By Thomas Cocciardi, LMK Clinical Research Consulting
In response to the increasing opacity of the trial master file (TMF), clinical trial decision makers have embraced quantitative metrics as a way of characterizing and understanding the health of a TMF. Quantitative metrics are easily generated through the reporting functionality of a modern electronic TMF (eTMF) and appear to add value by leveraging the data passively generated through modern clinical applications. Although helpful to address specific concerns, especially those related to completeness, these metrics are often unintuitive and do not readily describe the aspects of a clinical trial most instrumental for TMF health.
Consider the 81 percent of respondents to a recent Veeva survey who report the ongoing use of manual processes (like spreadsheets and emails) to manage study start-up.1 Regardless of their impetus, manual processes like the ones reported by these respondents continue to dominate the most crucial stage gates of a clinical trial. Because of the implausibility of manual data collection outside of what is automatically generated by clinical applications, existing TMF health metrics are biased toward describing the data most easily collected. Unfortunately for clinical professionals, the most pressing TMF health issues center on missing documents or broken processes, which by their nature are not captured in the data used to generate these automatic reports. Automatically compiled quantitative metrics, at least with current technology, cannot readily cope with exceptions like significant incompleteness, intentional or accidental nonconformity, or a sudden workflow change. As a result, despite the abundance of data, the TMF lacks transparency and “how healthy is our TMF?” is a question becoming increasingly difficult to answer.
The inability of quantitative metrics to fully characterize the TMF should not come as a shock. The health of the TMF, as determined by regulators, continues to be judged qualitatively and must be, at least in part, understood and communicated in qualitative terms. When peering into your TMF, an inspector may use quantitative metrics to inform his or her decision about the quality of your TMF; however, the inspector must ultimately find a lucid account of connected events—otherwise known as a narrative. Since the TMF is designed to contain the narrative of a trial, the basic elements common to every narrative (from novel to police report) can be found within: setting, characters, plot, conflict, and theme. These narrative elements can and should be identified and analyzed alongside quantitative metrics to produce a more holistic, more applicable, and ultimately more accurate view of TMF health.
Setting refers to both the time and geographic location of a narrative. For a paper TMF, the obvious setting would be its physical location. But even for a less tangible eTMF, setting is an important property that greatly impacts the story the TMF tells. The setting of an eTMF may include the IT and cloud service locations that service that eTMF. Perhaps more importantly, setting can refer to both the time and place where the events of a TMF’s narrative unfold and/or the structure in which a document is filed.
A document hierarchy and structure are specifically called for in ICH GCP R2 section 8.1: “The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document identification, version history, search, and retrieval.”2
In certain notable works of fiction, setting can play such a large role in a narrative that it can be considered a pseudo-character. Setting, for a narrative and a TMF, is more than a time, date, address, or regulatory region. A TMF’s setting fully encompasses where the TMF’s stakeholders reside, where documents are located within the TMF’s structure, and when these stakeholders interact with the TMF within the framework of a clinical trial’s timeline. Setting gives a TMF’s story a sense of place that informs its other narrative elements.
Characters are the people (or beings) that propel the plot of a story. Fictional characters should reflect the complex personalities of the individuals profiled in nonfiction works. Characters usually evolve dynamically along with the plot of a story and this evolution and/or interaction with other characters creates conflict. The characters propelling the narrative of a TMF along are the TMF’s stakeholders. Given the complexity of modern multicenter, multiregional clinical trials, the cast of characters can be large. Identifying, empowering, and communicating equitably to all the characters of a TMF can be challenging, but understanding the characters of a TMF’s story is both essential to TMF health and regulatory compliance. Trial and site team information like team lists, structure, and logs, as well as qualification documents like CVs and training, may represent a significant portion of a TMF and are called for repeatedly in ICH GCP.
Fully identifying the characters of a TMF is only the first step toward compliance and alone is not sufficient for TMF health. As mentioned above, a defining feature of characters, and the people who propel the story of a TMF, is their complexity. Every TMF stakeholder has individual resource needs and varied goals above and beyond the shared goal of TMF health. Just as in a narrative, the characters of a TMF can (and should) change over time in response to the changing conditions of a trial. The relationships between characters will also build the plot foundation of the story by taking actions that impact the TMF. A firm grasp on the characters of a TMF will help ensure stakeholders’ needs are satisfied, regulators’ expectations are met, and the complex resourcing and interpersonal issues native to every trial will not overwhelm the trial’s decision makers.
Conflict is the challenge or challenges a main character must solve to achieve a goal, and it results from a confrontation between two or more opposing elements. This conflict is often rooted in the drives or motivations of the characters. Conflict is usually considered essential to the cause and effect movement of the plot. Wherever there are relationships and personal drives, there will also be conflict, another essential narrative element. Conflict is an inevitable part of every narrative, and the narrative of a TMF is no exception. Avoidance of conflict should not be the primary goal of TMF management, and conflict is not necessarily indicative of a failing TMF.
In a narrative, conflict is often the product of a character’s drives, whether the opposing force is an antagonist (e.g., the fairy-tale villain), nature (e.g., the perfect storm), or one’s self (e.g., the personal crisis). Understanding the conflict in a TMF requires understanding the characters, drives, and constraints facing the TMF. For example, when executing a TMF plan, market forces (the desire for low cost) will come into conflict with the desire for quality and compliance. Stakeholders’ desire for work-life balance may come into conflict with the drive to shorten timelines. Resources are finite and, therefore, conflict is inevitable.
In a literary narrative, conflict, especially the unknown that conflict represents, drives us to turn the page. In the regulated environment in which the TMF exists, however, uncertainty is a gateway to noncompliance and is undesirable. While regulators expect conflict to exist, they also expect it to be mitigated. Out of conflict should arise balance, and this balance is the goal of the TMF—to show a narrative that the principles of patient safety and data quality were upheld despite the numerous opposing forces that seek to undermine or contradict them. Without the conflict created by new research pushing the bounds of medicine, new ideas would never be tested, and safe and effective treatments would never reach patients. Conflict must be embraced as part of every story – anticipated, not ignored.
Plot is the foundation of a story. Plot describes the events of a narrative but also describes a logical pattern or sequence of cause and effect. Plot is often broken down into five elements: introduction, rising action, climax, falling action, and resolution. The creation, maintenance, and closeout of a TMF also follows this same progression.
The introduction phase of a TMF’s plot is the pretrial planning period, where the main characters are introduced, the relationships are established, and, most importantly, the goals and motivations of the main character or characters are made clear. Once the introductory phase is concluded, where the “stakes” are outlined, the rising action begins, where conflict is introduced. In the case of the TMF, the rising action could be thought of as study start-up, when the ideals of the planning period are tested under the stress of limited resources. From this rising action comes the climax, thought of as a turning point or high point of a story. For a TMF, this climax may come just in advance of closeout or right before the big inspection, where a team is working at the greatest pace and in the moments where the health of the TMF is most clearly impacted. The falling action arrives once the closeout of a TMF is in sight and QC action items are being resolved. Unexpected incidents, though, can still add suspense to the outcome for the main characters. The conclusion or resolution arrives when the conflict is resolved and the goal, in this case the delivery of a correct, complete, and contemporaneous TMF to the sponsor, is achieved.
Recognizing that every TMF has its own unique plot can provide clarity when other aspects of the TMF may be overwhelmingly uncertain. Even though the real world in which a clinical trial is conducted may be exceedingly complex, a clinical trial professional can still orient him or herself within this chain of cause and effect. They understand that the events of every clinical trial are meant to propel that trial against entropy and toward a goal. The shared checkpoints of a trial and its TMF, like planning/kickoff, start-up, conduct, closeout, and delivery are waypoints to help direct both efforts and expectations. Tracing the plot of an existing TMF or comparing the plot of your TMF to a past one can help provide insight into logical next steps and inform the choices that lead to a healthier TMF.
Theme And The TMF Masterpiece
A theme is a narrative’s central idea or ideas and is often revealed over time. A theme is not simply a premise (a subject) but rather reflects the intentions of the author. The central purpose, or theme, of every TMF is stated in ICH GCP as to “permit evaluation of the conduct of a trial and the quality of the data produced”.2 Stemming from this fundamental purpose, inspectors and regulators uniformly expect the theme of your TMF to be one of the triumph of ethical research over the temptation to conduct poor or dangerous research for the sake of profit.
Every TMF, however, will have a theme, but not necessarily the theme regulators demand. Controlling the theme of a TMF requires overcoming the peculiar irony of the element of theme: although theme is the principal meaning of a narrative, and perhaps the most important narrative element, it does not possess any easily describable constituents like the other narrative elements. For example, setting has time and place; every story has identifiable characters; conflict arises where two opposed forces meet. Theme, in contrast, is revealed indirectly through the actions and thoughts of the characters, the movement of the plot, the nature of the conflict, and even through the choice of setting. Theme is not produced directly, but rather is a product greater than the sum of its parts and must be shaped indirectly by the interplay of other narrative elements. In order to shape the theme of your TMF for the better, you must carefully orchestrate the other narrative elements wisely.
So, beyond simple characterization, identifying the narrative elements within a TMF provides a precious opportunity to shape each element to produce the theme and narrative that regulators expect. In literature, it is the nuance with which an author brings the narrative elements together to deliver a powerful theme that transforms a humble story into a masterpiece. Of course, bringing balance and harmony to the people, places, forces, and events of a TMF may not always be possible. In seeking to tell a better story, TMF stakeholders can rest assured that every TMF has the mechanisms of a masterpiece within, no matter how complex or burdened. It is, however, the enduring challenge of a TMF’s authors to bring that masterpiece to life.
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 regulatory writer specializing in FDA Center for Tobacco Products (CTP) submissions. Cocciardi has gained wide-ranging experience, both in and out of the pharmaceutical industry, working as a TMF-focused clinical trial associate, TMF health specialist, 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 and the RAC (US) credential.