CRF /Source Document Investigational Product Monitoring Case Report Form and Source Document

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.

Part of the clinical study
Property of the sponsor

Source Document

• First place where the clinical observations were recorded
• Part of the subjects medical records (eg. OPD card, IPD chart, Laboratory report, ECG Report, subject’ diaries, film , Imaging (X-ray, CT, MRI, automated printout … etc.)
• Property of the investigator / hospital (and/or subject)
• Should be written in real time, (immediately, not days ,weeks or months after an event)

Clinical Trial Data/Source Document / CRF

In some circumstances, source data may be entered directly into the CRF		The monitor verifies that data in the CRF are the same as the Source Data within the Source Documents
		The monitor ensures that all data queries are completed correctly and verifies the data against the Source Documents

Source Documentation Fundamental Principles

• Source documents serve to

    - document the existence of the subject.
    - Substantiate the integrity of study data collection.
    - Serve as basis for subject’s future medical care.

• The first record value is generally presumed correct with all subsequent transciption considered secondary.
• Source documents are in line with usual medical practice, most closely record the original observation of the clinical event.

Why is Source Documentation important?

• Other departments need to be aware of the subjects’s involvement in the study medication (if known) esp. in the Emergency event.
• Subjects may want to claim compensation of any AE/injury. If no information in their notes, it may be delay the subject’s case.
• The regulatory authorities /the public need to be assured that the data are credible and reliable.
• Source Document may need to used as a “back up” to the CRFs (eg. CRF may be destroyed accidentally in the fire) , CRF can be reconstructed from the source document.

Why is Source Documentation important?
“It is the responsibility of the investigator to make all data available to the sponsor/monitor and relevant authorities for verification and audit and inspection purposes”

Recommended Contents of Source Documents

• Subject identifiers
• Medical history and Baseline presentation
• Clear evidence of study participation
• Study treatment information
• Clear evidence of study progress and ongoing clinical course/evaluation
• Documentation of adequate review / care for AEs & Lab results

Worksheets

• Worksheet could be the source document for all other data that are not yet captured anywhere else
• Supplement to primary sources

CRF Recording

• Accurate, Complete, Legible and Timely.
• Consistent with the Source document (or discrepancies explained)
• Must follow Instruction/Guidance/Advice provided by the sponsor
• To preserve confidentiality, the subject’s name should never be entered in the CRF (or any other documentation which will be returned to the sponsor)

CRF Recording (for paper CRF)

Must use Ballpoint pen (black). Do not use pencil. Audit trails should be maintained

- Not obscure the original / any entries

- Changes /corrections should be dated , initialed and / or explained (cross through with a single straight line)

- Must not use correction fluid (white-out)

• Only enter results in the fields provided.
• All date should be in recommended format (eg. dd/mmm/yyyy (12FEB2008).
• Do not leave the field blank;

    - If the answer is zero , write ‘0’
    - If the answer is “unknown”, write ‘not known’ (or ‘NK’, ‘UNK’ etc.)
    - If a requested test has not been done, write ‘not done’
    - If a question is not applicable, write ‘not applicable’ (or ‘NA’)

• Avoid abbreviations /signs other than Instruction/ Guidance.

Handling of Investigational Product
Investigational Product(IP)
A pharmaceutical form of and active ingredient or a placebo

• manufactured for being tested or used in a clinical trial

Investigator’s Brochure

• A compilation of the clinical and non-clinical data on the IP (ICH 1.36)
• To Provide the investigators and others involved in the trial with the information of IP
• To facilitate understanding of the rationale for protocol
• Provides insight to support the clinical management of the subjects during the course of the trial

- eg. Safety monitoring procedures, risk – benefit assessment .

• The sponsor should update when new significant information available

ICH GCP Principle of Investigational Product

• It should be manufactured, handled and stored in accordance with applicable good manufacturing practice (GMP).
• They should be used in accordance with the approved protocol. (ICH 2.12)

IP Accountability WHAT IS IT?

• The ability to be able to account for the IP from the time of packing until use or destruction
• Procedure to ensure, the IPs received at the site, Dispensed to and returned by subjects, and returned to sponsor are balanced and

    - properly managed
    - IP can be tracked
    - Prevent missing / disappearance/ discrepancy
    - IP are supplies only to subjects and according to the protocol. ( IP are supplied only to subjects who are eligible to receive it)

• Include Records/Documentation.

Handling of the IP

• Responsibility for IP at the site rests with the Investigator
• May delegate IP duties to appropriate person under the supervision of the investigator
• Identify who is authorised to administer the IP e.g investigator , pharmacist, study nurse
• Facilities must be available that assure the secure and proper storage of the IP

    - Temperature control (as required by the IP specification) and Checking and Record temperature of IP storage
    - Locked and limited accessed for only authorised person.
    - Ensure enough space to store IP, Inventory and Used IP

• Inventory checking, ensure adequately level of supplies with a suitable shelf-life.
• Store/inventory IP according to requirement
• Proper dispense IP by authorised person, to subject according to the protocol, drug-specific, eg.

    - amount, schedule
    - correct subjects , assignment, sequence
    - Route/ procedures.

• Explain the correct use to each subject and check that instruction is followed properly.
• Collect return and encourage each subject to return both empty and unused packs
• Checking subject’s compliance
• Record and update dispensing forms (dispenses and collect used drugs from subjects) , signed by authorised responsible person
• Complete and maintain on-going / up to date all records

Documentation of Handling of IP

• IP must be shipped together with Shipping Slip/ (Shipment/ Receipt of Shipment Record), providing details , allowing accountability by the recipient
• On Receipt , the IP must be checked the contents against the shipping slip. the correct IP was received at study site - coded identifiers on the labels agree with shipping forms
• The contents have not been tampered/undamaged
• Signed and dated to acknowledge receipt must be returned to sponsor and also filed in the study file

IP Documentation

• Receipt of IP Shipment / Return for Destruction of IP Shipment
• Drug Dispensing (and/or Returned by Subjects)
• IP Accountability Records & Reconciliation
• Case record forms
• Stored and dispensed according to the drug requirement / protocol. (Temperature Log, Log-In/Out Form)

All forms should be completed/checked at regularly intervals throughout the study. IP Documentation and Records


Monitor’s Role and Responsibilities
Monitoring
The act of overseeing the progress of a clinical trial, and ensuring that it’s conducted , recorded, reported in accordance with the protocol, SOP, GCP and regulatory requirement (ICH GCP 1.38)

Monitoring - Why do we do it?


The sponsor should ensure that the trials are adequately monitored.
“Monitor” acting as a main line of communication between the sponsor and the investigator/site staff
(to assist with any problems that may have arisen during the course of the trial)

Monitoring’s Responsibility

• Assessing/Sourcing Site/ Investigator (Qualification and Resources)
• Inform the investigator & site staff about the trial/investigational product
• Checking and Verification Activities

    - Source document verification, checking the accuracy and completeness of the CRF against the source document/trial record
    - Drug accountability verification
    - Checking all adverse events (AEs) are appropriately reported to the Sponsor and/or IEC/IRB with the time period required.
    - Verify that the investigator follow the protocol, GCP, obligation, regulatory requirement; eg. Written informed consent was obtained , only eligible subjects are enrolled etc.

• Communication with the investigator& site staff any trial related issues eg. Protocol deviation/Violation, new information, update of the trial progressing.
• Follow and reporting the Trial related issue, recruitment , trial progression.
• Documenting all trial activities