EU Clinical Trial Regulation Building A Successful Programme
EU Clinical Trial RegulationBuilding a successful programme
Table of contentForward3Introduction4Demystifying the Clinical Trial Regulation5Introduction to the CT Portal and Database9Timeline for CTR compliance10What does Brexit mean for clinical trial applications?11CTR touchpoints within the industry13Smart steps to develop your CTR implementation approach14Conclusion19Contacts20References21
EU Clinical Trial Regulation Building a successful programmeForwardThe Clinical Trial Regulation (CTR) is set to revolutionise the way clinical trial processes are run across Europe impacting allEU member states and companies who wish to run clinical trials in the EU. Diligent member states, ethics committees andPharmaceutical Companies are already preparing for this unprecedented change and those who have not, should soon beginpreparing to avoid facing significant challenges when the legislation comes into force.To be ready for the changes the regulation brings companies need to already be reviewing their current processes, systemsand supporting infrastructure for clinical trial applications and operations. They need to do so in every changing regulatoryenvironment where Clinical Trial and related data is being ever more scrutinised.This paper provides a synopsis of the new regulation, including insights on timing, the advantages of preparedness and theimpact that Brexit may have. It also provides guidance on how companies can set up a successful CTR programme.3
EU Clinical Trial Regulation Building a successful programmeIntroductionIn 2014, the European Medicines Agency (EMA) releasedClinical Trial Regulation EU No 536/2014 [1] to harmonisethe assessment and supervision processes for clinicaltrials on medicinal products for human use. It builds onDirective 2001/20/EC[2] and the ideals represented in theVoluntary Harmonisation Procedure (VHP)[3] by the Heads ofMedicines (HMA) Clinical Trials Facilitation Group (CTFG).Once effective, it will drive: efficiency through harmonisation of CT application processacross Europe greater transparency in clinical processes and data enhanced safety and efficacy of drugs.The new regulation is applicable for Investigational MedicinalProducts (IMP) for human use and does not apply to noninterventional trials or trials without medicinal products suchas devices or surgery etc. The regulation seeks to provide asingle, unified portal and database for both trial sponsorsand regulatory agencies in each member state. For sponsorsthe portal will be the main platform to submit applicationsand notifications and it allows regulators to perform theirassessments and supervise the trial.High level changes brought in by the new regulation include: streamlining the process for clinical trial application acrossEU procedures for assessing and authorising clinical trials,removing duplication and reducing delays in the process introducing a lighter regulatory regime for trials conductedwith medicines that are already authorised and which poseminimal risk compared to normal clinical practice simplifying reporting requirements, sparing researchersfrom submitting largely identical information on theconduct of the study to various bodies formally recognising co-sponsorship, which acknowledgesthat a trial can be led by more than one organisation introducing the concept of a single decision on a clinicaltrial, which will replace the previous separate approvalsgiven by the National Competent Authorities and Ethics(NCAE) committees. This also reduces the administrativeburden on the Member States Concerned (MSC),particularly the elected Reference Member State (RMS)Highlights of Directive 2001/20/EC & CTR 536/2014Directive 2001/20/ECClinical Trial Regulation 536/2014 Directive implemented in 2004 CTR published in 2014 Multiple application submission forrespective National CompetencyAgencies and Ethics Committee foreach MSC for single trial Harmonized process acrossEU-Single application submissionto all MScs Individual assessment conclusionand decision for each MSC with nocollaboration tool Limited information available to thepublic Introduction of a single platformfor submission of clinical trialapplication across the EU Collaborated assessment conclusion and decision using the CTPortal and Database All information (except agreedPersonally Protected Data andCommercially ConfidentialInformation ) available to the publicFigure 1: Highlights of Directive 2001/20/EC & CTR 536/2014In March 2017, the European Medicines Agency (EMA)presented their high level view [4] on the move fromthe directive to the regulation and the pathway toimplementation of the portal and database.4
EU Clinical Trial Regulation Building a successful programmeDemystifying the ClinicalTrial RegulationThe new EU CTR encompasses four main businessprocesses within the end to end clinical trial process. Itmandates industry to change their existing ways of workingin the short term and revolutionise the whole enterprisearchitecture in key areas of the clinical process in the encyFigure 2: Demystifying the CTRIndustry and member states will need to ensure that dataand documentation is submitted within the timelines definedby the regulation and adhere to strict business rules. Suchrequirements, if not met, may result in delays, higher costs5and increased effort. Missing critical milestones may leadto applications being considered either lapsed or validatedby default, dependent on the stage of application and withwhich party a critical activity lies.
EU Clinical Trial Regulation Building a successful programmeThe clinical trial applicationThe regulation requires a more comprehensive set ofapplication information. An application consisting of Part Iand/or Part II will be created centrally via the new CT Portal;Part I consists of information related to the trial, productand protocol whereas Part II consists of data specific to themember states where the trial will be run.There are four application types: initial application; the first application to be submitted bythe sponsor when applying for a new clinical trial in the EU substantial modification application; an application tosubmit a request for substantial changes to an authorizedclinical trial. non-substantial modification application; anapplication to submit non-substantial changes to anauthorised clinical trial. additional MSC application; An application to submit anadditional member state to an authorised clinical trial.Application assessmentApplications are assessed by the appropriate regulators fromindividual member states and based on strict timelines asdefined in the regulation. The assessment of Part I is carriedout by the RMS with the support of other MSC and theassessment of Part II is carried out by the MSC.The initial application assessment:Assess Part IValidationconclusionrecordedRMS should havecirculated draftassessment reportMSCs should havedocumentedconsiderationsPart IconclusionrecordedDay 0Day 26Day 38Day 45Validate ApplicationApplicationsubmittedRMSselectedBy Day 3Day 0MSCs expresswillingnessSubmit DecisionBy Day 6ValidationConclusionDuring this time,an RFI might beinitiatedPart I andPart IIconcludedAssess Part I can be extended by up to 50 days.During this time, the RMA may submit an RFI to thesponsor which extends the time for 31 days.By Day 10Assess Part IIDay 0During this time, the RMA may submit an RFI tothe sponsor which extends the time for 31 days.Day 0Day 45ValidationconclusionrecordedPart IIconclusionrecordedDay 5ApplicationdecisionrecordedFigure 3: Initial Application Assessment Timeline*For the purpose of consulting with experts, a trial involving an advanced therapy investigational medicinal product (ATMP) or a product defined inthe Annex of Regulation (EC) No 726/2004 [5], an additional 50 days may be taken by the reporting Member State beyond that of the 45 days sincethe validation date, for the submission of the final Part I assessment including its conclusion.Throughout the assessments, sponsor organisations are expected to respond to information requests raised by regulators.6
EU Clinical Trial Regulation Building a successful programmeClinical trial notification and submissionDuring the course of running clinical trials, sponsors arerequired to submit various notifications via the CT Portal andDatabase, such as key trial milestones and important safetyinformation. At the end of the trial, sponsors are expected tosubmit the necessary reports approval purposes.Clinical trial publicationThrough the CTR, EMA promotes transparency in theend to end process. With the exception of sensitive andcommercially confidential information, information storedin the database is published based on strict rules. Sponsorsare allowed to manage the deferral of the publication via theportal.EMA Policy 0070 [6] was published in 2014 and is the officialpolicy for EU clinical data publication and the promotion oftransparency of clinical data for the benefit of public safetyand expedition of products to market. This paper does notdiscuss in depth Policy 0070 which is a considerable topicin its own right, however by considering some high-levelcomponents of Policy 0070 and CTR publication, the scopecovered by both for the transparency of data for clinical trialsbecomes clearer.Policy 0070Clinical Trial RegulationCentrally authorised products onlyInvestigational medicinal products, regardless ofwhether they have a marketing authorisationClinical studies submitted to the Agency in thecontext of a MAA, Art 58 procedure, line extensionor new indication, regardless of where the studywas conductedClinical trials conducted in the EU and paediatrictrials conducted outside the EU that are part ofpaediatric investigation plansClinical data (clinical overview, clinical summariesand clinical study reports) and the anonymisationreportAll clinical trial-related information generatedduring the life cycle of a clinical trial (e.g. protocol,assessment and decision on trial conduct,summary of trial results including a lay summary,study reports, inspections, etc.)Publicationchannel Date itappliesEMA clinical data publication websiteFuture EU portal and database1 January 2015 (MAA or Art 58 procedure) or 1 July2015 (line extension or new indication)Expected in 2020PublicationfromOctober 2016Expected in 2020Medicinalproduct clinicalstudies coveredDocumentscoveredFigure 4: Policy 0070 vs CTRSource: EMA website [7], Appendix, on disclosure rules, to the “Functional specifications for the EU portal and EU database to be audited EMA/42176/2014” [8]7
EU Clinical Trial Regulation Building a successful programmeThe new CTR hopes to not only to attract sponsors to runresearch and development activities in the region but alsoto foster a patient centric and innovative environment. It willencourage increased transparency throughout the entireend to end process; from application submission to marketauthorisation.The regulation strongly promotes transparency of trial datawith it being publically accessible by default. There are afew exceptions as explained in the regulation [1] Article 81paragraph 4:The EU database shall be publicly accessible unless, forall or part of the data and information contained therein,confidentiality is justified on any of the following grounds:separate cases, in particular Policy 0043 – policy on access todocuments [9]: Case T-235/15 - Pari Pharma v EMA [10] Case T-718/15 - PTC Therapeutics International v EMA [11] Case T-729/15 - MSD Animal Health Innovation and IntervetInternational [12].As a result, rather than fighting the direction of travel forincreased transparency, organisations are likely betterinvesting their resources in their internal processes torecognise, minimize and allow appropriate redaction ofCommercially Confidential Information (CCI) and ProtectedPersonal Data (PPD) prior to a CT application.a. protecting personal data in accordance with Regulation(EC) No 45/2001;Safety reportingb. protecting commercially confidential information, inparticular through taking into account the status of themarketing authorisation for the medicinal product, unlessthere is an overriding public interest in disclosure;The regulation aims to also simplify the rules on safetyreporting so that:c. protecting confidential communication between MemberStates in relation to the preparation of the assessmentreport;d. ensuring effective supervision of the conduct of a clinicaltrial by Member States.In February 2018, the European General Court ruled infavour of the EMA’s approach to transparency on three not all adverse events (AE) and serious adverse events arerecorded and reported for clinical trials that involve more than one investigationalmedicinal product (IMP) a single safety report can besubmitted via the Eudravigilance system suspected unexpected serious adverse reactions (SUSARs)will be reported via the new Eudravigilance system annual Safety Reports (ASR) can be submitted via the CTPortal and Database by the sponsor of the clinical trial.8
EU Clinical Trial Regulation Building a successful programmeIntroduction to the CTPortal and DatabaseThe European Medicines Agency (EMA) will release andhost the CT Portal and Database which aims to support thenew CTR. The CT Portal and Database will be used by bothsponsors and member state authorities throughout theapplication, assessment and supervision processes. Theportal also enables the publication of relevant informationstored in the database into the public domain.Overview of business functionality Submission of Initial application Submission of Substantial or Nonsubstantial Modification applicationSponsorworkspace Assessment of application dossier(Part I and/or Part II) Submission of application decision Submission of Additional MemberState Concerned application Assessment of additionalinformation Respond to Request for information Submission of corrective measure(s) Submission of trial and subjectmilestone(s) Inspection planning and report Submission of Serious Breach(es),Serious Adverse Event(s) or NonSafety Measure(s) Request to defer publicationinformation Management of user roles andpermissions Deferral of publication ofassessment informationAuthorityworkspace Manage user roles and permission Overview of clinical trial statistics Download of data and documentsPublicworkspaceFigure 5: Overview of Business FunctionalitySource: EMA - Functional specifications for The EU Portal and Database, EMA, March 2015 [13]The CT Portal and Database offers features that will helpusers in the end to end processes such as document9management, task management, notices and alerts andreporting functionalities.
EU Clinical Trial Regulation Building a successful programmeTimeline for CTR complianceEMA originally published the timeline for CTR and the CTPortal and Database in 2015 [14]. However, due to delaysfor technical reasons EMA have been required to revise theschedule. The EU CTR is currently estimated to becomeapplicable mid 2020 instead of October 2018 as originallyplanned.In an update in March 2018 EMA stated:”The plan shows that the auditable version should beavailable for audit in early 2019, as required by the ClinicalTrial Regulation.2019Q1Q22020Q3Q4Q1Q2Auditable versionof the CT portalreleased for ndentAuditCompleted2023Q4Transition andImplementation PhasePreparation and Audit Phase1MQ3EU Commissionnotice published inOfficial Journalof the EUAuditendorsedby versiongo-liveDirective on CT2001/20/EC nolonger applicableNote on the Transition Period:Year 1: Clinical trial applications may be made either under thenew Regulation using the EU portal and database, or underDirective 2001/ 20/ EC.Year 2 & 3: Clinical trials authorised under the Directive willcontinue to be governed by that Directive.Year 3 : Any trials authorised under the Directive and stillongoing will be governed by the Regulation from that point on.Figure 6: Timeline for CTR ComplianceThe timelines shown are determined by starting with the updated audit commencement as expressed in EMA’s notification of delay and applying thedurations between milestones that EMA originally defined in December 2015 within document EMA/760345/2015 – Delivery time frame for the EUportal and EU database [14].1. Preparation and audit phaseDuring this phase, EMA will manage the developmentof the CT Portal and Database based on the regulation.A series of agile User Acceptance Testing (UAT) is beingperformed on the Clinical Trial portal and Databasewith consultation and feedback from Member State andindustry representatives (UAT 6 was recently completed).After this phase the portal will be prepared forindependent audit once its development is completed.Post go-live, an official notice will be published by theEuropean Commission (EC).2. Transition and implementation phaseWhen Regulation 536/2014 becomes applicable, there isa three year transition period where Directive 2001/20/EC will be applicable concurrently with the CTR. In thefirst year of the transition period, new CT applications canbe either be submitted under the old directive or the newregulation (via the portal).In the second and third year of the transition period, allnew CT applications (initial application) must be createdvia the CT Portal and Database. It is expected that allclinical trials that were authorised through the Directivewill remain, at least during the transition period, withinEudraCT. After three years, all clinical trial applications willhave to switch to the new regulation.10
EU Clinical Trial Regulation Building a successful programmeWhat does Brexitmean for clinical trialapplications?In 2016, the United Kingdom triggered Article 50 whichstarted the process of leaving the European Union. Basedon the regulation, regardless of where a company wishesto run clinical trials in the EU region, it will need to adhereto Regulation 536/2014. Depending on the outcome of theBrexit agreement, and the possibility that after exit the UK’sregulation could diverge from that of the EU, running clinicaltrials in the UK may result in additional compliance with UKbased regulation. There is also the question of how existingtrials that are currently run in the UK and the EU will bemanaged moving forward after Brexit. This will impact allpharmaceutical companies and regulators in member states,as well as existing patients.At the time of writing, EMA has prepared some Brexitprocedural guidance[15] and [16] and within its Brexitpreparedness plan [17] the Agency has stated that thecontinuation of the CT project to provide a Clinical TrialPortal and Database is a category one priority (the highestpriority) “Some projects with legal deadlines (clinical trials,EudraVigilance) as well as other projects (SPOR)” Substance,Product, Organisation and Referential master data. EMAhas also made it clear, as things currently stand, prior to anyformal agreement, that when the UK leaves the EuropeanUnion they will be considered a third country. “EMA isworking on the assumption that the UK will become a thirdcountry as of 30 March 2019.”[18]. While this message fromEMA goes beyond the CTR, when related to the Portal andDatabase, it means Brexit should not impact the timeline forthe remaining 27 member States to become compliant toCTR.For existing Marketing Authorisations, The EMA guidancediscusses the requirement to transfer UK MAs and that itis possible to do so during ongoing regulatory procedures[15]-4a. The EMA guidance suggests that “MarketingAuthorization Holders should consider the timelines of therespective procedures and plan in order to avoid a situationwhere decision making processes of the procedures willoverlap.” For an application/trial where the UK is an RMS orMSC, excluding product
Clinical Trial Regulation Building a successful programme 4 In 2014, the European Medicines Agency (EMA) released Clinical Trial Regulation EU No 536/2014 [1] to harmonise the assessment and supervision processes for clinical trials on medicinal products for human use. It builds on Directive 2001/20/EC[2] and the ideals represented in the
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