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Electronic data in clinical investigations: FDA revises draft guidance document to address industry comments.

LAST NOVEMBER, THE U.S. Food and Drug Administration (FDA or Agency) released a draft procedural guidance document relating to the conduct of clinical trials regarding electronic source data in clinical investigations that is intended to enhance the reliability, quality, integrity, and traceability of electronic source data. The draft guidance document, entitled Guidance for Industry: Electronic Source Data in Clinical Investigations, is directed toward a broad audience, including sponsors, contract research organizations (CROs), and data management centers as well as clinical investigators: the draft guidance document is directed toward any group that may be involved in capturing, reviewing, and archiving electronic source data for clinical investigations that are regulated by the FDA. The draft guidance document replaces an earlier draft released by the Agency in January 2011, and has been updated to reflect public comments received regarding the initial draft.

The scope of the original draft guidance document included the identification of the data element as the basic unit of information in the electronic case report form; the description of a source of each data element; information about the electronic creation, modification, transmission, and storage of source data and documents; investigator responsibilities with respect to reviewing and archiving electronic data; transmission of data to the sponsor and/or other designated parties; and preservation of data integrity. FDA received numerous and specific comments on the original draft guidance document from more than 40 sources, submitted over a six-month period ending July 2011. The commenting cohort was comprised of major and regional industry coalitions including the Biotechnology Industry Organization (BIO), Pharmaceutical Research and Manufacturers of America (PhRMA), Drug Information Association (DIA), and Association of Clinical Research Organizations (ACRO), pharmaceutical and biotechnology manufacturing companies (Amgen, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Med Immune, ViroPharma, Gla xo-SmithKlirie, Merck & Company, Novo Nordisk, Bayer HealthCare, Pfizer, sanofi-aventis, Allegro Diagnostics, and Nova rtis), CROs, and individual citizens.

Through the draft guidance document, as revised, FDA encourages capturing source data in electronic form, stating that doing so should be beneficial to "eliminate unnecessary duplication of data; reduce the possibility for transcription error; encourage entering source data at the time of a subject's visit; eliminate transcribing source data before entering the data into an electronic data capture system; promote real-time data access for review; and ensure the accuracy and completeness of the data." The draft guidance document discusses topics such as identification and specification of authorized source data originators, creation of data element identifiers to facilitate sponsors, FDA, and other authorized parties in examining the audit trail of data; capture of source data in an electronic case report form (eCRF) using either manual or electronic capture methods; and investigator responsibilities with respect to reviewing and retaining electronic data.

The Agency re-released the document in draft form to address and clarify a number of points raised by the submitting audience, and to gather additional feedback on the newly revised draft. Specifically, FDA stated it had revised the draft guidance document to address source data from clinical investigations integrated with predefined fields in an eCRF, which is an auditable electronic record created for each clinical trial patient generally provided to the sponsor in accordance with the established clinical trial protocol. As a preliminary matter, an "electronic record" is defined by regulation as "any combination of text, graphic, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system" (21 C.F.R. [section]11.3(b)(6)). Source data includes all information in original records (including certified copies thereof) regarding clinical findings, observations, and other clinical investigation activities used for reconstructing and evaluating the trial. Electronic source data are a subset of source data: those that were initially recorded electronically. This form of data presents management and traceability issues as it can be copied, transferred, changed, or even wholly deleted without easy detection unless the proper controls are i.n place.

According to the revised draft, when a sponsor intends to utilize an eCRF, information regarding it should be included in the protocol, including descriptions of the security measures put in place for data protection, electronic data flow, and the use of electronic prompts and data quality checks designed to address items such as data inconsistencies, missing data, and out-of-range entries. In an eCRF, a data element is the smallest unit of observation on a subject that is captured in a clinical investigation, such as patient race, age, or gender. Each data element should connect to an authorized data originator (e.g., an investigator, subject, automated laboratory reporting system, medical instrument, etc.), a list of which should be co-developed and maintained by both the sponsor and site's investigator for each protocol. The draft guidance document sets forth that the list should include unique identifiers and their respective periods of authorization, and should identify the systems, devices, and instruments transmitting data elements to the eCRF directly. These data can be manually or electronically entered into the eCRF. Data elements obtained on site during a visit such as subject blood pressure or weight are appropriate for manual entry into the eCRF by an authorized data originator. When data is entered directly, the eCRF is the source. However, FDA points out in the draft guidance document that pertinent supportive information, when available, could be requested during an inspection to corroborate direct entry data source elements.

The eCRF is also considered the source when data elements are transmitted directly to the eCRF from a medical device or instrument without an intervening process. When an intervening process is employed, such as an instrument's transmission to a central reading center, the source may be the instrument or the central reading center. Data elements may also be transcribed from paper or electronic source documents, making the authorized transcriber the data originator. In this instance, the documentation from which the data elements are transcribed, be they paper or electronic, are the source and must be maintained for potential inspection by FDA. With respect to data elements originating from an electronic health record transmitted to the eCRF automatically, the electronic health record is the source and is subject to FDA inspectional authority. In the draft guidance document, FDA points out that it understands that sponsors do not often have control of electronic health records, but insists that the access to these records must be consistent with those maintained in paper form.

The draft guidance document also details FDA's thinking on an investigator's responsibilities as it relates to data review. Investigators--those individuals who actually conduct a clinical investigation--have regulatory-based responsibilities to maintain accurate case histories, and attendant obligations to review and electronically sign each subject's eCRF before the data are archived or submitted to the Agency. The draft guidance document specifies performance by the investigator of the following: periodic review and electronic eCRF signing by the investigator during the clinical investigation (and evidence of such review should be part of the audit trail); tag the data element with computer-generated metadata that are included in the investigator-signed portions of the eCRF, indicating when and by whom the sign-off was conducted; and when the investigator both enters data elements and signs the eCRF, the metadata should reflect and associate both responsibilities with the investigator. When the investigator conducts his or her review, data elements may require correction or modification, which can be performed by either the investigator or the originator. Revised data elements should have new data element identifiers capturing the date, time, and originator of the revision, and the originator of the revised data should use an accompanying field to describe the reason for the change and its relationship to the original record. The new data element identifiers should not overwrite or eradicate the prior entry or entries.

The investigator should control access to a signed electronic copy of the eCRF. FDA reiterated that this documentation should be made available upon request in the event of an inspection. The draft guidance document also provides that sponsors, CROs, data safety monitoring boards, and other authorized personnel can view the eCRF data elements before the investigator has signed off on them. In the draft guidance document, FDA encourages viewing the data to facilitate early detection of study-related issues or site-related problems, but indicates that any interim analyses should be pre-specified.

The draft guidance document addresses many issues raised by industry comments, presenting a more linear perspective regarding the management of electronic source data in clinical investigations. While the original draft guidance document has been revised--clarifications made and gaps addressed--industry is encouraged to fully review the revised draft to evaluate the ideas and language used. FDA is requesting and accepting comments on the draft guidance, available at, through January 22, 2013, although comments on any guidance may be submitted at any time.

By Colleen Heisey, J.D., M.P.H. Hunton & Williams LLP

Colleen Heisey is a partner in the Washington, D.C. office of Hunton & Williams LLP ( and a member of the firm's Food and Drug Practice. She can be reached at
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Title Annotation:FDA WATCH
Author:Heisey, Colleen
Publication:Contract Pharma
Date:Jan 1, 2013
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