4 Best Practices eTMF Can Learn from eCTD

April 9, 2013

  • eTMF Best Practices

The electronic Common Technical Document (eCTD)  represents one of the first instances where a regulatory agency reviews a sponsor’s documents electronically and makes regulatory decisions based on the outcome of the review.  eCTD has now become an accepted standard for regulatory submissions at many health authorities, and most reviewers express a preference for reviewing documents electronically.  Agencies also believe that they can complete a higher quality review than when reviewing paper submissions, and can also complete reviews more quickly.

eTMF does not follow a published standard in the same way that eCTD does, but in a similar manner to eCTD, it represents a body of electronic documentation that a health authority (in the form of an agency auditor) must navigate efficiently and accurately in order to reach conclusions about the conduct of the clinical trial, the integrity of the trial data and the compliance of the trial with GCP.

eCTD is now a mature standard with a body of best practices based on years of interaction between sponsors and regulators.  During my career, I’ve been involved with eCTD in various ways, including designing and implementing document management systems to produce submission-ready documents, designing eCTD publishing systems, and working with regulators to fulfill their eCTD review and validation needs.  Recently, it occurred to me that some best practices used in assembling and reviewing eCTDs also apply to eTMFs.  Here are some examples.

  1. Think of your eTMF as a stand-along representation of your trial.  When a sponsor submits an eCTD, it must provide a complete picture of the information needed to reach a regulatory decision.   All necessary documents must be present and accessible to the reviewer; external hyperlinks to other information are generally prohibited (in fact, the FDA now checks for such links and reports them as errors).  For an eTMF, all of the required information must either be present or readily accessible to the auditor.  External hyperlinks in documents should generally not be present, especially if they require authentication to another IT system.  If documents that are logically part of the eTMF are not physically contained in the system (for example Case Report Forms or safety documents), an access mechanism must be provided for the sponsor – keeping in mind that total training time for all systems accessed by the auditor should not exceed one hour.
  2. Naming conventions for documents are important.  In an eCTD, reviewers dislike being presented with a set of documents in the same Table of Content (TOC) sections that have the same names – meaning they have to open a number of documents to find what they are looking for.  Likewise, in eTMF, an auditor who is presented with a set of documents all named “1572” or “Protocol Amendment” will quickly become frustrated.  Documents should be uniquely named, or at the very least always presented with metadata that will establish their context.  This is best accomplished by using auto-naming for documents in the eTMF.
  3. Correct filing is paramount.  In an eCTD, a document that is filed under the wrong TOC section is essentially “missing”.  It’s unlikely that the reviewer will find it – instead, the reviewer will send an inquiry back to the sponsor, resulting in a delay in reviewing the application.  (Or as I once heard an FDA official describe it – “You will have to fix it on your time, not my time.”)  Likewise, if eTMF documents are not properly identified and filed, an auditor will be unable to find them and will probably register an audit finding.  Proper training of personnel who upload and index documents along with a good quality QC process will help to ensure that the eTMF is properly organized.
  4. Duplicating documents should be avoided.  eCTD guidelines recommend that a document that applies in multiple sections of an application not be duplicated.  Instead, multiple links to the same content should be created.  This helps prevent the need for multiple reviews of the same document and prevents documents that should be the same from diverging. The regulatory authorities (especially EMA and MHRA) have also stated that sponsors should avoid duplicating any documentation in a TMF.  For eTMF, this generally requires the ability to index a single document against multiple planned documents – for example, associating a combined IRB/IEC charter and member list with two planned documents.

No doubt there are other parallels, but the conclusion I reached about eTMF was the same one always stressed in the eCTD world: sponsors should always think about how they can structure and present information to make it easier for the reviewer to do his or her job.  eTMF vendors need to give them the tools they need to create a truly audit-ready eTMF.