Many sponsors outsource a majority of their clinical trial activities to one or more contract research organizations (CROs). This strategy enables companies to leverage specialized expertise and take advantage of flexible resourcing, while minimizing the costs of recruiting experts, building a team and maintaining the necessary infrastructure.
However, it also adds complexity to the CRO's Standard Operating Procedures (SOPs) to meet its compliance obligations regarding clinical trial documentation.
goBalto's central platform offers significant cost savings, reduces GCP compliance risk and strengthens real-time collaboration across global study teams.
The Trial Master File (TMF) Defined
One of the most important aspects of the clinical trial documentation package is the Trial Master File (TMF). The TMF is a collection of the critical documents sponsors use to record how they have fulfilled the obligations for a conducting a clinical trial. The Code of Federal Regulations states in 21 CFR 312.50 that, "Sponsors are responsible for...ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND". The European Directive 2005/28/EC states that, "the trial master file shall consist of essential documents, which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated." ICH GCP, Section 8.1 defines these Essential Documents as those that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. The Medicines and Healthcare Products Regulatory Agency (MHRA) has also focused on the TMF compliance and statistics in their guide lines. This requirement is set down in both EU and UK legislation (2001/20/EC Article 15(5) and SI2004/1031 [as amended] 31A). The TMF forms the basis for an inspection to confirm compliance with regulatory requirements (Directive 2005/28/EC Chapter 4, Article 16). The TMF is normally composed of a sponsor TMF, held by the sponsor organization, and an investigator site TMF, held by the investigator. These files together are regarded as comprising the entire TMF for the trial (for which the sponsor is accountable) and should be established at the beginning of the study.
These documents serve to demonstrate the compliance of the study team, including investigator(s), sponsor, and CROs, with the standards of GCP and all applicable regulatory requirements. Beyond compliance, these documents actually form the basis for reconstructing the conduct of the trial itself. According to Chapter 10 of the MHRA directive, "The conduct of a trial must be able to be reconstructed during the trial and for some time after its completion from the documentation which is filed." As such, the files in the eTMF are all eligible for inspection by the regulatory authorities at any time during and after the study is completed and submitted for product approval. In today's regulatory environment, the files must be "audit ready" at all times. Regulatory authorities may contact the sponsor and request a particular document be provided to them for inspection. Therefore, the timely filing and organization of these documents is critical. There needs to be a consistent system employed such that documents can be located and provided for the study team’s use, as well as for regulatory inspection, in a timely manner.
But challenges remain to achieving these goals. eTMF generation is not only restricted to Sponsor organizations, but is also handled by CRO (Contract Research Organizations), which follow different business processes/SOPs, and which organize and track eTMF content in unique ways. Attempts to enforce a single and centralized sponsor maintained eTMF have been met with the realization that eTMF systems are in reality distributed across sponsor and CRO organizations.
Challenges in Transitioning to an Architecture that Supports Decentralized eTMF Systems
Organizations are increasingly moving away from paper-based TMFs, to a unified electronic format, to facilitate the indexing and retrieval of critical information required by regulatory authorities. eTMF (Electronic Trial Master Format) refers to specialized content management systems used to manage the documents electronically across the lifecycle of a clinical trial in a central manner. Though the goal is to have one authoritative electronic collection of documents, the reality is that many clinical teams work with pieced-together combinations of paper-based and electronic systems that lack universal communication.
Challenge #1. Multiple Partners, One eTMF. In the typical global clinical research environment, transitioning to a centralized eTMF is not practical—as trials are conducted under different SOPs by multiple sponsor and CRO companies—in a distributed fashion. The complexity of the global research environment (which increasingly relies on the use of multiple CRO partners) creates additional challenges. In particular, often CROs have either, no eTMF solution in place, or rely on an eTMF system that differs from the eTMF system used by the sponsor. This results in a lack of interoperability and homogenization, which in turn complicates the task of overseeing and controlling data to ensure compliance with regulatory standards. Using a CRO eTMF system puts a significant burden on sponsor teams to learn multiple systems and processes. Learning multiple systems from different CROs, each of which collects and archives metadata differently, is a real burden from a training, maintenance, and validation perspective. Moreover, the impact of working in multiple systems has a ripple effect throughout the organization and impacts Clinical, Regulatory, Quality Assurance and Data Management teams as well as proper study oversight.
Relying on many eTMFs from multiple CROs also impacts the sponsor's ability to gain insight into the trial master file content and process. One of the advantages of an eTMF is the ability to perform metadata analysis across studies in order to identify trends, issues, etc. Today, when a sponsor chooses to use multiple CRO eTMFs, they lose this ability to aggregate and analyze data across the portfolio. That loss of transparency also takes away any opportunity to evaluate process metrics, thus thwarting process improvements. This diminishes the value of the partnership for both the CRO and the sponsor.
On the other hand, CROs who do have eTMF systems often struggle to support varying client approaches to TMF management. Many cannot support the implementation of sponsor-specific TMF structures because their systems are based on hard-coded internal standards that cannot be easily modified, as they are optimized for the CRO's own operational efficiency. This means that sponsors are forced to use the CRO documented structure, which then may require mapping into the sponsor structure when the TMF is delivered at the end of the trial. The ongoing struggle to standardize internally and externally creates a great deal of redundancy, rework and adds to the cost of maintaining a compliant TMF.
Due to these issues, sponsors often rely on third-party Regulatory Functional Service Providers (FSPs) to merge and consolidate the TMFs from the various CROs at the end of a study. This adds significant cost to the process, while doing little to enable real-time information sharing during the study. Moreover, merging the TMFs after the fact is not an exact science. When merging TMFs containing differing schemas and metadata structures, the resulting consolidated eTMF may contain redundant files that must be cleaned over several iterations.
As companies implement outsourcing strategies, CROs and sponsor organizations are increasingly looking for a common foundation on which to build their TMF capabilities. This brings us to challenge number two.
Challenge #2. Lack of eTMF Standards. A current industry initiative to standardize the organization of TMF content is known as the TMF Reference Model, championed by the DIA. This model is helping standardization efforts across paper and electronic systems. The bad news is that it is still a defacto standard and represents a work-in-progress. Though the initiative is making good progress on standardizing the metadata and structure for a unified eTMF model, much is yet to be finalized—and it may be several years before we see an official version that is adopted across the industry.
Looking to the Future
At the end of the day, the goal of cross-organizational eTMF adoption is to provide a foundation for trial documentation that places sponsors and CROs on common ground, with controlled, common views of study data and documents. If structured properly, the system would support the rapid retrieval of key data points and documents to support regulatory audits, while enabling transparency between all of the players in the clinical research ecosystem, including sponsors, CROs, and even investigators who maintain investigational site files (ISF) with these documents as well.
Moving all parties onto a single and centralized eTMF system is not practical, and yet poorly-structured and decentralized eTMFs pose a significant risk that requires mitigation. The real solution is to have a system that is designed from the outset for distributed eTMF processing, that accounts for differences in data schema, while allowing all parties to track study tasks, activities, and documents. Instead of attempting to force changes in critical business processes within partner organizations, we should recognize that, in reality, eTMF data is collected from a distributed network of operational sourcing systems. Ideally such a distributed network would promote a standard data interchange based on the proposed DIA eTMF transfer specification.
The goBalto Solution
goBalto's Activate platform provides a controlled environment that supports TMF management activities from day one. It offers permission-based access and workflows, that support the TMF process and that can be configured to the artifact level. By enabling powerful management reporting across studies, sponsors can track activities and performance across CRO partners. It is a flexible solution that supports configurable TMF structures, thus minimizing traditional time consuming remapping exercises. Quality checks on eTMF content can be managed from within goBalto Activate, and then distributed via standardized and automated interfaces to multiple downstream eTMF systems for distributed filing. Many sponsors are using the goBalto system to standardize their interactions with CRO partners, particularly during, but not restricted to, the critical study start-up phase. Rules can be configured which automatically enable players to send authoritative versions of documents to the eTMF when appropriate, such as at key milestones such as Study Ammendments, and IP Release. When information is revised, it is tracked, and once quality data has been captured, those artifacts are automatically resubmitted to downstream eTMF partner systems. Data is distributed to eTMF systems at defined regulatory events, with all "audit ready" required meta-data for subsequent filing. This dramatically reduces the cost associated with merging, consolidation and maintaining multiple eTMF systems. In turn, study risk is reduced, enabling sponsors to be "audit ready" at any point during the study lifecycle.
Greatly reduces the need to engage a Regulatory FSP's, and/or hire additional staff, to merge TMF data, with significant cost savings:
- Allows individual CROs to follow organizational specific SOPs, yet still transfer artifacts to distributed eTMF systems in a standardized and automated manner
- Tracking of CRO performance for regulatory compliance across multiple CROs
- Significant cost and time savings by eliminating the manual remapping of tasks
- Automate eTMF filing of study documents into the sponsors eTMF system, while allowing CRO’s to track their own content and processes locally
- All participants are audit ready even on operational trials
DR. ROB WYDEN
VP of Technology & Engineering
Rob has been a computer scientist and programmer for over 28 years in the scientific programming, e-commerce, biotech, and healthcare industries. He implemented study startup and CTMS functionality at 9 bay area biotech companies, and invented a method that allows medical and biotech organizations to use cloud-based analytics to monitor patient data. He holds a BS in Computer Engineering from Sacramento State University and a PhD in Biological and Biomedical Clinical Informatics from UCSF.
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