1. Rare Diseases Clinical Research Network Data Management and Coordinating Center (RDCRN DMCC) Rosalie Holland LDN Investigator Meeting at WORLDSymposium 2016 March 4, 2016 The Rare Diseases Clinical Research Network (RDCRN) is coordinated by the Office of Rare Diseases Research (ORDR), NCATS. Funding and programmatic support is provided by ORDR in collaboration with participating NIH Institutes.

2. Discussion Protocol Activation Process Site Activation Process Regulatory Considerations Protocol Amendment Process Audit Overview Electronic Regulatory Binder Data Entry and Compliance Friendly Reminders 2

3. Protocol Activation Checklist Draft protocol, ICF template, MOO, and forms DMCC approval of protocol NIH approval of protocol Submit protocol and materials to site IRBs and submit forms to DMCC development team Forms promoted At least one site ready for activation DMCC sends protocol activation letter to study chair! Enrollment should not occur until this letter is received. 3

4. Protocol Document DMCC has RDCRN protocol template available – Template includes guidance on applicable sections as well as suggested and required language – The project submitted in the LDN grant application should be placed into a protocol document – Language regarding Eligibility, Schedule of Events, and Adverse Event Reporting is necessary Document will be reviewed by the DMCC – The DMCC will maintain version control Once DMCC approves, the protocol will be sent to NINDS and NIDDK for review and approval 4

5. Informed Consent Forms The DMCC will review and edit the ICF templates (can include Parental ICF and Assent) Reviewed to comply with: – 45 CFR 46.116 – ClinicalTrials.gov – Data storage at the DMCC – Data transfer to Federal repository dbGaP – USF and the DMCC in HIPAA authorization language Once the DMCC approves the ICF template, it will be submitted to NINDS and NIDDK with the protocol for review and approval 5

6. NIH Protocol Approval Process DMCC sends protocol and ICF template to NINDS and NIDDK for review The Protocol Review Committee will send comments and edits, or will approve the protocol and ICF documents While protocol is pending approval, collaborate with DMCC to finalize forms and MOO 6

7. Case Report Forms DMCC has standard forms available Consortium responsible for drafting forms Involve DMCC in forms creation process early Pay special attention to the schedule of events Consider special systems needed Forms need to be approved by the PI to be entered into the development queue 7

8. Manual of Operations Consortium responsible for writing and making changes to the Manual Of Operations (MOO) DMCC has RDCRN MOO template available – Template include guidance on applicable sections as well as suggested and required language The MOO should be used as a tool to describe how protocol procedures should occur Should continue to be a working document throughout the course of the study The MOO does not have to be reviewed and approved by NINDS/NIDDK or IRB 8

9. Protocol Activation Items IRB has approved NIH watermarked version of the protocol Case report forms have been developed and promoted MOO has been approved by the DMCC and PI Protocol lay summary has been posted to the RDCRN website One site has fulfilled the site activation items Even if you have IRB approval, your study cannot be activated for enrollment until all activation items have been accomplished. 9

10. Site Activation Checklist Send valid IRB approval memo and ICF(s) to DMCC – Protocol Title – Protocol Version Date (of current NIH approved, watermarked protocol) Send site delegation log (SDL) to DMCC Complete training Site activation letter sent to Site PI THEN Site can begin study enrollment! 10

11. Other Regulatory Considerations Sites are responsible for providing the DMCC with the following regulatory documentation: – Valid IRB approvals – Initial, amendment, continuing reviews – All IRB-approved ICFs, Assents, HIPAA Authorizations – Site Delegation Logs – initial and any updated versions Study PI is responsible for FDA submission to obtain an IND approval or exemption for a study drug 11

12. Amendments After activation, the DMCC, NINDS and NIDDK still need to review and approve amendments to the protocol and ICF documents The DMCC will review the amendment After DMCC approval, the protocol will be submitted to NINDS and NIDDK Once approved by NINDS and NIDDK, the protocol will be watermarked Only after you receive the watermarked protocol, should the amendment be submitted to the IRB. 12

13. Electronic Regulatory Binder What is the Electronic Regulatory Binder (E-Reg Binder)? – An online interface for receiving and tracking regulatory documents – Allows DMCC auditors to review all regulatory documents remotely and thereby negate the need for a regulatory review during the audit visit site Purpose – Streamline the audit program – Reduce costs – Reduce undue administrative burden at local sites 13

14. Electronic Regulatory Binder Implemented January 2015 – DMCC added historical documents (IRB approvals, ICFs, etc.) for consortia Adding documents to E-Reg Binder – Ability to view, download, and/or file documents are defined using RDCRN account permissions – Sites have the option to upload documents directly or send them to the DMCC for upload – All sites are expected to use the E-Reg Binder 14

15. Audit Overview Every LDN study will be audited – Will occur within 18 months of enrolling – Observational are audited at least every 3 years – Interventional are audited annually – DMCC will coordinate schedule with site Review of the electronic regulatory binder, ICFs, study charts, source documentation, data entry, and study drug administration (if applicable) will occur 15

16. Data Entry and Compliance The DMCC monitors data delinquency on an ongoing basis. Investigators will be queried for missing data forms that are not received within 30 days of the due date. The rate of data delinquency will be reviewed at the time of the audit. Persistent data delinquency may be considered a deficiency. Compliance reports are available on the RDCRN Members’ Website 16

17. Friendly Reminders Register your study on clincialtrials.gov per ORDR, NCATS guidance Acknowledge U54 on publications, presentations, etc. Include RDCRN & LDN logos on presentations, conference materials, etc. Send protocol amendments to DMCC prior to IRB submission Send Continuing Reviews to the DMCC Enter data in a timely manner (within 30 days of collection) 17

18. Questions 18