Transcript MAPS MP-7 Protocol Review

Responsibilities of Investigator
Kamila Novak
Investigator’s Responsibilities
Medical Care
of Trial
Subjects
Communication
with IRB/IEC
Safety
Reporting
Essential
documents
Adequate
Resources
Compliance to
GCP and reg.
requirements
IP
Protocol
Compliance
Informed
Consent
Site Noncompliance
Source
documents
Records and
reports
Adequate Resources
Adequate
resources
Adequate number of qualified staff,
adequately informed about the protocol,
IP and their duties
 Sufficient Time (competing trials)
 Motivation
 Adequate facilities
 Adequate equipment and support functions
ICH GCP Chapter 4.2
Potential for recruiting the required
number of suitable subjects
Medical Care
Medical care
• A qualified physician (or dentist), who is an investigator
or a sub-investigator, should be responsible for all trial
related medical (dental) decisions
• Investigator should ensure that adequate medical care
is provided to a subject for ANY adverse events,
including clinically significant laboratory values
• With subject’s agreement it is recommended for the
investigator to inform the subject’s primary physician
about the subject’s participation in the trial
• Investigator should make a reasonable effort to
ascertain the reason for subject’s withdrawing
prematurely from a trial
ICH GCP Chapter 4.3
Сompliance with GCP
Compliance
with GCP
Investigator should:
 Be aware of and should comply with
GCP and the applicable regulatory
requirements
ICH GCP Chapter 4.1.3
Сompliance with Protocol
Compliance
with protocol
Investigator should:
 Review the protocol
 Be thoroughly familiar with the IP as
described in the protocol, current
Investigator’s Brochure, and the
product information
ICH GCP Chapter 4.1.2
Two Roles: Physician and Investigator
Routine
Medical Care
Conduct of a
Clinical Trial
Person with symptoms is looking
for physician to diagnose
and treat the illness
Investigator is looking for
subjects with diagnosis eligible
for the clinical trial
Physician collects and reviews,
per medical practice, relevant
information to make a diagnosis
Investigator collects and reviews,
per protocol, relevant info to
select eligible subjects
Physician makes diagnosis and gives
standard treatment/therapy
of choice
Investigator enters eligible subject
into trial and is obliged to give
IP per protocol
Two Roles: Physician and Investigator
Routine Medical
Care
Conduct of a
Clinical Trial
Physician may change dose, route,
administration of drug or drug
itself and allow concomitant
medication according to
standard treatment
Investigator follows protocol for
dose, route and administration of IP
and use of concomitant medication
may be restricted
Physician performs examinations
and procedures to determine
Diagnosis and evaluates outcome
of treatment
Investigator performs examinations
and procedures per protocol to
obtain data for efficacy and safety
evaluation of IP
Physician determines schedule
of events for each patient
Investigator follows schedule
of events per protocol
Treatment ends when satisfactory
outcome is achieved
Subject participation in trial is
complete per protocol
Compliance with Protocol
Compliance
with protocol

The Investigator should sign the protocol (signature
page) to confirm his/her agreement to conduct the
trial in compliance with the approved protocol

The Investigator should not implement any deviation
from the protocol without agreement of the sponsor and
prior review and approval/favourable opinion of the
IRB/IEC
ICH GCP Chapter 4.5.1, 4.5.2
Compliance with Protocol
• Where necessary to eliminate an
immediate hazard to trial subjects
• When changes involve only logistical or
administrative aspects
The investigator should
• document and explain any deviation from the
protocol
• document, explain and report such deviation
 to IRB/IEC for review and approval
 to sponsor for review
ICH GCP Chapter 4.5.2, 4.5.3
Noncompliance
Noncompliance
Noncompliance with protocol,
SOPs, GCP and/or applicable
regulatory requirements
If serious and/or persistent
Noncompliance is identified
by auditors and/or monitor
Sponsor should act
promptly to secure
compliance (e.g.
corrective action plan)
Sponsor should
terminate
investigator’s
participation
Sponsor should
notify RA promptly
ICH GCP Chapter 5.20
Deviations from Protocol Reports to IRB/IEC

Deviations from, or changes of the
protocol to eliminate immediate
hazards to trial subjects
 Changes increasing the risk to
subjects and/or affecting
significantly study conduct

All adverse drug reactions that
are both serious and unexpected
 New information that may affect
No deviation from,
or change of protocol
without sponsor’s
agreement, IEC/IRB
approval
***
except when necessary
to eliminate an
immediate hazard(s)
to subjects or in case of
administrative changes
adversely the safety of subjects
ICH GCP Chapter 3.3.8, 4.5.4
Informed Consent (IC)
of Trial Subjects
 The voluntary confirmation of a subject’s
Informed
Consent

willingness to participate in a particular
trial, after having been informed of all
aspects of the trial relevant to his/her
decision to participate in the trial
Documented by means of
a written, signed and dated
informed consent form
(by subject and investigator)
Informed
Consent Form
Signature
ICH GCP Chapter 1.28
Date
Investigator’s Responsibilities
•
•
•
•
Consent the subject prior to participation in a trial
and before ANY trial procedure, including blood
tests for screening unless it’s part of normal clinical
practice
Ensure the subject is fully informed
Ample time and opportunity to ask questions must be
given
Should not unduly influence a subject to
participate
ICH GCP Chapters 4.8.8, 4.8.5, 4.8.7, 4.8.3
Investigator’s Responsibilities
•
•
•
•
Document the consent procedure in source
documents
Give the subject a copy of the signed and dated ICF
Obtain written approval from IEC/IRB on ICF and
all changes to ICF
Ensure the language is understandable to the
subjects
ICH GCP Chapter 4.8.11, 4.8.1, 4.8.2, 4.8.6
“Special” ICF Procedures
•
Witnessed consent by impartial witness
◦ e.g., if subject is unable to read
•
Legally acceptable representative
◦ e.g., pediatric trials, mentally ill subjects
•
Emergency situations
◦ e.g., unconscious subjects
ICH GCP Chapter 4.8.9, 4.8.15
Vulnerable subjects
Individuals whose willingness to volunteer is influenced
by the expectation of benefits of participation, or of
response from senior members of hierarchy:
* medical students
disease
* hospital/laboratory personnel
homes
* armed forces
* people under detention
* patients in emergency cases
* ethnic minorities
* patients with incurable
* persons of nursing
* unemployed/homeless
* pharmaceutical industry
employees
* incapable to give IC
ICH GCP Chapter 1.61
Investigational Product
IP
A pharmaceutical form of an active ingredient
or placebo being tested or used as a reference
in a clinical trial, including a product with a
marketing authorization when used or
assembled (formulated or packaged) in a way
different from the approved form, or when
used for an unapproved indication, or when used
to gain further information about an approved use
ICH GCP Chapter 1.33
IP – Investigator Responsibilities
• Receipt of IP only by authorised staff
IP
IP
• Dispensing, handling and appropriate use of IP according to
protocol
• IP given only to trial subjects, used package and unused IP returned
• Explanation of the correct use of IP to each subject to ensure
compliance with protocol
• Storage as specified by the sponsor (temperature regimen, proper
conditions/times)
• Secure, safe and appropriate storage with limited access by
investigator and authorised staff
ICH GCP Chapter 4.6.2, 4.6.6, 4.6.4, 4.6.3
IP – Records at the Site
 Maintain records of IP delivery, inventory, use by
IP
IP
each subject and the return to sponsor/destruction
Dates and amounts received from sponsor
 Confirmation IP received by authorised person
Dates and amounts dispensed to/used by patients
Dates and amounts returned to sponsor
Expiry dates (if applicable)
Unique code numbers assigned
Doses used by subjects
 IP accountability - RECEIVED = USED + UNUSED
ICH GCP Chapter 4.6.3
IP – Randomization & Unblinding
IP
Investigator should:
IP
 follow the trial’s randomization procedures
 ensure that the code is broken only in
accordance with the protocol
 promptly document and explain to the sponsor
any premature unblinding
ICH GCP Chapter 4.7
IP - Flow of Events
Investigational Product
Q/sponsor/vendor
Received at Site
IP receipt docs
IP dispensed to subjects
IP accountability docs
IP returned by patient
IP returned to sender
Destruction of IP
IP Reconciliation docs
Adverse Event
Safety
reporting
Any untoward medical occurrence
in a patients or clinical
investigation subject administered
a pharmaceutical product that
does not necessarily have
a causal relationship with this
treatment
ICH GCP Chapter1.2
Why Are AEs Important?

Medical Reasons

Regulatory Reasons
Adverse Event-Recording
Adverse Event
Page in the CRF
! All AEs must be assessed by investigators and documented
in the source documents first and then transferred to CRF !
ICH GCP Chapter 4.9.2
Adverse Event Page
Protocol:
Site Nr:
Subject Initials:
Visit Nr:
Subject Nr:
Visit Date:
Adverse Duration Intensity/ Causality
Event
Severity
Investigator:
Randomisation Nr:
Trial
Drug
Treatm.
given
Outcome
Seriousness
Investigator Signature ____________________ Date ___________________
Recording AEs
What information is generally collected:



- Adverse Event
- Dates of Onset and Resolution
- Severity:
Mild
= aware but tolerable
Moderate = interferes with activities
Severe = unable to do normal activities
- Causality:
 Not related
 Unlikely
 Possible
 Probable (AE stops when drug stopped)
 Highly probable (AE stops when drug stopped and
restarts when drug is reintroduced)
Recording AEs
What information is generally collected:
- Outcome




Resolved
Resolved with sequelae
Ongoing
Death
- Action Taken with Study Drug (dose)
 None
 Reduced or increased
 Interrupted (means temporarily)
 Discontinued (means permanently)
- Requirement for Treatment – Concomitant
Medication
- Seriousness
Adverse Drug Reaction (ADR)
New medicinal product
Marketed medicinal product
A causal relationship
between a medicinal
product and an adverse
event is at least a
reasonable possibility,
i.e. the relationship
cannot be ruled out
May occur at ANY DOSE!
A response to a drug
which is noxious
and unintended and
which occurs at doses
normally used in man
for prophylaxis, diagnosis,
or treating diseases or
for modification of a
physiological function
ICH GCP Chapter1.1
Unexpected Adverse Drug Reaction (UADR)
An adverse reaction,
the nature and severity
of which is not consistent
with the applicable
product information
ICH GCP Chapter1.60
Serious Adverse Event (SAE)
Any untoward medical occurrence
that at any dose results in:
 death
 life-threatening
 inpatient hospitalization or
prolongation of existing hospitalization
 persistent or significant disability/incapacity
 congenital anomaly/birth defect
ICH GCP Chapter 1.50
Planned Hospitalization
• Per project requirements, a hospitalization planned
prior to a subject’s inclusion in the trial might not
be considered an SAE
• If a hospitalized subject has an AE that prolongs
that hospitalization, then that AE would become an
SAE
Pregnancy and Subjects



Most sponsor companies will request that all
pregnancies are reported in the same way as serious
adverse events i.e., immediately, and using the SAE
report form or Pregnancy Notification Form
Upon consent pregnancies are followed until
delivery of the child
Child is assessed at birth for
any congenital anomaly/birth
defect and possibly longer
What is what?
AEs
ADRs
UADRs
SAEs
Serious Adverse Event - Flowchart
Episode of Myocardial Infarction
Is it an Adverse Event ?
YES
Is it a Serious Adverse Event ?
NO
Y
E
S
 Notify the Sponsor/CRO
 Complete SAE Report Form
 Notify IRB/IEC and RA
Complete
AE Page
Immediately
may mean
24 hours
Communication with IRB/IEC
Communication
with IRB/IEC
Written, dated approval/favourable
opinion (before initiating)
Ongoing applications of trial documents
(during the trial)
Ongoing Safety Reporting (during the trial)
Progress/annual reports (during the trial
Notification about trial completion,
early termination (end of the trial)
ICH GCP Chapter 3.1.2, 3.1.4, 3.3.8, 4.4.1, 4.4.3, 4.10.1, 4.10.2, 4.12.1, 4.13
Prompt Reports to IRB/IEC
Progress
Reports
• Deviations from, or changes of, the protocol to
eliminate immediate hazards to the trial subjects
• Changes increasing the risk to subjects and/or
affecting significantly the conduct of the trial
• All adverse drug reactions (ADRs) that are both
serious and unexpected
• New information that may affect adversely the safety
of the subjects or the conduct of the trial
ICH GCP Chapter 3.3.8
What are Source Documents (SD)?
SDs
Original documents, data and certified
copies of original records necessary for
trial evaluation and reconstruction
ICH GCP Chapter 1.52
Source Documents Include, But Are Not Limited To....

Medical records/clinical charts/subject's file

Laboratory results

Subject diaries/cards

Pharmacy drug dispensing records

Recorded data from automated instruments
ICH GCP Chapter 1.52
Source Documents Include, But Are Not Limited To....


Microfilm or magnetic media, x-rays, etc
Records kept at pharmacy, at labs and medicotechnical departments

Electronic records

Electronic signatures
ICH GCP Chapter 1.52
Case Report Form (CRF)
A printed, optical, or electronic
document designed to record all
of the protocol required information
to be reported to the sponsor
on each trial subject
ICH GCP Chapter 1.11
Minimum Requirements for SD

Signed and dated Informed Consent form
◦ source notes indicating that the subject has signed
and dated the consent prior to any study procedure

Subject Identification/Demographic data
◦ Unique study identifier (screening/randomization
number)


Medical history including diagnosis of the condition
under study
Physical examination
Minimum Requirements for SD (cont.)

Entries for each visit including screening, scheduled,
and unscheduled, to include:
◦
◦
◦
◦
◦
◦
◦
◦
Dates
Health status
Medical observations
Changes to medications with reasons
IP dispensing and accountability
Adverse events
Efficacy measures
Study procedures (both done and not done with
reasons)
Minimum Requirements for SD (cont.)

Concomitant medication

Concurrent medical conditions


Reports and printouts, radiology, x-ray, laboratory,
ECG, MRI, EEG, etc.
Date of completion or withdrawal from study with
reasons stated

Follow-up

Contacts with patients
Investigator’s Responsibilities
 Consistency of CRFs with SDs
 Up-to-date Source Documents maintained
 Accuracy, completeness, legibility and
timeliness of data collected, recorded
and reported
 Follow minimum requirements for recording
data in Medical Records
Source
documents
must not be
altered to match
the CRF
 Direct access to all trial documents for
monitor, auditor, IRB/IEC, RA
 Changes/corrections to CRFs dated, initialed
 Discrepancies explained (if necessary)
ICH GCP Chapter 4.9.1, 4.9.2, 4.9.3
Data Correction

Proper procedure for correcting CRFs
◦ Single line through error
◦ Legibly print correct data adjacent to error
◦ Initial and date correction
◦ Never back date
◦ Avoid pencil use
◦ Never use correction fluid or tape
ICH GCP Chapter 4.9.3
Source Document Verification (SDV)


Process of checking data consistency in the CRF
with source data, performed to maintain subject
safety
Requirements for data consist
ency:
 accuracy
 completeness
 explanation and documentation of discrepancies
ICH GCP Chapter 5.18.4k, 5.18.4m, 5.18.4n
General Reminders



Source documents/data must be maintained
individually for each subject and identifiable
to the subject
Only authorised personnel are to make
entries into source documents
All entries should be signed and dated by the
personnel responsible for entries
Essential Documents
Documents which individually and
Records
collectively permit evaluation of the
conduct of a trial and the quality of the
data produced
May include:
• CRFs
• Patients Medical Notes
• SDs
• Investigator Site File
ICH GCP Chapter 1.23, 8.1
Retention of Essential Documents
Records
• At least 2 years after last Marketing
Application approval in an ICH region and
there are no pending or contemplated MAs in
ICH regions
• At least 2 years after discontinuation of clinical
development
• Sponsor responsible for informing investigator when
no longer required
ICH GCP Chapter 4.9.5