responsibilities of investigator kamila novak investigator’s responsibilities compliance to gcp...

MP-7 Investigator MeetingJanuary 31, 2011

Responsibilities of InvestigatorKamila Novak

Investigator’s Responsibilities

Compliance to GCP and reg. requirements

SourcedocumentsProtocol

Compliance

InformedConsent

Communicationwith IRB/IEC

SafetyReporting

Adequate Resources Site Non-

complianceIP

Medical Careof Trial Subjects

Essentialdocuments

Records andreports

Adequate Resources

Adequate facilities

Adequate equipment and support functions

Potential for recruiting the required number of suitable subjects

Adequate number of qualified staff, adequately informed about the protocol,

IP and their duties

Sufficient Time (competing trials) Motivation

Adequateresources

ICH GCP Chapter 4.2

Medical Care

Medical care

ICH GCP Chapter 4.3

• 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

Сompliance with GCP

Investigator should:

Be aware of and should comply with

GCP and the applicable regulatory

requirements

ICH GCP Chapter 4.1.3

Compliancewith GCP

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


Compliancewith protocol

Two Roles: Physician and Investigator

Routine Medical Care

Conduct of a Clinical Trial

Investigator is looking for subjects with diagnosis eligible

for the clinical trial

Person with symptoms is looking for physician to diagnose

and treat the illness

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

Compliancewith 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


Noncompliance

ICH GCP Chapter 5.20

Noncompliance with protocol, SOPs, GCP and/or applicable

regulatory requirements

Sponsor should actpromptly to securecompliance (e.g.

corrective action plan)

If serious and/or persistentNoncompliance is identifiedby auditors and/or monitor

Sponsor shouldterminate

investigator’sparticipation

Sponsor shouldnotify RA promptly

Non-compliance

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


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)

InformedConsent Form

Signature Date

InformedConsent


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


• 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


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

Investigational Product

IP


A pharmaceutical form of an active ingredientor 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

usedto gain further information about an approved

use

IP – Investigator Responsibilities

IP

• 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

ICH GCP Chapter 4.6.2, 4.6.6, 4.6.4, 4.6.3

IP

IP – Records at the Site

IP


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 personDates and amounts dispensed to/used by patients Dates and amounts returned to sponsorExpiry dates (if applicable)Unique code numbers assigned Doses used by subjects

IP accountability - RECEIVED = USED + UNUSED

IP

IP – Randomization & Unblinding

IP

ICH GCP Chapter 4.7

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

IP - Flow of Events

Investigational Product

Received at Site

IP returned to sender

IP dispensed to subjects

IP returned by patient

IP accountability docs

Destruction of IPIP Reconciliation

docs

Q/sponsor/vendor

IP receipt docs

Adverse Event

Safetyreporting

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

WHERE ?

Adverse EventPage 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 !


Adverse Event Page

Investigator Signature ____________________ Date ___________________

Protocol: Site Nr: Investigator:

Subject Initials: Subject Nr: Randomisation Nr:

Visit Nr: Visit Date:

Adverse Event

Duration Intensity/ Severity

Causality TrialDrug

Treatm. given

Outcome Serious- ness

Recording AEsWhat 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 AEsWhat 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 aphysiological function

ICH GCP Chapter1.1

Unexpected Adverse Drug Reaction (UADR)

It is not as you said it would be !

An adverse reaction,the nature and severity

of which is not consistentwith 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


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

ADRsUADRs

SAEs

Is it an Adverse Event ? YESComplete AE Page

Is it a Serious Adverse Event ?

YES

Notify the Sponsor/CRO

Complete SAE Report Form

Notify IRB/IEC and RA

Episode of Myocardial Infarction

Immediatelymay mean 24 hours

Serious Adverse Event - Flowchart

NO

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)

Communicationwith IRB/IEC

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

ProgressReports

• 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


What are Source Documents (SD)?

Original documents, data and certified copies of original records necessary for

trial evaluation and reconstruction

SDs


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


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


Case Report Form (CRF)C

RF

A printed, optical, or electronic document designed to record all

of the protocol required informationto be reported to the sponsor

on each trial subject


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


Source

documents

must not be

altered to match

the CRF

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)

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


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

collectively permit evaluation of the

conduct of a trial and the quality of the

data produced

Essential

Documents

Records

ICH GCP Chapter 1.23, 8.1

May include:

• CRFs• Patients Medical Notes• SDs• Investigator Site File

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


responsibilities of investigator kamila novak investigator’s responsibilities compliance to gcp...

Documents

gcp investigator

clinical trial investigator

protocol investigator

diagnosis investigator

medical decisions

adequate medical care

medical doctors

routine medical practice