European collaboration on health technology assessment: looking backward and forward.

The establishment of health technology assessment (HTA) has been an important topic in Europe for many years. There have been a series of activities starting with first projects in 1994 leading to joint actions from the European Network of HTA (EUnetHTA) ending in 2021. This long interval of engagement with HTA structures, methodology, and processes by all member states led to a reliable basis for European collaboration in HTA. This article shows milestones and developments from EUR-ASSESS in 1994 through the progress of EUnetHTA and the accompanying EU-HTA-Network up to the recent elaboration of the EU-HTA-Regulation. With the EU-HTA-Regulation HTA collaboration is taken out of the trial phase of more than 15 years. Through the previous EU HTA collaboration, the appreciation and understanding of the differences and complexities behind the HTA processes in the EU healthcare systems have improved. It is now necessary to make the final steps toward a sustainable European Network for HTA.

Postlaunch evidence generation practices among health technology assessment bodies in Europe.

OBJECTIVES: The term Postlaunch Evidence Generation (PLEG) refers to evidence generated after the launch or licensing of a health technology. The aim of this paper is to provide an overview of the implementation of these practices in the European Union in order to explore cross-border cooperation opportunities. METHODS: In December 2019, a survey composed of nine closed-ended questions with multiple choice answers about the PLEG practices in each country was sent to all twenty-five dedicated work package (WP5B) partners of the European Network of Health Technology Assessment (EUnetHTA) Joint Action 3. In addition to the survey, the national practices were discussed during a face-to-face meeting with WP5B partners. RESULTS: Twelve Health TechnologyAssessment (HTA) bodies completed the survey. Of these, eleven reported procedures in place for official requests for PLEGs in their remit. In the large majority of cases, the requests are made at the time of the assessment/appraisal. Several agencies participate in the definition of the scope of the PLEG or review of its protocol. Data collection and analysis mainly lie with companies for pharmaceuticals, whereas it is more the responsibility of the HTA bodies for medical devices. Only one agency owns the data and is able to exchange them without asking permission. CONCLUSIONS: Most agencies recommend European collaboration on PLEG commence once the evidence gaps have been defined or during the production of the HTA report in the case of European joint assessment.

Early Dialogues for Pharmaceutical Products in European Network for Health Technology Assessment Joint Action 3: What Was Done and Where to Go in the Future.

OBJECTIVES: The aim of this article is to describe the process, results, and experiences of European Network for Health Technology Assessment (EUnetHTA) Joint Action 3's (JA3) Early Dialogue (ED) activities and to highlight opportunities for improving the processes. METHODS: A descriptive analysis of the steps of the EUnetHTA ED process and evaluation of the data from the EDs conducted by EU health technology assessment (HTA) bodies, published guidelines, and documents, as well as internal statistics. RESULTS: In JA3, an Early Dialogues Working Party (EDWP) was established, responsible for developing and improving processes and providing advice to pharmaceutical companies, supported by the ED Secretariat. From June 2017 to May 2021, 113 requests for pharmaceutical EDs were received and 38 conducted. The process was continuously optimized, and different approaches for involving patients were tested. Finally, a centralized procedure was chosen with the key documents produced by two responsible agencies and reviewed by the EDWP. Patient involvement was primarily done by interviewing a national patient representative to obtain general feedback on the disease and the planned study design. CONCLUSIONS: During JA3, EDs were established as an efficient, successful product. Pharmaceutical companies benefited not only from the positions of the individual agencies for the national HTA, but also from the recommendations that were common to all HTA authorities. In addition, regarding the European HTA Regulation, it will be important to conduct Joint Scientific Consultations with a view toward future Joint Clinical Assessments and to further develop processes aligned with the high demand for consultation.

The fourth edition of the European Network for Health Technology Assessment Forum: highlights and outcomes.

The European Network for Health Technology Assessment (EUnetHTA) organizes an annual Forum with stakeholders to receive feedback on its activities, processes, and outputs produced. The fourth edition of the EUnetHTA Forum brought together representatives of HTA bodies, patient organizations, healthcare professionals (HCPs), academia, payers, regulators, and industry. The aim of this paper is to provide an overview of the highlights presented at the 2019 EUnetHTA Forum, reporting the main items and themes discussed in the plenary panel and breakout sessions. The leading topic was the concept of unmet medical need seen from different stakeholders' perspectives. Breakout sessions covered the joint production of assessment reports and engagement with payers, patients, and HCPs. Synergies, pragmatism, and inclusiveness across Member States and stakeholders were emphasized as leading factors to put in place a collaboration that serves the interest of patients and public health in a truly European spirit.

[Ductal carcinoma in situ diagnosis: 3 French national guidelines]. / Diagnostic du carcinome canalaire in situ : 3 recommandations nationales françaises.

OBJECTIVE: Since the last guidelines published by the French National Cancer Institute (INCa) and the learning society "Société française de sénologie et de pathologie mammaire (SFSPM)" in 2009 about diagnosis and management of ductal carcinoma in situ, new data raised issues about overdiagnosis and its consequences, overtreatment. Therefore, an update was necessary, to provide healthcare professionals up-to-date guidelines and study therapeutic desescalation in particular. METHODS: The clinical practice guidelines development process is based on systematic literature review and critical appraisal by a multidisciplinary experts workgroup. The recommendations are thus based on the best available evidence and experts agreement. Prior to publication, the guidelines are also reviewed by more than 100 independent practitioners in cancer care delivery. RESULTS: This article presents French guidelines about MRI and vacuum assisted breast biopsy indications for DCIS diagnosis and the management of low-grade DCIS.

European regulation on orphan medicinal products: 10 years of experience and future perspectives.

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.

Clinical Trials Legislation - preparing for the revision of the European Directive Scheduled for 2011.

The aim of the Round Table was to make recommendations with regard to the imminent revision of the European Directive on clinical drug trials (2001/20/CE). While recognising the importance of compliance with this Directive, which is not optimal in some member states of the European Union, it would be constructive to simplify further and harmonise its application in every country. Without necessarily resorting to a revision, some of the Directive's dispositions could be improved, such as the definition of "investigational medicinal products" (IMP) and what should be considered as "substantial amendements", as well as harmonising and improving the way in which Ethics Committees are run, either on a European Commission level, or by relying more on the European Network of Research Ethics Committees (EUREC) which already exists in several European member states. Other points in the Directive do require revision, especially those relating to: the definition of the respective roles of Ethics Committees and Competent Authorities, the simplification of safety information to Ethics Committees (giving them access to the Eudravigilance database for adverse reactions occurring during clinical trials and providing them with only new safety issues or with a summary of the Annual Safety Report), the possibility of one single European authorisation for the trial, centralised and/or decentralised, when the trial is multinational. The recommended changes could be made within the scope of a European Regulation, avoiding the need to transpose it at a later date into each country's regulations, which is a source of possible lack of harmonisation. More specifically, for trials with institutional sponsors and/or investigator driven trials such as "drug therapy strategy trials", modulating restrictions according to the "risk added by the research" would enable the trial's organisation to be simplified regarding monitoring, adverse reactions reporting and study drugs labelling.

Exploratory clinical trials: implementation modes & guidelines, scope and regulatory framework.

The working group focused on defining exploratory trials on medicinal products and developing recommendations for their implementation in France (notably concerning non-clinical requirements, the pharmaceutical quality of the investigational medical product and the conditions under which this type of clinical trial may be performed).To this end, the working group took account of existing guidelines (notably those in the USA and Belgium) and a draft revision of the ICH M3 guideline.Exploratory trials are clinical trials performed early in Phase I, prior to dose escalation and safety and tolerability trials. These trials are de facto first-in-man studies but lack a therapeutic or diagnostic goal and do not seek to establish the maximum tolerated dose (MTD). The objective is to answer precise questions which condition the continuation or suspension of the drug's development program. Exploratory trials include a small number of patients or healthy subjects and expose them (over a short period of time) to a low dose of an investigational medicinal product.The draft revision of M3 describes five approaches (two involving microdoses and three with pharmacological doses).The group's main recommendations can be summarized as follows:An exploratory trial may be performed when it is (i) justified, (ii) useful for product development and (iii) consistent with prerequisites. The pharmaceutical dossier should take account of the low quantity of product available, the short period of product administration and the low doses used. Good Manufacturing Practices can be adapted accordingly. The non-clinical dossier should also be adapted to suit the development phase and particular features of product use. In this respect, the group has commented on the recommendations in the draft revision of M3. The protocol must be designed to provide answers to a set of specific, pertinent questions concerning this administration phase - particularly on choice of the initial dose, the size of the dose escalation and the rules for subject withdrawal and trial suspension. In general, so-called "vulnerable" populations should not be involved in this type of trial, apart from duly justified exceptions. The group considered that approaches 3 to 5 should only apply to a medicinal product intended for treatment of a severe or rare disease or a condition with significant unmet medical needs. Pre-filing at the Afssaps (the French Agency for Healthcare Product Safety) is recommended, notably for approaches using pharmacological doses.

Committee for the protection of persons.

The transposition into French law of Directive 2001/20/CE, which relates to good clinical practice in the conduction of trials on drugs for human use, has required the modification of certain provisions that concern the protection of persons participating in biomedical research, in particular those provisions concerning the conditions for the authorisation of biomedical research. Declaration to the competent authorities now comes prior to authorisation and, henceforth, the prior opinion of a Committee for the Protection of Persons (CPP) must be expressly favourable in order for a trial to be undertaken. Proposals are put forward by this Round Table in order to promote the stability and professionalism of the CPPs.

Adaptation of the clinical trials directive: recommendations on the contents of a dossier for the request for authorisation of the first trials in human subjects.

The European Directive on clinical trials of medicinal products will fall within the scope of the legislation of Member States on 1 May 2004. In France, this adaptation will be carried out by a public health bill concerning, among other things, the reform of the current Huriet-Sérusclat law, and by means of regulations. For trials concerning the initial administration of a product to human subjects, the group suggested the following recommendations: In French texts, to include a deadline of 30 days for the initial authorisation by the competent authority (Afssaps [Agence française de sécurité sanitaire des produits de santé]). To maintain an observed deadline of 20 days (35 official days) for the decision of the Ethics Committee (EC) [Committee for the Protection of Persons (CPP)]. To obtain a more specific evaluation of the pharmaceutical dossier of the investigational medicinal product (IMP) from the competent authority. To provide both bodies with nonclinical and possibly clinical data concerning the IMP information of the participants and their consent. To follow the recommendations posted on the Afssaps website for the entire IMP dossier. To submit a protocol under the International Committee on Harmonisation (ICH) E6 format adapted for phase I and, possibly as a separate document, justification of a certain number of points (a total of ten) that are more specific to this trial phase to facilitate and improve the document review while also providing the expected guarantees. To limit the 'substantial' amendments to those provided for in the European guidelines. To break the blind for every serious event reported to the sponsor by the investigator, and report to the competent authority any serious adverse event related to the IMP or to the trial or without documented cause, while keeping ECs and investigators informed. Furthermore, certain points concerning the authorisations for packaging, labelling and dispensing of the batches of medicinal products for clinical trials will need to be specified for these early studies. All these recommendations are intended to help promote the development of studies involving the initial administration of medicinal products in France.