1. MP-7 Investigator Meeting January 31, 2011
Responsibilities of Investigator
Kamila Novak

2. Investigator’s Responsibilities
Safety
Reporting
Medical Care
of Trial
Subjects
Communication
with IRB/IEC
Essential
documents
Informed
Consent
Adequate
Resources IP
Site Non-
compliance
Compliance to
GCP and reg.
requirements
Source
documents
Protocol
Compliance
Records and
reports

3. Adequate Resources Adequate number of qualified staff,
adequately informed about the protocol,
IP and their duties
Adequate
resources
Sufficient Time (competing trials)
Motivation
Adequate facilities
Adequate equipment and support functions
Potential for recruiting the required
number of suitable subjects
ICH GCP Chapter 4.2

4. 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
Medical care
ICH GCP Chapter 4.3

5. Сompliance with GCP Investigator should:
Compliance
with GCP
Investigator should:
Be aware of and should comply with
GCP and the applicable regulatory
requirements
ICH GCP Chapter 4.1.3

6. Сompliance 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
Compliance
with protocol
ICH GCP Chapter 4.1.2

7. 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
2 slides compare responsibilities of a physician treating his/her patients versus a physician acting as a clinical trial investigator. Investigators, being medical doctors on one hand, and participating in clinical trials as investigators, on the other hand, have two roles: to provide medical care and medical decisions for their patients in routine medical practice, and to conduct the clinical trial on subjects. So, investigators are "double-faced“, playing two roles that are both different and similar.
1. In routine medical practice, when a person is suffering from certain symptoms, he/she is looking for the physician to diagnose the illness and recommend an appropriate treatment. However, in a clinical trial, it is the investigator who is looking for subjects with a diagnosis who are eligible for recruitment into the clinical trial In routine medical practice, a physician collects & reviews, according to the doctrine of medical practice, relevant information in order to make a diagnosis. In a clinical trial the investigator collects and reviews, according to the protocol, relevant information in order to select eligible subjects.
3. In routine medical practice, once diagnosis is determined, the patient is prescribed standard treatment and the physician, based on his/her knowledge and guided by the established principles of standard treatment, gives his/her therapy of choice. In a clinical trial, the eligible subject will be given investigational product and the investigator is obliged to assign and dose the subject with the investigational product according to the protocol.
Physician makes diagnosis and gives
standard treatment/therapy
of choice
Investigator enters eligible subject
into trial and is obliged to give
IP per protocol

8. 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
4. In routine medical practice, depending on the course of the disease and on the presence of concurrent illness, the dose, route or administration of the drug or even the drug itself may change; the choice and use of concomitant medication is done according to the principles of the rational therapy In a clinical trial, the investigator should follow protocol instructions for the dose, route and administration of the investigational product, and the use of certain concomitant medications may be restricted.
5. In routine medical practice, the physician is responsible to perform examinations or available procedures that are relevant to determine the diagnosis and evaluate the outcome of the treatment. In a clinical trial, the investigator is responsible to perform examinations and procedures according to the protocol in order to obtain data that are relevant for the efficacy and safety evaluation of the investigational product.
6. In routine medical practice, the physician shall determine the schedule of events for each individual patient. In a clinical trial, the investigator should follow the schedule of events that is outlined in the protocol.
7. In routine medical practice, the treatment ends when a satisfactorily outcome is achieved. In a clinical trial, the subject’s participation in the trial is complete according to the schedule outlined in the protocol.
Protocol deviations may occur when physicians fall back into the role of the physician treating clinic patients and don’t follow the protocol
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

9. 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
Compliance
with 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
EXCEPT ...
ICH GCP Chapter 4.5.1, 4.5.2

10. Compliance with Protocol
Where necessary to eliminate an immediate hazard to trial subjects
When changes involve only logistical or administrative aspects
EXCEPT ...
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 also states (ch.4.5.2, 4.5.3, 4.5.4) that the investigator may deviate or change the protocol without agreement of sponsor and prior review and documented approval/favourable opinion from IRB/IEC
if it is necessary to eliminate an immediate hazard(s) to trial subjects, or
when the changes involve only logistical or administrative aspects of the trial (e.g. change in monitor(s), change of telephone number(s), etc.).
However, these deviations should be explained as soon as possible (with stated reason) and reported to:
- the IRB/IEC for review and approval/favourable opinion;
- the sponsor
the Regulatory authorities (e.g. for some European countries like Israel, Greece, etc.)
Example of eliminating an immediate hazard: administering medication prohibited by the protocol because of a life threatening event.
ICH GCP Chapter 4.5.2, 4.5.3

11. Noncompliance Sponsor should act promptly to secure compliance (e.g.
corrective action plan)
Non-
compliance
Noncompliance with protocol,
SOPs, GCP and/or applicable
regulatory requirements
Sponsor should
terminate
investigator’s
participation
If serious and/or persistent
Noncompliance is identified
by auditors and/or monitor
Sponsor should
notify RA promptly
ICH GCP Chapter 5.20

12. 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
adversely the safety of subjects
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
ICH GCP Chapter 3.3.8, 4.5.4

13. Informed Consent (IC) of Trial Subjects
The voluntary confirmation of a subject’s
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
Informed
Consent Form
Signature
Date
ICH GCP Chapter 1.28

14. 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

15. 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
It is country specific whether 2 originals should be obtained or if the ICF can be photocopied.
ICH GCP Chapter , 4.8.1, 4.8.2, 4.8.6

16. “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
For all special ICF procedures local requirements should be checked.
The process should be documented in the protocol
ICH GCP Chapter 4.8.9,

17. 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 * patients with incurable disease
* hospital/laboratory personnel * persons of nursing homes
* armed forces * unemployed/homeless
* people under detention * pharmaceutical industry
* patients in emergency cases employees
* ethnic minorities * incapable to give IC
ICH GCP Chapter 1.61

18. Investigational ProductIP
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

19. IP – Investigator Responsibilities
Receipt of IP only by authorised staff
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 IP IP
ICH GCP Chapter 4.6.2, 4.6.6, 4.6.4, 4.6.3

20. IP – Records at the Site IP accountability - RECEIVED = USED + UNUSED
Maintain records of IP delivery, inventory, use by 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 IP IP
ICH GCP Chapter 4.6.3

21. IP – Randomization & Unblinding
Investigator should:
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 IP
ICH GCP Chapter 4.7

22. 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
IP Reconciliation docs
Destruction of IP

23. Adverse Event 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
Safety
reporting
ICH GCP Chapter1.2

24. Why Are AEs Important? Medical Reasons Regulatory Reasons
Subject safety is the main concern for clinicians during a clinical trial. AEs can be a potential indicator of harm to the subject. The ability to provide appropriate medical treatment for subjects in response to AEs is a responsibility of the PI.
Regulatory agencies require sponsors and investigators to collect and report AEs for the protection of subjects. Expedited and routine reports of AEs are used to revise the IB or package insert. If AEs go unreported, subjects in the trial are at risk. Once the drug is marketed, the general public will be at risk in case of unreported AEs.

25. Adverse Event-Recording
WHERE ?
Adverse Event
Page in the CRF
At each visit if
AE occurred
WHEN ?
! 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

26. Adverse Event Page Protocol: Site Nr: Investigator:
Subject Initials: Subject Nr: Randomisation Nr:
Visit Nr: Visit Date:
Adverse
Event
Treatm.
given
Outcome
Serious-
ness
Duration
Intensity/
Severity
Causality
Trial
Drug
Investigator Signature ____________________ Date ___________________

27. What information is generally collected:
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)
How to complete the adverse event pages? All sponsor companies require the same information. However, each company will have their own method of recording the information. And, if investigators are working for more than one company, with different adverse events pages, there is little wonder why there is sometimes confusion! Sometimes, they are required to code information by letters, sometimes by numbers, and sometimes they do not need to code anything. Sometimes, they are asked for total daily dose of the investigational product; at other times they have to record the amount and how many times the medication is taken in a period of twenty four hours This is why it is vital that you understand each CRF and explain to the site staff how this particular one needs to be completed. Of course, we are talking about all adverse events. For those which are serious adverse events, there is additional information required on other forms.

28. What information is generally collected:
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

29. 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

30. Unexpected Adverse Drug Reaction (UADR)
An adverse reaction,
the nature and severity
of which is not consistent
with the applicable
product information
It is not as
you said it
would be !
ICH GCP Chapter1.60

31. 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

32. 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
The sponsor will let Quintiles know whether they intend to exclude pre-study planned hospitalizations from SAE reporting requirements for your project.
Unless told otherwise, the sites should report any and all hospitalizations as SAEs.

33. 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
Most trials require that subjects are using ‘adequate contraception methods’ as part of the entry criteria. The sponsor should clarify what they mean by “adequate”, if this is not already discussed in the protocol and/or the ICF. E.g., some sponsors will allow abstinence and others will not accept that (must formally agree to use condom, spermacide, birth control pills, diaphragm, etc. if have a sexual encounter during the trial)
While the SAE form itself is used for pregnancy reporting in some clinical trials, others have a separate form specifically for reporting of pregnancies. Some protocols may also require reporting of pregnancies in partners of male subjects participating in the trial (especially if the study drug is expected to affect sperm development in males).
Pregnancies must be followed to the outcome. Remember one of the previous slides stated that one category of a SAE is congenital anomaly or birth defects. Therefore, we must have a paediatrician's report. Provided that this report is positive, then most drug companies consider this the outcome. Some companies, however, may decide to have repeated reports for a defined period of time. You need to be aware of the sponsor’s guidelines with regard to pregnancy and you must inform the investigator of this.

34. What is what?
AEs
ADRs
SAEs
UADRs

35. Serious Adverse Event - Flowchart
Episode of Myocardial Infarction
Complete
AE Page
YES
Is it an Adverse Event ?
Is it a Serious Adverse Event ? NO Y E S
Immediately
may mean
24 hours
Let’s use an episode of myocardial infarction as an example.
Notify the Sponsor/CRO
Complete SAE Report Form
Notify IRB/IEC and RA

36. 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)
Communication
with IRB/IEC
ICH GCP Chapter 3.1.2, 3.1.4, 3.3.8, 4.4.1, 4.4.3, , , , 4.13

37. Prompt Reports to IRB/IEC
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
Progress
Reports
ICH GCP Chapter 3.3.8

38. 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

39. 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
In Medical Record:
Date of Birth
Age
Sex
Address (with tel. no.)
Personnel Administering Consent
Consent Procedure
The Subject randomization number should be referenced in source
Subject Initials to be used for the study should be referenced in the source (unless otherwise specified by regulatory authorities e.g., Germany must assign unique subject initials)
Use both Subject number + initials to refer to the subject throughout the study
ICH GCP Chapter 1.52

40. Source Documents Include, But Are Not Limited To....
Microfilm or magnetic media, x-rays, etc
Records kept at pharmacy, at labs and medico- technical departments
Electronic records
Electronic signatures
ICH GCP Chapter 1.52

41. Case Report Form (CRF) 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
CRF
ICH GCP Chapter 1.11

42. 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
Reference: ICH Monitoring Responsibilities
FDA CFR Investigator Recordkeeping and record retention
As per the FDA program compliance guidance CPGM , Bioresearch Monitoring; Clinical Investigators, source documents must be able to answer the following (e.g.,)
Did the subject exist?
Did the subject comply with the protocol ?
Were all safety data reported accurately ?
Were other relevant factors, (especially, Con. Med.) fully reported?
Were the primary end points for effectiveness supported?
Records of exposure of the subject to the “test article”/IP?
Identity of all persons and locations obtaining raw data or involved in the collection or analysis of such data evident?

43. 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)

44. 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

45. 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
Direct access to all trial documents for
monitor, auditor, IRB/IEC, RA
Changes/corrections to CRFs dated, initialed
Discrepancies explained (if necessary)
Source
documents
must not be
altered to match
the CRF
ICH GCP Chapter 4.9.1, 4.9.2, 4.9.3

46. 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

47. 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 k, m, n

48. 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

49. Essential Documents
Documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced
Records
May include:
CRFs
Patients Medical Notes
SDs
Investigator Site File
Essential
Documents
ICH GCP Chapter 1.23, 8.1

50. 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