Regulation, more than just stipulating what must be done, must also define whose job it is to complete the task. The assignment of responsibility within the regulatory framework surrounding the clinical trial is essential to protecting the well-being of subjects and the validity of the trial’s data. Clear demarcation of the primary roles of sponsor and investigator and their associated responsibilities ensures that those conducting a trial are qualified and enables regulators to hold individuals and industry accountable to the high standards of ethical research.
The trial master file (TMF), as the key deliverable of the clinical trial, is shaped to reflect these fundamental roles, most notably by the division between the investigator site file (ISF) and the sponsor TMF. The relationship between the ISF and sponsor TMF is important but also troubled. As the sponsor TMF continues to receive ever more regulatory attention, the spotlight has widened to include the ISF — but this newfound attention has not been flattering. In the most recent U.K. Medicines and Healthcare product Regulatory Agency (MHRA) inspection metrics, the single greatest category of major findings was record keeping. Of three critical findings issued over the one-year period, the first was related to patient diaries, and the third was issued for the complete systematic failure of a TMF.1 Of the non-records-related findings, many hold the central theme of poor oversight of the investigator by the sponsor. For fiscal year 2016, FDA BIMO (Bioresearch Monitoring Initiative) metrics show inadequate record keeping as the most common deficiency among investigator sites.2
The growing trend of negative findings suggests systematic dysfunction in the relationship between the sponsor’s TMF and the ISF. As regulatory expectations increase, the ISF continues to represent a poorly controlled and growing risk for both sponsor and investigator, and a solution is desperately needed. At first glance, it might appear that the same strategies that have given rise to the modern sponsor TMF could be applied: specifically, the use of electronic TMF (eTMF) technology and the expanded integration of clinical systems. Unfortunately, the paradigm shift of the eTMF has failed to reach the ISF for a variety of regulatory and nonregulatory reasons. The path toward a modernized ISF is unclear, but it has become increasingly apparent that progress can only be made after fully reflecting on the complex interplay of responsibility between the roles of sponsor and investigator.
ISF Challenges, Present And Future
When the sponsor TMF (hereafter called the TMF) and the ISF come together, they form the complete TMF. As one TMF, the ISF and TMF should be united in a dialogue, where each party both speaks and listens, and the clear story of the clinical trial shines through. Creating this crucial dialogue, however, is immediately disadvantaged by a cardinal difference between TMF and ISF: the TMF and ISF speak different languages. The “language” of the TMF is the structure of the reference model; this taxonomy of documents assigns every document a zone, section, and artifact, easily enabling consistent filing across a study. The reference model also applies a standardized system of metadata, ensuring that documents can easily be compared, moved, and grouped based on their attributes. The ISF, however, has no such standardized language, is unique to each trial site, and can vary significantly between protocols at the site level.
Beyond the challenge created by the fact that the TMF and ISF speak different languages, the workflows that support their communication are impractical and convoluted due to their physical and temporal separation. Over the course of a trial, most documents flow from the ISF to the TMF. Although the ISF and TMF are maintained separately, there are interdependencies between their documents that must be maintained to ensure the TMF is inspection-ready. There are several common challenges to maintaining this harmonious relationship between TMF and ISF:
Completeness: Without a one-to-one correlation between the zones of the reference model and components of the ISF, it can be difficult to determine what documents must be collected (whether filed in the ISF, TMF, both locations, or not at all).
Contemporaneousness: Without buy-in from the trial site, the sponsor of a trial may have to depend on clinical research associates (CRAs) to collect documents at oftentimes infrequent site visits. Delays between collection and filing in the TMF often permit more egregious compliance issues to develop.
Duplication: Lack of contemporaneous filing and the physical separation between ISF and TMF create the ideal conditions for duplicates to proliferate.
Document Quality: Regardless of format, document quality can degrade in the transmission from site to TMF. Furthermore, poor GDP (good document practices) at the site can create an unending cycle of rework, if documents need to be recollected.
Version Control: Keeping track of document versions can be a monumental task, especially when centrally produced documents incorporate site-specific changes.
Glancing at these issues, one might be tempted to see eTMF technology as the perfect resolution. eTMF technology already ameliorates many of these issues in the TMF. Unfortunately, even if regulatory issues are overcome, eTMF technology, in creating an eISF, introduces a new suite of practical and structural issues:
Metadata: The eISF system might apply and store metadata in a different way than the eTMF system does. This means that documents cannot be moved between systems without significant manual intervention.
Technology: Even if the eISF system does not require on-site hardware (because it is cloud-based), a site may not have the basic document handling technology (like a stable internet connection or scanner) necessary to efficiently utilize the system.
Expertise: Technical literacy at trial sites is variable. Site staff will require training and sites’ SOPs (standard operating procedures) and workflows will require updating to embrace an eISF solution.
Economy: Will the sponsor or site pay for the eISF? Sites will expect reimbursement for the costs associated with any sponsor-mandated system.
Security: The greater access afforded by an eISF is balanced with a greater need for access control. Electronic systems require significantly more complex security measures compared to physical documents.
Because of these challenges, most ISFs remain in paper format. Investigators, already overwhelmed by the many logins and systems incorporated into their protocols, are unwilling to invest the time to learn another system. Study coordinators prefer the flexibility of paper documents and fear micromanagement of their files if constantly available to the sponsor for review. Sponsors are reluctant to adopt eISF technology in fear of investigator pushback and the unlikelihood of a positive return on investment.
Although some technological solutions aim to bridge the gap between ISF and TMF, the ISF and TMF continue to speak different languages. The reason for this continued divide, however, isn’t just a lack of the right technology or the differences between the clinic and office — the divide is intentional and a product of the fundamental regulatory roles of sponsor and investigator.
Due to the principal investigator’s ultimate responsibility to his or her subjects and for reasons of patient confidentiality and control of source data, there must be a level of separation between the TMF and ISF. In a reflection paper from the European Medicines Agency, this necessary division is made clear: “The investigator should retain control of the documentation contained in the investigator TMF and the investigator TMF should never be sent to the sponsor organization.”3
Although the FDA and federal regulations do not specify exactly how much separation should exist between the ISF and TMF, it is clear that it is the investigator’s responsibility (not the sponsor’s) to maintain the CRFs (case report forms) of patients. “An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation…. An investigator shall retain records required to be maintained under this part for a period of two years following the date a marketing application…”4
To understand the rationale behind this separation on a deeper level, it is helpful to consider the documents that are found only in the ISF and not in the TMF:
Identification Lists and Consent Forms: Unless specific permission is obtained from subjects, the sponsor should not collect identifying information. Furthermore, in most circumstances, collecting and storing identifying information is not in the best interest of the sponsor. Collection of patient information increases the regulatory load on the trial, necessitating compliance with HIPAA legislation in the U.S., General Data Protection Regulation provisions in the EU, and other regional privacy regulations.
Case Report Forms and Source Documents: Source documents and CRFs, as the “primary source” of the trial’s data, must be given special care to ensure their accuracy. According to the MHRA, ownership of these primary source documents is central to the investigator’s control and oversight of the trial. It is crucial that the investigator maintains this independent copy of the transcribed data to ensure the integrity of the data.5 Furthermore, the investigator and the investigator’s delegates should be free to exercise their clinical judgement without undue influence from the sponsor.
Striking A Balance
Although the investigator and sponsor are committed to the safety of the subjects and quality of the data, each role contributes to the success of the trial by focusing on a specific domain of the trial. Consider their roles as defined by federal regulation:
Sponsors are responsible for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND [investigational new drug application], maintaining an effective IND with respect to the investigations, and ensuring that FDA and all participating Investigators are promptly informed of significant new adverse effects or risks with respect to the drug.6
An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation.7
The sponsor’s energy is directed toward management of the investigator and ensuring proper execution of the protocol. The investigator’s focus is the rights and well-being of the subjects. The way in which the goals of the investigator and sponsor are aligned produces a system of checks and balances for each role. While the sponsor may more heavily value efficiency and timeliness, the investigator ensures efficiency and timeliness do not compromise patient safety. While the investigator may occasionally stray from the protocol or neglect filing requirements, the sponsor is able to provide oversight to return the investigator to compliance. Ultimately, the divide between the ISF and TMF is maintained because its benefits outweigh the challenges of maintaining a parallel but separate ISF.
Because of comments received after initial iterations, the TMF Reference Model has adapted to consider the structural and functional differences between the TMF and ISF. Although many believe the Reference Model does not account for the ISF, this is a common misconception. Columns N through Q of the existing model indicate whether a TMF article is a sponsor or investigator document.
In January 2018, the TMF Reference Model Steering Committee joined with the Model Agreements & Guidelines International (MAGI) group to streamline the current structure of the Reference Model. From this collaboration, the work already conducted by MAGI will be fully integrated into the TMF Reference Model. Previous to their collaboration, MAGI produced a well-adopted standardized table of contents for site regulatory documents to assist with the difficulties in indexing documents in the Reference Model to the Sponsor TMF8,9.
According to MAGI and the Steering Committee, the goals of this collaboration are:
- to identify any missing artifacts relevant to the investigator TMF;
- to identify sub-artifacts that are relevant to the investigator TMF e.g. examples of source data that might be found in the investigator TMF;
- to review the structure of the content to ensure alignment with regulatory expectations and industry best practice;
- to ensure the content reflects requirements and best practice globally.10
The collaboration of MAGI and the Steering Committee will enhance the overall industry goal of a single and consistent model for both sponsor and investigator TMFs.
As the importance and complexity of the TMF continue to grow, however, it’s not clear that the current arrangement will remain beneficial or sustainable. As modern eTMF solutions continue to drive integration of systems across the clinical trial landscape, this desire for integration, while efficient and convenient, cannot (and should not) fully bridge the divide between TMF and ISF. To be effective, future ISF solutions will need to reexamine the fundamental relationship between sponsor and investigator and cannot rely on imposing homogeneity as the strategy to overcome all challenges. Only by embracing the complex and varied differences between the roles of sponsor and investigator can harmony be restored.
About The Author:
Thomas Cocciardi is a technical writer at LMK Clinical Research Consulting who is committed to expressing the human story behind each trial master file (TMF). In addition to technical writing, he also works as a TMF health specialist for a large CRO. Before specializing in the TMF, Cocciardi gained wide-ranging experience, both in and out of the pharmaceutical industry, working as a clinical research coordinator, preclinical data coordinator, intern medical writer, and intern brand writer. He holds an M.S. in regulatory affairs for drugs, biologics, and medical devices from Northeastern University.