CRP 106 Lecture 9

Question 1

Site Monitoring Visits

Answer 1

-Also may be called Routine Monitoring Visits, Interim Monitoring Visits
-Typically consists of an on-site visit by a monitor, although may conducted remotely if appropriate infrastructure is available.
-Occurs after site initiation visit and enrollment beginning at the site
-Timelines and requirements for visits will always be outlined in the monitoring plan

Question 2

Site Monitoring Visit Prior to Arriving at Site

Answer 2

-Knowledge of current state at site – review previous communications with site (including follow-up letters)
-Review protocol and ICF
-Review previous monitoring reports, if available
-Discuss with others in your team regarding current states at site and any major actions you may need to be aware of or activities or items they may want you to review at site
-go for high level targets first

Question 3

Site Monitoring Visit - Meet with Investigator – Entry Meeting

Answer 3

-If possible, schedule a brief meeting with investigator before beginning visit
-Provide information regarding timeline of visit and activities to be conducted
-Provide update regarding overall study progress and enrollment
-Provide/reinforce information from sponsor that may be pertinent to study conduct

Question 4

Site Monitoring Visit - Meet with Coordinator

Answer 4

-Scheduling time at the beginning of visit is extremely beneficial
-Can be oriented to site and documents
-Can be given some information about challenges in conducting the study at site
-Great way of continuing to create a positive working relationship
-Attempts should be made to accommodate coordinator and ensure meetings occur at reasonable time

Question 5

Site Monitoring Visit - SAE Review

Answer 5

-Get update from investigator and/or coordinator whether SAE occurred since previous visit
-If yes – reported to sponsor? REB?
-Regardless of status, monitor should review all pertinent information regarding SAE
-Information sources: research record, medical chart/electronic health record, supporting documentation
-May provide guidance regarding additional info that might be beneficial when submitting SAEs

Question 6

Site Monitoring Visit - Informed Consent review

Answer 6

-Check ICFs of all new participants enrolled since last visit
-Ensure ICF signed/dated by participant or substitute decision maker (SDM), if applicable
* site staff should not date ICF for participants*
-ICF signed and dated by person obtaining informed consent
-Ensure date/time on ICF is prior to study related procedures
-Ensure correct version used
-If updated consent:
-Ensure new participants have signed new consent
-Participants currently enrolled signed updated consent at next schedule visit
-If critical update, was another communication required prior to next visit? Was this completed?

Question 7

Site Monitoring Visit - Protocol Adherence

Answer 7

-In addition to CRF and source document review, monitor must be aware of global protocol adherence
-Items to review to ensure adherence:
-Eligibility reviews
Participants meet all inclusion/exclusion criteria
-Randomization
Randomized to correct condition, dispensed appropriate IP
-Protocol activities
Correct protocol procedures completed on participant each visit

Question 8

Visit Scheduling (Visit Windows)

Answer 8

-Visit window defined as flexibility allowed around projected study visit date
-Normally stated as plus/minus certain number of days
-E.g.: Participant due for visit on Feb 25. Window listed in protocol = ± 2 days
-Verify participants made visits as outlined in protocol and “within window”

Question 9

Site Monitoring Visit - Drug Dispensing

Answer 9

-Appropriate drug and amount provided to participant
-Unused study medication returned to site and documented
-Compliance assessed to ensure participant is taking medication at levels required for study

Question 10

Site Monitoring Visit - Case Report Form (CRF)

Answer 10

-When reviewing documentation, focus on completing one participant at a time
-If using an EDC system, CRF reviews will typically occur remotely together with DM, reviews will occur for completion and general appropriateness of data included
-Check each page for completeness
-Ensure legibility of information entered
-Participant identifier included on form
-All responses entered within range
-Check to see procedures are on proper date (ie: within window)
-Times of procedures are appropriate based on protocol
-Forms signed, if needed, by correct study staff member

Question 11

Site Monitoring Visit - Source Document Verification/Review

Answer 11

-Verification: process of ensuring data on CRF matches information included in source document
-Review: ensuring source document meets principles of ALCOAC
-This process can include:
-100% SDV – all points on CRF verified with info in source document
-Critical data review – review of data according to risk assessment completed and as outlined in the monitoring plan
-Many sites use EHR and may need to obtain read-only access for review
-If not available at site, may need to schedule time with coordinator to conduct review together
-Some EMRs provide access to monitors to review patient records remotely
-This would need to be included in the consent form
-Monitors would only have access to patients on study and not full access to the EMR

Question 12

Inconsistencies between Source and CRF

Answer 12

-Source usually takes precedence
but coordinator or investigator should be asked to clarify via a query
-Any changes to source to be appropriately made and discrepancies documented
-If using EDC, this system is a bit more streamlined
Create queries as required as shown in previous lectures
-If using paper based CRFs, this will typically be tracked on a query form
-A MONITOR IS TO NEVER CHANGE OR MODIFY ANY SOURCE DOCUMENT OR CRF

Question 13

Query Resolution

Answer 13

-Errors or queries found by monitor documented in log
-Issues discussed with coordinator
-When changes made to CRF by coordinator, resolution section completed by coordinator with date of correction and initials

Question 14

Error Correction

Answer 14

-Corrections made as single line through error, adding correct information and dating and initialing
-Whiteout, pencil/eraser should never be used
-When errors found, monitor should attempt to educate team as to why entry is incorrect and action that can be taken to prevent error in the future

Question 15

Site Monitoring Visit - Investigational Product

Answer 15

-Monitor to review IP records to ensure:
-Product is stored at appropriate temperature
-Stored and handled correctly
-Provided only to eligible participants
-Depending on logistics, IP may be stored at investigators site or in a pharmacy.
-Regardless of location, meticulous records must be kept
-Records regarding all steps in transit and dispensing must be maintained
-Monitor to ensure pharmacist or coordinator is keeping appropriate track of products
-Ensure appropriate product is available so no delay in enrollment or that participants run out of medication

Question 16

Site Monitoring Visit - Sample Collection

Answer 16

-If blood or other samples collected – confirm being done properly
-Timing of collection verified to match with protocol
-Ensure storage conditions are appropriate if samples stored
-Ensure staff have appropriate training if required, eg: Transportation of Dangerous Goods, phlebotomy, etc
-Ensure samples are being packaged and shipped appropriately

Question 17

Site Monitoring Visit - Study Documents Review (Study Binder)

Answer 17

-Thorough check should occur during first visit to make sure all documents are appropriately maintained
-Further review may occur periodically or at each visit
-Checklist should be used to ensure nothing inadvertently missed
-Ensuring equipment lists are current and equipment appropriately calibrated

Question 18

Site Monitoring Visit - End of Visit Activities

Answer 18

-Ensure items listed on previous reports are appropriately addressed and completed
-If not, continue to maintain active until resolved.
-Review quantity of study supplies
-If more required, ensure order is made
-If traditional approach, attempt to schedule next visit prior to leaving site.
-Meet with investigator for exit meeting
-Ensure documentation is appropriately submitted to sponsor and investigator

Question 19

Meeting with Investigator – Exit Meeting

Answer 19

-Should occur after all visits
-Investigator should be informed and time scheduled for this meeting
-Effective communication with -Investigator is key to study success
-Monitor provides update of:
-findings made during visit
-corrective and preventative actions that need to be taken
-budget or financial matters
-other matters pertinent to investigator
-If investigator will not meet after visits and all efforts exhausted, discuss with supervisor and document fact within visit report

Question 20

Site Monitoring Visit - General Considerations Site Management

Answer 20

-How was site functioning during visit?
-What was your global sense of how things were working on site ?
Other consideration:
-Documentation practices
-Timely response to correspondence and queries
-may need to consider allocating more time to get site back on track
-If there are issues you are not sure how to handle, speak with supervisor about ideal approach
-Monitor is to make sure there is progress and is essentially double checking that each site is conducting the study appropriately

Question 21

Study Closeout

Answer 21

-Official closure of a study site must occur for each site participating in a clinical trial
-Almost an exclusive task to be completed by a monitor

Question 22

Reasons for Site Closure Most common

Answer 22

Most common
-Study is complete (Enrollment stopped, All study related activities completed, Data is correct and complete)

Question 23

Reasons for Site Closure Other reasons: positive

Answer 23

-Intervention is overwhelmingly beneficial
-Unethical to continue trial with participants who are not receiving active treatment
-Overall enrollment for study is complete, Although individual sites may have not met their own enrollment figures
-Statistical stopping rule met
-Endpoint described in protocol / DSMB charter met

Question 24

Reasons for Site Closure Other reasons: negative

Answer 24

-Intervention found to be unsafe
-Intervention found to ineffective
-Unable to recruit and enroll sufficient patient population
-Sponsor determined product no longer viable for marketing
-Sponsor terminated for other reasons
-Funds no longer available to support project
-Protocol is too challenging to complete
-Investigator chooses to no longer participate in the trial
-Investigator leaves institution, passes away, retires and suitable replacement -investigator cannot be found
-Problems observed in manufacturing/stability of product
-Compliance or other significant issue occurring at site

Question 25

Site Closure

Answer 25

-In contrast to study closure, sites can be closed all at once or one at a time.
-Regardless of circumstance, procedure monitor will need to follow will be the same

Question 26

End of Study Safety Considerations

Answer 26

-If trial stopped suddenly and participants are still on study medications, plan regarding medication tapering and discontinuation to be communicated by sponsor to investigators
-Monitor to be aware of procedures to explain and ensure process being followed
-Investigator/site must also contact participants promptly and ensure:
-Suitable alternative treatment provided
-Appropriate follow-up care provided

Question 27

Closeout Procedures

Answer 27

-Most commonly, closeout will require an onsite visit
Items for assessment during this visit include:
-Case Report Forms/Source -Documentation Review
-Drug accountability
-Investigator study file
-Other administrative tasks

Question 28

Study closeout Case Report Forms

Answer 28

-Any outstanding CRFs not reviewed (if using paper) to be reviewed and outstanding queries addressed.
-Ensure all CRF documents and associated forms are complete and ready for storage

Question 29

Study closeout drug accountability

Answer 29

-Final inventory of investigational product to be completed
-Remaining drug to be packed and returned to sponsor as per policy OR occasionally if pharmacist on site, may have pharmacist destroy product

Question 30

Study closeout Investigator Study File

Answer 30

-Thorough review of essential study documents maintained at site completed including:
-all REB documentation present
-Protocol amendment approvals included
-Changes to ICF forms maintained
ICF (all versions as applicable) are present and available for each participant enrolled
-Use a checklist to ensure all documents appropriately reviewed
-Missing documents should be added to the study file (may be time consuming)

Question 31

Final Reports (Sponsor, REB)

Answer 31

-Investigator report to sponsor
-Enrollment summary: participants enrolled, completed, withdrawn and reasons for such
-Summary of AEs observed during the study
-REB final report:
-include similar information as above
-If investigator is also sponsor (IIS): Closure letter to Health Canada required
-Collect (if required) and verify all reports included in study file

Question 32

Study closeout Administrative Issues

Answer 32

-Ensure all payments are appropriately disseminated (if you are responsible for this)
-All study supplies returned or destroyed as required
-Sometimes equipment, supplies, etc are left at site after study – check contract to see what is stated
-All outstanding issues from previous visits addressed and documented
Record retention procedures discussed ( Health Canada regulated studies 15 years)

Question 33

Final Visit Report

Answer 33

-Like all other monitoring visits, a report should be filed after completion of visit
Report to list
-All items verified
-Documents prepared for archiving
-States that site is officially closed