FDA Registration Trials. Aisha Shah CRP Information Meeting, Conducting FDA Registration Trials

Transcription

1 FDA Registration Trias Aisha Shah CRP Information Meeting, Conducting FDA Registration Trias November 1, 2018

2 Goas Registration Tria Considerations DTL and RCR AE Submissions Essentia Documents Protoco Training Auditing and Monitoring PI Oversight FDA Inspection

3 REGISTRATION TRIAL CONSIDERATIONS

4 Aiance and NCI Initiatives: IND/NDA Trias Initiatives and Process Changes Impementation Improve reguatory authority inspection readiness; impement risk-based monitoring approach Centraized Monitoring Audits with TSDV in Rave Centraized Deegation of Tasks Log (DTL) Centraized Registration and Credentia Repository (RCR) CTEP-AERS/Rave Integration Aiance standardized approach to registration trias for a pharmaceutica partners

5 Deegation of Tasks Log (DTL) What is it? NCI to focus on registration trias with centra DTL Onine appication by CTSU that is used to define and maintain site personne isting and their roes/responsibiities Via CTEP s Registration & Credentia Repository (RCR) Cinica Investigator per protoco Study team per protoco per site Verifies quaifications of study personne e.g. ICF, H&P, eigibiity, toxicity, data entry, etc

6 Deegation of Tasks Log (DTL) Why? Ensures that there are no gaps at the site-eve per FDA requirements (DTL is compete before enroment) DTL + registration documents from RCR to create Study Site Registration Packet Registration types Investigator, Non-Physician Investigator, Associate Pus, Associate, Associate Basic Documentation that responsibiities are deegated to quaified personne Protoco-specific training

7 Deegation of Tasks Log (DTL) Why? Audit Per CTMB guideines (August 2017), The auditor wi review the og to evauate appropriate impementation and maintenance Deficiencies: Critica any finding identified before or during an audit that is suspected to be frauduent activity Major performing tasks not assigned to individua, faiure to keep DTL current, individua not isted on DTL, etc Lesser - other

8 Deegation of Tasks Log (DTL) Who? Site staff responsibe for conduct of protoco eading submitted study data Cinica Investigator (CI) responsibe for overseeing the conduct of the protoco at the site. Must have active CTEP registration w/ investigator-type & be on a participating site roster

9 Deegation of Tasks Log (DTL) Infusion nurses? Lab personne? Who? The DTL is designed to capture individuas that significanty contribute to the protoco data at the site in the genera task areas outined on the DTL. There is no forma definition of significant contributor, but guidance provided by the FDA on competion of the Form FDA 1572 can be found at Gui dances/ucm pdf In genera, hospita staff providing anciary or intermittent routine care are not considered significant contributors.

10 Registration & Credentia Repository (RCR) Sef-service onine registration appication for study personne FDA Form 1572 Registration Types require different reguatory documentation 1572, FDF, NCI Biosketch (education training, certification, icense), CV, HSP & GCP training Aows access to CTEP appications, e.g. Rave, OPEN, etc DTL access for site/protoco maintenance

11 Adverse Event Submission Requirements for Registration Trias Shauna Himan CRP Information Meeting, Conducting FDA Registration Trias November 1, 2018

12 AE Submission Requirements for Registration Trias Changes Instead of reporting the maximum grade that occurred during the treatment cyce, a changes in grade must be reported Additions Verbatim term Start date of the AE End Date of the AE On-going status AE user guide is avaiabe on the CTSU website Covers persistent, intermittent and recurrent AEs A ink to this user guide is avaiabe in the hep text

13 Exampe of Link to User guide Link is Avaiabe for Cabinet-Tria A021602

14 CTSU Website

15 Rave CTEP-AERs Integration Purpose: Synchronize routine and expedited Adverse Event (AE) data coection Purpose: Provide the site with guidance about whether an AE does/does not need to be submitted as a Serious AE in an expedited fashion Required for a trias where CTEP hods the IND starting October 2017 Impemented in A031501, A021502, A091605, A021602

16 Rave - CTEP-AERs Integration Main Changes The timing of AE reporting AE data must now be first reported in Rave A updates to AE data must be first made in Rave, then resubmitted for rue evauation A AEs > grade 0 must be sent for rue evauation

17 Rave - CTEP-AERs Integration Both soicited and other AEs are reported on the same form The report period end date shoud ony be recorded when the cyce is compete as this drives querying An Expedited Reporting Evauation Form must be submitted to send a AEs recorded on the AE form for rue evauation to determine if any need to be reported in an expedited fashion via CTEP- AERs

18 Tips for AE Form Submission A fieds required for rue evauation are identified with a red asterisk The site shoud eave report period end date missing unti after competion of the entire cyce and form

19 Do not respond to query, it wi go away automaticay when the report period end date is added. Pease eave as a reminder that the form is not compete. 19

20 This fied is derived from the AE form for cyce 1, if missing enter on the cyce 1 AE form 20

21 Verbatim term is new Indicator of whether AE is soicited AE evauated is defauted to Pending and must be updated when AE is evauated AE start/stop dates and ongoing status are new, ongoing status is derived based on presence of AE stop date After AE is submitted for rue evauation the AE specific recommendation can be found here 21

22 A query fires anytime a new AE is entered or an existing AE is updated. Check the checkbox and save the form to submit the AE for rue evauation If a query is present on the AE form, you wi NOT be abe to send the AE for rue evauation unti after the query is resoved, exception is the query that fires on the report period end date Link to CTEP-AERs here Recommendation provided here and is popuated after form is submitted, if the site disagrees they may override 22

23 A Aiance trias must use the new AE Form verbatim term, AE start date, AE end date and ongoing status fieds required for Registration trias ony A changes in AE grades must aso be captured for Registration trias ony Integration required for a trias where CTEP hods the IND 23

24 The sticky notes found on the Expedited Reporting Evauation Form are for instructiona purposes ony and there is no way to remove them from your Rave Task Summary The AE Start Date cannot be before the start date of cyce 1, if a pre-existing condition, enter the start date of cyce 1 24

25 You do not have to wait unti a soicited AEs are evauated to run the rue evauation, the form is designed for you to evauate AEs in rea time If a AEs are reported, you do not have to submit each AE for rue evauation, saving the Expedited Reporting Evauation Form wi resut in a AEs on the AE form being evauated. 25

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27 Essentia Documents at Sites (ICH E6, Section 8) 1. Investigator Brochures 2. Protoco and amendments 3. ICF (and any other study info distributed to patient) 4. Subject recruitment info 5. IRB/Independent Ethics Committee 6. Investigator CVs 7. Lab certification/accreditation 8. IP - handing instructions & shipping records & DARF

28 Essentia Documents at Sites (ICH E6, Section 8): 1. Monitoring etters 2. Correspondences b/w IRB & Institution 3. AE/SAE/SUSAR/UPIRSO sitespecific SOPs, if appicabe 4. Protoco-specific training 5. Screening/enroment ogs, per site SOP

29 Essentia Documents Don t Forget: Sites shoud aso have copies maintained of: 1. RCR 1572, CV, License, FDF 2. DTL 3. Reguatory Support System (RSS) reguatory approva, protoco amendments, continuing renewa, site termination etter from IRB, protoco-specific-training, +/- ICF tempates 4. COI Discosure Form

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31 Protoco Training Importance of maintaining og? Protoco amendments Staffing changes at the site FDA-inspection readiness Do you know your site s SOP? Aternative/Back-up documentation Webinars for Aiance registration trias posted to Aiance website Study-specific page -> suppementa materias

32 Monitoring Auditing & Monitoring Overseeing progress of a cinica tria and ensuring that it is conducted, recorded, and reported in accordance with the protoco, SOPs, GCP, and reguatory requirements Auditing Systematic & independent examination of tria-reated activities and documents to determine whether the evauated tria-reated activities were conducted, and the data were recorded, anayzed, and accuratey reported according to the protoco, sponsor s SOPs, GCP, and reguatory requirements

33 Monitoring Mandatory per federa reguations (21 CFR812.3 (j), , , and ) During a US reguatory audit, FDA has access to monitoring reports and their associated action items Importance of addressing action items on a monitoring etter/report in a timey fashion

34 Monitoring Depending on the study-specific monitoring pan, the foowing is routiney monitored: Informed consent Documents Eigibiity criteria Protoco compiance Source data verification for data accuracy Query resoution AEs occurrence and reporting IP accountabiity Essentia documents Cinica Investigator (CI) & IRB oversight CI is adequatey informed of responsibiities to recruit eigibe subjects & coect high quaity data

35 Centra Monitoring to Support Registration Trias Shauna Himan CRP Information Meeting, Conducting FDA Registration Trias November 1, 2018

36 Aiance Centra Monitors Tiffany Schafer Sara Goodman

37 Centra Monitoring Introduction Centra Monitoring (CM) is performed by Lead Protoco Organizations (LPOs) to ensure protoco compiance by sites It consists of remote review of source documents against data entered in Rave The Source Document Porta (SDP) is an appication on the CTSU website in the Auditing & Monitoring tab used to support the coection of source documents for CM review

38 Centra Monitoring-Current Status The CTSU SDP is not in use for any current Aiance trias Centra Monitoring (CM) is being conducted for the foowing trias A Ambassador A Atomic A Cabinet A Future tria CM is currenty being faciitated by upoading source documents on the Source Document Form within Rave

39 Exampe of Baseine Source Document Form for Atomic Tria

40 Source Document Reminders Redact a source documents before upoading The Informed Consent Document shoud incude a indications to the optiona correative studies When yes is provided for the disease assessment question, you must provide source documentation (imaging, biopsy, etc.)

41 Source Document Reminders Source documents required for treatment may not be required for every cyce of treatment Current requirements for Atomic

42 Where to Find the Needed Source Documents Data Submission Schedue for A & A021602, protoco for A031501

43 Data Submission Schedue SD Requirements for Monitoring CRF Data Fied Source Document: Need a source document that wi vaidate the data entered in the given CRF - data fied

44 Future Initiatives Aiance is in the process of seecting a future tria to impement the CTSU SDP There are no pans to impement the SDP for trias that are aready activated Aiance is working out how to use the SDP to faciitate both source documents needed for centra monitoring and source documents needed for eigibiity reviews and case evauations

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46 Auditing Quaity assurance function Auditors can assess a wider study sampe than monitors and can hep evauate trends at various eves singe or mutipe sites and/or mutipe studies tria vendors/sponsors Evauate compiance to recognized standards FDA s Code of Reguations Internationa Conference on Harmonization Internationa Standards Organization SOPs

47 Auditing Compiance snapshot Can assist in determining effectiveness of: Monitoring importance of addressing action items on monitoring reports in a timey fashion Study team Manage non-compiant sites Assess inspection readiness

48 Investigator Oversight How often do you meet with your investigator? Are routine meetings estabished? Process for obtaining signatures/assessments?

49 Investigator Oversight How to demonstrate? Timey signatures on source documents Diagnostic procedures Recist reads Lab resuts Eigibiity criteria Treatment authorization DTL appropriate and quaified staff deegation SAE/SUSARs - evauated and submitted in a timey manner

50 Investigator Oversight How to demonstrate? Feedback from the FDA suggests that they are concerned with one Cinica Investigator covering mutipe sites and protocos No hard rue as to how many sites/protocos a CI may cover May be a reason for triggering an audit

51 FDA Inspection Readiness On-going state of effectiveness and suitabiity monitored through periodic review an monitoring of compiance Not a preparation activity Requires Investigators and management to be activey invoved and committed to cuture of compiance FDA Bioresearch Monitoring (BIMO) Inspection Program Protects the rights, safety, and wefare of human research subjects Assures quaity, reiabiity, and integrity of data coected

52 FDA Inspection Focus at Sites: CI oversight Site management Data Investigationa product (IP) management Adverse Events

53 FDA Inspection Process: 1. Notification of inspection via FDA Form Opening meeting 3. Interview of site staff 4. Review of study-reated/source documents 5. Exit meeting Review findings Address issues or concerns 6. Response to inspection, as needed

54 FDA Inspection What to do if issued FDA Form 482? Aiance and/or pharmaceutica partner wi: Provide additiona instructions & guidance for preparing Provide a singe point of contact (SPoC) at Aiance for any issues that may arise during the inspection Site shoud aso provide daiy report to Aiance SPoC SPoC wi assist in preparing responses to the inspection findings, if needed

55 FDA Inspection Roe of Investigator/ Site Ensure avaiabiity of staff during inspection Aert other staff of section, so that they know to avoid ingering in areas hosting the inspection & to watch conversations near inspectors Ensure avaiabiity of study-reated records & provide copies to HA as requested Answer questions regarding your roe At the end of each day, request a summary from the inspector Forward summary to Aiance SPoC Respond to any inspection findings, as needed

56 FDA Inspection Roe of Aiance Assign SPoC to site Provide daiy status report to pharmaceutica partners Provide ongoing support to site/investigator before, during, and after

57 FDA Inspection Tips for Interacting with Inspectors When answering questions: Honesty Be concise & cear ony answer the question asked Don t argue with inspector Don t answer hypothetica questions Wait unti you have heard & understood the whoe question Beware of pauses don t fee ike you need to keep taking

58 FDA Inspection Findings: Criticaity determined by deficiencies that: Affects rights, safety, or wefare of subjects Impacts data integrity Indicates systematic probems within the study from the Sponsor Indicates probems with the investigator/site that may impact other studies FDA Form 483, Inspectiona Observations, documents & communicates concerns disovered during inspections Forward to Aiance SPoC, immediatey!

59 FDA Inspection Resources: FDA reguatory info for cinica trias: uidances/ucm htm FDA Cooperative Research Information Sheet: uidances/ucm htm FDA Bioresearch Monitoring Info: ns/bioresearchmonitoring/defaut.htm

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