The Beneluxa Initiative domain task force health technology assessment: a comparison of member countries' past health technology assessments.

OBJECTIVE: This study aimed to compare assessments between Beneluxa Initiative member countries' assessments and identify alignments and divergences. METHODS: A retrospective comparative analysis was performed that investigated (i) number and type of assessed indications (for Austria (AT), Belgium (BE), Ireland (IE), and the Netherlands (NL)); (ii) added benefit conclusions (for BE, IE, and NL); and (iii) the main arguments underlying differences in conclusions (for BE, IE, and NL). Data were retrieved directly from agency representatives and from public HTA reports. European Medicines Agency approved indications were included for drugs assessed between 2016 and 2020, excluding veterinary drugs, generics, and biosimilars. RESULTS: Only 44 (10 percent) of the 444 included indications were assessed by all four member countries. Between any pair of two countries, the overlap was higher, from 63 (AT-NL) to 188 (BE-IE). Added benefit conclusions matched exactly in 62-74 percent of the indications, depending on the countries compared. In the remaining cases, most often a difference of one added benefit level was observed (e.g., higher vs. equal relative effect). Contradictory outcomes were very rare: only three cases were observed (lower vs. higher effect). When assessing the underlying arguments for seven cases with different outcomes, differences were attributable to slight differences in weighing of evidence and uncertainties rather than disagreement on aspects within the assessment itself. CONCLUSIONS: Despite high variability in European HTA procedures, collaboration on HTA between the Beneluxa Initiative member countries is very feasible and would likely not result in added benefit conclusions that would be very different from added benefit conclusions in national procedures.

Patients, payers and developers of Orphan Medicinal Products: lessons learned from 10 years' multi-stakeholder dialogue on improving access in Europe via MoCA.

BACKGROUND: The Mechanism of Coordinated Access to Orphan Medicinal Products (MoCA) was established in 2013 with the intention of developing a coordinated mechanism between volunteering EU stakeholders and developers of Orphan Medicinal Products (OMPs) to support the exchange of information aimed at enabling informed decisions on pricing and reimbursement at Member State level and to evaluate the value of an OMP based on a Transparent Value Framework. The objective of the collaborative approach was to support more equitable access to authorised therapies for people living with rare diseases, rational prices for payers and more predictable market conditions for OMP developers. Over the past 10 years, the MoCA has conducted a series of pilot projects, examining a variety of different products and technologies at different stages of development; and with contributions from a variety of patient representatives, participation from EU payers from a range of Member States and, recently, with EUnetHTA members and the European Medicines Agency participating in the meetings as observers. RESULTS: 10 years on from the establishment of the MoCA, the European landscape has significantly evolved, not only in the field of drug development with increasingly transformative therapies based on novel technologies, but also in terms of larger numbers of approved treatments, increased budget impact and the resulting associated uncertainties; as well as in terms of stakeholder collaboration and interactions. The value of early dialogue with OMP developers, including the EU payer community via their national decision-making authorities, is a key element within this early interaction and contributes to identifying, managing and reducing uncertainties allowing a prospectively planned approach earlier in development and, consequently, to support more timely, sustainable and equitable access to new OMPs, particularly where there is a high unmet medical need. CONCLUSIONS: The voluntary, informal nature of the MoCA interactions creates a flexible framework for non-binding dialogue. A forum for such interactions is needed to achieve the aims of the MoCA and both to support healthcare systems in planning as well as to underpin timely, equitable and sustainable access to new therapies for patients with rare diseases within the EU.

The use of national reimbursement reports to support formulary decisions of the hospital's Drug and Therapeutics Committee: a comparative analysis.

Background New therapies that do not reach patients in need, have not achieved their goal. Drug and Therapeutics Committees in hospitals ensure access to patients by compiling a formulary on rational grounds. An evolving landscape of innovative molecules challenges timely formulary adaptation after national reimbursement. Aim To integrate national reimbursement reports in the hospital's appraisal, thereby promoting access for patients without delay. Method For 2019, the rationale for new molecules at Ghent University Hospital, Belgium, was compared with the public assessment report of the National Institute for Health and Disability Insurance, assessing a medicine in a specific indication following a reimbursement request by the manufacturer. Decision criteria (therapeutic value and cost) between matching medicines in both databases (national & hospital) were retrospectively compared [no (%), mean (SD)]. Results Two-hundred public reports and 30 formulary decisions were analysed (with antineoplastic & immunomodulating as most prevalent class: 41.0% resp. 36.7%). National decision often concerned hospital-only medicines (89; 44.5%) without patient co-payment (101; 50.5%). Of 13 matched medicines (same indication), time delay between national decision and formulary admission was on average 3.1 (SD 2.3) months. Comparative analysis showed that assessment in both committees was mostly based on the efficacy endpoints of Randomised Controlled Trials. Literature used in hospital appraisals was of more recent publication date: + 0.78 (SD 2.2) years. Using public reports as a horizon scan could enable quick identification of new indications. Conclusion To speed up patient access, the scientific evidence of national reimbursement reports can be used for the purpose of hospital formulary decisions.

Exploring the opportunities for alignment of regulatory postauthorization requirements and data required for performance-based managed entry agreements.

Performance-based managed entry agreements (PB-MEAs) might allow patient access to new medicines, but practical hurdles make competent authorities for pricing and reimbursement (CAPR) reluctant to implement PB-MEAs. We explored if the feasibility of PB-MEAs might improve by better aligning regulatory postauthorization requirements with the data generation of PB-MEAs and by active collaboration and data sharing. Reviewers from seven CAPRs provided structured assessments of the information available at the European Medicines Agency (EMA) Web site on regulatory postauthorization requirements for fifteen recently authorized products. The reviewers judged to what extent regulatory postauthorization studies could help implement PB-MEAs by addressing uncertainty gaps. Study domains assessed were: patient population, intervention, comparators, outcomes, time horizon, anticipated data quality, and anticipated robustness of analysis. Reviewers shared general comments about PB-MEAs for each product and on cooperation with other CAPRs. Reviewers rated regulatory postauthorization requirements at least partly helpful for most products and across domains except the comparator domain. One quarter of responses indicated that public information provided by the EMA was insufficient to support the implementation of PB-MEAs. Few PB-MEAs were in place for these products, but the potential for implementation of PB-MEAs or collaboration across CAPRs was seen as more favorable. Responses helped delineate a set of conditions where PB-MEAs may help reduce uncertainty. In conclusion, PB-MEAs are not a preferred option for CAPRs, but we identified conditions where PB-MEAs might be worth considering. The complexities of implementing PB-MEAs remain a hurdle, but collaboration across silos and more transparency on postauthorization studies could help overcome some barriers.

Regulatory and health technology assessment advice on postlicensing and postlaunch evidence generation is a foundation for lifecycle data collection for medicines.

The understanding of the benefit risk profile, and relative effectiveness of a new medicinal product, are initially established in a circumscribed patient population through clinical trials. There may be uncertainties associated with the new medicinal product that cannot be, or do not need to be resolved before launch. Postlicensing or postlaunch evidence generation (PLEG) is a term for evidence generated after the licensure or launch of a medicinal product to address these remaining uncertainties. PLEG is thus part of the continuum of evidence development for a medicinal product, complementing earlier evidence, facilitating further elucidation of a product's benefit/risk profile, value proposition, and/or exploring broader aspects of disease management and provision of healthcare. PLEG plays a role in regulatory decision making, not only in the European Union but also in other jurisdictions including the USA and Japan. PLEG is also relevant for downstream decision-making by health technology assessment bodies and payers. PLEG comprises studies of different designs, based on data collected in observational or experimental settings. Experience to date in the European Union has indicated a need for improvements in PLEG. Improvements in design and research efficiency of PLEG could be addressed through more systematic pursuance of Scientific Advice on PLEG with single or multiple decision makers. To date, limited information has been available on the rationale, process or timing for seeking PLEG advice from regulators or health technology assessment bodies. This article sets out to address these issues and to encourage further uptake of PLEG advice.

The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations.

AIMS: The parallel regulatory-health technology assessment scientific advice (PSA) procedure allows manufacturers to receive simultaneous feedback from both EU regulators and health technology assessment (HTA) bodies on development plans for new medicines. The primary objective of the present study is to investigate whether PSA is integrated in the clinical development programmes for which advice was sought. METHODS: Contents of PSA provided by regulators and HTA bodies for each procedure between 2010 and 2015 were analysed. The development of all clinical studies for which PSA had been sought was tracked using three different databases. The rate of uptake of the advice provided by regulators and HTA bodies was assessed on two key variables: comparator/s and primary endpoint. RESULTS: In terms of uptake of comparator recommendations at the time of PSA in the actual development, our analysis showed that manufacturers implemented comparators to address both the needs of regulators and of at least one HTA body in 12 of 21 studies. For primary endpoints, in all included studies manufacturers addressed both the needs of the regulators and at least one HTA body. CONCLUSIONS: One of the key findings of this analysis is that manufacturers tend to implement changes to the development programme based on both regulatory and HTA advice with regards to the choice of primary endpoint and comparator. It also confirms the challenging choice of the study comparator, for which manufacturers seem to be more inclined to satisfy the regulatory advice. Continuous research efforts in this area are of paramount importance from a public health perspective.

Adaptive Pathways: Possible Next Steps for Payers in Preparation for Their Potential Implementation.

Medicines receiving a conditional marketing authorization through Medicines Adaptive Pathways to Patients (MAPPs) will be a challenge for payers. The "introduction" of MAPPs is already seen by the European Medicines Agency (EMA) as a fait accompli, with payers not consulted or involved. However, once medicines are approved through MAPPs, they will be evaluated for funding by payers through different activities. These include Health Technology Assessment (HTA) with often immature clinical data and high uncertainty, financial considerations, and negotiations through different types of agreements, which can require monitoring post launch. Payers have experience with new medicines approved through conditional approval, and the fact that MAPPs present additional challenges is a concern from their perspective. There may be some activities where payers can collaborate. The final decisions on whether to reimburse a new medicine via MAPPs will have more variation than for medicines licensed via conventional processes. This is due not only to increasing uncertainty associated with medicines authorized through MAPPs but also differences in legal frameworks between member states. Moreover, if the financial and side-effect burden from the period of conditional approval until granting full marketing authorization is shifted to the post-authorization phase, payers may have to bear such burdens. Collection of robust data during routine clinical use is challenging along with high prices for new medicines during data collection. This paper presents the concept of MAPPs and possible challenges. Concerns and potential ways forward are discussed and a number of recommendations are presented from the perspective of payers.

Payers' Views of the Changes Arising through the Possible Adoption of Adaptive Pathways.

Payers are a major stakeholder in any considerations and initiatives concerning adaptive licensing of new medicinal products, also referred to as Medicines Adaptive Pathways to patients (MAPPs). Firstly, the scope and necessity of MAPPs need further scrutiny, especially with regard to the definition of unmet need. Conditional approval pathways already exist for new medicines for seriously debilitating or life-threatening diseases and only a limited number of new medicines are innovative. Secondly, MAPPs will result in new medicines on the market with limited evidence about their effectiveness and safety. Additional data are to be collected after approval. Consequently, adaptive pathways may increase the risk of exposing patients to ineffective or unsafe medicines. We have already seen medicines approved conventionally that subsequently proved ineffective or unsafe amongst a wider, more co-morbid population as well as medicines that could have been considered for approval under MAPPs but subsequently proved ineffective or unsafe in Phase III trials and were never licensed. Thirdly, MAPPs also put high demands on payers. Routine collection of patient level data is difficult with high transaction costs. It is not clear who will fund these. Other challenges for payers include shifts in the risk governance framework, implications for evaluation and HTA, increased complexity of setting prices, difficulty with ensuring equity in the allocation of resources, definition of responsibility and liability and implementation of stratified use. Exit strategies also need to be agreed in advance, including price reductions, rebates, or reimbursement withdrawals when price premiums are not justified. These issues and concerns will be discussed in detail including potential ways forward.

How aligned are the perspectives of EU regulators and HTA bodies? A comparative analysis of regulatory-HTA parallel scientific advice.

BACKGROUND: In 2010, the European Medicines Agency (EMA) initiated a pilot project on parallel scientific advice with Health Technology Assessment bodies (HTABs) that allows manufacturers to receive simultaneous feedback from both the European Union (EU) regulators and HTABs on their development plans for medicines. AIMS: The present retrospective qualitative analysis aimed to explore how the parallel scientific advice system is working and levels of commonality between the EU regulators and HTABs, and among HTABs, when applicants obtain parallel scientific advice from both a regulatory and an HTA perspective. METHODS: We analysed the minutes of discussion meetings held at the EMA between 2010, when parallel advice was launched, and 1 May 2015, when the cutoff date for data extraction was set. The analysis was based on predefined criteria and conducted at two different levels of comparison: the answers of the HTABs vs. those of the regulators, and between the answers of the participating HTA agencies. RESULTS: The analysis was based on 31 procedures of parallel scientific advice. The level of full agreements was highest for questions on patient population (77%), while disagreements reached a peak for questions on the study comparator (30%). With regard to comparisons among HTABs, there was a high level of agreement for all domains. CONCLUSIONS: There is evident commonality, in terms of evidence requirements between the EU regulators and participating HTABs, as well as among HTABs, on most aspects of clinical development. Indeed, regardless of the question content, the analysis showed that a high level of overall agreement was reached through the process of parallel scientific advice.

Standardized reporting for rapid relative effectiveness assessments of pharmaceuticals.

OBJECTIVES: Many European countries perform rapid assessments of the relative effectiveness (RE) of pharmaceuticals as part of the reimbursement decision making process. Increased sharing of information on RE across countries may save costs and reduce duplication of work. The objective of this article is to describe the development of a tool for rapid assessment of RE of new pharmaceuticals that enter the market, the HTA Core Model® for Rapid Relative Effectiveness Assessment (REA) of Pharmaceuticals. METHODS: Eighteen member organisations of the European Network of Health Technology Assessment (EUnetHTA) participated in the development of the model. Different versions of the model were developed and piloted in this collaboration and adjusted accordingly based on feedback on the content and feasibility of the model. RESULTS: The final model deviates from the traditional HTA Core Model® used for assessing other types of technologies. This is due to the limited scope (strong focus on RE), the timing of the assessment (just after market authorisation), and strict timelines (e.g. 90 days) required for performing the assessment. The number of domains and assessment elements was limited and it was decided that the primary information sources should preferably be a submission file provided by the marketing authorisation holder and the European Public Assessment Report. CONCLUSIONS: The HTA Core Model® for Rapid REA (version 3.0) was developed to produce standardised transparent RE information of pharmaceuticals. Further piloting can provide input for possible improvements, such as further refining the assessment elements and new methodological guidance on relevant areas.

Piloting international production of rapid relative effectiveness assessments of pharmaceuticals.

BACKGROUND: This article describes the lessons learned from an international pilot assessment using the first version of the HTA Core Model® and Guidelines for rapid Relative Effectiveness Assessment (REA) of pharmaceuticals based on input from three different perspectives: the assessors, the users (health technology assessment organisations) and the marketing authorisation holder. METHODS: A pilot assessment was performed of pazopanib for the treatment of advanced or metastatic renal cell carcinoma for which 54 individuals from 22 EUnetHTA member organisations from 16 European countries gave their contribution. The work was divided in eight domain teams. Subsequently, results of these domain teams were synthesised in one pilot report. Feedback on the outcomes of the pilot was gathered throughout the project and through structured surveys. RESULTS: The first version of the assessment was produced in six months and consisted of 55 question and answer pairs, 8 domain reports and a synthesis section that combined the results from the different domains. The organisation of the pilot required intense coordination. Main points of criticism on the assessment were the lengthiness of the document and overlap of information throughout the assessment. CONCLUSIONS: A reduction in the number of authoring organisations and individuals participating is necessary to avoid information overlap and increase efficiency in undertaking the assessment. Involving several organisations (e.g. five) in an in-depth review could still ensure the benefit of broad participation from various countries. The focus of a rapid REA should be on the first four domains of the Model.

Pdx1- and Ngn3-Cre-mediated PLAG1 expression in the pancreas leads to endocrine hormone imbalances that affect glucose metabolism.

Pleomorphic adenoma gene-like 1 (PLAGL1) has been linked to transient neonatal diabetes mellitus. Here, we investigated the role of the related pleomorphic adenoma gene 1 (PLAG1) in glucose homeostasis. PLAG1 transgenic mice in which expression of the PLAG1 transgene can be targeted to different organs by Cre-mediated modulation were crossed with Pdx1-Cre or Ngn3-Cre mice, resulting in double transgenic P1-Pdx1Cre or P1-Ngn3Cre mice, respectively. P1-Pdx1Cre and P1-Ngn3Cre mice developed hyperplasia of pancreatic islets due to increased ß- and δ- but not α-cell proliferation. In young P1-Pdx1Cre mice (less than 15 weeks) there was a balanced increase in the pancreatic content of insulin and somatostatin, which was associated with normoglycemia. In older P1-Pdx1Cre mice the pancreatic somatostatin content far exceeded that of insulin, leading to the progressive development of severe hypoglycemia beyond 30 weeks. In contrast, in older P1-Ngn3Cre mice the relative increase of the pancreatic insulin content exceeded that of somatostatin and these mice remained normoglycemic. In conclusion, forced expression of PLAG1 under the control of the Pdx1 or Ngn3 promoter in murine pancreas induces different degrees of endocrine hormone imbalances within the pancreas, which is associated with hypoglycemia in P1-Pdx1Cre mice but not P1-Ngn3Cre mice. These results suggest that once stem cell-derived islet transplantations become possible, the appropriate balance between different hormone-producing cells will need to be preserved to prevent deregulated glucose metabolism.

A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis.

Reduced intrahepatic endothelial nitric oxide synthase (eNOS) activity contributes to the pathogenesis of portal hypertension (PHT) associated with cirrhosis. We evaluated whether asymmetric dimethylarginine (ADMA), a putative endogenous NOS inhibitor, may be involved in PHT associated with cirrhosis. Two rat models of cirrhosis (thioacetamide [TAA]-induced and bile duct excision [BDE]-induced, n = 10 each), one rat model of PHT without cirrhosis (partial portal vein-ligated [PPVL], n = 10), and sham-operated control rats (n = 10) were studied. We assessed hepatic NOS activity, eNOS protein expression, plasma ADMA levels, and intrahepatic endothelial function. To evaluate intrahepatic endothelial function, concentration-effect curves of acetylcholine were determined in situ in perfused normal rat livers and livers of rats with TAA- or BDE-induced cirrhosis (n = 10) that had been preincubated with either vehicle or ADMA; in addition, measurements of nitrite/nitrate (NOx) and ADMA were made in perfusates. Both models of cirrhosis exhibited decreased hepatic NOS activity. In rats with TAA-induced cirrhosis, this decrease was associated with reduced hepatic eNOS protein levels and immunoreactivity. Rats with BDE-induced cirrhosis had eNOS protein levels comparable to those in control rats but exhibited significantly higher plasma ADMA levels than those in all other groups. In normal perfused liver, ADMA induced impaired endothelium-dependent vasorelaxation and reduced NOx perfusate levels, phenomena that were mimicked by N(G)-nitro-L-arginine-methyl ester. In contrast to perfused livers with cirrhosis induced by TAA, impaired endothelial cell-mediated relaxation in perfused livers with cirrhosis induced by BDE was exacerbated by ADMA and was associated with a decreased rate of removal of ADMA (34.3% +/- 6.0% vs. 70.9% +/- 3.2%). In conclusion, in rats with TAA-induced cirrhosis, decreased eNOS enzyme levels seem to be responsible for impaired NOS activity; in rats with biliary cirrhosis, an endogenous NOS inhibitor, ADMA, may mediate decreased NOS activity.

Halofuginone can worsen liver fibrosis in bile duct obstructed rats.

BACKGROUND/AIMS: Halofuginone (HF) is an antifibrotic agent in rat models of liver fibrosis caused by repetitive intoxications. A beneficial effect of HF on a biliary type of liver fibrosis has not been proven yet. METHODS: Bile duct-obstructed rats were given HF from the moment of obstruction onwards and compared with no treatment. After 3 weeks, respectively, 6 weeks, aminopyrine breath test (ABT) and haemodynamic measurements including of portal pressure were carried out. Liver pieces were taken for Sirius red quantitative scoring, as well as for semiquantitative determinations of collagen type I and III RNA levels. RESULTS: ABT was significantly worse in HF-treated rats as compared with no treatment (P=0.02). Haemodynamic data and collagen type I and III determinations were not significantly different between groups. Biliary fibrosis scores were significantly higher in HF-treated rats as compared with no treatment (P=0.03). More Sirius red staining was associated with more proliferation of bile ductules. CONCLUSIONS: HF may worsen biliary fibrosis. This contrasts sharply with antifibrotic effects in other models of liver fibrosis. Distinctive cellular mechanisms in biliary fibrosis may explain this discrepancy. One should be cautious for chronic application of HF in man with cholestasis.

Low NO bioavailability in CCl4 cirrhotic rat livers might result from low NO synthesis combined with decreased superoxide dismutase activity allowing superoxide-mediated NO breakdown: A comparison of two portal hypertensive rat models with healthy controls.

BACKGROUND: In cirrhotic livers, the balance of vasoactive substances is in favour of vasoconstrictors with relatively insufficient nitric oxide. Endothelial dysfunction has been documented in cirrhotic rat livers leading to a lower activity of endothelial nitric oxide synthase but this might not be sufficient to explain the low nitric oxide presence. We compared the amount of all nitric oxide synthase isoforms and other factors that influence nitric oxide bioavailability in livers of two portal hypertensive rat models: prehepatic portal hypertension and carbon tetrachloride induced cirrhosis, in comparison with healthy controls. RESULTS: Endothelial nitric oxide synthase was the solely detected isoform by Western blotting in all livers. In cirrhotic livers, the amount of endothelial nitric oxide synthase protein was lower than in healthy controls, although an overlap existed. Levels of caveolin-1 messenger RNA were within the normal range but endothelin-1 messenger RNA levels were significantly higher in cirrhotic livers (p < 0.05). A markedly lower superoxide dismutase activity was observed in cirrhotic livers as compared to healthy controls (p < 0.05). CONCLUSIONS: In contrast to prehepatic portal hypertension, cirrhotic livers had decreased endothelial nitric oxide synthase protein and enhanced endothelin-1 messenger RNA amount. We hypothesise that a vasodilator/vasoconstrictor imbalance may be further aggravated by the reduced activity of superoxide dismutase. Decreased activity allows enhanced superoxide action, which may lead to breakdown of nitric oxide in liver sinusoids.