The life sciences industry is facing tremendous pressure to contain costs while at the same time facing increasingly difficult regulatory requirements – all of which have increased the cost and complexity of clinical research. This is leading to the Contract Research Organization industry’s growth, as companies choose to outsource expensive and complex research activities. It is estimated that the global CRO market is poised to grow 14% per year during the next three years. That would make contract research a $35 billion industry by 2013.1The purpose of this article is to provide an overview of the Trial Master File Reference Model (TMF RM) and a discussion of how the implementation of the TMF RM could provide a competitive advantage for CROs.

Overview of the Trial Master File

There are many activities across the clinical development cycle that are non-negotiable; one is the creation, collection, management and storage of the documents that are contained in the Trial Master File (TMF). The TMF contains those essential documents that individually and collectively permit the evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of good clinical practice (GCP) and with all applicable regulatory requirements.2 In short, the TMF is the evidence of GCP compliance and of the trial’s scientific credibility.

All sponsors conducting clinical trials in the pharmaceutical and biotech industry are required to maintain documentation for each clinical trial. However, regulatory guidance, such as ICH E6 section 8, addresses only a sub-set of documents needed to reconstruct the conduct of a clinical trial. Until the release of version 1.0 of the Trial Master File Reference Model (TMF RM) in June of 2010, there was no comprehensive, common industry model or best practice for a TMF.

TMF RM Team

The initiative to create a TMF RM is supported by the Document and Records Management SIAC of the Drug Information Association (DIA), a recognized and highly respected professional association. The TMF RM team consists of more than 159 representatives from 105 biopharmaceutical companies, CROs, consultancies, technical vendors, industry groups, healthcare, academia, non-profit / NGO and regulatory agencies (MHRA and FDA). Moving forward, there are ongoing efforts to recruit additional regulatory members from the EMA, JDA, Health Canada and ICH.

Subsequent to the creation of the TMF RM Team in 2008, communication of the TMF RM effort involved presentations at DIA events, such as the DIA EDM Conferences in Europe and the U.S. After recruiting a critical mass, the inaugural meeting of the team was held in March of 2009, and subsequent meetings have been held every three weeks. By late spring, 2009, the team consisted of 69 members from 51 companies. Early communication efforts were facilitated by word-of-mouth and continued communication efforts through DIA venues. In September of 2009 the TMF RM was distributed to the team members – which had continued to grow – along with a request to circulate the RM for input and comment to their colleagues and associates. The TMF RM was sent to an additional 115 people from an additional 39 companies for review. In total, reviews were received from 114 people.

Goals

A primary goal of the TMF RM initiative is to provide a single, unified interpretation of the regulations in the form of a list of TMF artifacts that would be accepted by all clinical trial stakeholders and which can be adopted or adapted by any company, CRO, institution or other organization. The TMF RM is intended to provide a collaborative advantage to stakeholders in creating and managing their TMFs and will provide them with a mechanism to refine the TMF RM based on input and consensus from peers. Use of the TMF RM may significantly ease the administrative burden in industry partnerships, collaboration between sponsors and CROs or acquisitions.

Organization of the TMF RM

The TMF RM consists of standardized taxonomy and metadata and outlines the clear definition and organization of TMF content using consistent nomenclature. It is emphasized that this model is a reference and should not be considered mandatory, but rather as an opportunity for harmonization and alignment across the industry. The TMF RM can be adapted to an electronic or paper-based TMF and by design does not endorse, nor require, any specific technology for application. The document types defined in the model are called artifacts.

Artifacts are labeled as either “Core,” meaning they must be in the TMF as dictated by either the regulations or common practice in GCP, or “Recommended,” meaning they do not have to be produced but if created or collected, they are recommended to be in the TMF. Since the industry often uses unique names, alternate names and descriptions are supplied for each artifact.

Zones

The TMF RM is grouped into zones based on the type and source of documents. Artifacts are grouped together under the following Zones:

1.Trial Management

2.Central Trial Documents

3.Regulatory

4.IRB/IEC and Other Approvals

5.Site Management

6.Trial Supplies

7.Safety Reporting

8.Laboratories

9.Third Parties

10.Data Management

11.Statistics

Challenges

Communication and Member Recruitment: When the team was created in 2008, early communication efforts were facilitated by word-of-mouth and communication through DIA venues. The growth and success of the TMF RM team is due to the dedication and tenacity of the TMF RM co-chairs, Lisa Mulcahy and Karen Redding. In addition, there is a core group that has worked tirelessly to ensure that the artifacts in each zone represented input from all appropriate stakeholders.

Membership grew from a small core group in 2008 to 69 members from 51 companies by late spring, 2009 to 159 members from 105 companies today, and the team continues to grow as new members are recruited.

Management of Team Activities: As previously mentioned, the success of this effort is due to the dedication of the TMF RM co-chairs. After the team was created, the co-chairs established on-going meetings that have been held every three weeks since the team started in 2008. In addition, the co-chairs were responsible for the creation of all Zone teams and the on-going establishment of sub-teams as necessary. The ongoing management of the TMF RM activities has been and will continue to be a challenge that has been met through the involvement and dedication of the TMF RM team members. Now that version 1.1 of the TMF RM has been issued, the TMF RM team has launched additional subteams to explore Investigator Site Files and to establish a framework for the potential destruction of paper files that have been scanned into an eTMF.

TMF RM as a Standard: The team has emphasized that the TMF RM is a reference and should not be considered mandatory, but rather as an opportunity for harmonization and alignment across the industry. The team has also emphasized in all communications and publications that the TMF RM can be adapted to an electronic or paper-based TMF and by design does not endorse, nor require, any specific technology or application.

Utilization of TMF RM by CROs

Although in its early stages, adoption of the TMF RM has been encouraging. Many organizations, both sponsors and CROs, have adopted and/or adapted the TMF RM for the purpose of standardizing the collection, storage and management of TMF documents. Below is testimony that provides insight on how the TMF RM is being leveraged by CROs as part of their solution:

As biopharmaceutical companies accelerate their adoption of electronic trial master files, the DIA TMF Reference Model has become a valuable tool to help companies organize and structure their eTMF using an industry-vetted blueprint instead of relying on institutional knowledge, past experience and opinion. NextDocs recognizes the direct time and cost savings the DIA TMF Reference Model has on the implementation of electronic trial master files and, as a company committed to the proliferation of industry best practices, we have included it in our standard Microsoft SharePoint-based eTMF solution.

– Chet Shemanski, NextDocs Corp.

As clinical cost constraints and increased regulatory scrutiny continue to accompany clinical trial submissions, the creation of the TMF Reference Model is both timely and of strategic importance. CROs that engage multiple clients will benefit from the efficiency and consistency of the suggested taxonomy. PharmaVigilant supports the efforts of the DIA/SIAC team responsible for the TMF Reference Model, given our commitment to innovations that streamline inefficient processes and bring greater value to both sponsors and CROs.

– Robert Maio, PharmaVigilant

Phlexglobal has been utilizing the TMF Reference Model with many of its Clients since the release of version 1.0 in June 2010. As part of TMF structure design, workshops were held to assess each of the zones and the contents thereof. The workshops have been functional (assessing all zones applicable to that function) or zone-based (assessing all artifacts in the zone). Both approaches stimulate significant debate around not just the actual artifacts, but the clinical trial methodology as well. The focus of the workshops was to assess each artifact for relevance and naming convention. Missing artifacts, often driven by standard operation procedures, were added, while artifacts not relevant to the company were removed.

This exercise also supported the move to an electronic TMF by defining the dating conventions for the artifacts, restricted access artifacts and finally the metadata required per artifact. Phlexglobal has also incorporated the TMF Reference Model as the standard TMF structure within its eTMF system.

– Karen Redding, Phlexglobal

The TMF has long been something that companies have struggled to standardize. It is an issue with staff training, especially moving between companies, and can be a major issue in company mergers, divestitures and outsourcing. The TMF Reference Model is a welcome step forward in creating a model that all sponsors and CROs can use to map their own systems and hence improve standards and quality in record keeping that will also facilitate the audit and inspection process.

– Martin Lillis, Quintiles

Benefits and Future Opportunities

In addition to providing an opportunity for industry alignment, adoption of the TMF RM provides the potential to significantly improve TMF management processes. Defining and standardizing the structure and content of a TMF at study initiation provides a mechanism to monitor the TMF content across the life of the study, which provides a foundation to:

-Clearly define TMF governance, roles and responsibilities

-Implement standard SOP’s and training

-Measure TMF completeness

-Assess performance at a particular site

-Automate the monitoring of the TMF processes

-Identify process bottlenecks and quality issues

-Assess on-going inspection readiness

-Facilitate collaboration between CRO and Sponsor

-Provide a foundation for transition to eTMF

Transition to an eTMF provides significant benefits, especially as the industry moves toward more complex, global clinical trials. Mr. Shemanski of NextDocs remarked, “the benefits of using an eTMF include streamlined processes, increased transparency, simplified tracking and enhanced security. To get the maximum return of an eTMF, including significant cost savings, it has to be considered as a management tool rather than just an electronic document repository.”

The ability to harmonize TMF structures across multiple CROs greatly simplifies the exchange of TMFs and the integration of records in sponsors’ record management environment upon completion of studies. Similarly, implementation of the TMF RM by a CRO could simplify the exchange of trial master file records with multiple sponsors and could be viewed as an advantage in a CRO’s solution.

There are compelling reasons and a clear case for establishing a common model for the organization and management of the trial master file for all clinical trials. The TMF RM not only provides organizations with a starting point for the implementation of a comprehensive TMF structure, but also lays the groundwork for the facilitation of document collection and interchange. Implementation of the TMF RM could provide a CRO with a foundation for standardizing and simplifying their solution, thus enabling them to provide a more advantageous cost proposal to sponsors for the collection and management of TMF documents.

As the TMF RM continues to evolve, there is an opportunity to offset some of the challenges that industry is currently facing. Establishing consensus and working as a group rather than individually will ensure that the TMF RM continues to be enhanced as well as providing significant value to all participants in the R&D process.

References

1 FiercePharma Report: CRO Industry to Grow 14% Annually; April, 2009

2. ICH Guideline for Good Clinical Practice, E 6, Section 8

Maryanne Quinn is president, Integrated Submission Strategies (ISS). She has more than 25 years of experience in the life sciences industry and can be reached at [email protected].

Ivan P. Walrath is a Process Owner at Pfizer, Inc. He is currently managing a TMF initiative to redesign Pfizer’s trial master file process to design and implement a long-term, sustainable

solution. He can be reached at [email protected].