Perfect Clinical Trial Source Documents

As a CRA, I regularly visit the sites to review the study conduct, encourage study participant recruitment, evaluate the ongoing suitability of the investigative site, provide protocol specific training, track investigative supplies, and to review source documents.  Source documents are the roadmap and clinical record to let me (or anyone who is reviewing) know what happened, when, how, and by whom.  When I look through source documents I am checking that they follow the principle of ALCOA:

• A-attributable, who wrote this?
• L-legible, can I read this?
• C-contemporaneous, was this recorded at the time of trial conduct or later?
• O-original, is this unaltered or copied?
• A-accurate, is this a correct reflection of the conduct?

The burden for documentation in a clinical trial is actually much higher than the burden for documentation in a standard clinical record or office/physician visit.  When you see your doctor for a flu he might write 3-4 lines in your chart documenting the visit.  If you were a clinical trial participant, the doctor or the clinical trial staff would likely need to collect and record a lot of specific information to satisfy the data collection requirements of the trial.

It is never acceptable to use
correction fluid in source documents.

The first time the pen touches the paper to record observations in a trial, this generates "source documents".  If the nurse writes your blood pressure on her hand, her hand is a source document. If you stand on the scale and your weight is recorded on a post-it, that is a source document.  One of the most important rules of GCP is that the Principal Investigator (PI) is ultimately responsible to ensure that all source documents are maintained in their original form and that any alterations or corrections are indicated in a compliant fashion (changes should be striken through with a single line (so as not to obscure the orignal entry); correction fluid should never be used! The revision should be initialed and dated so there is a record of who made the change and when. An explanation of the change is optional but best practice).  The PI should instruct his staff not to write on their hands or sticky notes, to make observations using indelible ink (not pencil since that can be erased!) and to always observe the ALCOA principle when generating or modifying source documents.

Some sponsors actually provide source documents to the investigators to assist them to record all the required data during the study visits.  The source templates will typically have a blank header to record the subject identifying information and to indicate the date of the visit. Quality source will also include signature or initial blocks on each page so that the person(s) completing the forms can be identified later. If source documents are complete and accurate, the clinical trial data can be copied over and provided to the sponsor on Case Report Forms for analysis. I'll provide an introduction to data capture/EDC and analysis in a future blog topic.

During source document review I always find items that are incomplete (left blank), inaccurate (such as blood pressures that are inconsistent with life, headers that indicate a different patient entirely, birth-dates that don't match the age, units or counts that aren't possible), or otherwise erroneous source.  I use small colored post-it notes (stickies) to flag my findings and ask the PI or the study nurse to review and update the source with notation.  I never "fix" the source myself.  If the source errors are very wide in scope, I will note it in my monitoring report and I may also ask the investigator to generate a signed and dated Note to File on the site letterhead explaining what happened with the source documents and the corrections completed during our visit.  Experienced study coordinators and investigators will not be surprised or frustrated when I request source corrections or clarifications.  Also, discovering errors in the source does not upset me at all, this is part of my job and I am partnering with the site to help them keep their documentation totally complete and an accurate reflection of what was done.

Source documents are created during the patient visit and should not be fabricated a few days before a monitoring visit.

Do I want to see perfect source at my visits?  Actually, absolutely not.  Original source documents will be working documents and I am expecting source documents to be a bit tattered, thumbed through with bent corners, covered in the occasional stain, marked with revisions, and otherwise imperfect.  Perfect source or typed source makes me especially suspicious and can be an indicator of fraudulent or sloppy record keeping.  I hope this discussion is helpful to you and that you will know what to look for when reviewing source documents at your monitoring visits.


You may also like...from The Lead CRA archives:

• Investigational Product Accountability June 2010
• Correspondence March 2011 
• Sponsor Furnished Source April 2011
• Routine Monitoring Visits March 2008

Routine Monitoring Visits

Routine or Interim Monitoring visits are basically any visit that occurs after the site is initiated and up until the site is closed out. As monitors, we visit our sites periodically to ensure that they are compliant with all the regulations, subject safety is being adequately followed, data is being captured in a timely and reliable manner, the Investigational Product is being handled as per protocol and relevant regulations/guidelines, there are no significant deviations from the planned study protocol, all important study documentation is being generated and stored properly, and that the research site is adequately supplied in regards to lab kits and other pertinent study materials. The ultimate purpose of our job is to protect subject safety by monitoring the trial conduct for ICH/GCP compliance.

When planning your monitoring visits
it is helpful to have a reasonable expectation
of how think the medical records and source
documents will be. Know in advance how much
you will need to review so you budget enough
time to successfully complete your objectives.

Your agenda from visit to visit may vary slightly based on the length of the study and how many times you plan to visit, the amount of time you spend to plan at the site for this particular visit, the site's progress to date (if a site has yet to enroll any subjects you surely won't have any CRFs to review or pull), and where you are at with the general monitoring plan (for example, drug accountability may be done all along or just at close-out).

Prior to your visit you will contact the site to set up a suitable time for your visit. Visits typically last a day or two. Ideally, the PI would be available to meet with you during the visit. You will send a confirmation letter to the site once a date is set (be sure to confirm the address before you go if you haven't been there before!). More often than not, your study lead will provide you with a monitoring visit checklist or at the very least, a monitoring report template so you will know exactly what tasks you are expected to perform on-site and what topics to cover. Here are some of the specific tasks that are routinely performed at these visits:

1. Informed Consent Form (ICF) review: You are ensuring that every subject was adequately informed and consented to the study before any study procedures were completed (I recommend checking lab draw times and ECG times - if required at the screening visit - against the consent time to be extra sure that the consent was the first study procedure to occur). There are other state specific regulations you will need to know and monitor for. For example, in some states subjects must be 19 to participate and in California every subject must sign the 'CA Bill of Rights' document, etc. Sometimes there are multiple versions of a consent due to a change in the facility address or the details of the protocol. Ensure that all subjects signed on an IRB approved version (each page will be stamped in the upper right hand corner and the version date will be printed on each page). Proper consenting of subjects is critical to ensure the security and privacy of health data and that subjects are adequately informed of the study procedures, risks and, benefits. If the consent is not signed or properly completed inform the Study Coordinator and do not review this subject's medical chart until consent has been properly obtained.
2. Check for Serious Adverse Events (SAEs): Per the guidelines, an SAE is any untoward event that results in death, prolonged or new hospitalization (longer than 24hrs), significant disability, or congenital anomaly (birth defect). If the event has not been reported, assist the Study Coordinator in doing so and inform the sponsor immediately.
3. Review Protocol Compliance: In your chart and source document review, you can verify that subjects were sign at the right times and the right procedures were conducted as per the protocol. You will have study-specific procedures for reporting deviations. Deviations of a serious nature may be reported in an expedited manner and may need to go to the IRB (dosing errors, unblinding of study treatment, subject enrolled that did not satisfy entry criteria, etc.)
4. Compare source documents to Case Report Forms: You are checking that the data in the chart matches the Case Report Forms (which will be later entered into the clinical database and combined with other subject's data to complete the safety and efficacy analysis for the Investigational Product). Determine whether or not CRFS being completed in a timely manner. You also want to verify that the source is complete, neat (all corrections must be compliant with the regulations - white-out is not OK), attributable (who wrote it? Is it initialed and dated), contemporaneous (was it written at the time the procedure was completed?), valid (is the data collected even possible?), etc. Sometimes you will be asked to pull the case report forms and send them in to data management and other times they will stay at the site until the end of the study.
5. Review Investigational Product (IP): The study protocol will explain how the IP is to be stored, dispensed, and returned. Verify that all of this occurred properly by reviewing temperature logs, storage facilities, administration records, IVRS entries/reports for subject-specific IP accountability, and speaking to the relevant personnel.
6. Regulatory Binder / Essential Documents Review: Determine if any forms need to be updated or pulled for the Trial Master File (TMF). The TMF is meant to be an exact replica of all the documentation at the site. Specific information regarding the contents of the essential documents binder are covered in section 8 of the guidelines.
7. Confirm Site Adequacy / Site Status: Determine if there are new staff at the site or if staff have left. Can the site manage with current staff? Has the site or the lab moved? Confirm that there are adequate study supplies
8. Study-Specific Monitoring Tasks: Depending on the protocol, you may need to perform additional tasks such as shipping materials back to headquarters (for example lab specimens, xrays, etc.), calibrating or reviewing calibrations of equipment, site training, checking eDiary compliance, etc.
9. Review Ongoing or Pending Issues from Previous Visits: At some point during every visit work with the staff to resolve any items identified at previous visits as ongoing issues. Indicate in your report once these are resolved.
10. Review of findings with the site: Whether or not you find issues during your visit, keep the site staff posted on your progress and how things are going. Especially, if the Principal Investigator is not available during the visit, be sure to summarize everything accurately and completely in your follow-up letter.

Try to schedule your next (or next several) visits before you leave the site. After the visit, write your report and send the follow-up letter within a week or per your monitoring plan and refer to your company's SOPs. Always report significant compliance issues to your management, the sponsor, IRB, and QA as appropriate. Remember that you must document everything because of the adage, "if it isn't documented, it didn't happen". Please contact me if I can elaborate on anything or if you think I've left something important out.

You may also like...from The Lead CRA archives:

• Introduction to Monitoring December 2007
• Meeting with the PI August 2011
• Close-Out Visits July 2008