In Search of "Paperless" Clinical trials

The use of formal clinical trials for testing medical drugs was first documented by the Persian physician and scientist Avicenna in 1025 AD, but he would probably not recognize his invention today. The modern clinical trial involves the careful coordination of activities among the study sponsor, clinical investigators, Internal Review Boards (IRBs), Contract Research Organizations (CROs) and possibly others; the collection of enormous amounts of data; and of course, paper…lots of it.

The mountains of paper involved represent more than a cost to the environment; for the drug companies that sponsor the studies, they represent enormous expenses associated with managing it. The records management team at one pharmaceutical company estimates their cost just to manage and maintain paper records at $1.25 per page. And that does not include the initial printing, copying, and distributing costs, just the management of the record after the trial. With many studies generating more than 10,000 documents, the potential savings from paper reduction is substantial.

Over the last 20 years, all kinds of computer technology has been incorporated into the clinical study process, often accompanied by a vision of a “paperless” clinical trial at some future date. Clearly, that future date has not arrived yet. But technology clearly has changed the study process dramatically, and in fact has replaced many paper-based processes. So where are we in the quest for the mythical paperless trial? Have there been any sightings? Are there any encouraging signs that we may be closing in?

Clinical trial management syststems address the process—not the paper
Clinical Trial Management Systems (CTMS) have been one focal point for the use of computer technology in clinical trials. These systems are used to plan and manage the entire clinical trial, including site identification, patient recruitment, project budgeting, and tracking due dates and activities.

But while clinical trial management systems enable study managers to better address the enormous complexity of the clinical trial process, they do little to reduce the amount of paper actually generated by the study activities. You could even make the case that clinical trial management systems make it possible to manage more complex studies, which result in ever more paper.

To really replace paper, you need to automate the activities that are at the center of the trial process. And nothing is more at the heart of a clinical trial than collecting information about how each patient participating in the trial is reacting to the medication being tested.

The impact of electronic data capture and acquisition
Electronic Data Capture (known in the industry as EDC) solutions have had the biggest impact on the way paper is used in clinical trials. EDC solutions focus on the assembly, organization, and verification of clinical data and the preparation of case report forms. Along with “Electronic Data Acquisition” technologies such as interactive voice response (telephone-based collection of information from patients) and wearable monitors, the growth in adoption of EDC technologies has had a dramatic impact on how clinical studies are done, and how much paper is involved.

According to Carol Smith, director of Clinical Documentation at Cephalon (see related story on page 26), one of the world’s top 10 biopharmaceutical companies headquartered in Frazer, Pa., “of all the technologies we have adopted, EDC technologies have had by far the biggest impact on reducing the amount of paper involved in clinical trials. And it is not just the collection of the data; it is the compilation and preparation of Case Report Forms, which includes all the data on each participating patient at each site.”

So, with the widespread and growing use of EDC, are we on the brink of the paperless trial? Not even close, as it turns out. That’s because, according to Smith and her colleague Mark Carroll, a director in the IT organization at Cephalon, the gains from EDC have been significantly offset by increases in reporting requirements mandated by the FDA.

Two steps forward, one step back
Between the two of them, Smith and Carroll have well over 20 years of experience supporting clinical research. And in that time, they have seen substantial increases in the regulatory requirements for documentation throughout the trial process.

The area where reporting requirements have expanded the most is in the area of adverse drug reactions, also known as pharmacovigilence. Reporting requirements relating to adverse affects have increased substantially in the past decade, with more reports and forms driving an increase in paper. And according to Carroll at Cephalon, “two steps forward, one step back has been the pattern when it comes to reducing paper in the clinical trial process through paper. I feel like we have been playing “Whack-a-Mole” in that, for example, when we went after case report forms, other areas ballooned.”

So there is still a lot of paper involved today. One reason for that, in addition to increasing regulatory requirements, is that most of the technology applied to the clinical trial process has bypassed one of the biggest tree-killers of all, the Trial Master File (TMF).

Next up: the Trial Master File—what does itit accomplish?
The Trial Master File (TMF) includes all the regulatory documents required for a clinical trial, including what are sometimes called the “essential study documents”. Traditionally kept as a set of binders, they include a wide range of document types ranging from medical and scientific curricula vitae to investigator brochures, study protocols, and informed consent forms. And there can be many, many documents of each type, resulting in a total collection of thousands and thousands of documents in each TMF.

Despite all the technology applied to automating various aspects of clinical trials, the TMF is not often a target of these efforts. The focus to date has been more on the data than on the documents, probably because automating data-intensive processes is far easier than document-based processes. But it could be that moving to an electronic Trial Master File (eTMF) will be the key to the goal of reducing paper.

According to Carroll at Cephalon, there is “huge potential for paper reduction by moving to an electronic trial master file. And huge savings.” The biggest reason for that is that by having a single electronic copy that all the study participants can access, there is a dramatic reduction in the need to print, distribute, and store multiple copies at different sites.

For example, any time there are multiple copies of a document in existence, they need to be carefully managed and reviewed to ensure perfect accuracy between them. And at most companies, study documents are burned to CDs or flash devices along the way as part of their standard operating procedures.

Clearly, if there could be a single electronic copy of the clinical trial master file available to all study participants across all sites, the savings in paper and money would be substantial. So why aren’t we there yet?

Challenges to implementing Electronic Trial Master Files
According to Peter Benton, president of the eClinical Services Division of BioClinica (formerly Phoenix Data Systems), based in Newtown, Pa., the challenges relate to processes more than technology. His company provides the pharmaceutical and biotechnology industries with a comprehensive array of clinical data solutions, including full-service EDC.

In regard to the impact of EDCs, the preparation of clinical report forms and data analysis, Benton agrees with Carroll and Smith that there has been a dramatic impact from technology. He notes that these technologies all focus on the data, not the documents. When it comes to essential study documents, however, Benton feels that “going electronic requires getting control of your processes. You can’t use your paper processes to operate an automated system.”

Smith at Cephalon agrees that the challenge to implementing an electronic trial master file relates to people and processes, not technology. “The key obstacle is the resistance to change among individuals, especially in the actual clinics and doctors’ offices. Getting the technology into those settings and driving adoption requires a serious focus on change management and training to ensure effective adoption.”

While changing processes surrounding study documents may be the biggest challenge to moving to an automated trial master file, addressing that challenge may provide the biggest payoff of all. According to Benton at BioClinica, “The move to electronic documents will pay off in a big way, because the documents in a clinical study act as the punctuation marks to the whole process. If we can accelerate the production, review, approval, and submission of those documents, we accelerate the entire process.”

Whither extinction of the pulpwood vampire?
So despite the challenges, both Cephalon and BioClinica are pressing forward with initiatives focused on deploying automated systems for managing essential study documents and connecting study sites, investigators and managers. Both companies are in the process of implementing NextDocs’ Clinical Documents Module and related solutions, with a focus on using them to manage the regulated clinical study documents.

The NextDocs solution includes a complete set of document types, taxonomies, and metadata collections for managing eTMF documents as well as a portal to facilitate collaboration of study participants working from multiple environments in a secure extranet collaboration environment. And, more importantly for any drug development company, it includes all the features necessary to address the U.S. Food and Drug Administration’s (FDA) requirements for managing controlled content, referred to in the industry as FDA 21 CFR Part 11.

Given the history of automating efforts in clinical studies, it may seem like this next effort to reduce paper is just another battle in a war that cannot be won. After all, according to Carroll at Cephalon, “The question is, if we get this under control, what else will come up?”

His perspective indicates that no one is expecting a truly paperless clinical trial any time soon. Nonetheless, companies like Cephalon and BioClinica are committed to moving forward with their initiative, connecting study sites and participants to a single, central, clinical trial master file. While it may not eliminate all the paper, the benefits in terms of dollar savings, reduced risks related to documentation errors, and–most importantly—accelerating the time-to-market for new drugs simply demand it.

Ken Lownie  is vice president of Life Sciences at NextDocs Corporation. He is a frequent speaker and author on the adoption of content management technologies in life sciences companies. Visit www.nextdocs.com for more information.