Is the Clinical Database part of the Trial Master File (TMF)?

This was a question posed recently on the MHRA GCP Forum (see  I posted a response (though it wasn’t published by the Forum Moderator) pointing out that for several reasons the clinical database should not be considered an “essential document” and therefore not part of the TMF, though it would be advisable to retain the database for a number of other reasons (not least, for its ongoing research and development value). In my opinion, because the raw data (the CRFs/EDC data) and the derived data (the SAS datasets and the tables, figures and listings) are part of the TMF (and included in the TMF Reference Model), I would not consider the clinical database to be an essential inspectable component of the TMF, with the caveat that all of the supporting database records identified in the TMF Reference Model are retained (programming, specifications, validation records, QA/QC records etc). The MHRA take a different view.

On the Forum, the MHRA state:

“The MHRA will inspect all aspects of the database including the retained essential documents in the TMF and the database itself, which includes the clinical data and all the metadata (audit trails etc.). Direct (and guided) access to the database should be made available along with the TMF for inspection.”

This is a highly significant clarification, considering the retention period for clinical records per EU Regulation 536/2014 is a minimum of 25 years. I have great concerns regarding how a sponsor will be able to maintain all aspects of the clinical database – including “all the metadata (audit trails etc)” for a period of 25 years and provide direct access to the system for this period. Could you provide direct access to an MHRA inspector to the original clinical database from 1990? On the one hand, we’re directed to adopt a risk-based approach and to focus on issues that could potentially have a direct impact on patient safety. On the other hand, we get directives to retain derived/secondary data that has questionable GCP value when taken in the context of all other records that are maintained in the trial master file. I get the feeling we sometimes take one step forward and two steps back!

Posted in Compliance, e-records, Technology, TMF | 2 Comments

Vacancy: Ass. Director – TMF (Biogen Idec)


This position is responsible for managing overall Trial Master File (TMF) operations including third party vendors and TMF systems. Act as a single-point-of-contact for all vendor inquiries and for all TMF vendor management activities (e.g. performance management, issue resolution, etc.). He/She provides oversight of external TMF Document Specialists and ensures that all documentation activities are conducted in compliance with regulatory requirements. He/She is responsible for overseeing internal systems used for TMF records, and reviewing document quality audit outputs to identify trends across the portfolio to ensure quality documentation. He/She identifies root cause of performance issues, determines the appropriate remediation, and escalates issues with performance when required.

I. Duties and Responsibilities:

A. Essential Functions:

• Manage overall TMF operations and third party vendors, and act as a single-point-of-contact for all vendor inquiries and for all TMF vendor management activities. Lead resolution of issues and remediation activities with the vendor.
• Manage and provide direction to external TMF Document Specialists and ensure that all documentation activities are conducted in compliance with GCP, relevant SOPs, and regulatory requirements and meet appropriate quality standards.
• Manage and provided direction for internal and external systems used for TMF records. Work with stakeholders to identify issues and remediation activities with vendors.
• Review document quality audit outputs to identify trends across the portfolio to ensure quality documentation.
• Identify root cause of performance issues, determine the appropriate remediation, and escalate issues with performance when required.
• Prepare and deliver effective presentations for external and internal audiences.
• Represent Biogen to external vendors

B. Additional Functions:

• Contribute to organizational effectiveness.
• Effectively serve as a role model within regulatory and cross-functionally.
• Positively impact industry and agency organizations.

• 9 years pharmaceutical/biotechnology industry experience. Relevant clinical, regulatory and TMF systems experience preferred.
• Solid knowledge of applicable regulations.
• Experience in interpretation of regulations, guidelines, policy statements, etc.
• Foster effective, positive interactions with other functions, vendors, and partners.
• Ability to work both independently with minimal direction and within project teams, committees, etc. to attain group goals.
• Demonstrate excellent leadership and communication skills.
• Ability to represent the department in project teams, committees and external meetings.
• Demonstrate strong organizational and project management skills, including the ability to prioritize personal workload.
• Strong interpersonal skills and the ability to deal effectively with a variety of personnel including medical and scientific staff.
• Well organized, detail oriented, effective written and oral communication skills.
• Ability to influence without authority.
Bachelor’s degree required, Masters or PhD in Biology / Chemistry, Life Sciences, or Drug Development preferred.
Contact: m a t t . s o l o p e r t o @ b i o g e n . c o m
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Vacancy: Head of Trial Master File (INC Research)

Do you want to be a part of a global top 10 CRO? INC Research is a full-service clinical research organization, providing the full range of Phase I to IV clinical development services for the world’s pharmaceutical, biotech and medical device industries. We do this across six continents. We believe that therapeutic and operational experience forms the foundation for taking medicines successfully through clinical development. From our early days as an academic CNS research organization in the 1980s, to the formation of INC in 1998, to where we are today, we’ve continued to improve what we do.

At INC Research we appreciate the importance of having experts dedicated to the set up stages of the studies, and for this reason we have a devoted Study Start Up team with departments focused upon Site Identification and Feasibility, Site Contracts, Ethics and Regulatory and Patient Recruitment.

We are currently seeking a Head of TMF to be based in either USA or Europe.

A brief summary of duties you will be involved in are:

The Trial Master File (TMF) Process Owner, Regulatory Records Management monitors and manages overall performance of TMF build and certification process to drive quality and compliance across the organization. The Process Owner is the single point of accountability for TMF quality, compliance, and inspection readiness at the organization-wide level and retains decision-making authority for overall TMF build and certification processes. This role retains global authority and oversight of any official company TMF and sponsors and leads the TMF certification process. Additionally, this role oversees the creation maintenance and revision of the official TMF structure and approves changes or additions. Moreover, the Process Owner, in collaboration with Regulatory Records Management, determines retention periods for records making up the official TMF. This role is accountable to inspection readiness leaders in all therapeutic and functional business units This role will drive the transition of the adopted certification process into a quality-by-design process. This includes: ensuring the development and execution of all CAPA commitments for assigned process and driving the end-to-end process redesign of existing processes / systems / controls to ensure that quality is built-in and to enable breakthrough performance


· BA/BS required, advanced degree with scientific or health-care training preferred and minimum of 15 years professional pharmaceutical development experience, with a minimum of 8 years leadership experience.

· Experienced in industry with expertise in the areas of clinical operations development and strategic planning; experienced with early to late stage clinical trials,.

· Able to manage clinical operations for a product from pre-clinical through all clinical phases

· Demonstrated leadership in a clinical operations role, effective organizational skills, and excellent verbal and written communication.

· Willingness and ability to travel domestically and international as required.

· Experience developing, implementing and leading a broad range of clinical trials both in the U.S. and ex-U.S., building clinical operations infrastructure, including SOPs, and managing vendors.

· Experience with Clinical Operations line management, and mentoring and developing personnel.

· Extensive experience managing contracts (vendor and site) and clinical finance activities.

· Excellent working knowledge of FDA & ICH/GCP regulations and guidelines.

· Ability to execute and follow-through to completion and documentation.

· Ability to work effectively in a collaborative team environment where results are achieved through influence and the incorporation of multiple points of view.

· Independently motivated, detail oriented and good problem solving ability.

· Excellent organizational skills, sufficient to multi-task in an extremely fast-paced environment with changing priorities.

· Excellent communication skills and ability to influence across multiple functions.

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Vacancy: Head of Clinical Documentation (GSK)

Requisition ID: WD31952
Position: Full time
Open date: Jun 2, 2015 9:25:42 AM
Functional area: Medical and Clinical
Location: Uxbridge, Middlesex
Upper Providence, Pennsylvania
Required degrees: Bachelors
Experience required: Not Indicated
Relocation: Yes


Basic qualifications:  Bachelors Degree

Preferred qualifications:  Masters Degree


The Head, Clinical Documentation is accountable for leading and clearly defining the business strategy and operational implementation plan to meet GSK’s commitments and to focus R&D (multiple components of Pharma, Vaccines and CHC) on consistent, readily accessible, inspection ready and available clinical documentation in the shape of a Trial Master File for every study.

You will be accountable for implementing a tactical strategy to meet immediate needs and also continually evaluate future strategies that build on this and ensures GSK is in a strong position to deliver TMFs for all studies in a simple, consistent and sustainable way fully aligned with international regulatory expectations.You will play a critical and complex matrix leadership role with all parts of the R&D organization that contribute documentation to the TMF, and implement strategies that incorporate the many systems that hold TMF information. Furthermore you will also be accountable for leadership of other ongoing activities in the Clinical Information Management (CIM) team, including and not exclusively:

Implementation and embedding of eDX and eDX Safety and creation of a sustainable way of working. Integration of these capabilities into future TMF strategies

Sustain implementation of SSR Smartfile until such time its functionality is integrated with future TMF strategies

Establishing processes to support SHARE and/or Value Evidence & Outcomes/WW Epi information management needs

Incorporation of clinical information from external sources (e.g., CROs, in licensed partners) including processes and automation, and integration of this into future TMF strategies

Key Responsibilities:

As the Business Lead of the TMF project, they will drive the R&D organization to enable the timely, efficient & effective delivery of quality clinical documentation/TMFs to fulfill GSK’s Sponsor Obligations. Ensure sustainable model in place to build capability in the organization and ensure excellence in the creation and delivery of a TMF that meets regulatory needs for every clinical trial conducted in GSK

Lead the CIM team to define and operationalise a sustainable functional support model, integrating other aspects of the team’s accountabilities in a seamless way

Organize within and across groups (Vaccines, CHC), combining resources as needed to align effort to challenge thinking, to be innovative and flexible in meeting current business needs and new strategic directions

To provide strategic direction and leadership for end to end process improvements and delivery.  Acts to align GSK with industry-leading strategies and keep pace with the evolving regulatory environment in the Trial Master File arena.

Be a leader for GSK when working with other Pharma and/or alliances in order to drive both innovation and industry standards and uptake

Establish key performance indicators and monitor for continuous improvement for the TMF solutions in place

Design and develop new business processes and strategies while proactively identifying business risks and proposing and implementing strategies to manage the implications of these risks on the business.

Serve as a point of contact for senior management and senior level matrix teams, both internally and externally.

Have accountability for line leadership of a team of recognized subject matter experts/leaders who are also effective in influencing and engaging across multiple lines and regions.

Collaborate with GSK Regulatory Intelligence, other GSK stakeholder groups and external groups representing the Pharmaceutical Industry (eg Pharma, EFPIA and DIA) in commenting on the GSK position relating to TMF regulations.

Skills & Experience

Knowledge and experience with the use of Trial Master File systems and associated business processes, and the changing regulatory environment

Proven capability in delivering and embedding new ways of working

Demonstrated track record in leading and effecting significant change, innovation and results in multiple major processes/projects/systems /policies which span multiple functional/specialist areas

Ability to influence strategy, to anticipate and analyze complex and ill-defined business problems/opportunities and a track record of developing and delivering high quality solutions that will have broad impact organizationally

Able to build a project plan & business case (including costings and timelines) and lead a large cross-functional team to deliver technical/business solutions

Proven ability to clearly convey information orally and in writing (technical documentation, presentations to business stakeholders, etc.) to audiences with varied and sometimes limited technical knowledge

Superior interpersonal skills, including the ability to establish and maintain good working relationships with peers, colleagues and management

Ability to achieve work through others who do not report directly to them

Experience in a similar role (direct or matrix managed) in a large organization

Results orientation

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Now is the Time for the Electronic Investigator Site File (eISF)

The latest issue of Applied Clinical Trials included an article with some interesting statistics regarding clinical trial sites (see ‘Characterizing the Real Cost of Site Regulatory Compliance’ by Kenneth A. Getz). The statistics quoted come from a survey conducted at the end of 2014 involving 164 U.S. sites. I found some of the data particularly pertinent in the context of the implementation of electronic trial master file technology (eTMFs) by clinical trial sponsors and the equivalent implementation at the investigator site (electronic investigator site files/eISFs).

80% of sites questioned reported storing their clinical and regulatory documents using a combination of paper and electronic formats, with only 25% storing in paper format only. Whilst some of those using electronic storage means may have their technology provided by the sponsors or a CRO (an eISF), I think it likely that the sites themselves have actually moved into the digital age and are managing their own records electronically. This is born out by comments I have received from trial monitors who report that many sites maintain much of their documentation at the site in electronic form. It is surprising therefore that clinical trial monitors are still going out to site and requesting hard-copy documents for filing in the sponsor TMF, sometimes requesting paper documents which are then scanned back at the sponsor site and converted to digital format…. when they could be made available electronically by the site. Old habits die hard! At pre-study visits, the sponsor should be asking the site what format their records are routinely held in and what is the feasibility of the site delivering documents such as CV’s, IRB/IEC approvals etc electronically rather than in hard-copy.

The survey also reported that at least 20% of physical office space is dedicated to storage of paper regulatory documents, including printouts of emails and their electronic attachments. With 44% reporting that they exchange information electronically with IRBs/IECs, it begs the question why sponsors are still asking sites to maintain ISFs in paper. Commercial sponsors are increasingly exchanging documents with the site via email and web portals but the regulatory site binders are still maintained as hard-copy files. And this has a financial impact on the site. The survey estimated that sites are being reimbursed less than 50% of the true cost of regulatory compliance activities, such as maintaining and archiving files in binders and storage boxes.

We can see a gradual emergence of eISF solutions but given the significant uptake in sponsor eTMF technology over the last 5 years – currently over 44% using an eTMF and a further 48% evaluating, planning for or actively implementing an eTMF – I think it is time for sponsors to “give the sites a break” and help facilitate a shift from an inefficient paper paradigm to an efficient digital one.

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EMA Cancels Revision of Reflection Paper on Trial Master Files

On 1st February 2013 the European Medicines Agency (EMA) released for public consultation a draft reflection paper on GCP compliance, including management of trial master files. After a three month consultation period which ended on 30th April 2013, industry has been waiting for finalisation of the reflection paper.

This week – on 15th June 2015 – EMA announced the following:

“It has been decided that the revised version of the TMF document, based on the comments collected during the public consultation, will be incorporated into a guidance on TMF as part of the work related to the implementation of the new Clinical Trial Regulation (EU) 536/2014. A public consultation on the new guidance will follow in due course.”

So, having waited for over 2 years since closure of the initial consultation period, industry has to wait a further period until this important piece of guidance is finalised. In particular, we are keen to see if EMA has responded favourably to the following criticisms of its first draft:

  • the suggestion that all correspondence should be maintained “in an appropriate section of the file”, rather than classified according to the content of the correspondence;
  • there is no differentiation between “obsolescence” and “deterioration” in relation to digital archiving; this an important distinction to emphasise because both problems require differing preventative and remedial solutions;
  • it is important that the documentation generated by the CRO from following its internal procedures is retained as part of the TMF for the required retention period and sponsors must consider this part of the TMF;
  • there is no mention of draft documents. As a guidance document, it is recommended that the reflection paper specifically excludes draft documents from being considered TMF content. This is particularly relevant with eTMF systems where documents are created, drafted and reviewed within the same application as the final TMF content. It is important that draft documents are not subject to scrutiny as final documents are;
  • electronic correspondence (emails) should be retained electronically, provided the requirements for eTMF and electronic archiving are considered;
  • the recommendation to use .pst format rather than pdf is not sound as .pst is a Microsoft proprietary format and is not suitable for preserving content for the period of time required by regulations. Other e-mail formats such as Lotus Notes NSF files, would have to be converted to Outlook before saving. The.pst format is often used informally by staff for saving complete e-mail folders and could lead to irrelevant e-mails being saved in a disorganised manner. Whilst conversion to PDF results in a small loss of metadata related to internet transportation routing, taking a risk-based approach it is recommended that the .pdf format is used for the long-term preservation (archiving) of e-mails;
  • it is not clear whether the intention is to use the term “electronic signature” rather than “digital signature”. Electronic signatures are typically created during workflows whereas digital signatures may be used with or without workflow;
  • FDA guidance on scanning specifically states that 100% page-by-page QC is not expected. It would be helpful to include a similar statement in this document i.e. a risk-based approach should be used to determine the appropriate level of QC required;
  • the requirement to restrict access for archived TMFs to the named archivist only does not take account of the additional protection afforded to electronic records through use of read-only user accounts. If a read-only account is being used, there does not appear to be any justification for restricting access to named archivists only;
  • considering the typical retention period for TMF documents is in excess of 25 years, transportable media such as media drives, pen drives and even CD/DVD are not considered to be appropriate for this purpose. This conclusion is supported by The Digital Preservation Consortium and digital preservation specialists such as Tessella and Arkivum. These forms of storage medium are susceptible to media degradation within this time period. In addition, it is likely that hardware to access the content will not be available throughout the retention period (e.g. unavailability of 3.5” floppy disk drives). It is recommended that electronic archiving be carried out as part of a formal digital preservation strategy; and
  • the statements and conclusions regarding destruction of scanned originals is considered to be too strong and conflicts with prior advice given. Rather than making a recommendation to retain wet-ink originals, it is recommended that the reflection paper simply provides this as an option in a risk-based approach.

We await with interest publication of the next draft guidance document!

Posted in Compliance, Regulations, TMF | Leave a comment

Thoughts from the DIA EU Electronic Document Management Conference

[Also posted on LinkedIn Pulse]
I have just attended the 15th Drug Information Association (DIA) European Electronic Document Management conference in Berlin. Here are a few thoughts and observations that came to mind as I sat through some of the presentations:

Many speakers described issues relating to the conference theme of standardisation and how we could potentially improve interoperability and increase efficiency through use of technology. But it was refreshing to hear Russell Joyce (Heath Barrowcliff Consulting) talk about the importance of information governance…. a topic that is sadly missing from many people’s agendas.

We heard about functionality needed for regulatory submissions management but I really have to question the need for “archive and find” functionality for submissions. In general, submissions are a snapshot of source records…. the source should be stored and managed in their respective “system of truth”. Yes, we need to identify what goes into each submission and may have a need to go back and run queries several years after the event. But submissions are a published COPY of original records. So, ‘archive and find’ functionality is needed in the “systems of truth” i.e. for the source content. This is the content that needs archiving in compliance with relevant regulations….. the submissions can be destroyed as soon as there is no longer a business need for them (usually a relatively short period).

System implementation projects often take several years within our industry and so it was interesting to hear about a project that was delivered in just over 2 months. Impressive? Yes, but I just couldn’t help wondering the extent to which success was heavily dependent upon a team of external consultants (e.g. to rewrite applicable SOPs) and the fact that the system was implemented with “out of the box” functionality. It is not often projects are this straight-forward. Having said that, perhaps a prompt for us to think hard why our IT projects have to take quite so long? If we had to deliver in 3, 4 or 5 months, could we? I reckon we probably could!

Another presentation concerned a process harmonisation effort as part of an IT implementation project. It was interesting to see that a specific objective of the project was identification of activities that could be carried out externally by a vendor i.e. an assessment of core competencies to be retained in-house. Perhaps we need to be more open to out-sourcing activities that we “hold dear”?

Great presentation on digital preservation. Much more than electronic archiving. Every organisation needs a digital preservation plan….. not just a retention schedule that says we’ll archive the content electronically for 25 years.

It was interesting to hear that one of the over-riding principles when the Reference Models were initially established was that content taxonomy was not considered to provide any competitive advantage and hence, we could all share openly our practices and learn from each other. It got me thinking that perhaps recent GCP inspection experience suggests that NOT adopting a reference model increases the risk of inspection findings. On this basis, is content taxonomy now actually providing competitive advantage to those that adopt the reference models?

My final observation concerned some comments from one of the regulatory agencies who pointed out that our design and implementation of eTMF solutions should be based on our business needs and should facilitate trial conduct and management, rather than to please a GCP inspector….. a statement that I heartily agree with. It was therefore a little disconcerting to subsequently hear the same individual comment that our use of perhaps five distributed and varied IT solutions might result in an inability of the inspector to perform an inspection within the required timeframe and should therefore be avoided. I think there’s a disconnect here! If use of 5 disparate systems is chosen by the sponsor for sound business and quality reasons, the agencies need to adapt their inspection regime to accommodate this type of technology e.g. by use of remote inspection, rather than suggesting we choose an IT infrastructure that is more aligned with their inspection practices.

So, here’s to the 16th DIA EU EDM conference!

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