Clinical Research and Source Documents
(12/23/2009)

Question 1:

I am looking for information that addresses how to create source documents for a clinical research trial. Any suggestions, direction or help with finding links or any information would be greatly appreciated.

Answer 1:

FDA's regulations at 21 CFR 312.62(b) state:

(b)Case histories. An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study.

Although FDA's regulations do not define the term "source documents," source documents are what make up the case histories; they are the records where source data are first committed to a durable medium. For example, it is common for data about a subject to be recorded as part of the subject's medical care and entered into the patient's medical chart; in this instance, the medical chart is serving as the source document. In trials where the study procedures are not part of the subject's general medical care, sites may enter data directly on to a Case Report Form (CRF), and from FDA's standpoint, it is quite permissible to do so, if that is identified in the protocol as the practice that will be employed and if, indeed, this is the practice that is being employed. If data are entered directly onto a CRF, the CRF becomes the "source document." When FDA conducts an inspection at a clinical investigator's site, FDA will review CRFs and medical records pertaining to the study subject.

FDA's official guidance, ICH E6, Good Clinical Practice: Consolidated Guidance, defines "source data" and "source document"; see Sections 1.51 and 1.52.

1.51 Source Data: All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).

1.52 Source Documents: Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial).

You should also refer to Section 4.9, "Records and Reports," an excerpt of which appears below:

4.9.1 The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports.

4.9.2 Data reported on the CRF, which are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.

4.9.3 Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry (i.e., an audit trail should be maintained); this applies to both written and electronic changes or corrections (see section 5.18.4(n)). Sponsors should provide guidance to investigators and/or the investigators' designated representatives on making such corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain records of the changes and corrections.

4.9.4 The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial (see section 8.) and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents. 4.9.5 Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period, however, if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained (see section 5.5.12).

Here is a link to the complete text of that document: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf .

For other materials and references pertaining to Good Clinical Practice (GCP), please visit FDA's GCP webpage: www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm. In particular, you may find it useful to access the set of redacted GCP e-mails found at www.fda.gov/oc/gcp/redactedEmails/default.htm; the e-mails are sorted by general topic, and we find that many questions and concerns are repeated over time.


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