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

Introduction

In the early 1970s, the production of knowledge in health-driven mainly by international scientific policies-demanded new strategies to improve regulatory capacity and incorporate new technologies into health systems, strategies that are processes of health technologies assessment (HTA), a multidisciplinary field of public policy analysis. Its main role is to provide information about what works and for whom regarding practical alternatives with the lowest resource demands. HTA also assists managers in making decisions about the incorporation and use of interventions used for prevention, treatment, care, including health promotion.

Technologies constitute an important part of the Brazilian Unified Health System (SUS), whether they are soft technologies, such as clinical protocols, or hard technologies, such as medicines. To incorporate these technologies, HTA transcends the epidemiological field, interacting with the social, cultural, ethical, and political-economic dimensions for the promotion, maintenance, or rehabilitation of health. Traditionally, the life cycle of a technology consists of the phases of innovation, diffusion, incorporation, full use, and abandonment.

During the innovation phase, characterized by the production of research and development, the regulatory discussion also begins when registrations of new health technologies are requested, which is understood as the pre-commercialization phase. During the phases of incorporation and full use of technology, effectiveness and performance in the real world of health services is monitored. Life cycle assessments involve different bodies in the health system, such as the Ministry of Health, state and municipal departments and health services, in addition to regulatory agencies, such as the Agência Nacional de Saúde Suplementar (ANS - National Agency of Supplementary Health) and the National Health Regulatory Agency (Anvisa).

In this context, international regulatory agencies, such as Food and Drug Administration (FDA), in the United States, the European Medicines Agency (EMA), in Europe, and Anvisa, in Brazil, play a fundamental role in decision-making in the cycle of new products. These agencies are responsible for regulating the entry of medicines, vaccines, equipment, and medical devices into the market, authorizing or not authorizing the commercialization of technology in the country, in addition to providing information on safety, benefits, indications for use, and the price to be charged in the market (Garrison et al., 2013GARRISON, L. P. et al. Performance-based risk-sharing arrangements - Good practices for design, implementation, and evaluation: Report of the ISPOR good practices for performance-based risk-sharing arrangements task force. Value in Health, Amsterdam, v. 16, n. 5, p. 703-719, 2013. DOI: 10.1016/j.jval.2013.04.011
https://doi.org/10.1016/j.jval.2013.04.0... ).

In this way, the first steps towards product entry are the responsibility of regulatory agencies and, subsequently, of HTA agencies-such as the National Committee for Health Technologies Incorporation in the Unified Health System (Conitec)-when they refer to financing by health systems. In countries with national health systems, such as Brazil, HTA becomes increasingly necessary to support decision-making on the most efficient allocation of resources. The increase in the cost of health care, together with limited resources and the need to improve the quality and consistency of care, results in the implementation of HTA as a strategy to guide public health policies.

Although studies that evaluate the methodologies and values adopted in such HTA and health regulation assessments have been increasingly frequent, they are focused on evidence in the context of the pre-commercialization phases of new technologies, analyzing how the interaction between HTA and health regulation have contributed to the discussion about the coverage of health systems, their potential and challenges in the context of the use of real-world data, and how they have influenced risk-sharing agreements between companies and government bodies.

Incentives for regulatory interactions also came from the Health Technology Assessment International (HTAi) society, founded in 2003, whose purpose is to develop methods, strategies, and exchange of experiences in the introduction of innovations in health systems, permeating all fields of technology assessment in health, involving a multidisciplinary academic, scientific, and professional community, with the participation of public and private organizations and dedicated patients. The HTAi society has a specific interest group to study and promote greater coordination between regulation and evaluations of the incorporation of health technologies. In June 2020, this theme was incorporated into the new interest group created to promote the use of Real World Evidence for initial dialogues between the regulatory apparatus for product marketing and the standards of HTA agencies-responsible for technology evaluation and incorporation processes as a strategy for shortening the time to access technologies.

Nevertheless, the development of post-marketing effectiveness assessments using Real World Evidence is still insufficient. Also, the nature of these interactions is not known from the point of view of the context and interests involved, and neither is the convergence of evaluation dimensions used in the interactive processes between regulation and HTA.

Knowing about the interaction of HTA and health regulation is necessary to establish best practices for evaluating and incorporating new technologies into the SUS, in order to enhance the expansion of health coverage and guarantee comprehensive care. Furthermore, the institution of practices that combine HTA with health regulation in the health system has the potential to reduce the time it takes to incorporate technologies into the system, enabling new clinical and therapeutic options to reach citizens more quickly, in addition to contributing to the efficiency of resource allocation and the effectiveness and quality of services.

In this context, a review was carried out to analyze the interactions between the regulatory processes for commercialization of health technologies and those for evaluating technologies aimed at covering health systems, considering the regulatory cycles that involve entry, monitoring, and the disinvestment of health technologies.

Method

A narrative review was carried out with a view to identifying the experiences of countries that articulate regulatory processes for the commercialization of health products with HTA processes to cover health systems. The search strategy “health technology assessment” AND “regulatory” was used in the Pudmed, Embase, Cochrane Library, Scopus, Web of Science, and Scholar databases, as detailed in Annex A.

There was no publication date restriction, and studies in English, Spanish, and Portuguese were considered eligible. Primary studies that addressed the interactions between regulatory marketing processes and HTA processes aimed at health systems coverage were included. Secondary studies, editorials, letters to the editor and articles without full text available were excluded.

To select the included articles, selection was carried out first by title and abstract. For articles classified as eligible, a complete reading was carried out. In cases of doubt regarding the inclusion or not of the article, a decision was made between the authors to reach consensus on its inclusion. For data extraction, a table was used with the general description of the studies. For analysis purposes, we considered the location of the experience, period, function within the regulatory cycle and types of interaction process between HTA and health regulation used within the regulation cycle.

The regulatory function comprises prior commercialization analyses, the development of regulations, public consultation or hearing, the authority’s decision, implementation, inspection, monitoring, evaluation, and review of Regulatory Impact Analysis. The evaluation phases involve technical-scientific assessments of clinical benefits, economic, legal, and ethical aspects considering the technology cycle-innovation (research and development phase), initial diffusion (when analyses for commercialization of the country begin), incorporation (assessments for publicly funded coverage), full utilization (analysis of effectiveness and real-life performance of health services), and abandonment (withdrawal or disinvestment phase).

For the purposes of this review, a function in the regulation cycle is understood to be those actions that combine regulatory roles, namely: health approval and coverage in health systems, monitoring the wide dissemination of technologies involving real-life data for pharmacovigilance, surveillance in assistance devices, performance in health systems, and, to analyze effectiveness, adherence to clinical protocols and patient safety.

Results

The search in the databases resulted in the identification of 2,604 articles, with 1,219 single publications, of which nineteen articles were eligible after reading their titles and abstracts (Table 1).

Most of these studies reported the experience of interaction between health regulation and the technology assessment body that supports European Union health systems. Canadian experiences also stood out in the interaction between regulation and technology coverage in health systems. Most of these studies reported experiences from 2010 onwards, due to the maturity of the application of HTA for coverage of health services, requiring discussions even in the product registration and commercialization phase. The complete characterization of the studies is available in Appendix C.

Regarding the role in the regulatory cycle, the majority mention working with health approval and technology coverage for the population and in the pricing and reimbursement process. Regarding the type of process, a variety of interactions were identified, whose characteristics are shown in Table 2. Most interactions reported experiences on early dialogue, one that is focused on dialogue between industry, regulatory agency, and HTA agency in the phase of clinical studies of medicines and health products.

Also noteworthy is the scientific advice process type, in which companies meet with the regulatory or HTA body to establish a better understanding of the recommended assessment methodologies (Berntgen et al., 2014BERNTGEN, 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... ; 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... ; 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... ; 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-... ; 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... ; Vella Bonanno et al., 2019VELLA 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... ; 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... ).

Parallel advice, a process to fill gaps between the evidence requirements for regulation and incorporation of technology in health systems, was a point described on the reported experiences (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.; 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... ; 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-... ).

It was observed that the interaction processes described in Table 2 need to be better developed to avoid duplicate analyses and facilitate access to new health technologies (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... ; 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.; 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... ; 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... ; 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... ). Furthermore, the role of the industry at the moment of discussion and methodological alignments in the pre-market phase is highlighted. This triad-industry, regulatory body, and incorporation body in the health system-brings benefits to those involved. For the industry, investment in studies that are unlikely to be useful can be avoided; for the regulatory body, internal alignment around the clinical development of a product is further facilitated; and, for the health system coverage body, the possibility of obtaining real-world data to understand the benefits and risks of a technology is created (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... ).

For cases where the evidence is still uncertain, risk sharing agreements have been an alternative for mitigating the risks caused by technology. Such agreements are generally made between industry and governments, with predetermined deadlines.

Some studies have highlighted the need to align work processes between HTA agencies and regulatory agencies. Most of the evidence generated by the industry met regulatory requirements; however, they did not fully meet the HTA evidentiary requirements to support decision-making in the scope of health system coverage (Berntgen et al., 2014BERNTGEN, 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... ; Cox; 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... ; 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... ; 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... ; 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... ; 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... ; Wonder; Backhouse; Hornby, 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... ), for example, in regulatory agencies placebos are accepted, but in health systems coverage institutions, technologies already incorporated into health systems are preferred. The choice of primary and surrogate outcomes (Cox; 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... ; 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... ; 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... ) also differs between the requirements because for the coverage institution, outcomes that impact patients’ clinical conditions are preferred, leaving laboratory outcomes in the background. In relation to the population and population subgroups (Berntgen et al., 2014BERNTGEN, 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... ; Cox; 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... ; Wonder; Backhouse; Hornby, 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... ), the criteria of the entities that finance coverage are concerned with the magnitude and transcendence of the disease. Insufficient efficacy data was another critical point identified in the studies (Cox; 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... ; 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... ; 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... ; 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... ; 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... ; 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... ), because for regulatory agencies, phase I and II studies are accepted, while entities that decide on coverage prefer phase III studies because they address a larger number of research subjects.

Another issue identified in the findings was the communication gap between HTA and health regulation. There is evidence that when communication and coordination between agencies is improved, review processes can be improved and possibly reduce differences in work processes (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... ). However, it has been observed that agencies’ communication with health professionals and users is incipient, with little participation of organized civil society in the health regulation process (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... ).

Table 3 presents the barriers to interactions between HTA and health regulation identified by the studies included in this review. Based on the analysis, three dimensions were defined to categorize barriers: (1) organizational barriers; (2) work process barriers; and (3) regulatory cycle barriers.

It was observed that the articles would refer to interaction processes between HTA and health regulation in the context of medicines, with little or no reference to analyses of other technologies. Another issue observed was the focus on the entry of new technologies into the health system, with little reference by the authors to an interactive process when monitoring the wide dissemination and use of technologies (Cox; 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... ; 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... ). Finally, no study was identified that addressed the interaction between HTA and health regulation for the withdrawal or disinvestment of health technologies.

Discussion

The interaction between regulatory commercialization processes and technology assessment processes aimed at health systems coverage has proven to be effective for the entry of technologies-especially medicines-into health systems, reducing registration, and incorporation deadlines, contributing for expanding equity and access to health services. However, incipient interaction was observed in the processes of monitoring the use and performance of technologies already commercialized or incorporated.

The purpose of HTA is to ensure an adequate balance between patient access and rationality, considering the impact on budget/price within the jurisdictions of a country, thus playing a fundamental role in improving the production of evidence and ensuring that the health service is ready to adopt effective technologies (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... ; Vreman et al., 2020VREMAN, R. A. Differences in Health Technology Assessment recommendations among european jurisdictions: the role of practice variations. Value in Health, Amsterdam, v. 23, n. 1, p. 10-16, 2020. https://doi.org/10.1016/j.jval.2019.07.017
https://doi.org/10.1016/j.jval.2019.07.0... ). Furthermore, HTA is considered a tool to inform decision makers of the best evidence regarding the entry of new medicines, medical devices, and other technologies into health systems, being an effective way to achieve universal health coverage (Gonçalves, 2020GONÇALVES, E. Advanced therapy medicinal products: value judgement and ethical evaluation in health technology assessment. European Journal of Health Economics, Berlin, v. 21, n. 3, p. 311-20, 2020. DOI: 10.1007/s10198-019-01147-x
https://doi.org/10.1007/s10198-019-01147... ; Wasir et al., 2019WASIR, R. et al. The implementation of HTA in medicine pricing and reimbursement policies in Indonesia: insights from multiple stakeholders. PLoS One, San Francisco, v. 14, n. 11, e0225626, 2019. DOI: 10.1371/journal.pone.0225626
https://doi.org/10.1371/journal.pone.022... ).

Furthermore, there is a beneficial effect of the interaction between HTA and health regulation for the industry, which invests in studies more likely to be positively evaluated in the technology registration and incorporation phase, as they adequately meet the requirements, allowing new clinical options and therapies to reach the citizen. Also, interaction between agencies helps to align methodologies and work processes, reducing unnecessary differences in assessment requirements, in addition to defining governance limits between organizational aspects of 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... ; 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... ).

This time, a fundamental role of HTA in mitigating the risk of health inequities is observed, investigating the extent to which a new technology is relevant for the health system of interest, considering the local ethical, social, and economic contexts (Fontrier; Visintin; Kanavos, 2022). At the macropolitical level, technologies must be inserted into the health system to reduce rather than exacerbate inequities.

In this sense, it is highlighted that HTA can become more responsive with the inclusion of other actors in the evaluation process, more transparency, inclusion, and reflection from different perspectives in the incorporation of technologies, improving citizens’ access to more appropriate interventions and improving efficiency in the development of new technologies (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... ). Therefore, HTAi recommends that HTA approaches other actors for regulatory approval and coverage of health systems to promote comprehensiveness and equity in health. In addition to regulators, the participation of social control, patients, organized civil society, and the general public (users or not of public health systems) is necessary (Cowie et al., 2022COWIE, M.R. et al. How can we optimise health technology assessment and reimbursement decisions to accelerate access to new cardiovascular medicines? International Journal of Cardiology, Milan, v. 365, p. 61-68, 2022. DOI: 10.1016/j.ijcard.2022.07.020
https://doi.org/10.1016/j.ijcard.2022.07... ; 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... ). This will almost certainly require deliberative methods and localized decision-making (Chalkidou et al., 2013CHALKIDOU, K. et al. Health technology assessment in universal health coverage. The Lancet, Cambridge, v. 382, n. 9910, p. e48-e49, 2013. DOI: 10.1016/S0140-6736(13)62559-3
https://doi.org/10.1016/S0140-6736(13)62... ). Deliberative processes are expanded instances inserted in the technology assessment structure, being an important step for HTA agencies to improve and legitimize decisions and the definition of priorities (Novaes; Soárez, 2020)NOVAES, H. M. D.; SOÁREZ, P. C. Organizações de avaliação de tecnologias em saúde (ATS): Dimensões do arcabouço institucional e político. Cadernos de Saúde Pública, Rio de Janeiro, v. 32, sup. 2, e00022315, 2016. DOI: 10.1590/0102-311X00022315
https://doi.org/10.1590/0102-311X0002231... .

Nevertheless, the involvement of key actors in these processes often does not occur, hindering planned and practice-oriented decision-making, even though the importance of the institutionalized role of HTA in the continuous development of health actions is known. This contributes significantly to identifying strengths and weaknesses in the internal environment, as well as opportunities and threats in the external environment (Colpani et al., 2020COLPANI, V. et al. Clinical practice guidelines in Brazil - developing a national programme. Health Research Policy and Systems, Berlin, v. 18, n. 1, p. 1-6, 2020. DOI: 10.1186/s12961-020-00582-0
https://doi.org/10.1186/s12961-020-00582... ). On the other hand, when health technology evaluators work in isolation from regulators, some problems may arise, such as the alignment of mandatory requirements that meet both requests: HTA and health regulation (Blüher et al., 2019BLÜHER, M. et al. Critical review of european health-economic guidelines for the Health Technology Assessment of medical devices. Frontiers in Medicine, Lausanne, v. 6, 278, 2019. DOI: 10.3389/fmed.2019.00278
https://doi.org/10.3389/fmed.2019.00278... ).

It is worth noting that, within companies, HTA has strong credibility and reputation for producing evidence that proves the quality of use of medicines or other supplies. However, the institutional arrangement of industries has biases regarding the acceptability or incorporation of drug or vaccine technologies. The global economic order is clearly based on aspects of efficiency with the inclusion of cost-effective technologies aimed at new medicines/vaccines, among other supplies, especially when it comes to public health systems.

One study pointed out that while the focus of the evaluation for the commercialization of medicines and medical care equipment is the quality of the study and the safety of the product, the clinical evaluation carried out by public agents who carry out HTA in European agencies focused on the evaluation of comparative effectiveness in relation to the existing therapeutic alternative in the health system, concerning itself with the population that will have access to this technology (Gonçalves, 2020GONÇALVES, E. Advanced therapy medicinal products: value judgement and ethical evaluation in health technology assessment. European Journal of Health Economics, Berlin, v. 21, n. 3, p. 311-20, 2020. DOI: 10.1007/s10198-019-01147-x
https://doi.org/10.1007/s10198-019-01147... ). This methodological divergence was evident in the studies identified in this review, whether in the definition of population, comparator or outcomes, constituting a barrier to interaction between agencies (Berntgen et al., 2014BERNTGEN, 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... ; Cox; 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... ; 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... ; 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... ; 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... ; 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... ; 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... ; 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... ; 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... ; Wonder; Backhouse; Hornby, 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... ).

We reinforce that differences in work processes impact the interaction between these agents. The organizational structure of HTA and regulatory agencies can generate important noise in the context of health systems coverage and comprehensive care. In Brazil, HTA operates within the Ministry of Health via Conitec, responsible for covering technologies to be financed by the SUS, while Anvisa is responsible for marketing authorization within the Brazilian market. Despite both being administratively linked to the ministry, there are tensions in the application of regulations, producing barriers, such as the incipient inter-institutional communication for the implementation of normative requirements for evaluating effectiveness (Blüher et al., 2019BLÜHER, M. et al. Critical review of european health-economic guidelines for the Health Technology Assessment of medical devices. Frontiers in Medicine, Lausanne, v. 6, 278, 2019. DOI: 10.3389/fmed.2019.00278
https://doi.org/10.3389/fmed.2019.00278... ). It is necessary to develop permanent and inter-institutional flows to support dialogue throughout the life cycle of health technologies, mindful of limited resources, operating across jurisdictions and drawing lessons from other countries’ experiences (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... ). Improved communication between regulators, HTA and other actors can improve the efficiency of review processes and reduce the overall burden of evidence requirements throughout the product lifecycle and thus enable faster citizen access to useful products (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... ).

We also observed that the divergence in the agencies’ evaluation process allows limitations in other stages of the technology cycle. Notably, health technology assessors and regulators have different experiences, roles, and approaches, which can affect the interpretation of clinical evidence (Jaksa et al., 2022JAKSA, A. et al. A comparison of 7 oncology external control arm case studies: critiques from regulatory and health technology assessment agencies. Value in Health, Lawrenceville, v. 25, n. 12, p. 1967-1976, 2022. DOI: 10.1016/j.jval.2022.05.016
https://doi.org/10.1016/j.jval.2022.05.0... ). For evaluation and monitoring processes to converge, public agents must be considered as social beings, with primacy in the institutional dynamics of decision-making for health system coverage. In this sense, the need for ongoing education actions is highlighted to bring the decision-making process closer to the daily implementation of public health policies.

Bringing HTA closer to health regulation is an action that requires the adoption of clearly defined processes and strategies, such as those identified in this study. However, despite the contributions that this review can bring to decision-making, some limitations should be mentioned, such as studies being mostly from developed countries, far from the Brazilian reality, studies mainly focused on medicines as opposed to other types of health technology, such as diagnostic tests, vaccines, or hospital equipment. Despite the considerable relevance of medicines to public health, alignment between agencies also needs to include other health technologies, such as medical devices and equipment.

Final Considerations

The types of processes identified reflect the interaction between the entities responsible for HTA and health regulation, to expand coverage in health systems and comprehensive care. The processes identified in this review (early dialogues, scientific advice, parallel advice, real-world evidence, risk sharing) demonstrated benefits for coverage in health systems and comprehensive care, such as the adequacy of clinical effectiveness requirements and the reduction of deadlines for commercialization and coverage processes in the incorporation of health technologies.

Several barriers were also identified, such as the difference between the requirements demanded and the gaps in flows and communication, which are necessary to strengthen interactive decision-making processes. It is worth noting the need to adopt strategies to mitigate these barriers, such as including other players in the evaluation and regulation processes (industry, organized civil society and social control), aligning work processes, and encouraging ongoing education for all parties involved.

References

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