MONITORING OF

CLINICAL STUDIES I
Dr Raúl Bozzo Professor at FEFYM

Syllabus
❑Objectives and Responsibilities
❑Standard Operating Procedures (POEs)/ Standard Operating Procedures (SOPs)
❑Monitoring Plan / Types of Monitoring Visits
❑Essential Documents and Source Documents
❑Documentation File - Trial Master File located in the sponsor's office and part of the
documentation mirrored in the CI (labor monitor,,)

Conceptual Review
*What is Good Clinical Practice ???????
*Good Clinical Practice (GCP) is an international standard of ethical and scientific
quality for the design, conduct, registration and reporting of trials involving human
subjects.
*Compliance with this standard ensures:

*1That the rights, safety and well-being of trial subjects are protected,
*2That the data from clinical trials are credible (fundamental to evaluate the drug's
efficacy)

*What is the MONITORING of clinical studies ????? * It is

a quality control that is done on the EC, which makes the test
to be conducted according to that international standard BPC.
That the trial is conducted according to GCP, local
regulations and according to the protocol
Monitoring Objectives
* Protecting patient RIGHTS and SAFETY * Free consent,
adequate information and right to withdraw

* Adequate treatment and monitoring of the disease and adverse events are
reported
ICH E6 5.18 review

ConI is the first step in clinical research and the first thing we have to monitor
and the HC to see how that process was.

* Study DATA is ACCURATE, COMPLETE and VERIFIABLE in the Documents

Source (where the information is first loaded) with HC being the most important

* Verification of data entered in the paper or electronic Case Report Form

(CRF) must be in the source documents, which is where they are uploaded
for the first time (HC, nursing books)

(Source Data Verification- SDV monitor action) is the crossing

from those CRF data with source doc

* Check monitor that compliance is achieved

* PROTOCOL;
* GOOD CLINICAL PRACTICES-GCP;
* LOCAL REGULATION
ICH E6, Section 5.18

Key Players in Clinical Research

Sponsor (Pharmaceutical Labs)
CROs
Research Centers CEIC

ANMAT Regulatory Authority PATIENT Researcher -

Clinical research companies/CROs can be independent or a

division within the laboratory.

Cycle of a Clinical Study

Design and Planning (Feasibility Monitor and Center Selection)

Start up (Monitor the coming and going of documentation to the ANMAT Ethics Committee)
Home (MONITOR large focus on TRAINING; 2ND TYPE OF VISITS FOCUS ON TRAINING) Recruitment
(MONITOR MULTIPLE ROUTINE VISITS -- AUDIT AND INSPECTIONS -- DATABASE CLOSING
consent, inclusion exclusion criteria, protocol, procedures, and data
dumped into CRF is absolutely verifiable, soft
data verification. There may be quality audits from both the sponsor and regulators, and the center
must be prepared for these inspections.
Closing and analysis (MONITOR CLOSING VISITS, 3RD TYPE, EVERYTHING THAT GOES TO THE
SPONSOR IS SELECTED, OR DESTRUCTION OF REMAINING DRUGS, AND THE IEC IS INFORMED THAT THE
STUDY HAS BEEN CLOSED, THAT THE FILES THAT MUST BE KEPT AT THE CENTER ARE CLOSED, AND THE
CLOSURE IS COMMUNICATED)

Monitor or CRA (Clinical Research Associate)

* Scientific knowledge (frequently in the health field)
* Trained in GCP, Local Regulation, POEs/SOPs, of the company itself,
Protocol and Product under Investigation
* PERIODICALLY VISIT the centers according to a PLAN OF

MONITORING to meet Monitoring Objectives

* For each Visit do:
* LETTER or email notifying of the visit specific to each company
* EXTENSIVE REPORT to our Company and summary FOLLOW-UP
LETTER to the CI after each visit with findings, etc.

*Monitor: Employed by Sponsor or by Organizations of

Clinical Research Organizations (CROs: Contract Research Organizations). Periodically
visit the centers with a plan, a roadmap with the objectives, and for each
visit make a warning letter, a follow-up letter and a report.
* Career and position according to years of experience
* CRA or CRA-1; CRA-2; CRA-Sr 7 and from there you areas
can go to others

ANMAT6677 Monitor Responsibilities

1. Patient rights and well-being, above protocol.

2. Adherence to the Protocol (latest version), anything that is not complied with in the protocol is a violation, it

must be reported

3. Assigned Researcher and Team Trained with Specific Functions

4. Act as the primary link between the Investigator and the Sponsor

5. Approved by IEC and Competent Authority

6. Regulatory Documentation is up to date and current

7. Conduct Monitoring Visits

8. Informed written consent signed before entering the study

9. Check administration, provision, and return storage, of the accounting product, of the research product circuit

10. Subjects meet Inclusion/Exclusion Criteria

11. Recruitment rate is adequate

12. Ensure Accurate, Legible Documents and Consistent Source (Data Quality and CRF)

Complete, legible and consistent)

13. That the recorded, followed and reported Adverse Events and Serious Adverse Events in a timely and manner

are legible, consistent

14. That the regulations on Deviations applicable to the Protocol have been documented to the requirements and

reported by the IEC or

15. Resolving Discrepant Data (Queries/DCF) data clarification form when CRF pages are filled out the databases

review them. If the data is inconsistent from the database, they send a response, and then we communicate with the

center and this discrepancy must be resolved within a week, which may vary from protocol to protocol.

16. Tracking Findings During Monitoring

17. Writing a Report/Visit Report

18. Monitor the study file and document reconciliation

After consent, exclusion criteria are monitored

deviation anything that is not done according to protocol, must be documented and

report

Operating Procedures
* Standard Operating Procedures (SOPs)
* Definition: Detailed, written instructions to achieve uniformity in the execution of a specific
function (ICH E6).

forced to POE
* Sponsor and CROs
We have to know them
* How to Make Regulatory Submissions / How to Build the Document File
* How to Perform Monitoring Visits (Selection, Start, Routine and Closing)
* How to Report Adverse Events
* Ethics Committee
* POEs/SOPs available for Researchers and Monitors (web pages) to know them,
otherwise we cannot verify compliance

* Research Centers, POE incorporation

* Phase I / Bioequivalence Centers
* Centers with greater experience
CABA central committee of research ethics gcba can be seen
POES CEIS priv. Public CEI POEs, it is the function of the Central Ethics Committee to
accredit CEI caba
FEFYM page about
Standard Operating Procedures
Foundation for Pharmacological Studies
and Medicines

Index 1. Background and general considerations.......... 2. Aim............ 3. Responsibilities, Functions and Scope. 4. Operations.. 5.
Composition, responsibilities, selection and renewal mechanisms........................................ 6. Documentation

10. Adverse events 11. Researcher's Brochure..................................................................... 12.Reports from the investigator and the
study..................... 13. Closing protocol... 14. Contract and Insurance Policy... 15. Ethical monitoring / audit by the
ICD................................. 16. Communications of CIE decisions....................... 17. CIE relations with the Central Ethics Committee of the
Autonomous City of Buenos Aires and with the Ethics Committees in Research...

Monitoring Plan
*Definition: Guide, roadmap, on how the study will be supervised to ensure that
it is conducted according to Protocol, GCP and local regulations.

General Index (which may vary from company to company)

Content

Synopsis
Brief summary of the study protocol (specific aspects may be referenced throughout the plan)
Objectives and Responsibilities
What we saw based on GCP-ICHE6 and Local Regulation
Monitoring Team Structure
Project Leader; (monitoring) CRA Leader; CRAs;
Project Assistant,
SOPs / SOPs Training
List of SOPs/SOPs to be used Description of our training Selection of Centers
Procedures to be carried out during the center selection visit, such as the visit -
Characteristics of the Researcher / Center / Patients - Regulatory Aspects (Ethics Committee /
ANMAT) - Contract with the Center

Home Visit
Procedures to be performed during the initial visit
- “Training” focus, which was the 2nd type of monitoring visit - Collection of Documentation -
Delivery of Regulatory Folders of the Center - Verification of Supplies in the Center
Frequency of Routine Monitoring Visits and Reports
When to make the First Visit? Generally one week after screening or medication of the first
patient, preferably to avoid repetition of the error in subsequent patients. Duration of Visits?
Frequency of visits, every x weeks? What is the driving force behind the number of visits?
the number of patients/findings How long before the Notice Letter/mail? How long for the
 Generally one week to make the report x
Report and Follow-up Letter?
monitor and in 14 days the letter has to be in the center
Routine Monitoring Visit Procedures
Detailed description of Routine Visit procedures:
100% Review of Consents
100% Review of Inclusion/Exclusion Criteria
100% Review of Medication Randomization and Accounting
100% Verification of CRF Data against Source Data (SDV)
Process and Time for Clarifying Discrepancies (“Queries or Data Clarification Forms”) for
clarifying discrepancies
100% Review of “Adverse Events” and “Serious Adverse Events” 24.29 Review of Laboratory
Procedures and Special Procedures of the study. Review of Regulatory File and
communication with the Ethics Committee up to date.

Closing visit
Closing Visit Procedures and Document Storage (minimum 10 years)

Classic Monitoring
He sends the letter, schedules a visit, visits the employee physically, generates a monitoring
report two days later, which the supervisor corrects internally so that within 14 days or the
shorter time stipulated by the company, it is ready and in parallel to this monitoring report, the
monitor sends a letter stating what he has done, the most important findings and suggested or
pending actions.

1) Study monitor -----> 2)Study Site ------> 3) Monitoring report

2) study monitor arranges in-person meeting with study site

The study monitor arranges an in-person meeting with the study site

3) Monitor SDV conducts at site

Monitor performs SDV on site

3)Results.
Monitoring report generated.
Source documents are verified.
100% SDV
Verify data quality
Results
Monitoring report generated.
The source documents are verified.
100% SDV
Checking data quality

Challenges.
Labor intensive. (Monitor and site)
Issues with source documents are uncovered during monitoring visit.
Challenge to solve queries because patients are long gone.
Challenges
Laborious. (Monitor and site)
Problems with source documents are discovered during the monitoring visit.
Challenge in resolving queries because patients have been gone for a long time.

Remote and risk-based monitoring

Certain studies have a mix between in-person monitoring and remote monitoring.
26.17

Study site:
Record patient data on the device
Device, with EDC function, issues the automatic query and the source doc is corrected on the
spot.

<<-------------------->>

Centralized monitor:
Analyze the fundamental/crucial data points and review/check the source
SDV not needed (data received via source / EDC is the source of the data) issues/expends
additional queries >>

Results
Monitoring the generated report
Source doc verification
Checking the target data
data quality check

Benefits
Remove SDV
Calculate the effective cost for both the sponsor and the site
Fix data quality issues while they're fresh
Contains operational and site performance data
Ability to resolve questions while patients are still accessible
RbM (Risk Based Monitoring?) Friendly

Record patient data on the device.

Remote and Risk-Based Monitoring

CRA, SDV and Queries-DCFs
Much of the documentation is on the web, the monitor monitors remotely and then generates
the report.

What activities do you do at the center?

essential verification against source documents.

the flow goes from source, who produces it, researcher or other, dumps the information
from the laboratory or the HC in the CRF clinical research form?
We verify, as monitors, that it is accurate, complete and consistent.

This is loaded into a database, and when it is not consistent, clarification forms are generated,
and as a monitor I have the obligation to ensure that the center responds in a timely manner.

Once all patients are loaded, and the database and the people who do data management
have reviewed 100% of the data, there will be no more queries or data clarification forms, and
that is when the closure occurs.

Closing the database: I will obtain the preliminary data from the study and proceed to close
the center.

This flow, in which Source data verification is essential as a monitoring action, is the flow that
the study data generally follows.
center

CRA MONITORING VISITS

✓ Source Data Verification-SDV
✓ Clarifies database doubts
Study Data
CRF >Load into Database ---> a) or b)

DATA MANAGEMENT
a) >Data Clarification Forms (DCF or Queries) --------------------> return to center
b) > Close the database---------> STUDY RESULTS

Source Documents
*Definition
Original documents and records of the clinical data of a study, where the
information is recorded for the first time, from which the source data sdv is
obtained to compare which data loaded in CRF is consistent with that of
the source document.
The essential documents are all those that allow us to affirm that the study
is carried out in accordance with GCP, including the source, brochure, MI,
CINf, etc. etc., CV

* Medical record
* Surgical Parts
* Laboratory and Pathological Anatomy Reports
* Complementary Studies (X-ray; ECG; CT; MRI; etc.),
* Laboratory book and pharmacy records
* Nursing forms
* Visiting agendas
* Patient Diaries and Patient Questionnaires
* Source Data: Data contained in the source documents
* “Source Data Verification”: I verify that the data loaded in the CRF is
consistent with the data in the source document
ICH-E6-Chapter 8 Essential Documents
Def.: Documents that allow the evaluation of the conduct of the study and
the quality of the data
* Protocol; Brochure of the Invest.; Consent
* Confidentiality Agreement; Contract; Insurance
* Regulatory Approvals (IEC; Applicable Authorities), annual report and
correspondence *CV; Registrations; Researcher's Statements
* Laboratory: CV; Normal Values; Certification
* Drug: Label; Delivery notes; General Accounting Log; COA
* Monitoring Reports and Follow-up Letters
* Reports of Serious Adverse Events
* Security Alerts and Brochure Addendum
*CRFs

Essential Documents II of the ICH-E6 CENTER-Chap.8

* Essential Logs or Forms of the Center

* Delegation of Functions and Signatures Log
* Patient Screening Log
* Patient Enrollment Log
* Confidential Patient ID Log
* Individual Drug Accounting Log
* Drug Temperature Log
* Monitoring Visits Log
* Biological Sample Retention Log

ICH-E6-Chap.8
Describes all the essentials and documentation that must be in the center's file
and with the sponsor. It is a checklist to verify that the regulatory files are
complete.
There are a series of dynamic forms that are filled out all the time, which are
logs, online or on paper.

DOCUMENTATION FILES
* Def.:
Paper and/or Electronic File where essential study documents are kept
Contents: Chapter 8 ICH E6 and

TMF Headquarters trade master file

Local Archive Sponsor
Research Center Archive

document flow:

From the center, a copy is retained by invest, one to the local sponsor
archive and from there to the parent company, both in paper and electronic
form. according to sponsor regulations, paper and electronic.

Researcher's Archive
general folder (varies) content

Protocol and Amendments

All protocols submitted to that center's committee and all amendments
Researcher's Manual or Brochure
• Manual or Brochure of the Investigational Drug and
its
general annual updates
• Security Alerts: (addenda to the
manual, every time an Adverse Reaction occurs
Serious and Unexpected Medication)
CRF and Other Manual Guides
Study CRF templates and guide
for completing them
IWRS/IVRS Guidance Monitoring Plan GCP Regulation Declaration of
Helsinki; ICHE6; ANMAT Local Regulation
“Central” Laboratory
Laboratory Manual with Normal Values; Cv Director and
Laboratory Certificates
Training
All training sessions carried out at the center
Correspondence
All applicable correspondence

general folder; each company has its own index of how it creates files, but
generally that will be in the researcher's file.
There is another part where these logs are dynamic and we use them in the
monitoring visit

Specific Docs Folder Contents of specific docs for the center

LOGs or Essential Forms

❖ Monitoring Visit Log or Form; every time I go to the center, from the initial
visit to the closing visit. someone from the center verifies that I am there. an
active log, I leave the original in centrom and take a copy to my folder
❖ Log or form for Signatures and Delegation of Functions
❖ Log or form (confidential) of Identification and codes
of subjects
❖ Log or Screening and Inclusion form (“Enrollment”)
of Subjects (paper or electronic via web)
❖ Log or form for retention of biological samples of
the subjects (to apply)

Researcher's Archive
Monitoring Visit Log or Form
Signature
Date
CRA Name
CRA Signature
Signature Center

Type of Visit:
SIV MV1
MV2
MV3
MV etc...
V.Closure

1) Visit Form
then
2) Signature and delegation of functions form
3) Signature/Task Delegation Log
There is another form where any person who performs delegated functions is recorded, so that I can verify if it is
that person who completed this or that form.
I must have the resume of all those people, who are trained in GCP and know the protocol.
Many times researchers make a form in which they will comply with the protocol and GCP

4) Subject identification code list/subject enrollment

5) log form that is only in the center, but I have to verify that it exists and is complete for all
patients who have already signed a consent in case it is necessary to contact them.

each patient visit is listed (this form is only in the center TO BE RETAINED IN THE TSF ONLY
And all patients are here in case they need to be contacted.
We have a patient code, a screening/erollment log where the patient ID appears (not name)
IXRS interactive randomization system
To sum up, I have two forms for patients:
One on paper, with all the data, confidential, and it is only in the center
and an interactive system where I record evolution and it is the system that assigns
medication to the patient.

4451

Principal Investigator (PI) Documentation

and Subinvestigators (SIs) (according to EFCA 2- ANMAT 6677)
• Researcher's Curriculum Vitae
• Certified copies of the Title and Professional Registration
• Certified copy of the Specialist or Residency Title
• Note or Declaration from the researcher and his team to respect the
Protocol, the Declaration of Helsinki and the ANMAT GCP-EFCA Regime
• Signature Page: Protocol and Amendments
• GCP training certificates
We must have collected it so that the center is approved by ANMAT

IP Docs and Sis for FDA studies

• Affidavit of the Investigator-Form F1572 (1 per center)
• Financial Disclosure Form (F3455; 1 per researcher)

We must have efca 2 for approval of the center

and doc for fda (1572, from the center for fda) specific and form that there is no financial interest of
investing with sponsor.

CVs are abbreviated

Affidavit according to the CEI
Usually each researcher declares Nuremberg, Helsinki and birth

protocol acceptance form

GCP Certificate
Every person must have a certificate of having been trained in GCP

ANNEX 4: MODEL DIE SWORN DECLAIRMENT. FROM THE MAIN INVESHGA[)OR

I hereby undertake or express to carry out the following STUDY:
according to the Protocol or a:pr,ooodo by the CEI of FlLENI and the afmities of a:pneacion (if applicable) respecting the letter and the spirit u
of the Dedara,c-ones of Nf1rembe;rg and IHe:Jsinki ( c,on
all its amendments) and applicable national regulations
Signature of Principal Investigator
Aiclaration of Ila Fiirm a -
Place and Date of

Ethics Committee Documentation in

Research (CEI) corresponding to the Center
• Letter of approval of the PROTOCOL, CONSENT, AMENDMENTS by the
IEC
• Copy of CONSENT approved with CEI seal
• List of CEI members
• Presentation of the INVESTIGATOR'S Manual and CONTRACT
• Correspondence, includes: ✓ Annual (or semi-annual) reports, ✓
Security alerts ✓ Serious Adverse Events at the Center ✓ Major
deviations from the protocol
Authorities of the Center
• Letter of approval/authorization from the highest authority of the ANMAT
Documentation Center and the provincial Regional Authority (if applicable)
• Approval of Protocol, Consent and Center

Major deviations from protocol, notify the committee

Researcher's Archive
Legal and Financial
• Confidentiality Agreement
• Study Contract
• Current Insurance with its annual renewals
Monitoring Reports / Letters
• Pre-study evaluation letter
• Home Business Letter This is the email we sent
• Routine Visiting Letters
• Closing Visit Letter (includes email or letter of advance notice of visit)
Research Product Docs
• Copy of medication labels
• Operating instructions / Pharmacy manual
• Shipping/Pickup Notes
• Log or Temperature control form (essential)
Signed Informed Consents
• Original of all SIGNED CONSENTS (the first thing we will monitor)

MONITORING VISIT CONFIRMATION LETTER 5017

When and what am I going to do?

MONITORING REPORT 5041

section content

General
Center Data; Date of Visit; Who was there
Number of Patients
Table with Patients in Screening; Included/Enrolled (in treatment); Completed
Informed Consent
Summary of monitored consents
CRF monitoring and verification against SDV Source Documents
Summary of patients and monitored visits. With comments on the findings
Adverse Events
Review of how EA, EASerios and Security Alerts are being reported
Medication
How study medication is assigned and controlled
Others
Documentation of Researchers and Ethics Committee
Supplies and building capacity of the center Summary of Findings and Actions

At the end there is a section of findings and suggested actions.