September 24, 2013

  • eTMF Best Practices

In 1999, the FDA guidance document “COMPUTERIZED SYSTEMS USED IN CLINICAL TRIALS” first formalized the concept known as ALCOA:


To be acceptable the data [from clinical trials] should meet certain fundamental elements of quality whether collected or recorded electronically or on paper.  Data should be attributable, original, accurate, contemporaneous, and legible.”

In June 2010, the EMA added to the elements of quality in “Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials”:

“A number of attributes are considered of universal importance to source data and the records that hold those data. These include that the data and records are: Accurate, Legible, Contemporaneous, Original, Attributable, Complete, Consistent, Enduring, Available when needed.”

Although the principles were established for clinical data, many of them also apply to clinical (TMF) documents.  Today’s blog post examines these principles and how they apply to TMF documents.

Accurate: Agencies stress accurate and complete copies of records must be available during audits.  An eTMF can support this goal by providing a standardized QC process that ensures that records stored in the eTMF are complete and accurate in both metadata and content, and are correctly classified in the system by assignment to the correct document or artifact type.

Legible: Although it is not the primary responsibly of eTMF QC to ensure the legibility of handwritten annotations within a document, the QC process should ensure the overall legibility of the record by ensuring that scanned documents were scanned at high enough fidelity to ensure their readability, and that issues such as dog-eared pages, obscuring study notes, etc. are not detected.  Automated integration with a validated scanning process supports the generation of high quality images.

Contemporaneous: authorities require that “The TMF should to be up to date, with documents placed in the TMF in a timely manner with the aim to maintain the TMF “inspection ready” (Directive 2005/28/EC Article 16 and Recommendations on the content of the trial master file and archiving Section 3)”.  Use of an eTMF that tracks document due dates and reports on coming due and overdue documents supports the ability to use eTMF to support decision making (for example, IP Green Light).

Original:  Use of an eTMF is a pre-requisite for allowing certified copies to replace paper originals, according to the MHRA’s Good Clinical Practices Guide.  The use of a qualified QC process supports allowing an electronic copy to replace a paper original.   The 2012FRAMEWORK FOR THE DESTRUCTION OF PAPERcreated by the DIA Document and Records Management (DRM) Special Interest Area Community (SIAC) provides guidance around technology, regulatory, process, and other considerations that would allow an organization to consider an eTMF document a suitable replacement for a paper original.


Attributable: A properly designed eTMF will provide a complete audit trail that will make any regulated activity in the system attributable to a named person.


Complete: eTMF should inform you of not only which documents you have received, but which documents you expect and which should be considered overdue and missing.


Consistent:  A well-designed eTMF should excel at enforcing consistency in important processes. For example, a standard process should be used to determine the documents expected for a specific study.  Standard QC processes will minimize unwanted variation as well as quality issues.  Following standardized processes for monitoring and close-out of eTMF will also yield consistent results that can be improved over time.


Enduring:  Surveys have found that the complete contents of paper TMFs are often difficult or impossible to locate even a short time after a trial is closed out.  With an eTMF, if the records are available at the time of study archive, they should remain available indefinitely as long as steps are taken to migrate them forward as underlying technology changes.


Available When Needed:  A cloud-based eTMF is an ideal solution for making sure that documents are available when needed to support decision-making, prepare for site monitoring visits, and prepare for audits.


ALCOA is an important tool in convincing managers, quality assurance professionals and regulators that data is reliable and high quality processes were followed.   It also provides an important guideline for managing the documents in an eTMF.