CRP 106 Lecture 3

Question 1

What is monitoring?

Answer 1

-process to allow for the continuous oversight of study coduct by the sponsor

Question 2

purpose of monitoring

Answer 2

verify:
-rights and well being of human subjects protected
-trial data are accurae, complete, and verifiable from source docs
-conduct in compliance with protocol, GCP, and regulations

Question 3

Selection and qualifications of monitor

Answer 3

-selected by sponsor
-trained
-scientiic/clinical knowledge for trial
-documented qualifications
-familiar with IP, protocol, ICF/other subject material, SOPs, GCP and regulations

Question 4

monitor’s responsibilities

Answer 4

IO-main of communications between sponsor and PI
-verify PI adequate qualifications, resources throughout trial, facilities/staff/equiptment adequate
-verify IP storage conditions, supplies, proper dispensing and instructions to subjects for use/storage/return, documentation and control, disposal
-PI follow protocol, ICF for all subjects, PI has current IB and all trial supplies, all staff well informed of trial, and performing functions in acccordance with protocol, delegation of tasks only to authorized individuals
-only eligible patients enrolled
-reporting recruitment rate
-source documents follow ALCOA-C
-PI provides all reports, notifications, applications and submissions
-source data verification and case report forms (accuracy and completeness, dose modifications documented, AEs,conmeds reported and in CRFs, missed visits/tests reported, withdrawals and dropouts reported and in CRF
-raise queries to PI for CRF errors
-AEs reported within allowed time frame
-maintenance of essential docs by PI
-communicate protocol, SOP, GCP, regulations deviations to PI, take action to prevent reoccurance

Question 5

source documents

Answer 5

-anywhere data is first entered
-can include personal identifiers
-does not leave study sites
-i.e. medical images, lab reports

Question 6

Case Report Forms

Answer 6

-devoid of personal identifiers
-contain all key data endpoints
-can be sent to sponsor
-transcribed from source docs by study team, then verified by monitor

Question 7

nature and extent of monitoring

Answer 7

-sponsor determines what is adequate for study based on objective, design, purpose, complexity, size, blinding, endpoints
-monitoring needed on site before, during and after trial (study site startup, routine, closeout visit)
-100% SDV is expensive and time consuming
-instead ris based monitoring is being adopted

Question 8

risk based monitoring

Answer 8

-allows for flexibility in monitoring plan/visits
-must be predetermined and documented
-based on risk levels (ie IP, complexity, size, dropout rates, etc)
-centralized monitoring procedures compliment on-site monitoring and can help reduce frequency/extent of on-site visits
-combination of on site, remote and centralized monitoring

Question 9

centralized monitoring

Answer 9

-remote evaluation of accumulating data performed in timely manner by trained persons (data managers, biostats)

Question 10

remote monitoring

Answer 10

-actions taken by monitor to review study data while not being phsyically on site

Question 11

centralized monitoring can: (5)

Answer 11

-identify missing , inconsisten, outlier, unexpected data and protocol deviations
-examine data trends within and across sites
-evalute for systematic or significant errors in data collection and reporting, data manipulation or integrity issues
-analyze site performance and charactertistics
-select site/processes for on site monitoring

Question 12

monitoring plan

Answer 12

-document that describes monitoring methods, responsibilities, requirements
-commuication of results of monitoring, visit schedules, noncompliance managment, training and study-specific info, conditions for plan to be amended

Question 13

Site selection visit

Answer 13

-not always done if estalished relationship between site and sponsor
-sponsor assess ability of site to conduct study safe, cooperative, timely manner
-evaluates quaifications of staff, facilities, patient population for study needs
-not common for academic studies, usually suitability determined in grant application

Question 14

study/site initiation visit

Answer 14

review of study protocol and procedures
-provide protcol and procedure training
-confirm staff understanding of GCP and regs, IP, IB, product monograph
-outline PI responsibilities
-outline monitoring visit scheule and procedures
-answer questions on study
-regulatory approvals needed before this meeting
-recruitment cannot begin until after meeting

Question 15

routine monitoring visits

Answer 15

-ICF review, SAE reporting, protocol compliance, SDV, IP review, reg binder/essential docs, debrief on findings

Question 16

closeout visits

Answer 16

-no paricipants being dosed, all data collected and entered with no queries, all study conduct at site ended
-sometimes only occurs after database lock
-final review of docs to ensure study can be recontructed
-return study supplies, drug supply return/destruction, essential docs review (QI sign off), paricipants records (AE/SAEs followed to resolution per protocol, lab reports signed)

Question 17

on site monitoring benefits

Answer 17

-SDV, overall quality of conduct of study at site by staff and PI
-useful early on in studies to ensure training, good for complex studies or if PI new to area of study

Question 18

centralized and remote monitoring benefits

Answer 18

-saves time and money
-effective for oversight, issuing queries, trends, etc
-usefulness depends on extent of electronic systems used and acccess to data on the systems (ie medical records and other source docs)

Question 19

risk-based monitoring steps

Answer 19

-risk assessment
-define critical data and processes
-quality and risk plan
-monitoring plan
-monitoring execution

Question 20

Risk assessment

Answer 20

-determine program level risks (protocol, IP), identify critical data acorss all protocols
-determine risk level (risk assessment and categorization tool RACT)
-includes impact, liklihood, detectability
-risk mitigation documented in Integrated Quality Risk Management Plan (IQRMP)
-risk rating = liklihood x severity
-risk levels and monitoring can change during study
-no data is ignored, but is assigned risk level

Question 21

critial data and processes

Answer 21

-identify data used to make decisions regards IP safety and efficacy
-support primary and secondary outcome measures
-cirital to patient safety (i.e. SAEs, treatement discontinuation)
-processes that ensure ethical and safe participant invovlement (SAE follow-up, lab follow-up)
-processes ensure data quality (blinding)
-goal: obtain quality data and meet study objectives
-involves all stakeholders, but avoid duplication of processes acorss groups

Question 22

risk indicators

Answer 22

-thresholds associated with risks identified
-once threshold reahed action must be taken (site follow up, increase data scrutiny)
-indicators and actions documented in IQRMP and monitoring plan
-need to assess expected values of threshold
-determine risk to safety and data inegrity if threshold exceeded (high risk = low threshold)

Question 23

Monitoring plan

Answer 23

-remote based monitoring plans involve numerous parties
-any tasks not assigned to monitor need to be described in respective plan (i.e. DMP, stats plan)

Question 24

IQRMP

Answer 24

integrated quaity risk management plan
-study quality assessed and managed by all functions in clinical study
-defines each functions’ actions to identify assess and manage risks
-alignment of quality management plans acorss program so that critical data is managed appropriately by all teams
-descirbes how each function will ensure data quality and safety throughout study
-IQRMP - master plan that contains individul plans such as monitoring plan, DMP, statistical plan, training plan, medical monitoring plan etc)

Question 25

overall aim of risk based monitoring

Answer 25

-reduce number and extent of on site visits using approaches better at identifying issues
-use stats to identify trends that might suggest issues at site (deviations, SAEs, data distribution)
-leverage technology such as standard range checks for labs, data completeness which occur automatically with data entry
-complete admin tasks ie REB approval, CRF corrections
-optimize safety, data, integrity and costs

Question 26

Transcelerate risk assessment and categorization tool (RACT)

Answer 26

-risks assessed in domains (safety, phase, complexity, population, tech, etc)
-is a tool for determining risks, other tools are available as well from others