CTTM08 - Step-by-step Guide - SM

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Step-by-step guideHow to evaluate a SubstantialModification clinical trial applicationCTIS Training Programme – Module 08Version 1.1 – March 2022Learning Objectives Understand the process involved in the assessment of Substantial Modification Clinical TrialApplication (SM CTA). Remember the workload management functionalities in CTIS that allow users to monitor theirtasks during the evaluation of an SM CTA. European Medicines Agency, 2022Reproduction and/or distribution of the content of these trainingmaterials for non-commercial or commercial purposes is authorised,provided the European Medicines Agency is acknowledged as thesource of the materials.The European Medicines Agency developed this training material toenhance public access to information on the Clinical Trial InformationSystem (CTIS). This material describes a preliminary version of CTISand may therefore not entirely describe the system as it is at the timeof use of this material. The Agency does not warrant or accept anyliability in relation to the use (in part or in whole) or the interpretationof the information contained in this training material by third parties.

How to evaluate a Substantial ModificationSubstantial ModificationA Substantial Modification (SM) is an application to apply a change to any aspect of the ClinicalTrial (CT), which is made after the decision on a previously submitted application and which islikely to either: Have a substantial impact on the safety or rights of the subjects; or On the reliability and robustness of the data generated in the CT.In all cases, a modification is regarded as 'substantial' when one or both of the above criteria aremet.The evaluation process of SM CTAs is established in the Regulation (EU) No 536/2014 on ClinicalTrials (CT Regulation). This process includes Validation, Assessment of Part I and/orAssessment of Part II, and the Decision. Some SMs may concern Part I only, Part II only, orboth, depending on the scope of the modification.Users of the Member State Concerned (MSC) will be able to see what has been modified from therelevant section of the clinical trial application page (i.e. Form, MSC, Part I and/or Part II), underthe ‘Substantial modification details’.This Step-by-step guide includes:Evaluation of aClinical TrialApplication(CTA)Validation andAssessment ofan SMThis section outlines an overview of theevaluation of a clinical trial application process.This section outlines the steps that the MSC ofthe CTA has to follow to validate and assess anSM CTA.This section outlines the steps that each MSCDecision ofan SMperforms to submit a Decision regarding theSubstantial modification CTA (i.e. whether thetrial is ‘Authorised’, ‘Authorised with conditions’,or ‘Not authorised’).2

How to evaluate a Substantial ModificationEvaluation ofa CTAThe evaluation process starts once the sponsor has submittedan initial Clinical Trial Application (CTA). The MSCs canevaluate the documentation provided by the sponsor to ensurethe compliance with the CT Regulation. The evaluation is performedfor the following types of CTAs: Initial CTA, Substantial Modification(SM) and Additional MSC CTA (Add MSC).EVALUATION OF A CLINICAL TRIAL APPLICATIONInitial CTARMSselectionAssessPart IDecisionInitial CTAsubmittedAssessPart II*ValidationSubstantial Modification CTAValidationAnd/orAssessPart IDecisionAssessPart IIAdditional MSC CTAAssessPart IAssessPart IIDecisionFocus of this document.Content included in module 06 eLearning Step-by-step guide RMS selection.Content included in module 08 Quick guide Step-by-step guide SM Step-bystep guide Add MSC.Step in the process that may occur depending on the CTA submitted. An SM CTAcan include Part I and Part II, Part I only or Part II only. For an Add MSC CTAusers may raise considerations for Part I, but the conclusion cannot be modified.*In case of applications limited to Part I, the sponsor has two years from thenotification of the conclusion of Part I to submit an application limited to Part II.3

How to evaluate a Substantial ModificationValidation andAssessmentof an SMAccess SM CTAs1. Similar to other types of CTA, MSCs receive a notice establishing that a SubstantialModification application has been submitted. Users can access the tasks through thenotice received, the ‘Task’ tab or the ‘Evaluation’ section.2. On the ‘Tasks’ tab, users can view the tasks related to the validation and assign the ‘SMdocument consideration for validation’ task to users, using the appropriate button on theright side.3. Users perform the evaluation of the SM in the ‘Evaluation’ section of the CTA; regardless ofthe way they accessed the application (i.e. via ‘Notice & alert’ or ‘Task’ tabs).#CTISinsightsThe Substantial Modifications (SM) include the whole processof evaluation: Validation, Assessment (Part I and/orPart II), and Decision. It should be noted that some SMmay concern only Part I, Part II, or both, depending on thescope of the modification.4

How to evaluate a Substantial ModificationValidation andAssessmentof an SMValidate SM CTAs: create considerations1. Users can start the validation of the SM CTA by completing the task of documentingconsiderations for validation assigned to them. they can assign the task to users, usingthe appropriate button on the right side of the task.2. Users access the ‘Evaluation’ section of the CTA where they are able to start documentingtheir considerations of the substantial modification by selecting the ‘ New’ button.3. Users can populate the fields of the pop-up form and click on the ‘Save’ button.Drop-down list to select theapplication section parts.Drop-down list to select the CTAsection and document.Considerationfree text field.4. After documenting the consideration, users can select the consideration and click on the‘Share’ button.#CTISinsightsFor considerations of Part I,users can documentconsiderations regardingQuality, Non-quality,Clinical, Regulatory orStatistical.MSCs can comment onconsiderations. If aconsideration is commentedon, the RMS will receivean alert regarding thecomment.5

How to evaluate a Substantial ModificationValidation andAssessmentof an SMValidate SM CTAs: consolidateconsiderations and submit validationdecision1. After the considerations of the MSCs have been documented and shared, the ReportingMember State (RMS) can access the considerations from the ‘Consolidate Considerations’task in the ‘Tasks’ tab and assign the task to users, using the appropriate button on the rightside of the task.2. The RMS can select the considerations using the checkbox on the left, and click one of thefour buttons to consolidate them (i.e. ‘Not Included’, ‘Adapt’, ‘Merge’, ‘Accept’).3. The RMS can select the consolidated considerations in the ‘Consolidated considerations’sub-tab and click on the ‘Share’ button.4. After consolidating the consideration, the RMS can submit the validation decision by accessingthe ‘Submit validation decision’ from the ‘Tasks’ tab and assigning the task to users, usingthe appropriate button on the right side of the task.5. Then the RMS can determine if the application dossier is complete or incomplete from thedrop-down menu and select the ‘Complete’ button.#CTISinsightsAfter reviewing and consolidating all theconsiderations, if the RMS considers thatcertain information is missing or needsclarification in the application documentation,it can submit an RFI to the sponsor.6

How to evaluate a Substantial ModificationValidation andAssessmentof an SMAssess Part I and Part II: createconsiderations1. On the ‘Tasks’ tab, MSCs can view the tasks related to the assessment and select the ‘SMDocument consideration Assess Part I’ and/or ‘SM Document consideration Assess Part II’task by assigning the task to users, using the appropriate button on the right side of thetask.2. Similarly to the validation phase, users can document their considerations for Part I and/orPart II by selecting the ‘ New’ button and then selecting the ‘Share’ button.3. The RMS can circulate the Draft Assessment report for Part I by assigning the ‘CirculateDraft Assessment Part I report’ task, uploading one, many or all the Draft AssessmentReport (DAR) documents, as applicable, for the application dossier sections; selecting the‘Select all’ button, and then clicking the ‘Share’ button.Before adding adocument, a templatecan be generatedusing this button.#CTISinsightsTemplates are available foreach of the 7 parts of theDAR. Users can select thedesired part and click onthe ‘Generate template’button.MSCs can discussamongstthemselves duringthe assessmentphase, by using thediscussionfunctionality.Considerationscan be createdeven after thecirculation ofthe DAR.7

How to evaluate a Substantial ModificationValidation andAssessmentof an SMAssess Part I and Part II: consolidateconsiderations1. The RMS can consolidate the considerations for Part I by selecting the ‘ConsolidateConsiderations’ task. For Part II, each MSC will perform this task individually (if applicable).2. For Part I, the RMS can select the considerations using the checkbox on the left, and clickone of the four buttons (i.e. ‘Not Included’, ‘Adapt’, ‘Merge’, ‘Accept’).3. The RMS can select the consolidated considerations in the ‘Consolidated considerations’sub-tab and click on the ‘Share’ button.4. After consolidating the considerations of Part I, the user of the RMS selects the ‘Submit PartI Conclusion’ and click on the ‘Assign to me’ button. If the RMS considers that certaininformation is missing or needs clarification in the application documentation, an RFI can besubmitted to the sponsor.#CTISinsightsIf the substantialmodification applies to PartI only or Part II only, theassessment will belimited to Part I or PartII respectively.If the SM involves Part II of theapplication dossier, each MSCperforms its own assessment.8Only if the substantial modificationinvolves Part I, the RMS will have aleading role in the assessment.

How to evaluate a Substantial ModificationValidation andAssessmentof an SMAssess Part I and Part II: submitassessment conclusions5. In the ‘Submit Part I Conclusion’ task, the user of the RMS uploads two documents: onefor the assessment of the Part I quality documentation and another one not related to all thePart I documentation, except quality.6. Once the two assessment reports have been uploaded, the user of the RMS can select a finalconclusion from the dropdown menu and click on the ‘Submit’ button.7. If the SM involves Part II of the application dossier, each MSC provides its own individualPart II conclusion by selecting the ‘Submit Part II Conclusion’ task, uploading one PartII assessment report and submitting the final conclusion.#CTISinsightsThe conclusions on Part I andthe Final Assessment Report(FAR) should be based in thecontent of the DAR. The finalconclusion values can be:Acceptable, Acceptable withconditions and Not acceptable.When submitting the FAR,users need to uploadboth documents (qualityand excluding quality)regardless of whetherthere are any qualityparts.9

How to evaluate a Substantial ModificationDecision ofan SMSubmit a Decision1. After the assessment report has been submitted, users can assign the ‘Authorise’. task tousers, using the appropriate button on the right side of the task.2. On the Decision page, users can view information on the conclusions of the different parts towhich the corresponding SM can provide their decision via a drop-down list to establish if thetrial is ‘Authorised’, ‘Authorised with conditions’, or ‘Not authorised’.3. MSCs can add supporting documentation to the Decision and ultimately, click on the‘Complete’ button to finalise the evaluation of an SM.#CTISinsightsFor each SM type there will be aconclusion (Part I / Part II) followed by aMSC decision.10

European Medicines AgencyDomenico Scarlattilaan 61083 HS AmsterdamThe NetherlandsTelephone 31 (0)88 781 6000Send a questionwww.ema.europa.eu/contactClinical Trials Information System (CTIS)Step-by-step guide: How to evaluate a Substantial Modification: Assessment and Decision European Medicines Agency, 2022.Reproduction is authorised provided the source is acknowledged.

This Step-by-step guide includes: 2 Validation and Assessment of an SM How to evaluate a Substantial Modification This section outlines the steps that each MSC performs to submit a Decision regarding the Substantial modification CTA (i.e. whether the trial is 'Authorised', 'Authorised with conditions', or 'Not authorised'). Decision .

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