Source data validation (SDV) in clinical trials

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Source data validation (SDV) in clinical trials Powered By Docstoc
					Source Data Verification

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
• • • • • • • • • • • 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


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

• • Unclear with regard to process of SDV, frequency & extent Refers to data being verifiable from source documents

Source Document Verification
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 • Medication requirements

Investigator Brochure • Sponsor requirements Case Report Form guidelines Lab procedures • 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.

 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*
• • • • • • • • • • 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…….



Thank You!

•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)

•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

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

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