The document management and publishing system
Pharmaceutical documents are kept in systems that record every change, control who can reach them and publish them in the form a submission needs, and a writer works inside such a system and alongside the group that publishes what the writer produces.
What the system is for
Pharmaceutical documentation is often complex. By 2014 the conduct of the pharmaceutical industry had come under closer scrutiny and there was increasing pressure for greater transparency, so any changes to documents and versions should be reflected in an audit trail, to show that there has been no retrospective fiddling with the documents. Pharmaceutical companies often hold commercially sensitive information that needs to be protected, but barriers to access for appropriately authorised individuals may cost productivity. Large pharmaceutical companies are global operations, where the members of a project team who have to work on a document or approve it may be spread over different continents.
To cope with these requirements, large pharmaceutical companies will likely have a document management and publishing system, often built to specification. Besides password-protected access and a record of any changes to documents, the final published documents may be transferred to document repositories where other individuals can search and access them; a writer updating an investigator's brochure, for example, may need access to certain clinical study reports. Once final, some types of document may need to be distributed outside the company, and this should be carefully controlled. An investigator's brochure, for example, will need to be distributed to the appropriate investigators, so it is important that the persons responsible for distribution are duly notified and receive the correct version of the document.
A document management system will not in itself ensure that all documentation requirements are met. For large pharmaceutical companies, with increasingly complex documentation requirements and regulatory burden, such systems can however be considered a minimum essential requirement.
In 2011, a small startup company with only one product in the pipeline could get by for a good while with a relatively inexpensive means of managing its documents, such as eRoom or SharePoint, as long as its staff develop and follow a good version control and archiving process.
Part 11 and Annex 11
The FDA and EMA guidance set a high bar for the storage and tracking of electronic documents related to clinical trials. The FDA's 21 CFR Part 11 requires that systems are validated, secure and auditable, and that records are stored and retained as accurate and complete copies in readable and electronic formats; it also specifies that compliant systems will support electronic signatures and limit system access to authorised individuals. The EMA's good manufacturing practice Annex 11 was revised in 2011 in response to the increased use of computerised systems and their increasing complexity. Many of its requirements and principles are similar to those of Part 11, such as audit trails, electronic signature and document security, but it goes into additional detail on the use of third-party suppliers, the qualification of IT infrastructure and the validation project phase. By 2019 document management systems had long been established within large pharmaceutical companies, but there was increasing scrutiny to ensure that contract research organisations also store working copies of their trial documentation to these standards. This was especially so for documents containing protected personal data that may reveal sensitive medical information or the identities of trial participants, or confidential proprietary information, both of which are commonly found in documents authored by medical writers.
The medical writing department of one large contract research organisation held in 2019 that clinical trial data are rightfully protected by robust regulations, and that given these requirements and increasing demands from clients, a validated electronic document management system compliant with 21 CFR Part 11 and Annex 11 had become a necessity for established medical writing organisations and contract research organisations. In its view, even without that impetus, the improvements in administrative function, audit readiness and team collaboration can justify the investment required. With data security increasingly under the spotlight, manually tracking file names with ever-increasing dates or versions on a file share or drive is unlikely to meet client or auditor requirements.
Implementation in a medical writing organisation
ICON Medical Writing, with its vendor, implemented a cloud-based document management system on the software-as-a-service model, first installed in 2015, to comply with Part 11 and Annex 11 and to respond to clients' increasing document security requirements. Its implementation taught the following.
- It is highly unlikely that the out-of-the-box configuration of the chosen system will align completely with the processes in place within a medical writing organisation, so it is key during implementation to identify where the stock configuration should be modified to fit the procedures and where the procedures should change to fit it. It is important to keep a long-term view: the essence of a procedure must be maintained, but configuration changes that attempt to mimic previously manual procedures may result in imperfect compromises that negate the benefits of automation. It is important to test intensively before implementation, with input from writers of a variety of roles and experience levels, and at ICON this helped identify where the configuration and processes could be better adapted to the department's way of working.
- A well-executed training programme is essential for the smooth introduction of a new system. A combination of instructor-led training and detailed reference materials gives users the confidence to embrace it, and the vendor is usually best placed to provide the training. A successful programme teaches writers to work with the system according to their previous writing preferences while complying with the new procedures that govern it. Confidence in the system prevents new users from reverting to legacy systems, whose availability may discourage full buy-in, so there are benefits in revoking access to them as early as practical.
- It is important to adapt and improve the configuration as the project matures. A critical challenge for a large contract research organisation is maintaining inter-sponsor security when giving clients access to their documents. ICON first stored each sponsor's documents in a separate sponsor-specific environment, which maintained security very effectively, but each new environment increased the administrative and technical support required. In response, and after new functionality became available, the vendor and ICON redesigned the configuration to store all documents in a single environment, with dynamic security preventing sponsor users from gaining access to another sponsor's documents, and a large revalidation and testing programme confirmed the integrity of these security measures before it went live. The change reduced administration time and increased general engagement, as users had all their documents in a single location. With a true software-as-a-service model and innovations delivered on a schedule, there are continual opportunities to improve processes.
Benefits and drawbacks in a writing organisation
Automated workflows can track quality control reviews, capture the details of all participants and allow electronic signature, and a record of all reviews is kept on the system, from which reports and audit trails can be exported. Workflows allowed ICON Medical Writing to phase out hard-copy quality control forms, reducing the administrative burden of project filing. A software-as-a-service system, unlike a legacy on-premise one, makes it easy to involve sponsor organisations in the review process itself, leading to fewer review cycles.
Detailed metadata linking documents to specific projects, clients or therapeutic areas improves a writer's ability to step into a project and identify and work with the required documents with no loss of continuity, and automatic version management and its workflows give easy access to all incremental versions of a document and a quick overview of their place in its development. This is a significant step up from a manual file system, where even diligent writers with standardised structures in place can find it hard to get up to speed quickly on a new assignment without project knowledge.
A document management system and robust processes around it can notably reduce the preparation time, compliance risk and stress around a client audit or regulatory inspection. Replacing paper quality control forms with review workflows removes the risk of missing signatures, because the system requires the reviewer's electronic signature before completion, and comments can be stored and responded to within the system. Version control tracks all major and minor versions so that they can be identified and provided to auditors if requested, and users can export an audit trail detailing all actions taken with a document. This visibility of the document development process gives auditors and regulators confidence in the completeness of the data presented to them.
Some of the flexibility of a manual system has to be given up within the structure of a validated system, and configuration changes can take longer to implement because specification documents have to be updated and formal testing conducted. Organisations without an in-house validation department may want to consider how they will maintain their system's validation and regulatory compliance when its configuration has to change. Software-as-a-service solutions spare system owners significant effort on the lower levels of validation, such as installation and operational qualification, traditionally associated with on-premise systems. Writers will take time to adapt to a new system and may need additional support, and an important part of the transition is communicating a well-defined plan for moving work to the new system, which the vendor's materials supporting change management can simplify further.
The benefits of digitalised regulatory writing include regulatory information sharing, improved work efficiency, lower regulatory submission budgets and new employment opportunities. In the electronic system, draft and intermediate versions can be edited and all changes are traceable, in compliance with global archival requirements. Information security, the intellectual property of regulatory documents and the compatibility of electronic systems are potential risks of digital writing. In 2019 these issues, together with the public availability of medical research information, access to confidential regulatory documents and the qualifications of the professionals who can access them, were questions still to be discussed.
Publishing and the publishing group
The assembly and publishing of documents, usually as a hyperlinked PDF, will often be outsourced or at least performed by someone other than the medical writer, because it can be painstaking work, but the medical writer will still need to check the final document.
A writer who is also required to publish their own documents, rendering them to PDF and applying compliant hyperlinks and bookmarks, needs to stay current on submission specifications, because failing to do so could result in a refusal to file. Such a writer can count the extra publishing skill as a plus on their résumé, but should encourage their employer to hire publishing assistants, so that the writer can focus on the content rather than the formatting.
A symbiotic relationship is an intimate interaction between two or more species, which may or may not be beneficial to either. Bees and flowers are an example: the flower provides the bee with nectar, the bee provides pollination, and each benefits from interacting with the other, as they need each other to survive and prosper. The biopharmaceutical industry is a complex ecosystem with myriad interdependencies, whose organisms experience many moving parts, including shifting priorities and timelines, process changes, system upgrades, and internal and external requirements. Communication and collaborative interaction are the keys to a successful relationship, especially between a medical writing department and a document publishing and content management centre of excellence in regulatory operations. Creating a symbiotic relationship involves trust, collaboration, innovation, risk, people and leadership.
- Trust — whether each group trusts the expertise of the other and is willing to share insights. Ensure expertise is in the right areas, identify skills for each group and/or create subject matter experts, and ensure accountability. A document publishing and content management group focuses on providing documents that meet the electronic submission requirements: its members are Word and PDF experts who focus on formatting, publishing, quality control and submission readiness, and they interact with medical writers, statisticians and downstream submission publishers. It is important not to make one group responsible for work that can be done by experts in another group, so that each group can share and leverage its knowledge and expertise more broadly.
- Collaboration — whether the groups work cross-functionally and come together. Promote the interaction of group members, ensure all stakeholders are considered in the end-to-end timeline, and encourage representatives of the ecosystem to meet regularly and consult actively with project teams. The groups should have a general understanding of each other's role, because last-minute changes are known to happen in the clinical and regulatory space, and being able to identify the correct point of contact can save valuable time when compiling a submission.
- Innovation — whether there are processes to capture innovation, and whether they can be learned and repeated. Plan for success, keep everyone up to date on process and procedure changes, share across groups what processes work and what does not, capture the best practices in order to repeat the desired outcome, and then promote consistency. In one publishing group, regular meetings with medical writers on quality metrics, concerns, issues and processes, in which it is important that both groups participate, capture patterns, good and bad, so that a solution can be implemented and/or best practices perpetuated.
- Risk — whether the change is affordable, and whether its benefit outweighs its risk. The organisations have many moving parts that need to synchronise across departmental boundaries, so when a process or system requires an update in one area, time has to be taken to investigate its impact within the ecosystem. Where there is a symbiotic relationship, identifying the gaps to align the end-to-end process can become systematic and create opportunities for improvement across the organisations.
- People and leadership — whether the people involved are there to develop opportunity. Select people who can provide leadership: the ecosystem needs leaders who can prioritise projects or tasks, then create a strategy and execute it. Strategy is simple, a matter of focusing on the activity, while execution is complex and takes time to perfect; "without direction, simple clarity on strategy, execution is merely hysterical activity confusing effectiveness with activity".
These points allow for knowledge transfer, gap identification, project prioritisation, and consistency of process and procedure, with the end goal of delivering submission-ready components. All groups must interact in order to meet deadlines. A symbiotic relationship can improve performance, increase effectiveness, expand workload and outweigh risk with reward; only the flowers that interact with the bee prosper, and the investment in the relationship determines the outcome.