Fear, Indecision, And The Memo To File

February 23, 2018

“Just write a memo to file.”

How many times have you seen or heard this phrase? Perhaps it came in an email, echoed out of the conference room phone, or maybe you’ve even said it yourself?

A memo to file (MTF) is a document filed in the trial master file (TMF) that is intended to explain an irregularity in trial conduct or documentation. The memo generally contains a few paragraphs explaining the irregularity and is signed and dated by the author. The intent of the MTF is to clarify the irregularity, but when used too frequently or inappropriately, it can highlight unresolved problems, add confusing or extraneous information, or take the place of necessary corrective action. The FDA seems to hold a similar view as exemplified in the following warning letters:

Sanofi-Aventis, Oct. 23, 2007

  • “[The] generation of numerous memos to file after all subjects have completed the study does not adequately secure compliance of an investigator”
  • “The generation of more than 125 memos to file for protocol and informed consent deviations memo at the site was not adequate.”
  • “Memos to file are inadequate to address the falsification (backdating) of study documents.”1

Johnson and Johnson, Aug. 10, 2009

  • “The site generate[d] a Memo to File that documented the IV temperature stability conditions for previously enrolled subjects. However, the issue should have been addressed again prior to the 25 September 2006 unblinded monitoring visit. The Memo to File that was finally written on 16 November 2006… does not provide sufficient detail to ensure that temperature stability conditions for the drug were maintained adequately.”2

Clinical Investigator, Dec. 19, 2011

  • “Note To File” dated 7/7/2009 for subject (b)(6) indicates that the subject underwent study-related testing, such as the (b)(4) on 4/9/2008, and that you did not obtain informed consent until 4/18/2008…”
  • “Note To File” dated 7/10/09 for subject (b)(6) indicates that the subject completed all screening assessments on 2/14/2008 and that you did not obtain informed consent until 2/15/2008…  Your response has been noted; however, the delay in the implementation of the proper procedures is not acceptable.”3

In light of these well-publicized negative responses, why do we continue to depend on the memo to file? I believe the current dependence on the MTF is a fear-based response to several common contributing factors — all of which incentivize disenfranchised TMF contributors to reach for the MTF in place of using their own best judgment.

Regulatory Confusion

When faced with a regulatory question, the right choice is to return to the foundational regulation or guidance for clarification. Unfortunately, there is no regulatory framework supporting the creation of the MTF. Without a foundation of regulatory guidance, the industry continues to favor vagueness over commitment to a regulatory interpretation that could later be contradicted.

Consider the uncertainty and confusion surrounding the collection of “wet ink” documents. Currently there are no restrictions on what documents can be retained electronically. ICH E6(R2) goes so far as to eliminate the distinction between formats and suggests that all media should be treated equally. The FDA accepts electronic documents if they are 21 CFR Part 11 compliant. Despite the regulations’ lack of distinction between electronic and wet-ink documents, sponsors often choose to exceed the standard of the existing regulation and invest significant resources to collect original documents.

In one circumstance, I observed a QC (quality control) process flag more than 500 documents for lacking wet-ink signatures. The study team was asked to write a memo to file for each document. Hundreds of MTFs were written and filed in the TMF even though the sponsor’s and CRO’s SOPs both specified the acceptability of electronic documents from outside sources. Without clearly communicated standards for both the collection of wet-ink documents and the use of the MTF, especially in the absence of a regulatory foundation, the study team was put in a position where the creation of hundreds of MTFs seemed like the only viable way to satisfy conflicting policies.

Fortunately, the solution to regulatory confusion is simple: committing to a sensible regulatory interpretation. Although the path to regulatory clarity is a simple one, its execution can be challenging. For an interpretation to be successfully and uniformly implemented, buy-in by stakeholders must be as universal as possible. In order to encourage this widespread adoption, working out these regulatory gray areas must be part of TMF planning activities. Study teams often look to study management when faced with regulatory decisions; therefore, management should be prepared and willing to take a strong stance. The best solutions will result when the experience of all levels of engaged TMF stakeholders is leveraged.

Lack Of Flexibility

The “placeholder” MTF and the “missing document” MTF are often symptomatic of rigid TMF design. A placeholder MTF is generated to mark a section of the TMF as empty. A missing document MTF records that a document has not been collected. The authors of such MTFs may be concerned that an empty folder always indicates a missing document, or perhaps they believe that more documents makes for a better TMF.

Over the course of a trial, numerous documents will actually be missing; however, in many cases, a document that is thought to be missing is already filed elsewhere, not expected, or not applicable to the trial at all. Usually the missing document or placeholder MTF represents an unwillingness or inability to perform the due diligence necessary to separate the “false positives” from the actual missing documents. These false positives can quickly grow in number and overwhelm the project team, causing them to fall behind on their document collection and QC activities.

Contributing to the growth of these false positives is the growing adoption of the document matrix, most commonly the TMF reference model. Without sufficient maintenance and engagement by the project team, a document matrix can become a shortcut that replaces true understanding of the trial. TMF leaders must champion the belief that no expected document list, no matter how widely used in industry, is ever comprehensive.

For the modern TMF to reach its potential, both TMF design and conduct must embrace change.  Flexible thinking about the content of the TMF and the timing of document collection, paired with adaptable TMF systems and tools, can significantly reduce the need for the missing document and placeholder MTF by greatly reducing the number of falsely identified missing document action items. Additionally, a just-in-time approach — where filing locations are created at the time of document collection, rather than the creation of a folder structure in advance of the trial — can help curb this impulse to “fill” the TMF with a memo to file. The TMF index can also be leveraged and used to document those filing locations that have been intentionally left blank because no documents were generated.

Unsustainable QC

Although the industry continues to rely more heavily on automated and electronic systems, the TMF will always be the product of the people who are invested in its creation and maintenance. Metrics are an important part of the maintenance of a healthy TMF; however, one must also recognize that metrics cannot capture the human factors that play a dominant role in the success of the TMF.

The unprecedented transparency provided by eTMF systems can be a powerful tool for trial management, but it can also encourage unrealistic expectations. Recently, I observed a sponsor who, after some poor audit findings, began to focus solely on TMF completeness. Although the sponsor was right to be concerned about missing documents, especially since most sites had been closed, the pressure to collect missing documents was not balanced with an increase of resources to complete the task. The sponsor set a goal of 100 percent collection of all documents listed on a missing document report. As a result, thousands of MTFs were filed for documents that could not be collected without the assistance of CRAs and the remobilization of the whole study team.

For a TMF QC system to be successful, it must be supported with the proper resources and created in response to a balanced and flexible understanding of the TMF’s requirements and limitations. In the scenario above, the study team felt compelled to write MTFs as a tool to cope with the impossible task of collecting 100 percent of missing documents from sites that were already closed. The sponsor and CRO were unwilling to support the QC process with the reopening of sites or the creation of a corrective action plan out of fear of increased cost and damage to the sponsor’s and CRO’s image. Because of this unsustainable QC process, an already incomplete TMF became unnavigable as the correctly filed documents became obscured behind a forest of placeholder MTFs.

Absence Of Empowerment

Out of fear of noncompliance, stakeholders who are not empowered to understand and interpret the regulation surrounding the TMF will turn to the MTF. Out of fear of incompleteness, overworked or undertrained stakeholders will not adapt their TMF to changing needs and will fill the TMF with MTFs. Out of fear of unrealistic metrics and unsustainable processes, MTFs will be created to give the appearance that expectations are met.

Fear is positive when it helps us focus on what matters, but in excess, it can cause us to doubt our judgment or avoid necessary but difficult decisions. The MTF is the product of this crisis of confidence. It satisfies our desire to act in the face of a problem without requiring commitment to finding the right solution and risk-taking. It is a strategy that delays difficult decisions, but in doing so makes future choices even more difficult.

The only way to conquer the fear of decision making is by empowering the stakeholders who create the TMF. Along with the right tools and training, a culture that rewards positive risk-taking must be fostered. After all, tough decisions are essential to the health of the TMF — tough decisions like arriving at a regulatory interpretation as a team when the regulation is otherwise unclear, determining a document does not need to be collected when the circumstances change, pushing back against an unsustainable process when it is not properly supported, and advocating for greater resources in a time of need. Often, making a decision requires accepting risk. Still, even greater risk can come from writing a MTF. However, making no choice is the most risky decision of all.

References:

  1. http://wayback.archive=it.org/7993/20161023104138/http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2007/ucm076552.htm
  2. http://wayback.archive=it.org/7993/20161022234038/http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2009/ucm177398.htm
  3. http://wayback.archive=it.org/7993/20161023100405/http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm320980.htm

About the Author

Thomas Cocciardi is a technical writer at LMK Clinical Research Consulting who is committed to expressing the human story behind each trial master file (TMF). In addition to technical writing, he also works as a TMF health specialist for a large CRO. Before specializing in the TMF, Cocciardi gained wide-ranging experience, both in and out of the pharmaceutical industry, working as a clinical research coordinator, preclinical data coordinator, intern medical writer, and intern brand writer. He holds an M.S. in regulatory affairs for drugs, biologics, and medical devices from Northeastern University.