Guest Column | March 28, 2019

eTMF: A Paperless Paradise … Or Paradise Lost?

By Thomas Cocciardi, LMK Clinical Research Consulting

The quest to eliminate paper, both outside and within clinical research, is filled with ironic and unexpected consequences. Consider Amazon, a tech leader with a market capitalization today of more than $800 billion dollars. The company was founded in 1994 as an online retailer of physical paper books, but in 2007, it launched the Kindle e-reader to eliminate the need for bulky, heavy, dusty, old-fashioned tomes.¹ Despite Amazon’s (and others’) significant investment in the e-book space, e-book sales were down nearly 4 percent in the first three quarters of 2018,² while independent, physical bookstore openings are on the rise.³ In response to this trend, Amazon has opened three new more brick-and-mortar bookstores to accompany the other 15 it has opened over the last few years.⁴

The campaign to eliminate paper clinical documentation, especially in the trial master file (TMF) with the adoption of the eTMF, has been ongoing for more than a decade. Although the TMF has been transformed in appearance and now relies on computer hardware and digital media, significant regulatory risk presented by the TMF continues to persist. In fact, the implementation of the eTMF, while ensuring the elimination of paper, has created an entirely new category of risks.

This article, though, does not nostalgically pine for a return to paper — nor does it propose another innovative technology for innovation’s sake. Instead, it suggests that we reappraise the origin of our desire for a paperless eTMF, so we may gain greater perspective on our current eTMF success and ensure our precious clinical research resources remain aligned with our clinical goals.

A Brave New World

More than decade after the first eTMF promises were made, where has the journey taken us? According to the Veeva 2018 Unified Clinical Operations Survey, 66 percent of respondents have adopted an eTMF system.⁵ The move to early eTMF and hybrid systems (and, in many cases, a secondary move to a more modern, cloud-based eTMF) was a massive undertaking for clinical professionals. After huge initial IT investments, standard operating procedures (SOPs), working instructions, and processes were also revamped to accommodate the eTMF. This IT investment and growing eTMF workload necessitated an increase in the size of the average clinical team. Industry continues to struggle with an eTMF skills gap, and eTMF migration projects have consumed, undoubtedly, many millions of dollars in man-hours. Migration projects at many large CROs have only recently shown signs of tapering.

Even after overcoming the barrier of migration, eTMF stakeholders saw that their new eTMF, while eliminating some challenges pertaining to physical document handling and collaboration, also introduced new ones. Consistency and timeliness continued to challenge industry. Eliminating paper has allowed for teams to collaborate across the world, rather than sending documents to a core team of filing experts in one physical location. As a result of this democratization and decentralization of the TMF, eTMF filing expectations and expertise can vary widely across teams and sites. Industry has responded to this challenge by creating the TMF Reference Model⁶ and other standardized taxonomies. While the TMF Reference Model has been successful in improving uniformity across teams and organizations, timeliness challenges persist.

Heading into 2020, two key paradigm shifts are occurring: a unified call to harness the masses of data generated by the eTMF (and other clinical applications) and a renewed focus on the eTMF promise of increased transparency. The Veeva survey cited above revealed that 74 percent of respondents saw integrating multiple applications as their biggest challenge. A survey in 2016 of midsized and large clinical operations organizations found that 83 percent are using key performance indicators (KPIs) to monitor performance in their clinical operations functional areas.⁷ Despite this use of KPIs, other data suggests that current clinical operations stakeholders do not have access to the data granularity they need to monitor TMF health, as better visibility and oversight “is the primary driver for unifying clinical applications for 77 percent of respondents.” While new burdens have been introduced by the eTMF transition, clinical operations stakeholders still yearn for the same visibility and integration promised as a key justification for the elimination of paper. While regulatory expectations have increased, as has the amount of data generated by the TMF, it is unclear if the promise of eTMF transformation is unfulfilled or if the goalposts have drifted ever further away.

Shangri-La Has Modern Regulations

Any significant paradigm shift in TMF format will also require the support of regulators. ICH GCP E6(R1), introduced in 1996, and other period regulation had little framework to support electronic systems, as electronic systems were in their infancy. These early regulations viewed electronic systems as a data repository or, at most, an electronic form emulating a paper document. FDA, MHRA, and EMA regulation and guidance, until recently, paid deference to ICH GCP or intentionally provided more general requirements (such as FDA’s 21 CFR part 11⁸) in order to ensure existing regulation did not fall behind (or more accurately, come into conflict with) rapidly advancing document handling and eTMF technology.

No FDA regulation, including 21 CFR Part 11, identifies any specific documents that must be kept as hard copy originals, and recently promulgated regulation suggests health authorities have grown comfortable enough with the new eTMF paradigm to offer more specific guidance. ICH E6(R2), finalized in 2016, sought to reflect the increased trial complexity and technological advancement that occurred during the preceding decade. Among the many changes in ICH E6(R2), the introduction of the concept of the “certified copy” has had the greatest impact on the TMF and clinical documentation stakeholders, and it presents the greatest opportunity for modernization since the introduction of digital document handling.

According to ICH E6(R2), a certified copy is defined as “a copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure, as the original.”⁹ This new concept of the certified copy is then incorporated into the ICH GCP’s definition of source data, resolutely confirming that electronic copies can be ICH GCP compliant.

A Risk Of Lilliputian Or Brobdingnagian Proportions?

But does the concept of a certified copy mean any paper original document can be destroyed without incurring unnecessary regulatory risk?

The definition of certified copy provided by ICH E6(R2) is suggestive but inconclusive. The guideline’s language about the certified copy is applicable regardless of the type of media and plainly states that an original record can be the result of any validated processes (not just by a dated signature). Employing this reasoning, it follows that original documents can be in any format, and that the concept of the certified copy allows the media format of a document to be converted while still meeting the definition of source data.

Given a few months to review ICH E6(R2), the early reaction of regulators, especially the EMA and MHRA, offers hope that the time to rev up the shredders is nigh. During a Q&A session at a recent TMF summit, MHRA Inspector Andrew Fisher was asked if the creation of a certified copy allows for the destruction of the paper original.¹⁰ In response, Fisher noted that failure to destroy the paper document after certifying an original could be cause for further investigation and could spur investigators to request any available paper documents.

EMA’s recent final guideline on the content, management, and archiving of the clinical trial master file presents the greatest evidence yet that the death of paper clinical documentation is imminent. According to the guideline, although, “Sponsors and investigators/institutions should ensure that essential documents are not destroyed before the end of the required retention; however, creation of certified copies, meeting the requirements outlined in section 5.1 to an eTMF repository (either during the trial or for archiving) could enable earlier destruction of the originals.”¹¹ The guideline goes on to outline documents that have a “low risk from destruction”, including “a paper copy of an electronic original.”

Although EMA’s guideline offers a clear pathway for the destruction of paper originals, the language of the guidance suggests that there is inherent risk in creating a verified copy for the purpose of destroying paper. This is suggested by the phrase “low risk from destruction” above, and by Section 5.1 of the guideline, Certified copies. To fulfill the criteria for a certified copy, a document must have “all the same information, including data that describe the context, content, and structure, as the original.” EMA states that, “A process should be in place for risk-based QC checks of certified copies, before destruction of the originals.” Certified copies, therefore, have a high and exacting standard to fulfill. Mimicry is not enough. A certified copy must retain the same information, data, and structure — but also the same context.

A regulatory professional in charge of creating a validated process to identify and preserve the context of the thousands of clinical document types stored in the TMF would certainly recognize the risk that, in some cases, context can be intertwined with the document’s media or temporal circumstances. Simultaneously, this regulatory professional would also have concerns that maintaining paper original documents could cause the MHRA to doubt the confidence of an entire organization in their eTMF system. EMA’s new guidance does not necessarily disincentivize the adoption of the eTMF, but it does suggest migration activities might, in the risk-averse context of clinical research, be avoided. Of course, in failing to adopt the eTMF one might not meet other regulatory expectations. This dilemma must be resolved for the elimination of paper and for the full potential of the eTMF to be realized. This dilemma also encapsulates a poorly controlled regulatory risk — a risk that is the direct result of an industry-wide effort to reduce the regulatory risk of clinical documentation.

Is Paperless Paradise Lost?

Just as Amazon unintentionally stoked the resurgence of the independent book store, have we, in adopting the eTMF, unintentionally increased the clinical documentation burden? What exactly have we achieved, and what were the costs?

The eTMF has overcome barriers of time and space and has united teams across continents and time zones. The adoption of the eTMF has undoubtedly recovered millions of square feet of facility space for other uses and has freed clinical operations professionals from the drudgery of manipulating paper. The eTMF has increased the efficiency of some tasks by bringing information instantly to our fingertips and has allowed for data harvesting on an unprecedented scale.

At the same time, eTMF adoption has increased regulatory expectations surrounding the TMF and has threatened to overwhelm the story of the clinical trial in masses of extraneous information. The prospective management tools of the eTMF system that promised to transform clinical operations often lie waiting, as under-resourced teams struggle to meet their basic filing timelines.

Yet, even in the struggle, there are signs of positive change. Industry has begun to recognize the central importance of the TMF and has shifted its values accordingly. Specialized TMF teams are forming, more resources are being channeled towards the TMF, and the use of intelligent dashboards and quantitative metrics have been leveraged to improve decision making.

In light of the successes and challenges of the eTMF, it becomes clear that the battle for the paperless clinical trial has always been a proxy war. We loath paper mostly because of what paper has come to represent: tedium, bureaucracy, and inefficiency. We are more keenly aware of these failings because of the life-or-death consequences of delays and wasted resources in the clinical trial industry. Observing the pace of modernization in other aspects of our lives, clinical document stakeholders crave for this modernization to come to the TMF. However, in adopting these modern tools, we have discovered that tedium, bureaucracy, and inefficiency can exist without paper after all — persisting through antiquated processes and outdated regulations. Ironically, in reappraising the successes of eTMF adoption, it seems the greatest advances resulted not from the elimination of paper or the acquisition of new technology, but rather from the introduction of flexible thinking and the adoption of modern processes.

References:

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.

This website uses cookies to ensure you get the best experience on our website. Learn more

Guest Column | March 28, 2019

eTMF: A Paperless Paradise … Or Paradise Lost?

Like what you are reading?

Sign up for our free newsletter

Newsletter Signup