By Amy Lounsbury and Betsy Fallen
For an investigational trial, clinical site documentation encompasses many types of records. These cover every aspect of patient care, policy guidance, and study execution. Not only does the patient medical history and care need to be maintained, but documentation supporting the plan and evidence of execution of a clinical trial must also be managed. This extensive collection of information is always subject to regulatory inspection.
As a major deliverable of a clinical study, the collection of information is typically referred to as essential documents (ED) and is collectively called trial master file (TMF) content. The ICH Guideline for Good Clinical Practices (E6, R2)1 is considered the global reference for management of the collection of ED. The FDA (or any regulatory authority) may review the TMF content at any time for any reason but primarily to determine whether the data collected in support of the drug, device, or diagnostic product was collected under good clinical practices.
Clinical site documents were a hot topic of conversation for a panel of experts from clinical sites at the recent Exl Pharma 7th TMF Summit in Orlando, FL. Joining Amy Lounsbury were Amy Gunnett, clinical research coordinator III from the University of Florida College of Medicine, and Aryn Knight, clinical research oversight specialist at the Texas Heart Institute.
FDA Inspections Of Clinical Investigators
Historically and continuing today, investigative sites have collected essential documents in paper form and stored them in multiple enormous three-ring regulatory binders. Early discussions between the site and sponsor should clarify who will provide the binders as, according to Lounsbury, many sites are reluctant to use electronic investigator site file (eISF) systems, especially inexperienced sites. Lack of clarity on who provides the binders delays action and introduces the opportunity for documents to scatter. With resources primarily dedicated to patients and patient care, making do with multiple binders (we’ve seen up to 15-pound ones!), instead of evaluating innovative opportunities, has been the norm. Another topic to discuss at trial start is the potential retention time. According to Gunnett, sponsors may only budget for five years of archival at study start. With regulations requiring 25-year retention periods for clinical trial documents in approved marketing applications, that’s a significant gap.
The inspection of a clinical site requires the identification and centralization of all essential documents. Bringing together paper, CDs, flash drives, and the navigation to repositories and shared drives is a multifaceted effort. The expertise to manage documents digitally has been recognized in the organizations that have adopted formal systems; however, these are primarily the larger institutions. At the Texas Heart Institute, Knight reports her site has begun transitioning to an eRegulatory Binder while specifically retaining wet-signed documents. We hope the transition to fewer paper and more eISF systems continues at clinical sites of all sizes.
The FDA has provided a guidance document as a road map.2 The guidance is very clear that records may be hard copy or electronic, but electronic records and signatures have the added requirement of documentation that 21 CFR Part 11 requirements have been met. Per the FDA manual (“Do not personally access a firm’s electronic records, databases, or source data during an inspection.”)3, clinical site staff should not expect FDA inspectors to directly navigate their digital systems but rather provide a navigator. Anecdotally, there are reports this may be changing.
Driving Change: Not Just Digitized Paper
Clinical sites aside, other stakeholders (e.g., medical records, sponsors, or IRBs) have adopted systems to create and share ED in digital formats. These actions were driven by resource efficiencies achieved by eliminating massive storage rooms, the opportunity for timeliness, and the globalization of trials that scatter team members who require access to the documentation. The initial reaction by sites was to print the digital records for the binders. That trend looks like it may be slowing.
The transition we’re seeing reveals that documents are also being stored on shared drives, dedicated computers, or other electronic mediums including CDs or flash drives. However, Gunnett reports, “None of our laptops have CD readers so we’re moving to encrypted flash drives as a storage option.” Sponsors should be checking on the site’s ability to read a CD if one will be provided to a site.
What’s In It For Patients?
All clinical site documents support the trial and the safety of the patients in the investigations. The quality of the documentation and the timely management may also improve the patient experience.
In the regulatory inspection reports available publicly, many of the findings are related to the patient informed consent (IC) and safety related observations. If the IC documentation were available in a digital repository along with meaningful metadata, the record could be monitored in real time by accessing an eISF so that any discrepancies might be identified and addressed by a prompt visit and follow-up training as needed. Although generating excitement, adoption of eConsents appears to be limited, and the archival and retention opportunities are not broadly known across sites.
Several companies are now offering clinical sites specialized eISF platforms to collect, manage, and store their records securely. This innovative development is significant in bringing technology solutions to the clinical sites. The opportunity to access and be alerted by systematic notices will bring a more efficient and improved patient experience. Organization and document identification, however, remain individualized by each institution. Systematically, if the content models are aligned, common practices, reports, and evaluations could be a best practice across clinical sites.
Where Are We Headed?
There’s an even brighter horizon ahead, but it will take navigating some rough terrain. While sponsors and CROs have extensively developed Section 8 of ICH E6 R2 from 50+ documents into a potential 250+ artifacts (referred to as the TMF Reference Model),4 site documents have not been comprehensively addressed in a similar way. The clinical site-owned documents not collected by sponsors have not been comprehensively listed and organized in a model that might be developed and adopted by all stakeholders. Very recently, the Model Agreements & Guidelines International (MAGI) group5 formed a steering committee that is working to create a best practice tool for site regulatory documents. Clinical site representatives, eISF vendors, and other experts are collaborating to deliver what could ensure completeness, quality, and, ultimately, efficiency to the experience. The project is expected to support paper organization and provide tools enabling the transition to digital storage.
Hopefully, the days of managing significant volumes of paper for both medical practice and clinical trials are numbered. Delivering medical treatment of any kind, but especially in the investigational setting, should not be anchored by mountains of paper.
About The Authors:
Betsy Fallen is an authority on the business processes and associated use of information technology in drug development. A passionate advocate for moving life sciences business online, she is an expert on many areas of drug development, focusing on document management. Trained as an RN, Fallen is dedicated to ensuring the voice of the patient is heard as the drug development process continues the progression toward innovation and efficiency. She can be reached at (610) 716-3271 or firstname.lastname@example.org.
Amy Lounsbury is a skilled research manager with extensive experience in gastroenterology trials as research department manager for Minnesota Gastroenterology, PA. Throughout her research career, she has focused on educating participants on the importance of their roles in clinical trials and in the development of improved medication for their indications. As a manager, Lounsbury works at maximizing efficiency at her site by standardizing the organization of trial files and by streamlining the workflow for research staff. She can be reached at (612) 870-5595 or email@example.com.