Jennifer Goldsmith

We live in an electronic world today. We shop online rather than at the mall. We deposit checks via mobile device instead of a drive-up window. We talk through video-chat instead of sending letters. As consumers, we have largely adjusted to these changes and reaped the rewards—increasing our efficiency, becoming more productive, maintaining closer relationships with distant relatives. As professionals, however, we haven’t all adapted as smoothly. Nowhere is this truer than in life sciences, especially in the clinical development setting, where most organizations are already working in an electronic world but still thinking in “paper.” Often, the workflow follows paper principles but gets shared and captured in electronic format, resulting in redundancies and inefficiencies. 

Clinical trial sponsors have much to gain from going electronic—from cost reductions and improvements in trial efficiency, to increased compliance and reduced cycle times.

 With the costs of conducting clinical trials reportedly increasing 60 percent compared to just five years ago

, many life sciences companies are re-engineering clinical study processes to take advantage of the electronic world in their determination to improve the quality and efficiency of their trials. 

One of the major cost drivers is the mismanagement of trial documentation. According to a recent report by McKinsey & Company, “a 12-month delay in product approval due to improper management of clinical trial documents can increase development costs by tens of millions of dollars and drive significant lost revenue on the order of $1-2B dollars for a blockbuster product.”

Without a doubt, life sciences companies deal with a huge regulatory and operational burden to maintain the trial master file (TMF), and in many cases, the move to an electronic TMF failed to deliver the desired results. This article assembles the latest research and expert advice on how to transition successfully when adopting an eTMF. 

Many life sciences companies are stuck between paper and electronic.

 In fact, 48% of sponsors rely upon hybrid systems that combine paper-based and electronic processes, according to the lastest TMF Reference Model survey.

 Such hybrids often store some electronic documents, but are fundamentally static systems or fileshares for housing TMF documents. 

“These ‘pseudo-eTMFs’ may contain an electronic element, but they aren’t effective in the long term because, fundamentally, they are built around a paper framework. Even if the documents are stored electronically, they are exchanged using paper or email,” said Susan Nakayama, a pharmaceutical trials management consultant presenting at a recent eTMF Roundtable event.    

Donna Dorozinsky, president of DWD & Associates, a clinical research consulting and training firm that supports pharmaceutical leaders such as Abbott Laboratories, Bristol-Myers Squibb, Clinilabs, and Parexel International, added, “Companies are already living and working in an electronic world but they haven’t had time to fully transition to paperless processes, so they have created band-aids. Many already have an electronic Clinical Trial Master system (eCTMS), for example, but still use a paper TMF. Or, some leverage document management systems that are not Part 11-compliant or validated.” 

An eTMF application can elevate business processes and lead to better clinical trial execution. In fact, according to a 2013 survey of life sciences companies titled “The State of Trial Master Files,” respondents cite increased productivity, reduced time to prepare for study milestones and improved audit results most often as the key benefits of adopting an eTMF.

 Understanding the potential benefits is important to setting the correct expecations for changes to processes and systems. For example, establishing a clear organizing structure by using the DIA TMF Reference Model helps users know where to place TMF documents, and an eTMF’s innate rich metadata and search capabilities also helps users address one of their most important concerns: the need to locate documents quickly.

“One of the most common responses that we get from clients who are now fully transitioned to an eTMF is ‘we can find things now and what we find is complete and inspection ready,’” said Dorozinsky. “In the past, clients filed a compound but still had an incomplete TMF for their pivotal studies, resulting in significant challenges during regulatory inspections. With an eTMF, documents are readily available, quality-checked, and all in one place so gaps can be easily identified and quickly corrected. It’s a huge timesaver and can provide a competitive advantage when racing to get a new therapy to market.”

Making the most of an eTMF requires technology and processes that bring people to the documents instead of documents to the people—this is a fundamental difference from how things are typically handled today. According to a recent survey of 250 TMF business owners, the two most common ways to exchange TMF documents between a sponsor and a contract research organization (CRO) are email and physically shipping paper. The reported use of email at 68% was greater than the use of structured mechanisms like content management systems (29%) and eTMF applications (15%) combined.

 Both email and scanned paper represent chaotic and error-prone methods of exchange.     

When moving to an eTMF application, both quality and efficiency can potentially be improved by using system workflows to orchestrate document authoring, collaboration, and collection processes. Spending the time upfront to specify the appropriate access and roles for trial members within each study, allows the eTMF to function as a hub for distributing and collecting documents. Structuring the document exchange within the application removes the cost of shipping paper and the complexity of emailing individual files.  

When designing an eTMF, the following three areas help lay the foundation for success:

Alignment around the TMF Reference Model: 

The adoption of any application will be more successful if everyone using the system shares common terminology.

 The DIA TMF Reference Model taxonomy outlines the clear definition and organization of TMF content using standard nomenclature. This common vocabulary allows people from different organizations to communicate freely and without the burden of translation. The zones, classifications, and metadata form a shared language that all participants—CROs, sponsors, and sites—can use to work with one another. “With the DIA TMF Reference Model, companies adopt a standardized approach with granular specifications down to the document metadata for all studies globally. Standardizing reduces error that comes with variation and the additional training needed for internal and CRO staff when using custom taxonomies,” said Tamika Jackson, president of the consultancy Corementum.

Direct eTMF access for all study stakeholders: 

Cloud-based eTMF systems provide a secure and globally accessible location for all clinical partners (sponsors, CROs, sites, regulators, and ethical committees) to access, contribute, and collaborate on trial content. Without direct access through the cloud, organizations are forced to manually reconcile documents from contributing parties—a process that introduces delay and human error. By having one single source of truth, sponsors gain reliable visibility into the trial process and improved inspection readiness. 
    
  “We were looking to move from our hybrid system to a single, digital solution for TMF management to improve quality, efficiency, and control while allowing our colleagues and clients to access our data through the cloud,” said Linda Danielson, chief operating officer for IDDI, a global CRO that recently transitioned to an eTMF solution.
  
  

Visibility and performance with reporting and dashboards: 

In addition to providing easier access and greater visibility, eTMF systems increase the control sponsors have over many aspects of trial operations. Real-time status reports highlight gaps and issues as they occur, improving organizations’ ability to get issues resolved, and decreasing the amount of effort and time required for inspection preparations. Quality metrics generated from the eTMF can help organizations prepare for audits and inspections, and contribute to a broader risk-based monitoring (RBM) strategy. 

Advanced Clinical, a global clinical outsourcing organization, recently transitioned to a cloud-based eTMF for use of all of its customers worldwide. Julie Ross, executive vice president at Advanced Clinical, said, “We can speed document collection from start-up through trial close, and our clients get the visibility they need throughout the entire study.” 

Fully transitioning from paper to electronic gives life sciences companies the opportunity to re-imagine the way they operate and then make changes to increase efficiency and improve collaboration with CRO partners, affiliates, and investigator sites. In a white paper published by eTMF consultancy Phlexglobal, researchers note, “The transition from paper to electronic trial master files promises improvements in capability, capacity, and quality.”

 However, making this transition requires diligence. To successfully manage the change from a paper-based TMF to an eTMF, it’s crucial to first thoroughly assess the current state of the organization. These questions can help guide the transition: 

First, understand your current state and partner ecosystem:

How are you currently maintaining your TMF? Through your CRO or on-site?

How do you gain or share visibility into the TMF with your partners?

When you receive a TMF back from your CRO at the end of the study, how is it transmitted?

Does it provide sufficient long-term access or facilitate content re-use?

Next, understand how your TMF is being managed throughout the trial:

Do you have SOPs to manage your TMF from creation to inspection?

How does each functional area file its documents? How does the process differ when documents are paper versus electronic?

Do you file documents as you go to maintain an inspection-ready TMF or do you put it off until the end? 

Which studies will be the first to leverage eTMF?

How will active and archived studies be addressed?

What role will the central records team play in managing the eTMF? 

What SOPs need to change to reflect process changes when going electronic?

What is the difference, if any, between your planned structure and the TMF Reference Model? 

What training is needed and who will provide it?

Answers to the above questions will vary by organization; the value lies in the act of discussing and coming to agreement around each answer. Once armed with a comprehensive understanding of both the current and desired state, organizations are ready to begin transforming their processes while piloting an eTMF. Consultants at McKinsey suggest that companies shift to electronic slowly, applying it to just one or two studies initially rather than all studies simultaneously.

 If the eTMF is incorporated into daily operations, its dashboards and reports will enable organizations to monitor study status in real-time. At study close, organizations can compare the operational results of the pilot to historic performance to see the value of their investment and plan for future trials. 

Implementing an eTMF application creates an opportunity to automate and improve processes rather than just streamline outdated paper processes. If electronic documents still get printed, signed, scanned, and manually tracked, the eTMF can be adding steps to the process rather than removing them. “System efficacy is directly impacted by the strength of an organization’s underlying processes,” said Jackson. “In truth, it is as much about how you re-engineer your processes as it is about upgrading your technology. In order to adopt an eTMF successfully, managers must align people and process to leverage the new capabilities.”  

When transitioning to an eTMF, some of the first things to change are the roles and responsibilities for filing documents. Historically, organizations used a central records management function, but as documents are born electronic, they should be placed directly in the eTMF as part of the normal course of work rather than as a separate step. This can introduce a notable change in employee roles/responsibilities. Companies must document and clearly communicate who is responsible for placing every type of document in the eTMF, otherwise they’ll find an incomplete record since few individuals consider it to be their responsibility and most assume someone else is filing the documents.  Additional emphasis must be placed on clearly defining the roles of study partners. Partner on-boarding and training programs should be developed to establish clear expectations around process. And a tech support mechanism should be established to address partners’ questions about the software. 

Configuring roles and responsibilities within the eTMF application is part of building a repeatable framework that helps enforce and standardize the process changes to come. And, in building a repeatable framework, organizations are also defining the content types, workflows, and expected timeframes for completing a given action.

The process changes that are built into system workflows must also be reflected in the SOPs. This provides a good opportunity to examine current bottlenecks and identify where the eTMF—potentially with cloud access for partner—can eliminate or automate steps in your process. Table 1 lists the typical SOPs that should be updated when moving to an eTMF.

For many organizations, the transition from paper to an eTMF is an evolution that spans regions, functions, and skill sets, driving enormous efficiencies and cost savings throughout the organization. To succeed, the process redesign effort must include the following elements: 

Developing a comprehensive understanding of the processes already in place.

Establishing a clear and attainable vision for the future. 

Training staff on the specific requirements and changes for their role.

Defining the methods and metrics for monitoring and managing change. 

Each step creates clarity and helps keep the organization on track. According to Jackson, “Transitioning to fully electronic systems and processes allows us to change the way we think about running clinical trials. Rather than trying to modify what’s already in place and largely maintaining business as usual, eTMFs help companies let go of the paper mindset altogther. You cannot conduct ‘business as usual’ when you are making an intrinsic operational change.”

Kythera Biopharmaceuticals had been using a homegrown hybrid paper/fileshare system that was exceedingly difficult to access by important trial partners such as its CROs, investigators, and other internal staff across clinical and regulatory functions; it was also fraught with too many opportunities for error. The company, which was preparing for rapid growth, decided to transition to an eTMF and selected a cloud-based solution built specifically for the global life sciences industry. Recognizing the challenges in store while making this conversion, Kythera decided to change processes and overhaul many of its SOPs to fully leverage the new system’s capabilities. Although learning the taxonomy took a little time and integrating electronic-driven processes into Kythera’s daily workflows required some upfront work, the company hoped it would also help all involved re-envision the process and embrace the new system. 

“We have had to adjust the way we think—from a paper mindset to electronic. As an organization, Kythera cannot just adopt a sophisticated electronic system yet maintain old paper processes. … We knew it was critical to re-engineer our workflows, our processes, our team,” said Renee Fate, senior manager, document management, for Kythera. “The biggest issue when it comes to transitioning to a new type of system is the fear of losing control. But when employees and partners see the increase in efficiency that comes from a more streamlined, repeatable process, then they are more likely to adopt the system and accept a new ‘digital’ business environment.”

Although the adoption rate of electronic trial master file systems is rising,

 the promised efficiencies are just starting to be fully realized. Life sciences companies that recognize that implementing an eTMF is not as simple as installing a new technology but really a fundamental change in the way they do business will get the most from their new system for years to come.

As the 2013 “State of the TMF” survey suggests, the No. 1 measure of eTMF success is increased productivity.

 By reimagining corresponding processes to leverage eTMF capabilities, an eTMF can contribute to powerful cultural changes around operational efficiency. With the increased transparency, trial teams take a higher degree of ownership in ensuring the quality and timeliness of study documentation. 

Most importantly, the eTMF delivers value to organizations that paper simply cannot—a TMF that is inspection-ready at all times, a focal point for sponsor-CRO collaboration, and visibility into operational performance that spans the clinical organization and its partners.   

Jennifer Goldsmith is vice president of Vault at Veeva Systems, email: 

State of Trial Master Files (TMF) Survey Results

, by NextDocs Corporation. Jan 2014.  More details available [http://info.nextdocs.com/StateofTMF_DIARegistrationPage.html]   

Clinical Development and Trial Operations (PH192)

, by Cutting Edge Information. November 2013.  More details available [http://www.cuttingedgeinfo.com/research/clinical-development/trial-operations/].

Trial Master File Management: Emerging Trends and Best Practices

, by Jerel Davis, Edd Flemming, Gary Mao, Lawrence Wal and Rachel Zhang.  2012. More details available [http://solutions.mckinsey.com/clinicaltrialimpact]  

Managing Regulatory Information as a Corporate Asset Industry, Health Authority, and Vendor Trends

, by Steve Gens and Greg Brolund. Fall 2013.  More details available [http://gens-associates.com/Knowledge_to_Share/]   

, by NextDocs Corporation. Jan 2014.  More details available [http://info.nextdocs.com/StateofTMF_DIARegistrationPage.html] 

DIA TMF Reference Model 2012:  Results of 2012 TMF Survey #2

, by DIA Document and Records Management SIAC. November 2012.  

Transforming Costly Paper Processes into Value Driven Compliance

, By Karen Redding. 2013. More details available [http://www.phlexglobal.com/wp-content/uploads/Phlexglobal-PhlexEview-White-Paper_Final.pdf] 

, by Jerel Davis, Edd Flemming, Gary Mao, Lawrence Wal and Rachel Zhang.  2012. More details available [http://solutions.mckinsey.com/clinicaltrialimpact]

. Survey conducted by Fierce Biotech, concluding March 2014. 

Articles

In the clinical development setting, most organizations are already working in an electronic world but still thinking in "paper."

Jennifer Goldsmith

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Working in an Electronic World - How to Make a Smooth Transition to an eTMF