Coordinating Regulatory Electronic Documents Management Systems and Electronic Trial Master Files (eTMFs)

The ultimate goal of clinical trials is to gather evidence concerning the safety and efficacy of a drug, biological or medical device that will convince a health authority to approve it. To support this goal, certain documentation created or collected during the course of the clinical program and each specific trial must be included in regulatory submissions.

In the past, most sponsors managed paper Trial Master Files (TMFs) but rolled out electronic document management and publishing systems for regulatory submissions. Coordination of documents needed for both the TMF and regulatory submissions was, in most cases, handled manually and on an ad hoc basis.

More recently, electronic Trial Master Files (eTMFs) have grown in use as regulatory document management systems have matured. A few sponsors even have enterprise Electronic Document Management Systems (EDMS) that encompass both regulatory submission documents and eTMFs. Now that electronic systems are more common and feature-rich, sponsors are seeking systems that automate the coordination of the documents needed for clinical trials and submissions. In addition, sponsors want systems that can ensure that documents are submission ready—i.e., prepared to standards established by health authorities for electronic submissions.

Coordinating regulatory EDMS and eTMFs is possible, both through automated and manual processes, and doing so will further increase the efficiency around clinical trial documentation. Sponsors must first identify the documentation and data shared between TMFs and regulatory submissions. Then, by understanding (and potentially changing) the processes and responsibilities around those documents and data, sponsors can integrate regulatory submissions with eTMFs, ultimately reducing costs and saving time when meeting clinical trial reporting requirements and preparing submissions, as well as ensuring that correct documents are available to those who need to use them.

Identify Documents

Regulatory submissions and clinical trials share certain key documents. They include the following:

  • Investigator’s Brochure (IB). Most sponsors author and approve this document in their regulatory EDMS and transfer a copy to the eTMF for CRAs and (directly or indirectly) to investigators. The IB is ultimately submitted in the U.S. Investigational New Drug Application and New Drug Application (IND/NDA) in Module 1, the Canadian New Drug Submission (NDS) in Module 1, and in the European Clinical Trial Authorisation (CTA).
  • Clinical Protocol. Many sponsors create the protocol in the regulatory EDMS, but some create it in a Clinical Trials Management System (CTMS) and occasionally in the eTMF itself. The protocol is ultimately included in many submissions as both a stand-alone document and as a component of a published study report.
  • Other TMF documents appearing as Study Report appendices. The International Conference on Harmonisation guidance document “E3 Structure and Content of Clinical Study Reports” defines the elements required for a study report. Some of these elements also originate as documents in the TMF—for example, the sample Case Report Form (CRF), Audit Certificates, Investigator CVs, etc. These documents are often scanned from paper.
  • Case Report Forms (CRFs). CRFs may be completed as handwritten documents, generated from an Electronic Data Capture system, or sometimes completed in electronic forms. Although CRFs are a key element of both the study report and the TMF, CRFs aren’t necessarily managed in an eTMF. This is usually because they are already stored in other systems (often simple file shares) to support scanning, cleanup, and data entry into a Clinical Data Management System. CRFs are submitted routinely to the FDA in NDAs and occasionally to other authorities.
  • Other documents to support the Clinical Trials Authorisation. A number of TMF documents, such as the Informed Consent form, IEC/IRB favorable opinions, etc., are required for the CTA. These are received electronically or as paper documents from outside of the organization.
  • Final Study Report. The final study report is usually created in the regulatory EDMS. However, the preferred option for formatting a study report (at least in the U.S.) is now the “modular” format, in which many individual components are submitted as stand-alone documents rather than as a monolithic PDF. Therefore, it is no longer a hard requirement to assemble all of the report components in one location as long as they are accessible to the electronic publishing tool. The report is a component of the sponsor TMF as well as the Investigator TMF. The modular report may be difficult for an investigator to work with, so the report may be furnished in a partial or alternative form.

Establishing Ownership and Responsibility

The first step in determining how to handle these documents is to identify who actually owns each type of document that needs to be shared. Sponsors must decide who is responsible for creating, reviewing, approving, and providing records management for these documents. Once responsibility is established, sponsors should determine which electronic system will be used to complete each step of the process.

Ensuring Access to All Stakeholders

After identifying the owner of each document, sponsors must determine who needs to access the documents and for what purpose. The specific needs of users will often dictate whether sponsors can offer access to the document in its home location or if they need to push a copy out to users.

For example, Clinical Research Associates (CRAs) and investigators need access to IBs and clinical protocols. However, they don’t need to edit these documents. CRAs would rarely have access to the documents in a regulatory EDMS, so they need a copy of the final version in the eTMF, and in turn to provide it to investigators if they don’t have access to the eTMF. If the document is updated or amended, CRAs and investigators must be notified that the update has occurred and provided with the updated document or amendment.

Another example is the need for regulatory publishers to access Case Report Forms. Some sponsors choose to upload CRFs to their regulatory EDMS to release them for publishing. Others use their submission publishing software to access the CRFs in their original location without uploading to the EDMS. Most major publishing tools have this capability as long as the CRF repository is a file share or a common commercial repository such as SharePoint or Documentum.

Regardless of the selected approach, users need consistent role-based access to documents in the chosen repository.

Automating Availability

Once the ownership and availability of a document type have been established, sponsors can determine the possibility—and value—of automation to ensure document availability. If users cannot access a document in its home location, sponsors should look into pushing a copy to a location available to that user.

Requirements might include establishing a specific location (such as a folder) for the copy, applying security, and applying metadata (which may not be identical to metadata in the original system). Usually, sponsors will make a document will be pushed only when it reaches a key point in its lifecycle (such as approval). Once the copy is replicated, it may later need to be removed or updated if the original in the source system is modified.

When considering whether to automate this process, sponsors should keep several factors in mind: the total cost of ownership for the software configuration or customization, the benefit in terms of time savings, and the potential for increasing increased compliance. A sponsor with only a few ongoing studies is unlikely to benefit extensively from automation.

If the process is to be manual, the sponsor should establish and document responsibilities and procedures.

Ensuring Submission Readiness

Ensuring submission readiness for eTMF documents is often a secondary consideration. Ultimately, eTMF documents that will be submitted electronically must comply with regulations established by health authorities around PDF version, security settings, fonts, margins, and more. Sponsors can address most issues for documents created from templates by ensuring the use of compliant templates along with basic author training.

Scanning eTMF documents to make them available for submissions also requires attention to detail. The FDA’s portable document format (PDF) specifications state, “Scanned documents scanned at a resolution of 300 dots per inch (dpi) ensure that the pages of the document are legible both on the computer screen and when printed and, at the same time, minimizes the file size. The use of grayscale and color significantly increases the file size and should be used only when these features improve the reviewability of the material.” However, adhering to these standards is probably unnecessary for documents that won’t be submitted and use of more relaxed standards can save effort and money. The sponsor’s scanning procedures should specify applicable standards and which all types of documents in the TMF.

Finally, CRFs have their own very specific standards when submitted, including bookmarking by domain and visit. Sponsors must decide whether to prepare all CRFs in this manner or apply navigation only as they are identified as required for a submission.

Failure to address these issues as documents are created will result in significant late-stage rework for regulatory publishing.

Consistency and Mining of Metadata

Sponsors need to ensure consistent metadata when coordinating regulatory EDMS and eTMFs. Both systems generally make use of product or study data that may be managed in one or both systems, or in an external product database or CTMS.

If possible, sponsors should establish a single source of truth for both systems so that product names, study titles, and other information remain consistent when appearing in document text or when used for search or navigation.

Finally, the eTMF might contain data that assists in the preparation of study reports or summaries. For example, study reports must include a list of IECs or IRBs (plus the name of the committee chair if required by the regulatory authority). If this information is captured in the eTMF, users could run a simple query on IRBs and copy the results into a Word document rather than having to open a large number of individual documents to find this information.

In Conclusion

Depending on a sponsor’s size, business processes, and IT systems, coordination between regulatory EDMS and eTMFs can be achieved in a number of ways, both automated and manual. Upfront planning to define roles, responsibilities, and procedures (including change management) and cost/benefit analysis can help a sponsor to choose the best option for the organization.