Know Your Regs: A TMF Regulatory Overview

Part 3: 21 CFR Part 11

As part of a recent webinar series, LMK Clinical Research Consulting was lucky to host Marie-Christine Poisson-Carvajal, Head of TMF & Registry Operations at Pfizer, to discuss the main regulations that predicate the Trial Master File. During the webinar, Marie-Christine outlined the four most common relevant regulatory authorities and their associated TMF regulations: ICH GCP, EMA Clinical Trial Regulation and Guidance, the MHRA Gray Guide, and 21 CFR Part 11. Marie-Christine established that these regulations are the foundation of every TMF and that the TMF is the foundation of every clinical trial.


To learn more about these essential TMF regulations and best practices for applying them to your TMF business processes, watch the recording of Marie-Christine’s webinar, or read on, as we cover the far-reaching implications of 21 CFR Part 11. Check back regularly to catch the next post in this multi-part series and gain the regulatory knowledge base necessary to achieve TMF health!


What is 21 CFR Part 11?

The regulatory basis of FDA’s oversight of electronic systems is 21 CFR Part 11. First published in 1996, the legislation was ratified in response to escalating concerns about the security of documents and data used to support FDA marketing applications and the continuing safety of marketed products. 21 CFR Part 11 sets FDA’s standards for any records in electronic form, whether created, modified, maintained, archived, retrieved, or transmitted to others, and therefore applies to a wide range of industry activities.


As with most other topics, the items in the Code of Federal Regulations (CFR) only form a general foundation for further administrative rules and guidance and are not frequently updated to reflect technological advances or current thinking. The most recent (and likely most useful) tool for understanding FDA’s current perspective on Part 11 and the TMF is the June 2017 draft guidance document, “Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 – Questions and Answers”. For a clinical professional creating or maintaining a TMF, 21 CFR Part 11 most directly impacts the TMF by setting the criteria with which electronic quality and record systems are created, defining e-signature and access control standards, and specifying how electronic documents can substitute for paper documents.


What does 21 CFR Part 11 say about digital originals/copies of documents?

While ICH E6 R2 is the best reference to overcome confusion surrounding the terms ‘copy’ and ‘original’, FDA doesn’t define a method for certifying copies in any regulation or 21 CFR Part 11. The Agency, however, mandates that record keeping entities must have processes in place for the compliant generation of digital documents or copies. A copy of a document is therefore acceptable for filing in the TMF if it is a “certified copy” according to ICH GCP. A document becomes a certified copy, according to ICH E6 R2, through the creation of a certified copy SOP that generates supporting documentation for each document. Any system used to create the certified copy would have to comply with the basic principles in 21 CFR Part 11 (see Are my systems 21 CFR Part 11 compliant? below)


What does 21 CFR Part 11 say about e-signatures?

The FDA defines an e-signature as “a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.” The question then follows, what, according to FDA, makes an e-signature a legally binding equivalent to a handwritten signature on a paper document. According to FDA, this equivalency comes from compliance with 21 CFR Part 11; more specifically, electronic signatures must meet the following criteria:

  • Are unique to one individual
  • Clearly indicate the printed name of the signer
  • Record the time and date of execution
  • Define the meaning associated with the signature
  • Are linked to an electronic record/ledger to prevent easy duplication or transference to another individual
  • The ledger/software that records this information is compliant to the systems regulation under 21 CFR Part 11

Are my systems 21 CFR Part 11 compliant?

For the average clinical professional, your organization’s strategic thinkers and IT leaders have likely already provided you the tools (as part of validated systems) necessary to create original electronic documents and certified copies through the implementation of 21 CFR Part 11 compliant systems and the ratification of compliant SOPs. Your use of ALCOA (Attributable, Legible, Contemporaneous, Original, Accurate) good documentation principles and adherence to company policy and SOPs, is therefore likely enough to ensure a document (whether certified copy or original) belongs in the TMF and is 21 CFR Part 11 compliant.

For those in decision-making and system administration roles, however, 21 CFR Part 11 compliance can be broken down into 5 general principles:

  • System Functionality: audit trails, security, file export, intended use
  • Vendor Oversight: vendor audits, vendor SOPs, records retention
  • Policies and Procedures: appropriate SOPs, work instructions
  • Validation: systematic documented assurance that a system meets the technical needs of users and regulators
  • Training: system-specific and role-specific documented training for all users

It is important to note, that despite 21 CFR Part 11’s central importance to the life science industry, the regulation reflects the thinking of the age of the floppy disk. It is intentionally vague to ensure the regulation does not fall behind (or more accurately, come into conflict with) continually advancing document handling and eTMF technology. For this reason, clinical professionals should consult those with the expertise necessary to extrapolate the basic principles of 21 CFR Part 11 to their specific situation, platform, program, or technology. 


Contact LMK Clinical Research Consulting today for a complimentary consultation and take the first step toward achieving a healthy, successful, and 21 CFR Part 11 compliant TMF in 2020.