Source Data Verification
Objectives
By the end of this presentation we will know:

What are source data, source document &
source document verification (SDV)?

Importance of source documents & of doing
SDV
 Common findings in source documents
I. Source Data
Source Data
ICH E6: 1.51 Source Data
•
All information in original records & certified
copies of original records
•
Information of clinical findings, observations; or
other activities in a clinical trial
•
Necessary for the reconstruction & evaluation
of the trial.
Source data = Raw data
Source Data Examples
•
•
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•
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•
•
•
•
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Informed consent narrative
Demographic data: DOB, gender, age,
race, height, weight
Medical history
Medical examination results
Lab results
Concomitant medications
Drug dispensing & accountability information
Visit dates
Inter-current illness
Patient ID number
Study number
Corrections to Source Data
Four items must be visible each time a raw
data value is changed:
(1) The old value
(2) The new value
(3) The date of the change
(4) By whom the change was made
[the reason for the change must either be apparent or
an explanation be provided]
II. Source Documents
Source Documents
ICH E6: 1.52 Source Documents
•
Original documents, data, and records
ICH E6: 8.3.13 Source documents are one of the
“Essential Documents”
-document existence of patients
-substantiate integrity of trial data collected
Source document = Medical record
USFDA Requirements of
Source Documents
IND Regulations 21 CFR 312
•312.62 Investigator record keeping and
record retention
•Case Histories- must be adequate and accurate
IND Regulations 21 CFR 11
–Electronic Records
What do good source documents do….
• Record all events that transpired while subject
was in the study
• Include statements describing informed consent
process & copy of ICF given to subjects
• Site specific, protocol specific
What do good source documents do….
•
Decrease generation of data queries
•
Compliance with GCP
•
Signed by study personnel listed on site
signature log
Serve as the basis for the subject’s future
medical care.
Source Document Template
•
Speed data collection process
• Guide the investigator to collect all required
study data
•
Should allow for additional comments for
unplanned/ unexpected situations
• Help diminish mistakes
Source Document Examples
•
Physician Progress Notes
•
Nurse’s Notes
•
Diagnostic Test Reports
•
Medication Records
•
Laboratory Reports
•
Participant Diaries
•
Informed Consent Forms
Case Report Form v/s Source Documents
CRF : Tool to collect the data and provides
condensed picture of participant’s involvement
in the study
CRF not intended to replace Source Documents
Can CRF act as Source?
Yes, for some data items!
Though not encouraged by many sponsors.
–ICH E6: 6.4 Trial Design6.4.9:The identification of any data to be
recorded directly on the CRF’s (i.e., no prior written
or electronic record of data), and to be considered
to be source data.
CRF as source…………...
• CRF may suffice as the source document for
data needed solely for study purposes.
•
Such data is NOT essential to the clinical care
of subjects & NOT routinely recorded in clinical
practice.
(e.g., psychiatric rating scales, subject self-rating assessments, visual
analogue scales, repeated vital signs, repeated lung function
tests,information relating to pharmacogenetic research, some data
collected for Phase I healthy volunteer studies, data collected for vaccines
studies in volunteers)
•
Source data items to be recorded directly into
the CRF must be documented.
Source Document Agreement
•
Agreement between investigator & sponsor
•
Made at or prior to study initiation
•
Type of documents/documentation to be
done for each data item is defined
•
Place of filing of each document is defined
•
CRF, if source for any data, is also defined
Custody & Archiving of
Source Documents
•
Should be retained until at least 2 years after the
last approval of a marketing application
AND
• Until there are no pending marketing applications
OR
• At least 2 years have elapsed since the formal
discontinuation of clinical development
investigational product
of
Custody & Archiving of
Source Documents
• Investigator/institution should take measures to
prevent accidental or premature destruction
• It is the responsibility of the sponsor to inform the
investigator/ institution when these documents no
longer needed
III. Source Document
Verification
Source Document Verification (SDV)
Process to ensure that source data reported
by an investigator is:
• complete,
• accounted for,
• follows a logical sequence of events, and
• support entries in CRF
ICH GCP is:
•
•
Unclear with regard to process of SDV, frequency
& extent
Refers to data being verifiable from source
documents
Source Document Verification
When?
-
Preferable undertaken before data are
retrieved from investigator site
Soon after first subject is enrolled
Data forwarded to data management thus
valid & accurate
What to check?
-
Defined in sponsors’ SOPs
Documenting SDV
The process of SDV must be documented so that
the following are clear:
• The CRFs that were checked
• The data items checked for each CRF
• The types of source data/ documents examined
• Nature & frequency of any errors/problems
• Corrective action taken
Ensure Good Documentation by
Knowing…...
•
Study protocol
•
Investigator Brochure • Sponsor requirements
•
Case Report Form
guidelines
•
Lab procedures
• Medication requirements
• Regulations
Importance of SDV
One of the fundamental reason why monitoring
exists!!
CRF is sponsor owned document!
Original is taken by the sponsor
CRF copies may be :
• Banned from being included in patient medical
record
• Difficult to retrieve in case of an emergency
Importance of SDV
SDV required to provide confidence in any data
reported, for e.g.,in published manuscripts,
at scientific conferences
Rigorous source documentation protects study
staff and sponsors from accusations of fraud,
misconduct etc..
Implication of not performing SDV

Danger of collecting inaccurate or spurious
data

Relatively small amount of information collected
from a small number of patients result in massive
patient exposure
 Rejection of clinical trial data by the regulatory
authorities, if not satisfied with the integrity of the
data
Case Report Form Review v/s SDV
Case Report Form Review
 Performing an overall review of each CRF for:
internal consistency, completeness, logic & legibility.
 Without reference to the corresponding source
documentation.
SDV
 Verifying CRF data against information in
supporting source documents held at the site.
SDV and Electronic Records
• Principles for SDV on electronic records are the
same as for paper records.
• Monitors may perform SDV by viewing
computer screens or by using printouts
Methods of SDV
X
Back to Back
Investigator holds all the source documents &
answers specific questions asked by the monitor
regarding the data without letting the monitor look at
the documents

Direct method
Direct access as per ICH GCP
Suggestions for efficient SDV
• The monitor
documentation
assessment.
should
with
always discuss source
investigator at the site
• The new monitor should be accompanied by a mentor
/senior monitor to get practical exposure to the
problems in real life settings.
• Plenty of time should be spared to undertake SDV
particularly at early visits when you may be unfamiliar
with the patient files.
Suggestions for efficient SDV
•
Undertake SDV in peace without interruption.
•
Avoid doing CRF review and SDV at the same
time.
•
Be honest - only report that you have undertaken
SDV on certain CRF books / items if you have in fact
done so.
Suggestions for efficient SDV
• All the different facilities involved in the clinical
trial should be considered
(e.g. pharmacy, laboratory, X-ray room, etc.)
•
Associated documentation related to the study,
may contain valuable information
(e.g. subject diaries, appointment logs etc.)
•
Concentrate on items affecting the outcome of
the study
(e.g. patient inclusion criteria, key measures of
efficacy and safety)
Suggestions for efficient SDV
•
Important and often overlooked part of SDV is
that of determining the actual process
employed in generating the data.
•
Investigator be given the message that the
monitor is not a policeman, rather
investigators’ own QC manager
Common problems encountered
during SDV
• Missing , scant data
Investigators’ say………..
“We checked off the boxes in the CRF history and physical
examination page-we didn’t think to question the
patient further……..”
“The patient didn’t offer any complaints, so we
didn’t ask…..”
Common audit findings about source
data*
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Conflicting data
Data entered directly on to the CRF
Short/brief medical history
External source data
Surrogate medical records
Source document/CRF mismatch
High error rate
Illegible handwriting of investigator/sub-investigator
Original source altered without explanation/signature/date
Signed by personnel not listed on the study signature log
*Compiled from review of FDA warning letters 2002-2004
Elements of Data Quality
When examining data consider its quality
–Attributable
–Legible
–Contemporaneous
–Original
–Accurate
When FDA Calls…….
MAY THE SOURCE BE WITH YOU!!!
Questions???
Thank You!
Bibliography
•Malcolm L. Schuyl, Thim Engel, A Review of the Source
Document Verification Process In Clinical Trials,
Drug Information Journal, Vol. 33, 789–797, 1999
•R. Khosla, D.D. Verma, A. Kapur, S. Khosla, Efficient
Source Data Verification, Indian Journal Of Pharmacology
2000; 32: 180-186
•Vernette J. Molloy and Douglas R. Mackintosh,
Source Documentation: Clinical Auditors’ Observations,
Clin. Research & Reg. Affairs, 18(4), 367-374 (2001)
Bibliography
•T Winchell, ‘Source Documentation:What’s the
Mystery?’ Good Clinical Practice Journal, 11, 5, 2004
Page 26-29
•Clive Jenkins, ‘In the search of true source data’
Good Clinical Practice Journal, 11, 8, 2004 Page 21-24
•S Wollen. ‘The facts about source documents’ DIA Annual
Meeting June 1999
Documentation of Informed Consent
Mrs Smith came to Hospital today in Surgery OPD-II for treatment of
wound. She was diagnosed of secondary infected traumatic wound
(SITL). Dr Jones- the PI of study on SITL briefed her of trial drug. Mrs
Smith asked to know more. Hence Dr Jones got Mrs. Smith and her
husband to trial room. Dr Jones told them of risks and benefits of trial
and read out the informed consent form. Then Mrs. Smith had a small
discussion with her husband and asked following questions:
: What happens if the trial drug doesn’t cure my wound?
: _______________________________
:If my wound heals before visit 5, do I still have to come
for all 5 visits?
Dr Jones
:_______________________________
Mrs. Smith agreed to participate in trial and signed and dated the
informed consent form. She was given a copy of form.
Mrs. Smith
Dr Jones
Mrs. Smith
Signature Dr Jones, PI 05 Apr 2005
Example of GCP-compliant history in a patient’s chart
Study inclusion/ exclusion criteria
Patient of 18 year of age or older
History of elevated blood pressure (may be controlled by medication)
No smoking for two years
No previous history of cancer
No history of alcohol or drug abuse
Medical record entry
15/ April/ 2005
Mr.Jones, a white 36-year-old male, presented in clinic today for possible
inclusion in the study EPI 40272. No history of ETOH or drug abuse.Smoked 1
pack of cigarette for 5 years, but stopped 3 years ago. Patient states history of
high blood pressure but has been controlled by medication during past year.
No history of carcinoma or pulmonary disease. Explained study protocol and
reviewed informed form. Patient states he wants to take informed consent form
home to discuss with wife. Scheduled to return tomorrow at 10:00 am.
Dr Sheila Bhave, Sub Investigator
Example of GCP-compliant drug administration in a patient’s
chart
Study protocol for drug administration
•5 cc of blinded dose for first dose
•10 cc on all subsequent visits
•IM in left arm, unless no arm then use right arm
•Drug should be administered at room temperature, although stored overnight in refrigerator.
Medical record entry
22/April/2005 10:15 a.m.
Mr. Jones here for first dose of study medication (EPI 40272). Drug
ampoule removed from refrigerator at 09:45 am today. 5 cc of study
drug given IM left deltoid at 10:05 am, Mr. Jones reported tingling at
the site of administration. Tingling ceased at 10:10 am. Scheduled to
return in one week.
Mini George, Study Nurse
Document 5 R’s of investigational product
• Right drug
• To Right patient
• At the right time
• In the right route
• In the right amount
Example of GCP-compliant Adverse event source documentation
12/JAN/2005 08:45 am
Patient c/o diaphoresis. No increase in exercise, no
s/s viral illness. Called family physician.
Stopped study drug and began XYZ medication 2 tabs
BID stat. Route: Oral, strength 50 mg. XYZ was given
for diaphoresis.
Event resolved by 10:00 am same day .Not related to
study drug. Not serious event.
Dr U Menon, MD
Example of GCP-compliant study termination
source document
18/Jan/2003
Patient called at 11:15 am to report several instances of
severe hypoglycemic events during the night. She called
her physician at 08:00 am today. He advised her to take
ABC medication and stop study drug. Patient reported she
followed her MD’s advise and no longer wishes to continue
in the EPI 40272 study. Patient states blood sugar has
been stabilized. Will visit clinic tomorrow and return unused
meds and completed diary card. PI notified.
P. Amudha, Study Nurse