CMRSC Division of Hematology/Oncology

1. CMRSC Division of Hematology/Oncology Training Standard Operating Procedures for Good Clinical Practice at the Investigative Site Section: PROJECT MANAGEMENT

2. CMRSC 3.0 – Site-Sponsor/CRO Communications Purpose: To describe the various ways of communicating with the sponsor/CRO as all regulatory, medical, and ethical requirements are fulfilled. These include telephone and written interactions. These communications serve to protect the safety and well-being of subjects by keeping sponsors/CROs aware of study activities and to ensure that studies are conducted appropriately.

3. CMRSC 3.0 – Site-Sponsor/CRO Communications Communications overall: • Communicate regularly and appropriately with the sponsor/CRO about all study-related activities • Document important conversations Job aid!Telephone Contact Log • Keep originals or photocopies of all relevant documentation, including facsimile confirmations, e-mails. File these in the study binder with appropriate documents.

4. CMRSC 3.0 – Site-Sponsor/CRO Communications Pre-study communications: • Send sponsor/CRO signed confidentiality agreement (if needed). • Notify sponsor/CRO of decision to participate in the study by telephone, fax, letter, e-mail, etc. • Send sponsor/CRO signed protocol signature page (if appropriate). • Submit all pre-study regulatory documents. • Send updated/revised documents as necessary

5. CMRSC 3.0 – Site-Sponsor/CRO Communications Communications while the study is on-going: • Send the following by whatever means the sponsor/CRO has requested (fax, remote data entry, hardcopy, e-mail): • Screening/enrollment forms • Case Report Forms • Respond promptly to data queries as requested

6. CMRSC 3.0 – Site-Sponsor/CRO Communications Communications while the study is on-going (cont.): Copy sponsor/CRO on IRB communications such as : • Serious Adverse Event (SAE) reports • Investigational New Drug (IND) safety reports • amendment approvals • revised informed consent form • continuing IRB approval for the study

7. CMRSC 3.0 – Site-Sponsor/CRO Communications Communications when the study is complete: • Inform the sponsor/CRO promptly if notified by FDA of impending inspection. • Provide the sponsor/CRO with copies of all FDA documentation (Form FDA 483, letters, etc) generated as a result of the inspection

8. CMRSC 3.1 – Interactions with the IRB Background: The Institutional Review Board (IRB) is a group appointed by CCHMC to protect the rights and welfare of research subjects. Federal regulations require that the IRB ensure that certain criteria for approval of research are met prior to approving a study. By signing the Form FDA 1572, the PI ensures that the IRB reviewing the research complies with the regulations. The PI agrees to inform the IRB of any changes to the protocol and any materials used to recruit subjects, as well as any additional risks to subjects associated with the investigational article.

9. CMRSC 3.1 – Interactions with the IRB Purpose: To describe how the Hem/Onc Division communicates with the IRB throughout the research process in order to ensure compliance with the regulations and to protect the safety and well-being of study subjects. This SOP applies to those members of the CMRSC involved in communicating with the IRB to ensure appropriate management of all clinical trial activity.

10. CMRSC 3.1 – Interactions with the IRB Documenting IRB Compliance: As requested by the sponsor/CRO, request a copy of the IRB membership list and the general assurance number.

11. CMRSC 3.1 – Interactions with the IRB Communicating with the IRB at study start-up: • Complete the initial IRB submission of the protocol. IRB-approved forms and checklists can be found at http://www.cincinnatichildrens.org/research/administration/irb/guidelines/researchprep.htm • Obtain documentation of full IRB approval for the protocol and informed consent form prior to study start. Copy sponsor/CRO on correspondence. • Maintain all documents in the appropriate study regulatory binder.

12. CMRSC 3.1 – Interactions with the IRB Communicating with the IRB while the study is on-going: • Notify the IRB of any changes to the protocol and/or informed consent, and of any new information from the sponsor regarding the investigational drug or article. • Submit periodic report form for renewal of the protocol at a frequency specified by the IRB. The report form can be found at: http://www.cincinnatichildrens.org/research/administration/irb/guidelines/default.htm • Obtain documentation of IRB approval of amendments and revisions to study-related documents, such as advertisements or subject diaries, prior to implementation, except to eliminate apparent hazard to subject safety

13. CMRSC 3.1 – Interactions with the IRB Communicating with the IRB while the study is on-going (cont.): • Notify the IRB promptly of all serious adverse events occurring during the approval period for the study. The SAE report form can be found at: http://www.cincinnatichildrens.org/research/administration/irb/guidelines/default.htm • Promptly submit to the IRB all IND Safety reports received from the sponsor. • Report all routine AEs to the IRB as part of the periodic or annual reporting requirements. • Maintain all documents in the appropriate study regulatory binder.

14. CMRSC 3.1 – Interactions with the IRB Communicating with the IRB when the study is over: • Send a letter to the IRB stating that the study has closed and the reason for closure (e.g., by sponsor because study is complete, poor recruitment, etc.) Include in the letter: • Number of patients on study • Adverse events (if any) • Date study closed • When the monitor came for the close-out visit (if such a visit was required).

15. CMRSC 3.2 – Regulatory Files and Subject Records Purpose: To describe the steps for fulfilling all regulatory and clinical requirements for collecting, filing and storing study-related documents and records. The regulatory files and subject records, which are periodically reviewed by the sponsor, and upon request by the FDA, serve as the site’s record of compliance with Good Clinical Practice (GCP)

16. CMRSC 3.2 – Regulatory Files and Subject Records Definition: Source Documents: Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at the medico-technical departments involved in the clinical trial.

17. CMRSC 3.2 – Regulatory Files and Subject Records Collecting, filing, and storing study-related documents and records: • Regulatory Binder - For each study, create a series of file folders or start a binder for documents collected during the study. Job aid!Regulatory Binder Checklist • Maintain and update the regulator binders as needed • Retain copies of all original and revised documents (protocol, investigator’s brochure, informed consent form) • Maintain a history of the conduct of the study.

18. CMRSC 3.2 – Regulatory Files and Subject Records Collecting, filing, and storing study-related documents and records (cont.): • Ensure that subject records and regulatory binders are kept confidential and are stored in a secure, limited-access location. HIPAA! HIPAA! HORRAY! • Prior to monitoring/auditor visits, review content of regulatory binders and subject records for completeness. Ensure files are organized and complete after their visit.

19. CMRSC 3.2 – Regulatory Files and Subject Records Collecting, filing, and storing study-related documents and records (cont.): • When the study is over, review the contents of the regulatory binder and subject records by comparing with the checklist (Regulatory Binder Checklist) • Archive regulatory binders/subject records • Label storage boxes clearly • Document inventory of storage boxes • Store in a secure location for the required period of time (as specified by sponsor).

20. CMRSC 3.3 – Sponsor/CRO Monitoring Visits Purpose: To describe the steps followed by the CMRSC from the time the monitor schedules a monitoring visit until all follow-up activities associated with the visit have been completed. Monitoring visits are necessary to: • Assess adherence to the protocol • Review regulatory files for completeness • Ensure appropriate study drug storage, dispensing, and accountability • Verify data in case report forms with source documentation • Meet with the Research Team and PI to discuss study progress and any concerns raised as a result of the visit.

21. CMRSC 3.3 – Sponsor/CRO Monitoring Visits Scheduling the monitoring visit: • Work with the study monitor to schedule a mutually convenient date and time for the monitoring visit. Consider the PI’s schedule as well. Job aid!Regulatory Binder Checklist Preparing for the monitoring visit: • Schedule a suitable space for the monitor to work • Ensure all regulatory documentation and case report forms are complete and available • Ensure all data queries are resolved to the extent possible • Have needed patient HIM records available for the visit • Inform the study pharmacist to prepare for drug storage and accountability records review

22. CMRSC 3.3 – Sponsor/CRO Monitoring Visits Managing the monitoring visit: • Ensure that the monitor signs the visit monitoring log (should be in the regulatory binder) • Ensure that the monitor has all the documents he/she will need, update the monitor on any study-related issues. • At the end of the visit, meet with the monitor to review any issues pertaining to: • Adherence to the protocol • Review of the regulatory binders • Verification of data in the CRFs with source documents • Study drug storage, dispensing, accountability

23. CMRSC 3.3 – Sponsor/CRO Monitoring Visits Managing the monitoring visit (cont.): • Discuss any payment issues, if necessary Following-up after the monitoring visit: • Ensure that all issues identified for resolution or follow-up at the monitoring visit are addressed.

24. CMRSC 3.4 – Study Termination Visit Purpose: To describe the process followed when the sponsor’s monitor conducts a study termination visit to: • Review all regulatory files for completeness • Complete the verification of all data in case report forms with source documentation • Meet with the research team to discuss review of the above, drug accountability, possibility of a QA and/or FDA audit, and requirements for data storage Exception: Consortium group studies, upon closure or termination, may not result in a study termination visit; however, all steps in this SOP should be considered for proper closure of even those studies at CCHMC

25. CMRSC 3.4 – Study Termination Visit Scheduling the study termination visit: • As soon as possible after the last patient has completed all scheduled visits associated with the study, arrange a mutually convenient data and time for the study monitor to conduct the study termination visit. Job aid!Study Termination Visit Checklist Preparing for the study termination visit: • Ensure all regulatory documents and case report forms not previously monitored are complete and available for review • Ensure all data queries have been resolved to extent possible • Ensure the patient’s medical records are available • Inform the study pharmacist that study drug will be inventoried and drug records will be reviewed

26. CMRSC 3.4 – Study Termination Visit Managing the study termination visit: • Ensure the monitor has all documents required to complete the termination visit. Update him/her on any study-related issues. • At the end of the visit, meet with the monitor to discuss any issues related to: • Regulatory files, source data verification, study drug reconciliation, possibility of QA and/or FDA audit, and requirements for data retention and storage

27. CMRSC 3.4 – Study Termination Visit Managing the study termination visit (cont.): • If study data was submitted via remote data entry (computer entry), determine when hard copies of all CRFs will be provided to the site. • Review the sponsor’s requirements for protecting the integrity of the electronic data. • Discuss the sponsor’s requirements for patient follow-up for serious adverse events. • Discuss the possibility of publication of the data, and future studies. • If necessary, discuss final payment(s).

28. CMRSC 3.4 – Study Termination Visit Following-up after the study termination visit: • Ensure that the study drug is either prepared for return shipment to the sponsor or disposed of at the site per the sponsor’s WRITTEN request. • File copies of the study drug packing slips and shipment receipts – or – provide the sponsor with documentation of the previously authorized study drug disposal and file site copy in regulatory binder • Ensure return or destruction of all other study-related materials. • Ensure that any equipment on loan is returned. • Inform the IRB that the study is over and submit the final report….copy the sponsor. • Resolve final data queries, check study files for completeness, send files to secure storage if needed.

29. CMRSC 3.5 – Investigational Drug Accountability, Storage, Dispensing, and Return Purpose: To describe the processes for the order, receipt, storage, dispensing, reconciliation, and return or authorized destruction of the investigational drug (study drug). This SOP applies from the time the drug is ordered until it is either returned to the sponsor or destroyed on-site at the sponsor’s request.

30. CMRSC 3.5 – Investigational Drug Accountability, Storage, Dispensing, and Return Definitions: Blinding/Masking: a procedure in which one or more parties of the trial are kept unaware of the treatment assignment(s). Single blinding usually refers to the subject(s) being unaware, and double-blinded usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s) Investigational Product: a pharmaceutical form of an active ingredient OR placebo being tested or used as a reference in a clinical trial Randomization: the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias

31. CMRSC 3.5 – Investigational Drug Accountability, Storage, Dispensing, and Return Ordering study drug: • Only those authorized by the PI may order study drug. This is indicated by the 1572 form or other authorized means of delegation per the study. Receipt/inventory of study drug: • All investigational drugs should be shipped to the CCHMC Investigational Drug Pharmacy • Upon receipt of investigational drug, inventory the shipment, ensuring the packing slips match exactly what was sent (check amount, lot numbers, quantity per container) • Resolve discrepancies promptly • If required, acknowledge receipt as requested by sponsor/CRO • Retain copies of everything for the regulatory files • Ensure any supplies needed for the blinding of the study are available

32. CMRSC 3.5 – Investigational Drug Accountability, Storage, Dispensing, and Return Storage of study drug: • Study drug must be stored: • In a secure location • According to storage requirements (temperature, humidity, light) • Maintain logs of storage conditions, if required • Follow any special requirements for controlled substances • Ensure that the randomization code, if being used, has been received

33. CMRSC 3.5 – Investigational Drug Accountability, Storage, Dispensing, and Return Dispensing of study drug: • Each time study drug is dispensed, complete the drug accountability form (usually done by Investigational Pharmacy) • The study may require that used containers are returned to the study pharmacist; document if containers are missing • Document discrepancies between amounts used by the subjects and amounts expected to be returned. Document reasons. • Ensure study drug is within an appropriate expiration date • If appropriate, alert the monitor when additional supplies will be required • If emergency breaking of the study drug blind is medically necessary, document all circumstances appropriately.

34. CMRSC 3.5 – Investigational Drug Accountability, Storage, Dispensing, and Return Return/destruction of study drug: • At the conclusion of the study, ensure all documentation regarding receipt, storage, dispensing, and return of used containers is complete, accurate, and ready for review at the monitor’s termination visit. • Destruction of the study drug at this site, upon written authorization from the sponsor to do so, may be undertaken so long as such procedures are permitted by the CCHMC Biohazard Materials Policy and Safety policies • Provide the sponsor with written documentation of the destruction of the study drug. Maintain a copy in the regulatory files.

35. Of course there’s another quiz! • CMRSC SOPs – Project Management Section Quiz