Embracing the electronic trial master file (eTMF) has become a key strategic move for contract research organizations (CROs) looking to streamline clinical trial operations. How they are using this solution, in its various formats, has been measured in a comprehensive eTMF survey conducted by Veeva Systems, a provider of cloud-based solutions for the life sciences industry. Among the 252 TMF owners who responded to the survey, the largest of its kind to date, Veeva carved out a subset of data profiling 43 contract research organizations (CROs) versus 118 sponsors. The intent was to hone in on similarities and differences between these two pivotal cohorts and to identify how the eTMF presents opportunities for better collaboration. 

CROs are working closer than ever with sponsors, as evidenced by continuing expansion in the $23.6 billion CRO marketplace. Although the industry is facing consolidation, this figure is projected to grow at a 7.9% compound annual growth rate (CAGR) between 2014 and 2018 as the rate of outsourcing continues to rise.

It is not surprising that both CRO and sponsor survey respondents were generally aligned, yet there were some notable differences, likely rooted in their innate functions. For starters, there was minimal difference in the types of eTMFs CROs and sponsors utilize, and both groups reported modest barriers to their organizations adopting paperless TMFs. Also, both claimed that similar departments were still clinging to paper, for example almost 50% of clinical operations documents continue to be managed on paper (CROs: 47% vs. sponsors: 41%). Yet, in terms of what CROs and sponsors are seeking in an eTMF application, integration with a clinical trial management system was vital for CROs (58%), but much less so for sponsors (43%). And, for exchanging documents with stakeholders, CROs were more likely than sponsors to use older technologies such as non-secure e-mail (80% vs. 64%), and paper shipments (65% vs. 52%).

The survey’s focus on comparing what CROs and sponsors expect from an eTMF, and the driving forces behind their adoption of this technology provides a useful benchmark of this major trend. This article takes a look at an array of factors described in the survey, namely methods used to exchange documents among stakeholders such as investigative sites, regulatory bodies, and institutional review boards or ethics committees (IRBs/ECs). It also describes the types of eTMFs being used, and the business benefits of the eTMF. The purpose of this article is to highlight how CROs value eTMFs as they try to build a competitive edge to distinguish them from the ever-expanding competition in a consolidating marketplace.

Who Participated
The full result summary of Veeva’s online survey of 14 questions was presented in June 2014, with the CRO sub analysis results presented in October 2014. Because respondents were asked if they were among those at their company with primary responsibility for the TMF, the survey generated data from actual users, and not casual observers. In fact, if a potential respondent was not a primary user, his or her responses were discarded, resulting in a defined group of 161 CRO and sponsor respondents. As shown in Chart 1, nearly three-quarters of respondents represented sponsors or CROs.

Key Findings
The survey focused on identifying methods used to exchange documents among stakeholders; the driving force behind eTMF adoption; the types of various eTMFs being used; and, expected benefits of the eTMF. A subset of the research focused specifically on CROs.

Regarding exchange of documents, the survey provides a litany of results, comparing rates of exchange for sponsors and CROs to each other and to other stakeholders, such as sites, regulatory authorities and IRBs/ECs. Chart 2 shows a portion of those results, namely document exchange method rates between CROs and sponsors. Results highlight that CROs are more likely than sponsors to use older methodologies such as e-mail, paper, and fax, yet at the same time, are more likely to use an eTMF application. It is possible that this is because most eTMFs being using by CROs do not allow external collaboration, which is a key requirement to moving to a paperless TMF. The use of cloud file share is roughly the same between the two cohorts, at 33% for CROs and 32% for sponsors.

E-mail remains the key method for document exchange for both CROs and sponsors. While email is electronic, it introduces many of the same challenges as paper shipments – version control issues; tracking and management documents; securing sensitive data outside secured processes. Moreover, e-mailed documents are often printed for review and re-scanned into the system, creating duplicate versions and a hybrid process that is difficult to reconcile during and after a clinical trial. Manual tracking is still required and search is also difficult.

The survey also asked CROs and sponsors to identify the driving forces behind eTMF adoption. Not surprising, anticipated cost savings topped the list for CROs (63% for CROs vs. 51% for sponsors), followed closely by speeding study start-up, which topped the list for sponsors, (59% for CROs vs. 54% for sponsors). Audit and inspection readiness as well as improving central and remote monitoring were also major considerations. And, when questioned about types of TMFs most recently used, answers fell into several categories, such as local file share or cloud file share. The most common response was cloud file share, and in this category, CROs and sponsors responded similarly, 33% and 35% respectively.

Half of CRO respondents with an eTMF classify theirs as a file share, whether a local file storage system (26%) or a cloud file share (21%). File systems offer access to a shared folder structure and online storage, whereas cloud file shares offer additional capabilities, including accessibility for external partners. The next eTMF type in the maturity continuum is the purpose-built eTMF application, which is typically built on a content management platform and provides workflows and configurations specific to TMF documents. Process-driven content management functionality such as search, versioning, workflow as well as tracking and reporting capabilities also tend to be included.

One of the most telling findings of the study was the reported benefits of the eTMF. The fact that CROs and sponsors alike have enough experience with eTMF to recognize benefits indicates the growing use of this methodology. As shown in Chart 3, CROs overall report more benefits than sponsors in all categories questioned.  Some of the largest differences occurred in ‘Increased TMF SOP Compliance’ (41% for CROs vs. 23% for sponsors) and ‘Easier Collaborations with Sites’ (45% for CROs vs. 28% for sponsors). These factors may be more important to CROs as they tend to handle more of the operational aspects of clinical trial conduct.

“We implemented a multitenant cloud-based eTMF to help take our clients through the rigorous trial process efficiently and accurately,” said Rachel Stahler, chief information officer of inVentiv Health Clinical, one of the world’s largest CROs. “An accessible cloud portal also makes it easier to collaborate with site personnel to facilitate study start-up. At every possible point in the process, the system enhances visibility, closes gaps, and increases efficiency. It matches the needs of our clients and the needs of our company.”

There was, however, some degree of similarity between the two groups in response to the question about real-time tracking and viewing of documents. This was the most frequently cited benefit of eTMFs, with CROs naming it 61% of the time as compared to 53% for sponsors. Also, both pegged cost savings as a pivotal benefit (35% for CROs vs. 29% for sponsors).

The eTMF Environment and Challenges
With these benefits becoming a reality, it is understandable that forward thinking CROs are forging ahead with eTMF implementation. Jessica Vicari, director of regulatory startup and document management at Advanced Clinical, a Chicago-based CRO, notes that the eTMF is being adopted to address the specific challenges and needs that sponsors face in each clinical trial. As she explained, “The eTMF is part of a strategy to adopt a flexible model, meaning that we need to be able to scale up or back based on changing priorities and drivers, and make ourselves a true extension of the sponsor. This is the only way to make a long-term relationship work.”  

Vicari comments further that the advent of cloud technology is making flexibility possible, providing for improved collaboration and better visibility for both partners into the clinical trial process as it is unfolding. “In this shared environment, we can track execution in real time. And with cloud technology, we no longer have to waste time mired in the complications of technology integrations or have sponsors install a certain software or having documents getting caught in their quarantine. The technology is now an enabler, not a hindrance,”  Vicari added.

An encouraging regulatory environment supports this effort.  For starters, there is a 2013 Draft Reflection Paper from the European Medicines Agency on GCP-compliant trial master files.  The Draft Reflection Paper dedicates an entire section to the eTMF, and acknowledges the increasing role of CROs in clinical trials. The document comments further that given the sponsor’s responsibility for the trial, the sponsor may need to access the eTMF remotely or have the CRO provide specific documents (Chart 4). In the U.S., the Food and Drug Administration (FDA) has not put forth a TMF or eTMF-specific guidance, but did release a guidance in 2007 entitled Computerized systems used in clinical investigations, which details the qualities that must define electronic clinical trial data, and acceptable system features. And finally, many industry stakeholders have participated in the Trial Master File Reference Model Group, a supported initiative of the Drug Information Association’s Document and Records Management Community. The Reference Model is an opportunity for harmonization across the industry for TMF content, naming and structure, and can be adapted to an eTMF.

This regulatory and industry support for the eTMF is a solid foundation for the rising volume of collaboration between sponsors and CROs. Drug developers, faced with intense pressures to produce more for less, are ramping up R&D budgets and allocating more of those resources to CROs. Other research indicates that the size of CROs across all therapeutics areas and phases has doubled in the past decade, and the largest pharmaceutical players are outsourcing nearly 100% of Phase IIIB and Phase IV studies, as well as laboratory services to CROs. One positive outcome of today’s CRO-sponsor collaboration is the high number of pharmaceuticals and biologics that received FDA approval in 2014, the biggest number since the all-time record of 1996. In total, there were 44 product approvals: 39 pharmaceuticals and 5 biologics. This total was up substantially from 27 approvals in 2013.  

To accommodate and sustain this growth, CROs need to continue their adoption of eTMF technology, specifically those offering ease of use, minimal infrastructure, audit readiness, and data visibility. But, in an industry often slow to implement technologies, making the switch can be slow. Jessica Vicari explained, “Cost to change technology can seem prohibitive, so exploring the anticipated benefits is important to make a compelling justification for your investment.”

inVentiv’s Rachel Stahler added, “For us, this is about more than being cost conscious; it’s about being value-conscious.
eTMFs are definitely the way to go for both CROs and sponsors, but we need to demonstrate the value proposition. Service is our product, so any investment we can make into service to drive better value for the client is well worth it.”

Just Ahead
The eTMF allows CROs to organize the flurry of essential documents that typify global clinical trials, plus exchange and manage them in a highly efficient manner. This is a dramatic improvement from older systems in which sponsors had to print documents, sign and scan them, and then upload them to a shared e-room or email content back to the CRO. But is it enough? Going forward, CROs are facing a world of consolidation, and will need to differentiate themselves to remain competitive. One approach will be through implementing an eTMF application that improves collaboration and audit readiness, and integrates with other systems, such as the clinical trial management system. In this way, the CRO will be able to use the eTMF as a strategic asset that will help sustain the CRO as a valued partner able to speed study start-up and share needed information. For CROs in an ultra-competitive market landscape, this is a bold opportunity. 

Sources

1. Veeva 2014 Paperless TMF survey: An industry benchmark, conducted by Veeva Systems, October 2014. Available at: http://www.veeva.com/tmf-survey-2014/. Accessed January 8, 2015.
2. Veeva 2014 Paperless TMF survey: The state of CRO TMFs conducted by Veeva Systems, October 2014. Available at: http://www.veeva.com/cro-report/. Accessed January 8, 2015.
3. Schafer A. CRO Market Size: Growth in a Flat R&D World. Applied Clinical Trials. February 3, 2014. Available at: http://www.appliedclinicaltrialsonline.com/cro-market-size-growth-flat-rd-world. Accessed January 12, 2015. 
4. Martorelli MA. Pharmaceutical Outsourcing Monitor. Challenges across the CMC landscape. Fairmount Partners. November 3, 2014.
5. Reflection paper on GCP compliance in relation to trial master files (paper and/or electronic) for management, audit and inspection of clinical trials. Draft. European Medicines Agency. February 1, 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/02/WC500138893.pdf. Accessed January 11, 2015.
6. Guidance for Industry: Computerized systems used in clinical investigations. U.S. Department of Health and Human Services. Food and Drug Administration (FDA). May 2007. Available at: http://www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.PDF. Accessed January 11, 2015.
7. Trial Master File Reference Model. Drug Information Association. 2014. Available at: http://www.diahome.org/en-US/News-and-Publications/Publications-and-Research/EDM-Corner.aspx. Accessed January 11, 2015.
8. Brooks K. CRO Outlook & Market Trends. Innovation Tied to globalization & collaboration. Contract Pharma. June 2013. Available at: https://www.ppdi.com/~/media/Files/PPDI%20Files/Expert%20Community/Articles/Contract-Pharma-2013-June-CRO.ashx. Accessed January 12, 2015. 
9. Lewis J. ACRO survey shows strong growth of CRO industry. Association of Clinical Research Organizations. September 16, 2014. Available at: http://www.acrohealth.org/acro-survey-shows-strong-growth-cro-industry/. Accessed January 12, 2015.  
10. Hughes J, Rayer E., Wadd J. Sponsor-CRO Collaboration Study. Vantage Partners. 2013.  Available at: http://www.vantagepartners.com/ResearchAndPublications/ViewPublications.aspx?id=12626. Accessed January 12, 2015.
11. Munos B. 2014 New drug approvals hit 18-year high. Forbes. January 2, 2015. Available at: http://www.forbes.com/sites/bernardmunos/2015/01/02/the-fda-approvals-of-2014/. Accessed January 12, 2015.  
12. Munos B. The FDA Approvals of 2013: A watershed? January 3, 2014. Available at: http://www.forbes.com/sites/bernardmunos/2014/01/03/the-fda-approvals-of-2013-a-watershed/. Accessed January 12, 2015.