TMF Clinical Trial Study Rescue

A Trial Master File (TMF) is a collection of essential documents that highlight the framework of study implementation and provides a snapshot of the study team’s compliance with Good Clinical Practices (GCP) guidelines. Recently, the TMF has gained importance and receives closer scrutiny during audits.

The situation: A medical device start-up in the midst of financial challenges, manages to stay afloat through an acquisition; senior management owns the ongoing clinical study and the technical file as a lesser priority until they can hire a clinical team to resurrect the study.

The acquisition gave the study a new home and new leadership, but there was still little clinical input. The sponsor had no designated clinical area; the file cabinets containing study data were scattered; study documents remained stacked in boxes; study sites were followed-up but not monitored. These factors left the sponsor open to a litany of regulatory, clinical, and quality non-conformities, both at the sponsor and across all 15 study sites, 13 of which were in the US (there were two in the EU).

RQMIS took a leadership role as acting Vice President of Regulatory and Clinical Affairs and served as the sponsor’s clinical department. RQMIS:

• Reinitiated active communication with the FDA
• Identified qualified candidates to serve as clinical monitors to re-establish site monitoring and regulatory compliance
• Assigned a Clinical Team composed of:
  • Clinical Project Manager (CPM)
  • Data Manager (DM)
  • Clinical Trial Assistant (CTA)
  • EU-based Clinical Monitor
  • EU-based Clinical (Regulatory) Consultant

The clinical study was a paper study, with most subjects approaching their seven-year follow-up visit. Document collection was an archeological dig. In addition to the scattered paper, the client had multiple location data built out on a server; each with a network of sub-folders containing critical data from various third parties and multiple Contract Research Organizations (CROs). Large contributors to the project had changed professional positions, moved to other companies, or had their contracts dissolved.

RQMIS first created a chronological timeline to gain a better understanding of who the key document holders were and then adapted the TMF reference model to meet the audit needs of the medical device study.

The project CTA took the lead to reconstruct the TMF. The new clinical team filled binders with sponsor-required documents, creating tables, and shared the data online with site monitors who identified document gaps and wrote memos to file for unrecovered documents.

With the TMF starting to take shape, the team restored long overdue site communication. Study subjects still in active follow-up were encouraged to return for upcoming visit dates; study management reports accounted for study subjects lost to follow-up, and all data were collected and submitted to the data-management CRO in anticipation of an upcoming database lock.

RQMIS created two electronic TMF reference models:

• A Master TMF, which would be the basis for the final TMF, and
• A Holding Tank TMF, which is identical to the Master TMF, but could be used for document exchange during the study rehabilitation

In summary, RQMIS got this sponsor back on track by

• identifying, collecting, and organizing paper documents in accordance with the reference model
• writing memos-to-file to address gaps
• ensuring all subject data is collected in accordance with the study protocol
• establishing communication networks for document collection
• creating an e-TMF for onsite audits

Prior to the FDA audit, RQMIS will train the team on document locations, advise the team on documents requiring additional explanation, and continue to work onsite to ensure consistency across all levels of the company.