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European Pharmaceutical Contractor

On the Record


Seamless and immediate exchange of data and documents is usually now expected within clinical trials. However, the electronic systems that facilitate document handling pose a number of challenges for the small- and medium-sized enterprise.

Electronic document handling is a hot topic in the healthcare industry. The number of documents is rapidly growing and regulators are putting increasing emphasis on electronic data and document handling. Importantly, the regulatory requirements for electronic document handling demand extensive built-in quality control measures and data security safeguards. Common office tools such as file sharing servers cannot fulfil these requirements.

In the clinical research context most providers offer relatively large, expensive, all-encompassing document management tools which often double as project management applications. These tools are on the one hand barely affordable for small- and medium-sized enterprises (SMEs). On the other hand they may not really meet their needs, as an SME may not require all the features included. In particular, SME CROs often need tailored solutions to match the tailored services demanded by their clients. While there are stand-alone applications on offer for particular clinical research processes, such as remote data capture (eCRF systems), or interactive web response systems (IWRS) for subject randomisation, there is very limited choice for a standalone application for managing essential clinical trial documents.

The shift from paper-based to electronic document management is inexorable and cannot be ignored. Seamless and immediate exchange of data and documents between stakeholders is increasingly a key factor for success in our highly networked clinical trial environment. Also, SMEs will have to find ways to cope with the changing environment and address the new challenges in spite of their limited resources and capabilities. For instance, SMEs often do not have dedicated IT departments or experienced document management specialists.

This article provides an introduction into the principles of document management and the relevant regulatory requirements, and discusses possible strategies which SMEs may adopt in order to cope with the requirements of electronic document and data management.

In information management there is a distinction between the terms ‘document’ and ‘record’, especially when it comes to the juridical relevance of a document. A record can be understood as a unit composed of individual documents or sets of documents that are essential for the manifestation of business processes and/or are legally binding. Yet as the overwhelming majority of clinical trial documents carry pieces of evidence and are thus to be considered ‘essential’ in the sense defined above. Thus, for all practical purposes in clinical document management the distinction between ‘document’ and ‘record’ is not warranted.

In this paper, we will use the two terms interchangeably, unless specifically mentioned otherwise (see Definitions).



Legal Requirements for Documents

Document forgery is a statutory offense in every jurisdiction with a functioning legislation, and so companies and individuals are obliged to apply due diligence in order to prevent documents from adulteration and falsification. The ISO 15489:2001 standard defines the following legal requirements for a document:

  • Authenticity: documents must be genuine and original, and the authorship and date of creation as declared must be verifiable
  • Integrity: a document must be complete and unaltered, that is no parts should be removed or changed a later stage
  • Reliability/trustworthiness: data and information must be provided in a credible, complete and accurate manner
  • Usability/accessibility: document must be legible and retrievable – if it cannot be accessed it is as if it didn’t exist (1)
The above considerations apply for all types of documents, electronic or paper. Nevertheless, for document handling and management information technology creates additional challenges. The authenticity of a paper document can easily be determined: for instance a ‘wet ink’ signature on paper cannot easily be forged. A digital document, however, is an artifact beyond ordinary human control. It may be altered, inadvertently or intentionally, which may be difficult to detect without proper safeguards. Electronic document management systems must allow verification that documents are authentic, whole, reliable and usable.

Document Management

This is a complex series of interrelated processes along the document life cycle. According to Götzer et al it includes document identification and description; editing and reediting; filing, storage and archiving; distribution and transfer; document and information retrieval; document preservation; protection from loss, adulteration, misuse or destruction; access to documents; document disposal; and management of responsibilities in relation to all the mentioned processes (2).

Each of these processes can be described by metadata, often, although not quite accurately, referred to as ‘data about data’. In the context of document management, metadata describe the properties of documents, and metadata are crucial for the identification, organisation and retrieval of documents. However, at present no universally accepted standard for metadata of clinical documents has been established. The Drug Information Association (DIA) has proposed reference models for electronic document management (DIA EDM Reference Model), and for the trial master file (DIA TMF Reference Model) with defined sets of metadata which may serve as a basis for a universal standard (3-5).

From an organisational perspective it is useful to distinguish between context, content and life cycle management metadata. Context metadata describe to what file, dossier or record an individual document belongs, whereas content metadata specify the information contained in the document (or parts thereof). Notably, the mentioned DIA TMF Reference Model uses only these two types of metadata (see Table 1) (6). Life cycle management metadata describe administrative elements associable with a document, such as date of creation, author, language, date of modification, status and version.



In electronic document management generally a set of metadata is created automatically by the systems, in particular life cycle management metadata. Context and especially content metadata often need to be entered manually, also in an electronic system. Alternatively, automatic full-text indexing may be applied for text documents. By contrast, metadata for paper documents can only be created manually by writing, stamping or printing, if they are created at all.

Document Life Cycle

Ideally, document management encompasses the entire life cycle of a document (see Figure 1). The eight principle stages of the document life cycle are:

  • Creation or capturing within or outside of the organisation; if created within a document management system, templates associated with the applicable prerequisite metadata should be available; capturing applies to documents that were created outside of the system and are entered in a second step (for example by scanning)
  • Classification is a stage subsidiary to creation or capturing; both processes should be designed to require classification by adding metadata such as title, author, date, status, confidentiality
  • Review, modification and approval is the commonly used release process, which may require several cycles
  • Publishing and distribution is one of the core functionalities of a document management system; access rights have to be defined by document class and user
  • Storage and safe-keeping must ensure the prevention of data loss and document destruction or corruption
  • Retrieval should be redundantly enabled by multiple processes and search methods
  • Re-use, including re-application and re-editing of entire documents or parts thereof, may lead to the creation of new documents restarting the life cycle. Parts of documents may be integrated in new documents
  • Disposal of documents and data is a process that is often neglected and under-estimated; a disposal policy with retention schedules needs to be defined and all redundant data from back-ups and extra copies need to be disposed in parallel


Implementing a Document and Records Management System

A differentiation between documents and records must be made when defining the management processes and the corresponding functionalities that need to be implemented in specialised IT applications, with a focus on either document or records management, or both.

The most commonly available document management systems focus on central storage of documents, control of workflows, approval processes and provide interworking capabilities. In these systems, documents may be modified and several versions of documents may be stored in parallel. These systems do not qualify for record management, since a record is a “unit composed of individual documents or sets of documents that are essential for the manifestation of business processes and/or are legally binding”. This definition requires inter alia that records are safeguarded against unauthorised modification and deletion, and also that identification of the ‘final’ authorised version is unequivocally possible.

Thus, typical records management systems prevent documents from being modified or deleted other than under strictly defined and controlled terms and conditions. Usually they allow only one final version of a specific document to exist. Interworking capabilities is not the primary focus of typical record management functionalities (6).

For clinical document management, record management functionalities are mandatory. But support of interworking and networking capabilities are also very important. As a result, an electronic document management system in the clinical research context is expected to have both document and record management functionalities.

Relevant Standards and Regulations for Electronic Document Management

In Europe and the US the requirements for electronic document management in the pharmaceutical industry are regulated by the guidelines concerning computerised systems in good practice (GxP) environments. For Europe, applicable regulations can be found in the legislations for Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP). The European Commission has specified the de facto standard Model Requirements for the Management of Electronic Records (MoReq2), which defines how electronic records may be processed in compliance with the existing legislations (7). MoReq2 is set up in accordance with the ISO Standard 15489:2001 (8).

ISO 15489:2001 focuses on the organisational requirements of document management systems, and the processes of implementing record management and record management systems. In contrast, ongoing monitoring for compliance as well as auditing and user training are only discussed marginally.

21 Code of Federal Regulation, Part 11 (21 CFR Part 11), the applicable US legislation, is more specific regarding systems requirements and emphasises the fundamentals concerning electronic signatures when compared with ISO 15489:2001. Also, 21 CFR Part 11 focuses much more on quality aspects, such as systems validation and audits. Notably, in ISO 15489:2001, the term validation does not appear at all. Still, the two regulatory frameworks do not exhibit any apparent contradictions.

State-of-the-Art

A number of different vendors currently offer clinical documentand records management systems. The backbone of such systems consist of database-servers for administration of metadata, file-servers for storage of files, archiving and back-up systems and, if needed, also converting-servers for long term document preservation. Often, communication and application servers provide connections to networks and client applications. The systems usually allow access from anywhere to centralised repositories, reduce redundancy and ensure compliance with regulatory requirements. Systems may be entirely established in-house or hosted out-of-house by a service provider.

Such a system needs to be configured, implemented and validated in accordance with established business processes and workflows, which represents a major challenge for any size enterprise. See Key Success Factors for essential considerations when implementing an electric document management system. Notably, system implementation is a dynamic process. The system needs to be monitored, adapted and improved on an ongoing basis.



Importantly, many stakeholders in clinical research and pharmaceutical development still require ‘wet ink’ signed documents. This implies that hybrid paper-electronic documentation capabilities are an essential requirement for a clinical records management system in the healthcare industry.

Strategies for Small- and Medium-Sized Enterprises

The multi-tiered client-server architectures of fully integrated clinical document and records management systems are far more complicated than the file sharing server systems generally in use at SMEs. Also, the efforts to implement such a system in most cases would exceed the financial and resource potential of an SME.

As opposed to fully integrated documentation and records management systems, pre-configured specialised applications addressing only individual functionalities in the context of clinical information management may be more appropriate for the SME, such as:

  • Clinical study documentation systems, known as electronic trial master file (eTMF) systems
  • Quality documentation systems for managing SOPs
  • Regulatory document management systems (for preparation and maintenance of eCTD)
  • Remote data capturing systems, usually known as eCRF systems
  • Systems for randomisation, drug assignment and drug shipment
  • Statistical analysis systems

These by definition have the disadvantage of covering only parts of the documentation management requirements a company will have to address, if at all. In addition, they are usually not easily compatible with each other and with common business applications, resulting in interfacing issues. On the other hand, they are much easier to implement, scalable and significantly more economic.

Any entrepreneur has to define whether he or she requires an integrated solution or only a specialised application and then weighing up the pros and cons. For an SME, a standalone eTMF system with record management capabilities might be an optimal first step towards a fully integrated document management system. The eTMF system would be used to manage all clinical study essential documents, while corporate documents that may not fall under 21 CFR Part 11, for example, would be kept on a common shared drive. Having said that, the available eTMF systems are not yet technically matured to the level required by an SME, and to the level achieved by stand-alone eCRF tools for example. Especially for CROs that work with different sponsors, current eTMF systems cannot be sufficiently customised.

For an SME that cannot afford to acquire an integrated system and that is in a position to wait, we thus recommend waiting to implement an eTMF solution until they are as numerous, matured and established as current eCRF applications, which is likely to be in two or three years.

References:

  1. International Standard ISO 15489-1:2001, Information and Documentation Records Management Part 1: General
  2. Götzer K, Schmale R, Maier B and Komke T, Dokumentenmanagement 4, Auflage, pp3-5, 2008
  3. Drug Information Association DIA: EDM Corner, available at www.diahome.org/en/HomePage/EDM+Corner.htm, accessed 17th January 2012
  4. Drug Information Association DIA, EDM Reference Model, available at www.diahome.org/NR/rdonlyres/DF24257F-EC0E-4FBC-A213-F37918D646F2/0/GuidetotheEDMReferenceModel.pdf,%20accessed%207th%20January%202012, accessed 7th January 2012
  5. Drug Information Association DIA, TMF Reference Model 1.2, available at www.diahome.org/NR/rdonlyres/643AA4BA-5845-4EE4-B3BA-A55DC5D9F616/0/TMFReferenceModel_Version12Final02Dec11.xls, accessed 17th January 2012
  6. Hohnston G, Bowen B, The benefits of electronic records management systems, Records Management Journal 15(3): pp131-140, 2005
  7. European Commission: Model Requirements for the Management of Electronic Records MoReq2, available at http://ec.europa.eu/transparency/archival_policy/moreq/spec_moreq2_en.htm, accessed 17th January 2012
  8. European Commission, MoReq2 Specification, p198, 2008, available at http://ec.europa.eu/transparency/archival_policy/moreq/doc/moreq2_spec.pdf, accessed 17th January 2012



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Rolf Marugg has a BSc in Information Sciences from the HTW Chur, Switzerland. He has worked with Appletree since 2009. As Head of Drug Regulatory Affairs, he has experience of Regulatory Authorities and ethics committees submission and reporting studies with drugs and medical devices in UK, Central and Eastern Europe. As a Manager of Clinical Documentation he is responsible for several trial master files and for the organisation of corporate records. Email: mailto:contact@appletree-ag.ch

Georg Mathis is a doctor of veterinary medicine with a PhD in Pharmacology. He has an MBA from the State University of New York at Albany and the GSBA Zurich in Switzerland. After medical practice, he spent 10 years in medical research. He has been Medical Adviser at Ciba Vision Ophthalmics, Managing Director of Sana Care and CEO of Sucampo Pharma. In 2002 he founded his own boutique CRO, Appletree Ltd, and is currently Managing Director. Email: contact@appletree-ag.ch
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