The CenterWatch Monthly (ISSN 1556-3367). Volume 23, Issue 12. © 2016 CenterWatch centerwatch.com

Audit support; faster startup and remote oversight top motivatorsBy Lisa Chontos

I n today’s clinical trials industry, trial master files (TMFs) pose a costly, time-consuming challenge. In September, the

U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA) found that 31% of inspections must be extended due to criti-cal and major TMF findings. These findings included study team members being unable to find requested documents, inspectors lacking direct access and the quality of the documentation being called into question. These results are coming two years after the MHRA revised its definition of critical TMF findings upon noting that 35% of inspections required additional days. Each day added to a study, especially in phase III trials, results in significant costs for sponsors and pa-tients. Clinical trials account for almost 70% of all R&D spending, primarily because of inefficient processes required to work with disconnected systems.

A solution to help counter this is electron-ic TMF. Improving alongside technology, eTMF is being increasingly adopted and in-tegrated with other systems, and is becom-ing an essential component of clinical trials in the future, despite certain difficulties that must be surmounted for successful imple-mentation.

Today’s eTMF technology

“The advantage of a cloud eTMF applica-tion is the universal access provided, along with continuous compliance. All TMF doc-

uments, related information and processes are managed in the same system, at the same time they are being executed. An automatic result of an executed clinical process, the TMF is in a constant state of inspection-readiness,” said Jill Johnston, Veeva Systems’ vice president of Vault Clinical. Provided with the study access they seek, regulatory authorities can easily reconstruct the study.

Cloud-based eTMFs allow teams and ex-ternal partners to collaborate efficiently, and are especially useful when archiving. A final benefit is the ability to track key metrics to measure quality and cycle times.

The DIA’s efforts to standardize the eTMF reference model have also transformed to-day’s eTMF. Mark Vermette, principal con-sultant at Halloran Consulting Group, said, “Now in version 3, it’s done a lot to organize documentation between systems and to im-prove interoperability.”

With current eTMF technology, when a monitoring trip report is completed in a clinical trial management system (CTMS), a trip report follow-up letter is generated, sent to the site and forwarded to the eTMF with

the correct metadata applied. Integration of all the systems enables the metadata from the document in the eTMF to trigger the CTMS to automatically send more supplies. The integration also saves auditors time in recreating the trial.

“The most advanced organizations are looking to deploy best-in-class clinical ap-plications on a single, integrated platform to avoid messy and customized integration points that are so common—and debilitat-ing—today,” Johnston said.

Current eTMF use and adoption

In the Veeva 2016 Paperless TMF Sur-vey, results showed that eTMF adoption has nearly doubled since 2014, with 24% of spon-sors now using it. Sponsors using local file systems for eTMF is down from 26% in 2014 to 8%. According to Veeva, paper is now used in only 28% of most or all TMF docu-ments, compared to 41% in 2014.

In step with this, trial partners are in-creasingly relying on centralized systems to communicate and work together. Like-

eTMF adoption and integration acceleratingDecember 2016 A CenterWatch Feature Article Reprint Volume 23, Issue 12

Adoption of electronic TMF document capture by activity typeTo what extent is your organization doing the following electronically with TMF documents?

Percent of organizations

Source: Veeva Systems 2016; n=137 sponsors and 49 CROs

51%

39%

Sponsors CROs

46%40%

34%

59%

41%

28%

Document signatures

Creation of source documets

Collaboration documents with external partners

Archival of documents

wise, following the MHRA’s regulation for TMF accessibility, 80% of sponsors using an eTMF application will provide remote access to inspectors and auditors in the next year.

In the survey, 98% of respondents with an eTMF application reported major improve-ment in one area or more, including miss-ing, duplicate or incomplete documents.

Data gathered via the Veeva TMF Maturity Model, based on information from 156 orga-nizations, showed that the industry maturity average is 2.6 on a scale of one to five, with five being a fully mature TMF operating model. The area that requires the greatest improve-ment was the monitoring of performance metrics and key performance indicators (1.8 on a scale of one to five). Very few organiza-tions reported using clinical project manage-ment tools (2.1 on a scale of one to five).

Furthermore, eTMF adoption has been much slower in the EU versus the U.S. John-ston said, “This is quite typical with any technology, not just with eTMFs. There is often a two or three-year lag time.”

Keys to successful implementation

At Rho, the TMF Reference Model (TMF-RM) was recently implemented, as well as an eTMF system. “Subject Matter Experts (SMEs) from each functional area contribut-ed to the new business process development and system implementation. This collabora-tion was critical to the success and devel-

opment of a robust process,” said Kristin Snipes, project director at Rho.

Adoption of the TMF-RM and review of the artifacts prompted a review of procedur-al documents and documentation practices at Rho, focusing on the content generated in study execution, signature requirements and procedural documents in conjunction with the TMF-RM requirements. This resulted in a streamlining of processes, signature re-quirements and increased efficiencies. The SMEs also acted as change leads and early adopters of the eTMF system, discussing concerns with their functional areas and helping reduce resistance to the new TMF business process and eTMF system.

For Jamie Toth, head of TMF Operations at Daiichi Sankyo, the change management aspect must be fully planned. “eTMF adop-tion takes a village. Identifying key stake-holders in the business across many func-tions takes time, and then engaging them during the lifecycle of the implementation phase is important. Keeping them engaged during pre-launch and after is a must as these folks will become the voice of the sys-tem in the future and help keep their func-tional groups informed and excited about the new system and its capabilities.”

Relying on consultants with specialized expertise can also help companies imple-ment eTMF more smoothly. Halloran’s Ver-mette said, “We’ve helped smaller clients get up and running—it becomes a pressure

2 The CenterWatch Monthly | December 2016 centerwatch.com

IndustryNewsCenterWatch Publications and ServicesClinical Trials Data Library A valuable online resource providing access to comprehensive charts and tables on the life sciences and clinical research industry.

CWWeekly A digital newsletter that reports on breaking news in the clinical trials industry distributed every Monday morning. Annual subscriptions are $249.

CenterWatch News OnlineA free, virtual newsletter that covers news, developments, drug and professional updates of the clinical research enterprise as it unfolds.

Research PractitionerA bimonthly publication providing educational articles and practical insights and tools for study conduct professionals. Subscribers can earn up to 18 ANCC contact hours each year. Annual subscriptions start at $143.

JobWatchA Web-based service featuring clinical research jobs, career resources and a searchable résumé database.

Drugs in Clinical Trials DatabaseA searchable database of 4,800+ detailed profiles of new drugs in development. Custom drug intelligence reports covering a variety of medical conditions can be prepared.

Clinical Trials Listing Service™An international listing service of actively enrolling clinical trials to support sponsors, CROs and sites in their patient enrollment initiatives.

Market Research Analytics ServicesData-driven and analytic market research services offered to assist orga-nizations in gaining competitive insights into market trends and their business.

Training Guides/SOPs/Reports l Benchmark Data Reports lCompilation Reportsl Protecting Study Volunteers in

Research, 4th Ed.l The CRA’s Guide to Monitoring

Clinical Research, 4th Ed.l The CRC’s Guide to Coordinating

Clinical Research, 3rd Ed.l The PI’s Guide to Conducting

Clinical Research l SOPs for Clinical Research Sitesl SOPs for Sponsors/ Medical Devices

ContactSales: (617) 948-5100, or sales@centerwatch.com

Top three eTMF adoption drivers for sponsor companiesFactors most motivating organization adoption

Percent of total

Source: Veeva Systems 2016; n=137 pharmaceutical and biotechnology companies

53%48%

67%

Remote/central oversight of TMF

Faster study startup

Improved audit and inspection readiness

cooker as the volume of paper gets bigger. The software out there now helps this pro-cess more than ever. Cloud-based is best; on premise is unwieldy. We have a dozen suc-cess stories—we’ve helped companies get up and running in six to eight weeks. The key is to stick to the script—you can’t be special.”

eTMF providers can help companies iden-tify their needs and implement the processes required. Bruce Pfannenstiel, senior direc-tor of Information Governance and Compli-ance at PPD, said, “Anyone considering the move to an electronic filing system should understand that the route to adopting eTMF as your corporate standard typically takes 18 to 24 months due to the complexity of inte-grating processes and systems across func-tional groups. The processes designed by our eTMF business and strategy team allow PPD to support hundreds of projects for a variety of clients. The ongoing collaboration we of-fer our clients helps them define their own eTMF needs and assists in the creation of their eTMF processes.”

Challenges posed by eTMF

When preparing to implement eTMF, one of the first challenges is recognizing the amount of work entailed. Laurie Hal-loran, CEO of Halloran Consulting Group, said, “Some sponsors are unprepared for the amount of change they need to do to make sure it’s integrated. It’s not Facebook.”

Vermette elaborated, “Sponsors can un-derestimate the care needed to ensure qual-ity. Someone still has to make sure the sig-nature and all the pages are there. It might only take one minute per document, but it still must be done. Without having them in-house, they have to deal with this. They can’t just ignore it. Small studies may only have 10 sites, with six patients per site, but it would still require 10 minutes per document, which is six documents per hour, and 1,200 docu-ments coming in—that’s not part-time.”

Halloran said, “The little details are im-portant, especially document naming, when

you’re finalizing everything. People don’t understand what it’s like to retrieve 10 boxes of paper for a study done last year.” To make it more manageable, companies may set up eTMF for current studies first.

Snipes echoed this. She said, “Infrastruc-ture and training are key to a successful eTMF implementation. The software alone will not ensure success and quality. A robust business process is critical and the software is the tool that ensures compliance to the process and quality of the TMF. We like to say the software is the ‘carrot’ or the ‘widget’ we are providing to our teams to facilitate the new business process. We hope this ‘car-rot’ will increase adoption and compliance with the new business process.”

Pfannenstiel also underscores the impor-tance of processes, along with interoperabili-ty. “Internally, one challenge is the alignment of multiple functional departments,” he said. “As a large global CRO, we need to use a va-riety of systems to deliver our clients’ data securely. Establishing higher-level processes to unite these systems often requires intense collaboration and creativity. From the cli-ent’s perspective, another challenge is the interoperability between CRO and client sys-tems. This is still being explored within the industry, and PPD participates in DIA work-groups that are defining those standards.”

Another basic challenge is the execution, perpetually limited by time. Vermette said, “It’s a fast-moving landscape, and collabora-

tion with sites is still a problem. Sites don’t have time to carefully categorize and upload documents the way sponsors want. The mod-el we’ve put in place suits the reality of giving sites easy access, so they can do their best in uploading and have someone take it from there. It puts more burden on the sponsor.”

Technology evolving and integrating with IT systems

Several years ago, companies sought inte-gration and a scanning solution to improve the paper process, but technology was not yet able to support it. “Back then, the mar-ketplace for eTMF systems was much small-er and the systems needed to be hosted on premise,” said Daiichi Sankyo’s Toth. “Fast forward six years and systems are in the cloud alleviating companies from having to maintain servers and hardware.”

Integration is also becoming a reality. As capturing information in multiple systems can lead to ambiguity and inconsistencies, many companies are looking to reduce that redundancy. Snipes observed, “TMF tech-nology is evolving to integrate and leverage data with other systems used in clinical tri-als, such as EDC and CTMS. Business data is useful but only when collected consistently.”

Electronic signature is also becoming more common, while still facing some legal resistance. Vermette said, “Protocol docu-ments will be in paper form for 30 more

IndustryNews

3 The CenterWatch Monthly | December 2016 centerwatch.com

Top three eTMF adoption drivers for CROsFactors most motivating organization adoption

Percent of total

Source: Veeva Systems 2016; n=49 CROs

57% 55%65%

Cost savingsBetter visibility into performance metrics

Improved audit and inspection readiness

years. Technology has outpaced acceptance and adoption. Some eTMF applications let you index automatically, but many are skep-tical. I’d like to see eTMF completely data-driven. It could exist as data and be put up on a screen as if they were documents. The technology is there, but people are still tac-tile.”

Pfannenstiel sees not only the logic, but also the possibility of an eventual trans-formation into data. “All forms of technol-ogy are moving fast and eTMF technology is no different,” he said. “As our industry progresses, it has become more evident that traditional information technology and information security teams need to play a more active role in addressing eTMF devel-opment, processes and the maintenance of eTMF data. The integration of direct site ac-cess to eTMF seems a logical next step with-in the industry, along with evolving toward totally electronic project data.”

eTMF is only one part

Many in the industry see eTMF as part of a suite of tools. Vermette said, “Clients know they can’t afford to pick an eTMF that doesn’t help them with SOPs, etc. They have to think about them as an ecosystem, because the processes are intertwined. We

see a lot of people skipping around between systems. Certain processes won’t change because they work and are quite efficient. Inefficiencies come in when people try to use technology, but use it incorrectly. While eTMF is integrating with EDC and CTMS, it varies between vendors and by implementa-tion.”

Daiichi Sankyo’s Toth said, “eTMF will need to be fully integrated with other sys-tems like CTMS, startup apps such as GoBalto or others, Safety database and EDC to support the clinical trial lifecycle from end to end and minimize the manual efforts of data integration.”

Johnston said that Veeva Systems al-ready offers a suite of clinical applications with eTMF as a critical component: Veeva’s Vault Clinical Suite includes applications for clinical operations (CTMS, eTMF and Study Startup) and now data management (EDC and eSource).

“Clinical teams need to access both op-erational and subject-level data to run their clinical studies from start to finish,” John-ston said. “Within clinical trial operations, customizations of legacy systems and manu-al work-arounds that are often the hallmark of eClinical portfolios hamper development and innovation. Processes move across ap-plications and, while an API can allow dif-ferent applications to talk to each other, it’s only when they are all natively built on one platform that you can achieve the efficien-cies sponsors are looking to gain from their clinical technology investments.”

Many organizations are also seeking the best way to access patient data from elec-tronic health records (EHR), as connecting clinical operations to EHRs has become in-creasingly popular in the past few years.

“A link to EHRs would be a logical exten-sion of these systems,” Johnston observed. “Important data from EHRs—both medi-cal records and claims data—could benefit a clinical study. Fortunately, the wall between content and data is starting to disappear as

IndustryNews

4 The CenterWatch Monthly | December 2016 centerwatch.com

Benefits attributed to an eTMF

Percent of total agree Pharmaceutical companies (n=137)

CROs (n=49)

Easier to search and find documents 69% 74%

Improved audit and inspection readiness 50% 56%

Improved central/remote auditing 37% 56%

Automated tracking and reporting of documents

34% 56%

Better visibility into performance metrics 35% 44%

Easier external collaborations 48% 37%

Cost savings 32% 35%

Source: Veeva Systems 2016

Investigative site ratings of select technology solutions

How well do these technology solutions meet your operating needs? (percent select

‘very well’)

How easy are these technology solutions to use? (percent select

‘very easy’)

How reliable are these technology

solutions? (percent select ‘very

reliable’)

EDC 21% 23% 33%

eCRF 17% 18% 29%

IVRS 28% 35% 39%

AE reporting 13% 10% 28%

CTMS 7% 9% 19%

ePRO 8% 11% 15%

eTMF 8% 8% 15%

Source: CenterWatch-ACRP, 2016; n=252 global investigative sites

IndustryNews

new technology provides a meaningful way to aggregate and analyze all of these sources. Done right, this will uncover important, new insights and shave valuable time off the development cycle.”

eTMF in the next 5 to 10 years

The eTMF industry is broad and its many stakeholders have opinions on the pos-sible direction it may take in the next few years. Industry Standard Research recently reported that within the next three years, more than 50% of sites are expected to take advantage of eTMF. Rho’s Snipes anticipates increased system integration as external us-ers and partners become more efficient in taking advantage of eTMF systems. Toth predicted, “Scanning paper will hopefully become a thing of the past, with electronic signatures used for document approvals rather than wet ink, and paper slowly fad-ing away.”

PPD’s Pfannenstiel expects several trends to surface in the next five to 10 years. “First, there will be an emerging leader in the com-

mercial eTMF platform arena. Second, in-teroperability standards will be identified for the first time in our industry. And third, I expect that most eTMFs will evolve from traditional archives to be utilized as metric-generating operating systems.”

eTMF solution adoption could be on the verge of a tipping point, according to Veeva’s Johnston. She predicts that advanced eTMF applications will soon be part of all eClinical technology portfolios. “It’s reminiscent of the EDC adoption curve from a decade ago,” she said. “Like EDC, the benefits are too hard to ignore and the arguments against are similarly unconvincing. Ten years ago, many in clinical operations worried [about whether] a regulator would accept an elec-tronic case report form or if their sites would adopt and use an EDC system. It was unten-able to think that investigators would con-tinue to complete paper CRFs and manu-ally enter the data into another system or that inspectors would not accept data from a validated system. Furthermore, regula-tory agencies today are very clear on their expectations, driving life sciences compa-

nies to rapidly adopt easily accessible eTMF systems. We are only starting to open eTMF environments to investigator sites, so we’ll see adoption rapidly increase over the next five to 10 years.”

However, Halloran Consulting Group’s Vermette feels that before eTMF can move forward, process problems must be ap-proached. “We’ve been paving a cow-path—applying technology to old processes. For us to advance eTMF in five years, we need a discussion about process. These are health-care providers and what we’re asking is an imposition on their conversation with their customers, by asking them to do extra work. We need to stop asking for double data en-try. If their interface of choice is EHR, we need to do whatever it takes to extract that. You have to look at it from the patient/physi-cian perspective.”

Lisa Chontos is a freelance medical writer with 15 years of experience writing for hospi-tals, biotech firms, pharmaceuticals compa-nies and publications like CenterWatch. You can contact her at lisa@lisachontos.com.

5 The CenterWatch Monthly | December 2016 centerwatch.com