Clinical trial monitoring

MONITORING IN CLINICAL TRIALS
Prepared By: Mukesh Kumar Saroj
Edited By: Dr. Ashish Singh parihar

MONITORING
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The act of overseeing the progress of a clinical trial, and of
ensuring that it is conducted, recorded and reported in
accordance with the protocol, SOPs, GCP, and any
regulatory requirements”.
ICH GCP Section 5.18

Purpose of Monitoring
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 Protection of rights and wellbeing of human participants
Ensure consent in place for record access.
 Trial data are accurate, complete and verifiable from source
documents.
 Conduct of trial is in compliance with the currently approved
protocol, GCP, and all applicable regulatory requirements.
ICH GCP Section 5.18.1

Qualities of a goog Monitor
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 Appropriately trained.
 Adequate scientific and/or clinical knowledge.
- Documented with training logs and CVs.
 Thoroughly familiar with:
- IMP
- Protocol
- Consent form
- Sponsor & trial SOPs
- GCP
 Knowledge of local laws, regulations, customs & local
language.

Extent & nature of Monitoring
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 Monitoring should be proportionate to:
- Objective
- Purpose
- Design
- Blinding
- Size and complexity
- Outcome measures
- Risks

Types of Monitoring
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1) Central monitoring.
- Determination of key eligibility criteria through collection of:
- Consent forms
- Scans
- Pathology reports
- Statistics
- Unusual patterns of data. ICH GCP 5.18.3

Types of Monitoring
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2) Risk Based monitoring. ICH GCP 5.18.3
 Limited resources should be used to where it is really necessary.
High risk part.
- For subject protection
- For reliability of trial results
- For protection of future patients
 Risk-based approach! (6 Rs)
1- Risk Identification
2- Risk Evaluation
3- Risk Control
4- Risk Communication
5- Risk Review
6- Risk Reporting ICH GCP Sections 2.13, 5.0 (, 5.20.1)

Types of Monitoring Cont..
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3) On site Monitoring.
- Staff training
- Access to necessary documents
- Confirm pharmacy and lab resources in place
* Count study drugs
- Adherence to protocol and GCP
- Check medical records
* Consent forms
* Eligibility
* AEs
- Source Data Verification (SDV)

Monitoring Process Continued..
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1) Before Monitoring Visit :
- Review the status of data entry
- Review action item from last visit
- Review regulatory binder
- Check PI & site staff availability
- Get the internal team approval
- Send confirmation/agenda of monitoring visit

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2) During Monitoring Visit.
- The monitor will assess or discuss:
Site, staffing, research labs or other facilities
Regulatory file and study records
Clinical procedures if possible or appropriate
Any problems and issues identified
Debrief at end of visit

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3) After Monitoring Visit.
The monitor will………
Complete site visit report
Submit the report to the sponsor

4 Types Monitoring Visits
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1) Site assessment(pre trial) Visit
2) Site initiation Visit
3) Routine(interim) visit
4) Close Out Visit

4 Types Monitoring Visits
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1) Site assessment(pre trial) Visit
Purpose :
It’s a face to face meeting with the investigator to
explore the overall feasibility of the site and the
investigator to participate into the study.

4 Types Monitoring Visits Cont..
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Site assessment(pre trial) Visit

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2) Site Initiation Visit
Purpose :
- to uniformly provide study specific information to
investigator(s) and study staff prior to study start
up.
- reassess resources and capability to conduct a
research study.

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2) Site Initiation Visit Cont..
 The monitor will meet with the study staff to discuss
research obligations under GCP:
Investigator administrative responsibilities
IRB approvals and communications
Regulatory file requirements(ICH GCP E6 8.2)
Informed consent forms and process
Protocol and protocol amendments
Source documentation
Study product handling and accountability
Safety reporting
Protocol specific training
Archiving of study documents

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The monitor will
Review sponsor policies , standards and
procedures for the conduct of clinical trials.
Reassess the site facilities
Provide additional guidance to the site as
determined by his/her findings.

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The monitor will
Review sponsor policies , standards and
procedures for the conduct of clinical trials.
Reassess the site facilities
Provide additional guidance to the site as
determined by his/her findings.

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3) Routine(interim) visit
Purpose :
Protection of human subjects rights and wellbeing.
Accuracy, completeness and verification of reported trial
data.
Trial conduct in compliance with protocol/amendments,
GCP and regulatory requirements.

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3) Routine(interim) visit Cont..
 Review /assess the following:
A) Enrollment status, rate and any drop outs of study subjects
B) Resources
C) Laboratory
D) Study supplies
E) Investigational Product
F) Compliance & Progress
G) CRF (Case Report Form)
H) SDV (Source Data Verification)
I) Informed Consent Form
J) Reporting
K) Regulatory files
L) AEs/SAEs
 Follow up on previously identified issues.

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B) Resources:
Verifying
1 that the investigator has adequate qualifications and
resources and remain adequate throughout the trial period,
2 that facilities, including laboratories, equipment, and staff,
are adequate to safely and properly conduct the trial and
remain adequate throughout the trial period.

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C) Laboratory:
Verifying
- Relevant SOP
- QC/QA process-Facility, reagents, equipment, results etc.
- Appropriate specimen storage
- Functionality of equipment
- Tracking subject-specimen-result-CRF

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D) Study Supplies:
- Ensuring that the investigator receives the current
Investigator's Brochure, all documents, and all trial supplies
needed to conduct the trial properly and to comply with the
applicable regulatory requirement's.
- Shipment process, temperature maintenance, storage
of product/reagents, disposal mechanism etc.

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E) Investigational Product :
(i) That storage times and conditions are acceptable, and that supplies are
sufficient throughout the trial.
(ii) That the investigational product(s) are supplied only to subjects who are
eligible to receive it and at the protocol specified dose(s).
(iii) That subjects are provided with necessary instruction on properly using,
handling, storing, and returning the investigational product(s).
(iv) That the receipt, use, and return of the investigational product(s) at
the trial sites are controlled and documented adequately.
(v) That the disposition of unused investigational product(s) at the trial
sites complies with applicable regulatory requirement(s) and is in
accordance with the sponsor.

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F) Compliance & Progress :
Verifying
- that the investigator and the investigator's trial staff are performing
the specified trial functions, in written accordance with the protocol
and any other agreement between the sponsor and the investigator
/ institution, and have not delegated these functions to
unauthorized individuals.
- that the investigator is enrolling only eligible subjects.
- that written informed consent was obtained before each subject's
participation in the trial
- that source documents and other trial records are accurate,
complete, kept up-to-date and maintained.

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G) CRF :
Verify that CRF’s are:
- Correct and accurately completed
- Consistent with corresponding SD where Separate
- Only authorized persons complete
- Corrections made are signed, dated & backed by
accurate SD
- Data related queries accurately documented
- Storage and/or shipment is secured

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H) Source Data Verification (SDV):
Source data:
all information in original records and certified copies of
original records of clinical findings, observations or other
activities in a clinical trial necessary for the reconstruction an
evaluation of the trial. (ICH GCP 1.51)
Source documents:
 original documents, data and records(e.g. hospital records,
lab notes, clinical charts, subjects diaries, pharmacy dispensing
records, x-rays, subject files etc.) (ICH GCP 1.52)

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H) Source Data Verification (SDV) Cont..:
 SDV: evaluation of the conformity of the data presented in CRFs
with source data.
Main aim: confirm that the data collected is complete, accurate,
reliable and verifiable so as to give confidence to sponsor and
regulatory authorities in the data being used to support a marketing
application.
Without SDV, no scientist can have confidence in data presented and
conclusions derived.

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Key data :
10 efficacy data
Inclusion/exclusion criteria
Medical/medication history
Physical exam/vital signs
visit dates
Adverse events
Concomitant medication
Record that patient entered clinical study and date of consent
Any gross errors in these might be detrimental to the scientific and ethical quality of the clinical
trial.

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Methods of SDV:
Back to back
Direct method- monitor has direct access to source data (ICH
GCP E6 1.21,5.15)
Extent of SDV ???
Depends on: clinical trial phase, quantity of data, time
availability, man power availability, investigator research
experience, company policy.

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Methods of SDV:
Back to back
Direct method- monitor has direct access to source data (ICH
GCP E6 1.21,5.15)
Extent of SDV ???
Depends on: clinical trial phase, quantity of data, time
availability, man power availability, investigator research
experience, company policy.

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 Common approach:
Critical data: focal to aims and objectives of study and must be
correct.
Informed consent to participate
Clinical notes
Conformance to inclusion/exclusion criteria
Primary efficacy endpoints
Secondary efficacy endpoints
Recording and reporting of SAEs
Documentation that that study drug was prescribed and at
the specified dosage.
Visit dates as per protocol
Non-critical data e.g. very neat, high numbers of overwriting, rapid recruitment,
lack of SAEs when they would be expected etc.

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Common problems
Data entered directly to CRF
Brief medical history/ scanty clinical notes
Several volumes of SD
SD/CRF mismatch
Illegible handwriting
Maximum acceptable error rate
Document the SDV process
SD examined
CRFs checked and why they were selected
Critical and non-critical data items checked
Nature and frequency of errors
Any corrective actions undertaken

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I) Informed Consent Document.
What to check:
Each participant has personally signed and dated ICD prior
to study procedures.
Appropriate use of independent witness
Correct version being used
Names of subjects/person giving consent, date and time
Investigator appropriately signed ICD and dated.
All pages of ICD present

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J) Reporting
Reporting
- Reporting the subject recruitment rate
- Trial progress
- Problems at site
- Needs at site
- Solicit solutions

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J) Regulatory files
- Review all relevant section of files
- Ensure it is up to date
- Ensure documents are placed in relevant section

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J) AEs/SAEs
- Ensure AEs are captured in CRF
- Ensure no AEs are unreported
- Ensure proper reporting and documents are
placed in case of SAE

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Plan
Do
Check
Review
MONITORING &
AUDITS

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References: E6R2, ICH GCP, Indian GCP, CT Rules 20119

Clinical trial monitoring

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