From the November/December 2015 issue of Contract Pharma contractpharma.com

Mike BurtonDirector, CRO Alliances, Veeva Systems

The Veeva 2015 Paperless TMF Survey: Annual CRO Report examined contract research organizations’ (CROs) switch from paper to electronic processes and systems across a

number of content-intensive areas such as clinical operations, regulatory, drug safety, and data management. The survey results analyzed 50 unique responses from CROs globally and found that 38% use electronic trial master file (eTMF) applications in comparison to 21% just one year ago—a sudden, 17 percentage point increase, striking especially for a market that traditionally moves more gradually. Also, as compared to 2014, greater num-bers of CROs now exchange TMF documents with sponsors via eTMF applications (36% today, up from 24%), and are much less reliant on paper (46%, down from 65%).

Paper is becoming ancient history in the life sciences industry, but in other areas this switchover has been taking place slowly, over time—not in the leaps and bounds seen in the move to eT-MFs. Consider the life science industry’s glacial transition to elec-tronic data capture (EDC) beginning in the mid-1990s and not reaching critical mass until 2006-2007. The major benefits of EDC were clear from the get-go—accuracy and faster time to mar-ket—yet the changeover inched along for more than a decade.

Technology has become far more sophisticated, but that fact alone is not enough to explain the rapid pace of eTMF applica-tion adoption by CROs. The domino effect of success from early CRO adoption of eTMF applications has lit a fire that’s spreading quickly in the broader market. And, it’s the monumental benefits that CROs are reporting from eTMF adoption that continue to fuel the flames.

After all, seeing is believing and the Veeva study makes it evi-dent: CROs today recognize the tremendous impact eTMFs can have on vital areas, like study start-up, in the clinical trial pro-cess. This technology is being adopted faster than those in the past, and it’s already reaching the tipping point at least among CROs. These advanced technologies can help CROs dramatically increase speed to market, which ultimately benefits sponsors and patients as well.

MANAGING MOUNTAINS OF TRIAL MASTER FILESA typical TMF consists of thousands of documents that track trial activities occurring simultaneously across sponsors, CROs, regulatory authorities, and investigator sites worldwide. In fact, the amount of paper generated by a single, global clini-

Seeing is BelievingNew survey reveals eTMF adoption has hit the tipping point

ETMF ADOPTION

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cal trial – if not managed appropriately—can cause delays to product development, adding overhead to clinical operations. And yet, these documents are crucial. TMFs are the evidence that a clinical study was conducted ethically, safely, and in ac-cordance with global regulations. When a company submits a new drug application (NDA), or equivalent, to regulatory au-thorities, the submission refers back to documents in the TMF to support its assertions.

Traditionally, life sciences companies that sponsor clinical trials and/or outsource trial op-erations to CROs have maintained a TMF rooted in fundamentally paper-based processes. The recording and maintaining of research data is done manually, often on Excel spreadsheets, and TMF operational processes are slow with excessive document printing, scanning, and e-mailing. Over time, organizations began storing all of their clinical trial information in vast online warehouses called cloud file shares. These appli-cations were an improvement over paper records, but had very little functionality for searching, or-ganizing, or analyzing data and documents.

More recently, cloud eTMF applications have surged to the forefront of clinical research document management. These solu-tions are typically built on a content management platform and provide life sciences functionality that is specific to TMF process-es including workflows, automation, and reporting.

However, even despite the growing roster of CROs switching to eTMF systems, e-mail is still the most frequently used method for TMF document exchange between CROs and sponsors, ac-cording to Veeva’s 2015 study. E-mail, of course, presents many of the same challenges as paper: version control; difficulty track-ing, slow document search; and data security as content travels through non-secure channels. The good news is that CROs sur-veyed report substantial declines in the use of email (80% in 2014 versus 68% in 2015) as a TMF document exchange method, along with an analogous rise in use of eTMF applications to share docu-ments with sponsors—up 12 percentage points (24% in 2014 ver-sus 36% in 2015).

“Over the last two years, the industry has embraced eTMFs in unprecedented fashion. At Advanced Clinical, it is rare to re-ceive requests for anything other than eTMF services because the benefits are so clear. Clients and CROs see results in real-time, with full visibility and added study controls, which enhance au-dit-readiness overall,” said Julie Ross, executive vice president of CRO operations at Advanced Clinical, a global supplier of drug development services.

RESEARCH REVEALS LARGE DROP IN PAPERThe Veeva 2015 Paperless TMF Survey: Annual CRO Report indicates that today’s CROs are aggressively shedding paper across all clinical areas, undoubtedly as a result of a faster up-tick of eTMF application adoption, too. Survey respondents estimated the extent to which different departments manage TMF documents on paper at any time during a document’s life-cycle. CROs reported double-digit reductions in the number of TMF documents managed on paper within clinical operations

(34%), regulatory (31%), and drug safety (20%). Data manage-ment saw the largest decline in the use of paper, plummeting 19 percentage points from 27% of all TMF documents on paper last year to just 8% in 2015. In addition, clinical operations—which manages most of all TMF documents—experienced a significant decline from 47% of all TMF documents managed on paper in 2014 to 34% today.

Paper-based processes are likewise being swapped for elec-tronic processes in clinical. Veeva survey participants were asked to identify which TMF processes their organization currently conducts electronically. Two-thirds (66%) of CROs report they electronically archive TMF documents and half (52%) conduct remote document review. Surprisingly, how-ever, only one in five (20%) of CROs report using e-signature and just a quarter (24%) report they create source documents electronically. Electronic signature is also the capability CROs cite most often (54%) as missing, but required for their orga-nization to go paperless. Of note, the International Confer-ence on Harmonization of Technical Requirements for Regis-tration of Pharmaceuticals for Human Use (ICH) guidelines only require a handful of documents to be signed and many regulatory authorities and have instituted broad acceptance of electronic signature.

WELL-DOCUMENTED BENEFITS Surveyed CROs that use an eTMF reported a broad range of benefits due to increased efficiency in managing trial master files. Most claim a reduction in the number of missing docu-ments (92%), misfiled documents (89%), duplicate documents (86%), incomplete documents and/or those with missing signa-tures (84%) and expired documents (81%). More than half of the CROs in the study (57%) achieved improved audit and inspec-tion readiness as a result of adopting an eTMF. Half report that cost savings (50%) are a top driver of eTMF application adoption while better visibility into performance metrics is seen by 44% of respondents as key.

“The impact of eTMF applications on clinical trial execution is growing year on year,” said Robert Bolduc, director of docu-ment management at inVentiv Health Clinical. “As the regula-tion and scrutiny of clinical trials increases, maintaining a trans-parent and well organized trial master file is key to conducting a successful study.”

ETMF ADOPTION

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THE NEED FOR SPEED AT START-UPBoth CROs and sponsors must orchestrate clinical research projects faster than ever before, but they struggle to efficiently onboard and activate investigator sites to begin conducting re-search. Study start-up is a document-intensive process reliant upon external collaboration and is integral to meeting key study deadlines. It takes an average of 17 months to move from proto-col approval to 100% approved sites initiated for a clinical trial, according to a 2012 study conducted by the Tufts Center for the Study of Drug Development. Not only does this impact costs but it also delays time to market. During the two-year or longer pe-riod between initial concept and study activation, scientific ad-vances may even render parts of a clinical study outdated before it gets underway.

Lengthy site activation is largely caused by grossly inef-ficient start-up processes and manual document handoffs across functional areas and regions. In fact, speeding study start-up is the topmost cited driver (56% of Veeva survey re-spondents) of eTMF adoption while two-thirds (66%) of CROs surveyed say that development time decreases when start-up documents are managed in an eTMF application. Until very re-cently, technology advancements have not fully addressed this challenge because many CROs and sponsors use proprietary tools or custom clinical trial master solutions to track start-up documents and site initiation activities but none of these tools interoperate. Without study-wide views, CROs must conduct tedious manual reviews and verifications of site status. This slows site initiation. New integrated technologies, however, are crossing that chasm.

STREAMLINING CLINICAL PROCESSESCROs also report that the move to an eTMF application addresses their need for improved efficiency. For example, advanced eTMF applications with robust reporting tools allow study team mem-bers to aggregate data, create ad-hoc reports, and customize data visualizations. This enables the discovery of meaningful patterns in the data and provides real-time data sets that help manage-ment teams make fast and reliable decisions. Risk can be con-tinuously tracked and mitigation strategies can be adapted much earlier in the decision cycle. With the availability of real-time data, the project management team can also focus on other issues and bottlenecks affecting the clinical study. Automatic alerts help de-cision makers intervene immediately or before a major setback has occurred, instead of after the fact, when it’s too late.

MEASURE TWICE, CUT ONCE When Veeva survey participants were asked to choose which were the most useful metrics to shorten trial time from a list of eight, more than two-thirds of CROs asserted that access to in-formation about the cycle time from site selection to institutional review board (IRB) approval (70%), and the time to collect essen-tial site documents (68%) are the most important metrics.

Over the long term, the broad array of quality, perfor-mance, and operational metrics from multiple sites collected in an eTMF can enable well-informed business decisions that allow CROs to meet sponsors’ needs and thrive in a competi-tive marketplace. Currently, only 16% of CRO respondents say

they ‘extensively’ use TMF metrics to improve trial processes and 40% use the data ‘sometimes’—which is largely in line with sponsors as well. As increasing numbers of organizations adopt more sophisticated eTMF applications, the use of met-rics by CROs to improve study processes is expected to rise. According to the full Veeva 2015 Paperless TMF Survey: An-nual Report, organizations with eTMFs are twice as likely to broadly leverage metrics versus those just using local or cloud file systems.

The use of metrics by CROs has even greater impact on clini-cal trial progress as CROs can leverage eTMF applications to capture performance data from multiple studies across different therapeutic areas and geographies over time. Learning from such broad data analysis can lead to breakthroughs in overall trial pro-cess improvement for long-term efficiency gains and faster time to market.

OPENING NEW WINDOWS TO SPONSORSVisibility into the status of clinical trials is another crucial benefit delivered by cloud-based eTMF applications and that are par-ticularly important to CROs who seek to establish a more open partnership with sponsors.

“CROs have to be agile in their ability to adapt to client and industry needs and the systems they use must match this re-quirement,” said inVentiv’s Bolduc. “Modern eTMF solutions are continually evolving and advances in this space are providing more flexible and effective options. Advancing technology in the eTMF space allows CROs to provide clients and regulators with the access and transparency they are expecting; this reduc-es hurdles on the path to market which is a win for all involved.”

The benefits of eTMF applications are, indeed, becoming well documented. When all parties—internal and external—have access to an eTMF application that contains a single version of each document, much of the time-consuming manual exchange of documents is eliminated and a complete electronic audit trail is established for improved compliance and inspection-readiness at all times. Plus, CROs can see which study sites need the most attention and sponsors gain real-time visibility into the status of the trial. All told, eTMF technology advantages empower CROs to differentiate their organizations and secure long-lasting part-nerships with trial sponsors—the ultimate goal.

Successful CROs have grown from specialized executors of clinical trial strategies dictated by sponsors to global organiza-tions, staffed with experts capable of managing an entire trial with only high-level guidance from sponsors. In fact, nearly 40% of all clinical trial operations are managed completely by CROs. As a group, today’s CROs may have the power to influence the entire industry on various issues, as landmark studies like Veeva’s annual TMF survey suggests. Are CROs driving industry-wide adoption of eTMF applications, for example? Only time—though, not too much time—will tell. CP

MIKE BURTON is responsible for Veeva’s CRO partnership pro-gram for Vault eTMF. He has 15 years of clinical trial operations experience and has been implementing eClinical technologies since 2000. He can be reached at mike.burton@veeva.com.