Controlled human infection trials: Legitimacy and conditions of implementation in France.

This round table is the result of an observation. The observation being that controlled human infection clinical trials (also called "infectious challenge" trials or "Controlled Human Infection Models", "CHIM") recommended or even encouraged in the context of vaccine developments in particular, are not carried out in France. However, there are no formal prohibitions within regulations or ethical principles, which point to the prior assessment of risks and benefits for individuals and for society. The participants in this Round Table thus wished to examine, through the prism of their respective disciplines, the scientific and medical relevance of conducting such trials in France and, if possible, to imagine the conditions under which they would be carried out, thus resulting in recommendations on (1) the advisability of their conduct in France (2), the conditions under which they would be implemented in terms of logistics and regulations, and (3) their social acceptability. The recommendations on which the participants of the Round Table came to an agreement are presented as the analysis progresses.

Clinical Trial Authorisation: A Final Look Back to Better Appraise the New European Regulation.

The implementation of the new European Clinical Trial Regulation on 31 January 2022, is a major step to promote clinical research in Europe. The French National Agency for Medicines and Health Products Safety (ANSM) proposes to share some key aspects of the preparation for the application of the Regulation initiated in 2017 and to discuss shared indicators that should be considered to monitor clinical trials opportunities on a territory with regards to access to innovation for patients and attractiveness for sponsors. New criteria based on the time from the first request for authorisation to the first inclusion could be of particular interest to appraise the implementation of the European Clinical Trial Regulation.

[Main characteristics of the new authorisation procedure for clinical trials with medicinal products according to regulation (EU) no 536/2014 and the cooperation between the member states]. / Grundzüge des neuen Genehmigungsverfahrens für klinische Arzneimittelprüfungen im Rahmen der Verordnung (EU) Nr. 536/2014 und der Zusammenarbeit zwischen den Mitgliedstaaten.

With Regulation (EU) No. 536/2014 on clinical trials on medicinal products for human use, which became applicable on 31 January 2022, full harmonisation of the authorisation and monitoring procedures of clinical trials with medicinal products in the European Union (EU) and the European Economic Area (EEA) has been achieved. In addition to an entirely paperless application procedure, communication between all parties involved is done through the Clinical Trials Information System (CTIS), which was developed specifically for the Regulation and through which all non-proprietary information and content of the clinical trial application and results are also made available to the public. As was already the case under the old legal framework, the authorisation of a clinical trial is granted by each Member State concerned; however, the assessment of the common part of the dossier of a clinical trial that is conducted in more than one Member State is jointly done by the respective Member States under the coordinating lead of a reporting Member State. The present article outlines the authorisation procedure with its deadline concept and addresses further aspects of the Regulation, such as details on the protection of the trial subjects, safety reporting and transparency rules.

[First experiences with the implementation of EU Regulation 536/2014 (CTR) from the perspective of non-commercial academic research]. / Erste Erfahrungen bei der Umsetzung der EU-Verordnung 536/2014 (CTR) aus Sicht der nichtkommerziellen akademischen Forschung.

With the implementation of the new EU Regulation 536/2014 (Clinical Trials Regulation - CTR) on 31 January 2022, the approval and conduct of clinical trials with medicinal products for human use are to be harmonized within the European Union (EU). Approval is granted via the electronic Clinical Trials Information System (CTIS) portal of the European Medicines Agency (EMA). In addition to commercial sponsors, sponsors at academic institutions are also affected by the implementation of the CTR in the context of investigator-initiated clinical trials (IITs). Numerous changes in the process map for regulated drug trials are necessary.New aspects concern the general user structure and the role and permission concept of CTIS. Requirements that previously applied only to investigational medicinal products/placebo now also apply to auxiliary medicinal products. Investigational and auxiliary medicinal products not yet approved in the EU must be registered in the XEVMPD drug database. Other significant changes include the reporting of "serious breaches," the publication of relevant study documents, the introduction of a "summary in layman's terms," the archiving period of 25 years, the implementation of "low intervention clinical trials," and the possibility of co-sponsorship.First experience with the application process shows that the new system needs to be further improved. This concerns, for example, the EU-wide harmonization of requirements and the elimination of technical deficiencies. In the medium and long term, however, simplifications with regard to regulatory processes should be noticeable. What is needed here are intensified agreements with national higher authorities and ethics committees, effective knowledge management, and improved communication.

[The national legislation accompanying the approval procedure for clinical trials of medicinal products for human use under Regulation (EU) No. 536/2014]. / Die nationale Begleitgesetzgebung zum Genehmigungsverfahren klinischer Prüfungen mit Humanarzneimitteln im Rahmen der Verordnung (EU) Nr. 536/2014.

The Regulation (EU) No 536/2014 (Clinical Trials Regulation [CTR]) on clinical trials on medicinal products for human use is a challenge not only for sponsors but also for national authorities and ethics committees. Thus, fundamental structural changes were necessary for the establishment of the novel authorisation procedure. The necessary accompanying law was created in 2016 with the Fourth Law on the Amendment of the Medicinal Products Act (4th AMGÄndG) and in 2017 with the Clinical Trial Assessment Procedure Ordinance (KPBV).The 4th AMGÄndG provided for legal amendments to the Medicinal Products Act (AMG) that came into force in advance of the date of application of the CTR. Essentially, this concerns the introduction of a registration obligation for ethics committees at the Federal Institute for Drugs and Medical Devices (BfArM). In addition, the 4th AMGÄndG contains regulations that came into force at the beginning of 2022, in parallel with the date of application of the CTR. The Regulation on the application of Good Clinical Practice in the conduct of clinical trials of medicinal products for human use (GCP-Regulation, GCP-V) was repealed. The 6th section of the AMG on the protection of humans in clinical trials has been rewritten to supplement the requirements of the CTR and to fit the procedural flow into the national legal system. In particular, this concerns the regulations on the cooperation between higher federal authorities and ethics committees, such as responsibilities, deadlines, procedures and fees. Regulations were also made for the national procedure of release authorisation for clinical trials with medicinal products containing or consisting of genetically modified organisms (GMOs) as well as special protective regulations for special groups of participants.

[Clinical trials with investigational medicinal products-initial experiences with the new EU clinical trial regulation 536/2014 and challenges and opportunities for contract research organisations]. / Klinische Prüfung von Arzneimitteln ­ erste Erfahrungen mit der neuen EU-Verordnung 536/2014, Herausforderungen und Chancen für Auftragsforschungsinstitute.

The new authorisation procedure for clinical trials on medicinal products according to Regulation (EU) No 536/2014 (Clinical Trial Regulation - CTR) became applicable in the European Union and the European Economic Area on 31 January 2022. All involved parties communicate digitally via a specially programmed IT system, the Clinical Trial Information System (CTIS), provided by the European Medicines Agency (EMA). This article highlights the cooperation between sponsors and Contract Research Organisations (CROs) when applying the CTR and CTIS.First experiences and observed trends are described focusing on user administration in CTIS and on activities related to the protection of personal data and commercially confidential information (CCI) when clinical trials are published. Challenges for CROs are multifaceted and are discussed from different angles. For example, it is necessary for CROs to temporarily maintain a Quality Management System that serves both "systems": clinical trials under the EU-Directive 2001/20 as well as under the CTR. CTR and CTIS offer not only new tasks for CROs; they often become advisors for sponsors on the basis of their extensive experience, for example, regarding the cooperation model between sponsors and CROs and/or the strategic model for submission of a clinical trial. The article concludes with a look into possible future sponsor outsourcing strategies.

[Evaluation of clinical trials on medicinal products by ethics committees: changes due to the new EU Regulation 536/2014 (CTR) and necessary harmonization measures]. / Bewertung klinischer Arzneimittelprüfungen durch Ethikkommissionen: Änderungen durch die neue EU-Verordnung 536/2014 (CTR) und nötige Harmonisierungsmaßnahmen.

After Regulation (EU) No. 536/2014 (Clinical Trial Regulation, CTR) of the European Parliament and of the Council took effect on 31 January 2022, the application process for clinical trials fundamentally changed. This article describes the fundamental procedural changes and the resulting changes for Germany and, in particular, for the ethics committees. The harmonization efforts of the ethics committees at the EU level are discussed.According to the new EU regulation, only one ethics committee is involved in the approval of a clinical trial of medicinal products in Germany. The previous consultation procedure involving several locally competent ethics committees has been replaced. Instead, there is now closer cooperation between the ethics committees and the federal authorities through the preparation of a joint assessment report as well as with the other EU member states as part of the consolidation of the respective country-specific requirements. The regular mutual exchange between the ethics committees that had previously accompanied the consultation procedure helped to harmonize the decision criteria but also the discretionary decisions. Due to the discontinuation of this exchange, more detailed procedural recommendations are required but also other regular exchange possibilities in order to not only maintain but also to advance harmonizations already in place. The Working Group of Medical Ethics Committees (AKEK), as the representative of the individual ethics committees, also maintains an intensive exchange with federal authorities, applicants, other European ethics committees and European institutions.

Impact of the Clinical Trials Act 2018 on clinical trial activity in Japan from 2018 to 2020: a retrospective database study using new and conventional Japanese registries.

OBJECTIVE: To clarify the impact of Japan's Clinical Trials Act (CTA), which was enacted in April 2018, on subsequent clinical trial activity through an analysis of Japanese registry data. DESIGN: Retrospective database study. SETTING: We extracted information on clinical intervention studies registered between 1 April 2018 and 30 September 2020 in the conventional University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) and the new Japan Registry of Clinical Trials (jRCT). We collected and analysed information on registration dates, intervention types, funding, secondary sponsors and use of designated staff in multidisciplinary roles (research planning support, research administration, data management, statistical analysis, monitoring and auditing). The temporal trends in clinical trial activity after CTA enactment were examined. RESULTS: A total of 577 CTA-compliant specified clinical trials (ie, studies funded by pharmaceutical companies or studies evaluating the efficacy and safety of off-label drugs or devices in humans) were registered in the jRCT. During the same period, 5068 clinical trials were registered in the UMIN-CTR. The number of specific clinical trials increased immediately after the implementation of the CTA and stabilised in late 2019, whereas the number of clinical trials registered in the UMIN-CTR generally declined over time. Specified clinical trials that received industry funding and public grants were more likely to use designated staff in multidisciplinary roles. CONCLUSIONS: The implementation of the CTA has not reduced the number of specified clinical trials, but has reduced the total number of intervention trials. The use of designated staff in multidisciplinary roles is associated with funding, secondary sponsors and multicentre studies. It was inferred that funding was needed to establish research infrastructure systems that support high-quality research.

[Implementation of the European regulation 536/2014 in Italy: the neverending story.] / Implementazione del regolamento europeo 536/2014 in Italia: la storia infinita.

The European regulation 536/2014, unapplied for several years due to the inoperability of the European Portal, represented an epochal turning point in the legislation concerning pharmacological clinical trials. Although, unlike the directive, it could be directly applied without national transpositions, in Italy this has not been possible and for three months now we have been witnessing a haemorrhage of guidelines/operational proposals/decrees that to date do not make us ready to fully operate according to the new rules. Il regolamento europeo 536/20141, in vigore dal 16 giugno 2014 e rimasto per diversi anni non applicato per un ritardo nella messa in funzione del portale unico europeo, ha rappresentato una svolta epocale nella normativa inerente le sperimentazioni cliniche con farmaco. La normativa precedentemente in vigore2, infatti, pur rappresentando la prima trasformazione in legge delle Good Clinical Practices e un primo tentativo di armonizzazione tra le procedure regolatorie dei diversi stati membri, aveva portato a una serie di risvolti negativi, come un aumento vertiginoso dei costi e dei tempi necessari ad avviare uno studio. Tutto ciò, negli anni, si è tradotto in una deflessione delle richieste di autorizzazione delle sperimentazioni e in una grande difformità tra gli stati membri3,4. Il regolamento introduce delle novità mirate a ottimizzare profondamente l'iter regolatorio di approvazione delle sperimentazioni, primo fra tutti il nuovo processo di autorizzazione, che prevede l'espressione di un unico parere a livello europeo e la singola decisione, a livello di singolo stato membro, di accettare o non accettare tale decisione. Il nuovo processo, molto ambizioso da un punto di vista della riduzione dei tempi, doveva rappresentare una occasione storica per l'incremento delle performance di Paesi come l'Italia, da sempre penalizzata da una burocrazia molto complessa e dalla necessità di procedere con molteplici valutazioni da parte dell'autorità competente e di numerosi comitati etici5,6. I ritardi nella messa in funzione del portale, inizialmente prevista per maggio 2016, hanno portato a un lungo e continuo slittamento dei tempi di applicazione del regolamento, alla fine calendarizzata per il 31 gennaio 2022. Sei anni di attesa che, almeno sulla carta, hanno fornito l'occasione a tutti gli stati membri di prepararsi al meglio a tutti i cambiamenti che il regolamento avrebbe comportato.La scelta, da un punto di vista prettamente legale, di un regolamento piuttosto che di una nuova direttiva aveva lo scopo di evitare una ulteriore difformità di azione tra le diverse nazioni; il regolamento, infatti, a differenza della direttiva non necessita di successivi passaggi legislativi a livello nazionale e poteva essere direttamente implementato nei singoli stati membri. Alcune nazioni si sono preparate all'applicazione del regolamento procedendo con una profonda revisione e semplificazione del proprio apparato regolatorio; è il caso, per esempio, della Spagna, che ha optato per un unico decreto in grado di regolare tutti gli aspetti inerenti le sperimentazioni interventistiche con farmaco7.Situazione completamente opposta in Italia, dove l'implementazione della vecchia direttiva aveva causato una emorragia di decreti ministeriali e di altri atti legislativi che difficilmente potevano venire riorganizzati, come accaduto in Spagna, in un unico atto. Uno stato che ha portato, ancora una volta e forse in maniera ancora più complessa di quanto accaduto a inizio millennio, a un lungo processo di riorganizzazione legislativa, avviato con il decreto Lorenzin e ancora molto lontano dall'essere completato con tutti i decreti attuativi necessari.

Trends in Investigator-Initiated Clinical Studies at a University Hospital after Enforcement of the 2018 Clinical Trials Act in Japan.

In April 2018, the Clinical Trials Act pertaining to investigator-initiated clinical trials was passed in Japan. The purpose of this study was to investigate activity in investigator-initiated clinical studies before and after enforcement of the new Clinical Trials Act. This was done by analysing the records of the Ethics Committee of Tokushima University Hospital, which reviews studies based on the Japanese government's Ethical Guidelines for Medical and Health Research Involving Human Subjects prior to the Clinical Trials Act, and records of the Certified Review Board established at Tokushima University under the Clinical Trials Act in 2018. The number of new applications to these two review boards during fiscal years 2015-2017 (pre-Act) and fiscal years 2018 and 2019 (post-Act) were used as an indicator of activity in investigator-initiated clinical studies. The number of new applications to the Ethics Committee was 303, 261, 316, 303, and 249 in 2015, 2016, 2017, 2018, and 2019, respectively. The data show that the total number of new interventional studies decreased from 50.3 in average in 2015-2017 (pre-Act) to 42 in 2018 and 40 in 2019 (post-Act), respectively. These results suggest that fewer interventional studies were started following enforcement of the new Clinical Trials Act. To confirm this trend and identify contributing factors, further studies are required. In addition, possible way, such as broader contribution of clinical research coordinators, to promote clinical studies in the new Clinical Trials Act era should be examined.

Adaptive Platform Trials to Transform Amyotrophic Lateral Sclerosis Therapy Development.

Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in neurology. Here, we describe a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS, with the goal of rapidly identifying novel treatments, biomarkers, and trial endpoints. ANN NEUROL 2022;91:165-175.

Why are emerging countries popular for clinical research?

BACKGROUND: The business of clinical research has changed in the past two decades, shifting from industrialised Western countries to so-called emerging markets such as Eastern Europe, Latin America and Africa. An appraisal of the trends could identify associated factors that may have implications for the local populations and their endemic diseases. OBJECTIVES: To identify potential reasons why emerging countries have become attractive places for international sponsors to conduct their clinical trials. METHODS: Using ClinicalTrials.gov, the Pan African Clinical Trials Registry, the National Health Research Database and the Nigeria Clinical Trials Registry, trend data on clinical research development were determined for two emerging African markets, Nigeria and South Africa (SA), from 2010 to 2018. Also, health data on the two countries from the fact sheets of health statistics of the World Health Organization were compared, as well as regulatory and ethical conditions. Available data were analysed using descriptive statistics and trend analysis. RESULTS: The impact of globalisation is evident from the upward trend in clinical trials in SA before 2010, and the clear downward trend thereafter. One reason for this change could be the alignment of SA's regulatory and ethical frameworks with the Western world. In contrast, the upward trend is only just beginning in Nigeria, with the introduction of ethical/regulatory frameworks, and supportive institutions making the business of clinical research more attractive on an international level. Although the number of international and local sponsors increased in Nigeria from 2010 to 2018, only the latter increased in SA, with the former decreasing over the same period. Overall, there is a mismatch between country-specific diseases and the drugs being tested, to the extent that leprosy, which is endemic in Nigeria, and tuberculosis in SA were not in the list of top 10 study areas in either country. CONCLUSIONS: The globalisation trend is evident in the clinical trials business, but cannot be generalised to all emerging countries. Timing and intensity vary from country to country relative to factors that advance the existing profit-orientated business models of the sponsors. Furthermore, various diseases have been localised, which entails a diversely increasing need for research.