Questions we’ll answer: What is a TMF? What are eTMFs and their benefits? What is a DIA TMF Reference Model? How do IRBs/Sponsors/CROs/Sites benefit? How does moving to an Electronic TMF put my company in the fast lane?
What is a TMF? Traditionally kept as a set of binders, the Trial Master File (TMF) includes an array of document types ranging from Site Contracts to Clinical Study Reports with numerous documents of each type, often resulting in a total collection of thousands of documents in each TMF. According to Good Clinical Practice (GCP), “These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.” – ICH GCP E6 (R1)
Essential Documentation Collectedduring a Clinical TrialPre-site selection Site Selection Regulatory Site Set-up•Investigators Brochure •Confidentiality agreement •Notification of IND # or •Protocol signature page•Protocol •Pre-study visit (investigator CTA approval •PI & Sub-I cv•Informed consent selection,site •Registration in •Form FDA 1572•CRF suitability, items concerning Clinicaltrials.gov •Financial Disclosure overall study conduct) •IRB/IEC SubmissionMonitoring Investigational Product Safety Centralized Testing•Trial initiation monitoring •Instructions for handling •Safety Management plan Facility report •Accountability •SAE reports •Normal ranges•Site training documentation Documentation •Pharmacovigilance •Certificate of accreditation•Monitoring visit report Database Line Listing•Protocol deviationsThird party Oversight Data Management Statistical Analysis Clinical Study Report•Confidentiality Agreement •Data Mgmt. Plan •SAP•Contractual Agreement •CRFs •Randomization Plan •EDC •Datasets •Programs
Essential Documents Documents which individually and collectively permit evaluation of the conduct of a trial and quality of the data produced. Usually the documents are audited by the sponsor’s independent audit function and inspected by Health Authorities as part of the process to confirm the validity of the trial conduct and the integrity of the data collected.
TMF Challenges The Life Science industry is facing pressure to cut costs while facing increasingly challenging regulatory requirements- which have increased the cost. With more clinical studies being conducted globally, paper TMFs are becoming more of a challenge as file numbers increase. A study by the multinational defense, security and aerospace firm BAE Systems showed that 80 percent of employees waste an average of 30 minutes per day retrieving information, while 60 percent are spending an hour or more duplicating the work of others (Dukart, 2007; Martin, 2004).
What is an electronic TMFSystem? An eTMF system is the application of a 21 CFR part 11 compliant electronic document management system. Documents and content are stored centrally on a computer server “cloud” eliminating the need for regulatory binders. The system is accessed via a secure internet connection globally with auditable security. An eTMF automates time consuming error-prone paper-based processes.
Features of an eTMF System TMF taxonomy – includes document names, descriptions, categories TMF metadata –standards-based data about the documents that become part of the TMF document record Allows customization of the eTMF taxonomy for addition of new document types and metadata Notifications can be sent to key information to stakeholders An intelligent, precise search
What is the TMF ReferenceModel? In 2009, the Drug Information Association (DIA) embarked upon an effort to define a standard clinical trial master file taxonomy or “reference model” for use by industry. This collaborative effort involved 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).
Goals of the TMF RM 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 document types/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.
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.
Metadata Alternate names, Definition/Purpose, Unique ID Number, Study No/Trial No/Protocol No Used for metadata and to define paper TMF format: Trial Level Document, Country, Site No/ID Inherited Metadata from Trial No: Product/Compound, Indication, Trial Phase, Route of Admin Artifact date as defined by convention, Map to Current Sponsor Document Name, Location of Artifact
From regulatory binders toelectronic file folders
Why resist change? Most resistance is due to stakeholders seeing no need for change. They have a long history of working with paper-based data collection that have what they consider to be “good results.” According to Neuer (2010), most companies cite the upfront cost to be a major barrier to implementing a new electronic system. As part of this perception, they may believe that solutions are too big for smaller companies, or they may be unsure about the vendor’s ability to deliver high-quality technology, training, and customer service. There are many questions as to how the system will be implemented and how processes, standard operating procedures, and jobs will change to accommodate the new technology.
Stakeholders Site Sponso IRB Trial r Master File (TMF) Health Authorit CRO y
Goals for Stakeholders Reduce time associated with file requests, audits, and submissions Increase quality Easily locate all documents Enforce security and regulatory compliance Conserve resources (personnel, time, money) Save trees
Challenges for Stakeholders The document intensive nature of the business requires a great deal of internal and external collaboration and management of numerous documents in accordance with regulations. Time and money spent on the tracking, routing, review, approval and archiving Difficulties finding documents Issues with audits/compliance/inspections Storage space, shipping, supplies Slow organizational responsiveness
Barriers to CollaborativeManagement Lack of a centralized globally accessible platform to manage and store essential study documentation. Inconsistent document management processes across and between organizations. Inconsistent or incomplete work assignments. Inefficient notification of key events. Incomplete, missing, expired or redundant documentation.
How will eTMF help? Provides operational efficiency, improves quality, and can help companies reduce the internal costs of maintaining electronic filing systems and reduce the administrative expense of locating documents . By strategically integrating business process, people, and technology, companies can make more effective business decisions, exponentially increasing value.
Operational Efficiency When operational efficiency is improved: The same total number of employees can do a greater amount of work Employees can be re‐assigned to new/different roles that add greater value Standardization and consistency of processes is improved The time to market will be shorted, thus increasing profit margins and revenues Quality will be enhanced
Quality The quality of Regulatory documents is being compromised as companies try to do more work with less people. One survey estimates that business-technology professionals in the industry are spending up to 22 percent of their work week on compliance (Smith, 2003). Standard Operating Procedures are estimated to cost a Pharmaceutical organization $1-2 million a year (Semple, 2003; Whalley).
Quality cont. Research suggests that while costs associated with drug development are increasing at an annual rate of 11.8 percent, sales are only growing from 2% to 5% in the United States (Neuer et al., 2010). All the while, staffing is not increasing.
Cost Focusing only on the upfront costs overlooks the significant downstream cost savings being realized by being able to reduce human error and time spent on quality assurance. These benefits tend to be cumulative as efficiencies linked to new technologies generally increase over time as end users gain familiarity with them through repeated use. Dramatic reduction in the need to print, distribute, and store multiple copies at different sites
Benefits beyond time, cost andquality Management of Regulatory Changes: State, Federal and industry regulations continue to grow and evolve. Risk Management: Significant risks and penalties for non-compliance, including fines, and customer lawsuits. Access to the trial data that sponsors need quickly and effectively Clients can better isolate trial inefficiencies and achieve significantly higher quality and cost savings Centralized documentation Security (restricted access)
More benefits Investigator relationship management Investigator and site identification and recruitment Site management (monitoring actual enrollment relative to planned, IRB approval and decision, etc.) Protocol and study documentation preparation Reporting Integration with other systems Consistent archive format
So why should I move toeTMF? Increased compliance Enhanced security Operational efficiency Increased transparency Simplified tracking Significant cost savings No new hardware Better document quality Easy and fast search and retrieval
Get out of the slow lane! By the year 2020, the life sciences market is expected to reach $1.3 trillion, and larger companies may have over 100 active compounds in development, as well as numerous compounds on the market (Sichort & Booth-Genthe, 2010). According to the National Center on Education and the Economy (NCEE), “taking a month off development time can generate an additional $40 million in sales for the average drug.” You need to make changes to get in the fast lane
Wrap up Today we learned about TMFs, eTMFs, and how having an eTMF can keep your company moving forward at a fast pace and make you a front runner in the race. It’s time to move into the fast lane with an eTMF. For more information contact Mission3 at firstname.lastname@example.org or follow us on Twitter @adair_turner or @dirkbeth.