Digital documents: Can electronic tools ease biopharma's clinical trial file headaches?

Clinical trials have increased in complexity over the past decade, with sponsors working with an increasing number of sites, countries and service providers. These massive globalized studies place new strains on the organization of essential study documents, collectively known as the trial master file (TMF). In response, vendors have pushed a technological solution: electronic TMF systems.

Vendors pitch eTMFs as a way to easily and securely share clinical study documents with internal and external teams, while also realizing many of the benefits electronic systems have over paper-based processes. Whereas paper files can be lost or destroyed and are only accessible where they are physically located, documents stored in an eTMF are less vulnerable to physical damage and can be viewed from anyplace with access to the web.

Biopharma companies rarely move quickly to adopt electronic clinical trial systems, but survey data suggest that eTMFs are on the rise. In its 2013 TMF survey, the Drug Information Association (DIA) found that 13% of respondents use a fully electronic system, up from 7% in 2010. Even more organizations have adopted a hybrid paper/electronic system. In 2010, just 27% of respondents took this approach. Now it has replaced paper as the most popular model, with 42% of people choosing a hybrid system. In 2012, almost half of the respondents to the DIA survey said eTMFs make internal and regulatory audits less burdensome.

The need to improve document management

Companies are going electronic to simplify research documentation.

The technology is particularly well suited to the modern era, in which sponsors have formed deep collaborations with service providers. William Blair analyst John Kreger has asked biopharma executives about outsourcing for the past three years and found penetration rates to be rising steadily. In 2013, respondents said 59% of late-phase research is outsourced, up from 54% in 2011.

Sharing paper documents in an outsourced system is a headache for sponsors, and the problem is magnified by the globalization of late-phase trials. In the four years ending in 2010, companies utilized study sites in almost twice as many countries as they did in the previous four-year period, according to the Tufts Center for the Study of Drug Development.

French drug giant Sanofi's ($SNY) planned rollout of a portal to manage study documents clearly shows the scale and impact of third parties on TMFs. Sanofi expects 3,000 internal staff and 40,000 external collaborators to have access to the system.

The typical clinical trial generates up to 25,000 documents, creating a huge logistical challenge for sponsors, sites and service providers--one that many are failing to meet. In 2012, nine of the 11 critical deficiencies reported by European Medicines Agency (EMA) clinical trial inspectors in their "general" category related to documents. Overall, almost 60% of the general failings of any severity seen by EMA trial inspectors were tied to problems with source documentation and essential files.

Advocates of eTMFs see the systems as a way to avoid such run-ins with regulators. "You can quickly determine the completeness of the TMF and see where there are any gaps," says Maryanne Quinn, a chair of one of DIA's TMF Reference Model teams. "That way it isn't a shock when you have a regulatory inspection."

Some industry watchers predict that eTMFs will do much more than just relieve study-management headaches. In the William Blair survey, more than 5% of people listed eTMFs as the technology with the most potential to improve R&D productivity over the next few years. Small and mid-sized biopharma companies were particularly effusive about eTMFs.

Overcoming challenges of eTMFs

This rosy picture of eTMFs differs dramatically from some users' views of the technology, though. Retrieval of eTMFs should be quick and easy, but the task becomes much harder when users fail to properly code the records. The effect of these human errors is magnified by the failings of some eTMF systems. "Every auditor I've spoken to dreads having an eTMF assignment," says Tina Avanzato Chiodo, founder of the clinical research consultancy GCP Works. Chiodo has worked in clinical research for 20 years and is far from a Luddite--she is active on Twitter and runs a web domain name business--but she's frustrated by eTMFs. For example, she says, it should be easier to spot misfiles and track down errant documents in an electronic system, but flawed search functions actually make it slower than working with paper. "It's not like Google," she says.

Other people tasked with reviewing eTMFs have encountered similar problems. A summary of issues faced by EMA inspectors gives a taste of the annoyances of eTMFs. "There was poor, often repetitive, sometimes incorrect labelling of files, resulting in excessive time wasted opening and closing PDF documents in the eTMF when attempting to locate documents," the EMA wrote. Usability problems also mean it can take auditors and inspectors a frustratingly long time to learn how to use the system.

Even so, regulators are inspecting eTMFs. The 225 respondents to the DIA survey have collectively reported 50 eTMF inspections by FDA, EMA and other regulators. Some regulators may even prefer eTMFs: The survey found nine instances of regulators refusing paper and requesting eTMFs, including six by the United Kingdom's Medicines and Healthcare products Regulatory Agency. In contrast, only one eTMF was rejected in favor of paper.  

Moving toward intuitive, interoperable eTMFs

Despite the teething problems, eTMFs could ultimately be a boon for regulators and monitors. Travel to and from trial sites is a major drain of time and money for anyone reviewing files but was essential in the paper era. Cloud-based TMFs make it possible to view the files from any computer. And some regulators are already trying this approach, with the DIA survey finding seven such examples of remote TMF inspections.

Many of the problems with eTMFs could be eliminated by the development of more intuitive, standardized software platforms and filing systems. Chiodo has already seen a vendor demonstrate a system that addresses some of her concerns with other portals. Quinn, meanwhile, is part of a DIA initiative to standardize eTMFs, which should make it easier for auditors to navigate files and overcome obstacles to sharing documents.

Traditionally, each sponsor had its own interpretation of which documents to file in the TMF. That made sense in a paper-based system in which the sponsor ran everything. However, as companies began trying to share electronic documents with their growing pools of collaborators, the inconsistencies between platforms caused problems. In response, the DIA began developing a reference model to give companies a standardized framework for their eTMFs and associated metadata.

In DIA's 2013 survey, 57% of respondents said their company uses the model. Pfizer is one of the companies to use it as a guide for building an internal list of TMF documents. The more companies that do so, the more likely platforms are to be interoperable. If the model becomes an industry standard, the DIA predicts that companies will face fewer obstacles to sharing files. There are potential benefits in mergers and acquisitions, as well. "The model will simplify consolidation of acquired drugs in ongoing trials," Quinn says.

Still hooked on paper

While sponsors are moving toward a system in which TMFs are shared electronically with internal and external teams, one important part of the clinical trial system is still stuck firmly in the paper era. Investigator sites have been left behind, with the DIA survey finding that 80% of people are not working on any trials in which electronic investigator site files (eISFs) are used.

In a public consultation document published in February 2013, the EMA reported that its inspectors had yet to see any trial sites use electronic systems for their portions of the TMF. Technical and financial constraints are limiting uptake, but by far the most common reason given for not using eISFs was even simpler: It just wasn't considered. Until this changes, the seamless, real-time sharing and tracking of documents across the whole clinical trial process will remain a pipe dream.

With a few tweaks, hybrid systems could still prove a productivity-boosting stopgap on the road to fully electronic records. As with any technological advance, platforms will become more intuitive, and the work done by the DIA could bring down barriers between different systems. In addition, the spread of best practices should cut misfiles and end some of the glitches of transitioning from paper to electronics, such as the creation of huge, unsearchable PDFs.

The shift to eTMFs appears inevitable. The challenge now is to ensure that systems work well for users. -- Nick Paul Taylor (email | Twitter)