. DOI: 10.1017/s0266462312000591 https://doi.org/10.1017/s026646231200059... ).
Parallel advice	Similar to scientific advice, parallel advice aims to bridge the gap between evidence requirements for different decision makers and can be initiated at any point in the technology development life cycle, although it is often requested before the development program reaches the crucial phase (Tafuri, et al., 2016TAFURI, G. et al. How aligned are the perspectives of EU regulators and HTA bodies? A comparative analysis of regulatory-HTA parallel scientific advice. British Journal of Clinical Pharmacology, London, v. 82, p. 965-973, 2016. DOI: 10.1111/bcp.13023 https://doi.org/10.1111/bcp.13023... , 2018TAFURI, G. et al. The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations. British Journal of Clinical Pharmacology, London, v. 84, n. 5, p. 1013-1019, 2018. DOI: 10.1111/bcp.13524 https://doi.org/10.1111/bcp.13524... ).
Real world evidence	Real-world evidence is that collected from medical records and the pharmacovigilance system. Increasingly being preferred over surrogate data, they can contribute to the evidence base needed for coverage and reimbursement decisions, such as demonstrating how a medicine works in populations or under conditions not covered by the study or concerning another medicine not included in the study (Cox; de Pouvourville, 2015COX, J. L.; POUVOURVILLE, G. Achieving access: addressing the needs of payors and health technology assessment agencies. European Heart Journal, Oxford, v. 17, supl. D, D15-20, 2015. DOI: 10.1093/eurheartj/suv041 https://doi.org/10.1093/eurheartj/suv041... ; Kanavos; Angelis; Drummond, 2019KANAVOS, P.; ANGELIS, A.; DRUMMOND, M. An EU-wide approach to HTA: an irrelevant development or an opportunity not to be missed? European Journal of Health Economics, Berlin, v. 20, p. 329-332, 2019. DOI: 10.1007/s10198-019-01037-2 https://doi.org/10.1007/s10198-019-01037... ).
Risk sharing or managed entry	These are agreements between agencies and industry that occur when evidence of effectiveness and safety is not clear enough. Sometimes these agreements are designed to facilitate the generation of key evidence while using technology in the healthcare system (Henshall et al., 2014HENSHALL, C. et al. Understanding the role and evidence expectations of health technology assessment and coverage/payer bodies: what are they looking for, and how and why does this differ from what regulators require? Therapeutic Innovation & Regulatory Science, London, v. 48, n. 3, p. 341-346, 2014. DOI: 10.1177/2168479013512488 https://doi.org/10.1177/2168479013512488... ).
Information sharing	Sharing information reduces duplication of work between HTA and health regulation, making access to technology faster for the patient (Frønsdal et al., 2012FRØNSDAL, K. et al. Interaction initiatives between regulatory, health technology assessment and coverage bodies, and industry. International Journal of Technology Assessment in Health Care, Cambridge, v. 28, n. 4, p. 374-381, 2012. DOI: 10.1017/s0266462312000591 https://doi.org/10.1017/s026646231200059... ; Wang et al., 2018WANG, T. Building synergy between regulatory and hta agencies beyond processes and procedures-can we effectively align the evidentiary requirements? A survey of stakeholder perceptions., Amsterdam, v. 21, n. 6, p. 707-714, 2018. DOI: 10.1016/j.jval.2017.11.003 https://doi.org/10.1016/j.jval.2017.11.0... ). However, information sharing may face legal limitations, as some agencies have strict legislation on data confidentiality (Frønsdal et al., 2012FRØNSDAL, K. et al. Interaction initiatives between regulatory, health technology assessment and coverage bodies, and industry. International Journal of Technology Assessment in Health Care, Cambridge, v. 28, n. 4, p. 374-381, 2012. DOI: 10.1017/s0266462312000591 https://doi.org/10.1017/s026646231200059... ).
Flexible access and reimbursement pathways (FRP)	They provide options to manage the introduction of new medicines, to reduce the uncertainty present at the time of accelerated regulatory approval. This process occurs through the evaluation of a robust practical experience database. They can address regulatory data limitations and provide opportunities for managed divestment if products do not meet initial clinical expectations (Mcauslane; Liberti; Connelly, 2019MCAUSLANE, N.; LIBERTI, L.; CONNELLY, P. The confluence of accelerated regulatory and Health Technology Assessment access pathways. Clinical Pharmacology & Therapeutics, Hoboken, v. 105, n. 4, p. 935-942, 2019. DOI: 10.1002/cpt.1315 https://doi.org/10.1002/cpt.1315... ).
Harmonization of HTA - reimbursement and regulatory activities	Harmonization involves the rationalization of regulatory processes, in addition to the alignment of evidentiary requirements These initiatives can have positive implications across and within the healthcare system in terms of patient care, innovation, and system sustainability, creating economies of scale in clinical data generation, promoting good interactions, defining the boundaries of governance and leadership and ensuring organizational security (Tsoi et al., 2013TSOI, B. et al. Harmonization of reimbursement and regulatory approval processes: a systematic review of international experiences. Expert Review of Pharmacoeconomics & Outcomes Research, London, v. 13 n. 4, p. 497-511, 2013. DOI: 10.1586/14737167.2013.814962 https://doi.org/10.1586/14737167.2013.81... ).
Parallel review of medical devices	It is the enhanced sharing of information between agencies used in the regulation of medical devices (Frønsdal et al., 2012FRØNSDAL, K. et al. Interaction initiatives between regulatory, health technology assessment and coverage bodies, and industry. International Journal of Technology Assessment in Health Care, Cambridge, v. 28, n. 4, p. 374-381, 2012. DOI: 10.1017/s0266462312000591 https://doi.org/10.1017/s026646231200059... ).
Parallel submissions	It concerns the submission of the product’s preparation proposal to HTA and health regulatory agencies at different times. However, it must be noted that due to this time variation in the evaluation process, it is necessary to add some restrictions to these parallel submissions, such as the recommendations, publication, or authorization of one agency cannot be publicized before the other agency gives its decision (Frønsdal, et al., 2012FRØNSDAL, K. et al. Interaction initiatives between regulatory, health technology assessment and coverage bodies, and industry. International Journal of Technology Assessment in Health Care, Cambridge, v. 28, n. 4, p. 374-381, 2012. DOI: 10.1017/s0266462312000591 https://doi.org/10.1017/s026646231200059... ).

Dimension	Barriers
Organizational	- HTA and regulatory agencies linked to different entities;
	- Difference between agencies’ mission;
	- Different legal structures;
	- Limitation on sharing information between regulatory and HTA institutions due to secrecy legislation;
	- HTA and regulatory agency operating at different levels of centralization;
	- Possible lack of resources to adopt and/or continue with interaction initiatives
Work process	- Use of different evaluation methodologies, including population and population subgroups, comparators, and endpoints;
	- Overlapping activities;
	- Lack of communication between agencies;
	- Different vocabulary between HTA and health regulation agencies
Regulatory cycles	- Little evidence of effectiveness presented for the entry of technology into the health system;
	- Lack of monitoring over the use of technology;
	- Inefficient technology divestment process;
	- Low participation of healthcare professionals and patients in discussions about regulatory cycles and processes

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