Running a regulatory writing project when the requirements keep changing
A regulatory document whose requirements will not hold still long enough for a stepwise plan can still be developed under control, with practices borrowed from agile project management. The approach turns on where a stepwise plan suits regulatory documents, how the COVID-19 pandemic undid the predictability that plan relies on, what three projects of that period changed, and what the borrowed practices cost.
Where the stepwise plan suits regulatory documents
The most popular project management methodologies across industries include waterfall, Kanban, the adaptive project framework, lean and critical path. Regulatory writing projects have usually been planned by the waterfall method, which suits an environment that requires sponsors to implement and maintain quality systems. The standard operating procedures behind those systems are often prescriptive, setting out steps that can be documented to show compliance. Timelines tend to mirror these procedures in a fixed, stepwise progression toward controlled content. Project management software captures the progression as predecessor and successor tasks and can turn it into outputs that coauthors and stakeholders outside medical writing can follow. The method's benefits include ample time for the writer and coauthors to think, research and then write, and to align reviewer comments and changes across the document before the next iteration. Waterfall is ideal for a project with a predictable path. The format and content of nonpivotal clinical study reports, annual investigator's brochure updates and development safety update reports (DSURs) are well described in the regulations, which generally limits stakeholders' influence on their structure, and their timelines may be set by regulation, as for the DSUR, or driven by fewer extrinsic factors, such as a competitive landscape.
How the pandemic unsettled the requirements
The waterfall method relies on predictability, but the regulatory writing environment changed dramatically once the pandemic began. Regulations for COVID-19 and other studies, contract research organisation and site procedures, and sponsor priorities shifted to enable accelerated clinical evaluation of diagnostic, therapeutic and preventive products. Projects were started without well-vetted concepts, without access to real-time investigator clinical observations, or without an assessment of requirements, as when a full protocol was begun without identified study endpoints because understanding of the clinical course of the disease was still evolving. Writers were consequently asked to coauthor in real time, in a way that diverged significantly from the stepwise collaboration the waterfall method affords. The pandemic challenged regulatory writers to rethink the structure of their workdays and the nature of their interactions with colleagues, and to use technology and strategic project thinking to help their teams meet aggressive timelines while working in a virtual workspace. The field had also become more dynamic, influenced almost daily by decisions of regulators, research committees, health care professionals, venture capitalists and, most importantly, the scientific method itself. Delivering quality regulatory documents in it requires adapting the methodology to an evolving landscape. A recent rise in requests to support projects with accelerated timelines and imperfectly defined parameters, like those of the COVID-19 projects, led one regulatory writing provider to wonder whether a linear way of working might become a relic.
Three projects under shifting requirements
Each of the projects one regulatory writing provider reviewed in the first half of 2021 needed several resources within the company, such as a regulatory writer and operations support, and more than half of the regulatory writer's time for a discrete period. In each, one or more authoring steps ran concurrently rather than in sequence, so the writer was unavailable for other projects, and coauthoring with the client was done through collaborative technology. Each had a timeline that the regulatory writer created prospectively, maintained or both, and that the resourcing manager could review. A project that meets some but not all of these criteria, such as a COVID-19 impact assessment for a clinical study report, may need a combination of strategies depending on the context.
The first was an investigational new drug application (IND) for a COVID-19 treatment by a medium-sized pharmaceutical company with no established medical writing department, written by external consultants. It began shortly before the pandemic was declared, when the COVID-19 studies on clinicaltrials.gov could be counted on two hands.
The writer used software and searches of clinicaltrials.gov for recruiting COVID-19 treatment studies to gather clinical intelligence and develop a protocol synopsis, which then served the interactions with the agency, the contract research organisation and the sites. The timeline allowed three weeks for the pre-IND meeting request package and two weeks from the pre-IND feedback to the IND. The stakeholders were US regulators and later global regulators, institutional review boards and independent ethics committees, the internal team and management, the study sites, external philanthropy groups funding the work and the contract research organisation. Guidance was still being drafted, none was yet available on endpoints and objectives, and the application cross-referenced heavily to an existing IND in another indication. To meet the timeline, the team wrote the protocol and consent form at risk ahead of the pre-IND feedback. It deferred many of the testing and analysis details to ancillary documents such as the pharmacy manual because the details were not yet available: emergency use authorisation for diagnostics had come only a few weeks before.
After the US Food and Drug Administration's (FDA's) feedback on the pre-IND package and about two weeks before the IND submission, the FDA issued guidance on COVID-19 study conduct. With the protocol nearly final, the team had to interpret the guidance quickly, make any changes addressing conflicts with prior clinical intelligence and an evolving standard of care, and confirm them with internal and external stakeholders, for example by checking that the FDA's oxygenation cutoff for disease severity matched the site's. Traditional stepwise methods were recognised as too rigid for this environment, so the team took up strategies from more adaptive methodologies.
Change was communicated rapidly through a phone tree and scheduled check-ins every other day, with ad hoc meetings called for specific topics or live edits. The core authoring team was limited to the writer, the clinician and the clinical trial manager, with supplemental members reviewing specific language in the protocol, which enabled efficient, focused authoring in short work sprints. All authoring was in Teams, with access managed by a dedicated IT professional who was part of the phone tree. A regulatory writing operations associate supported the writer by formatting, locating references and managing citations.
The document had a single round of management review in the sponsor's PleaseReview, in which most reviewers gave substantive feedback through the commenting feature. The team vetted management comments together, the core authors discussed outstanding issues with their line management outside the review and reported back, and roundtables of all core and supplemental authors and the management reviewers aligned on resolving any pending comments. Structured communication and cloud-based tools let the small core team respond efficiently to shifts in the regulatory landscape while still authoring, consulting management and subject matter experts and reaching consensus, and the team delivered a quality document.
The second was a marketing application for a COVID-19 preventive by a medium-sized pharmaceutical company with an established medical writing department, written by the contract research organisation's writers, internal staff, and external consultants who worked as an embedded full-service provider. The work ran in Teams, the contract research organisation's PleaseReview and Veeva. Its timeline of 12 weeks was cut to eight, and it needed a review of new interim data and of cumulative data. The stakeholders included global regulators, among them several US bodies, and the regulatory landscape was evolving rapidly, with constant feedback from multiple agencies, divergent feedback to resolve, and a prior emergency use authorisation and global conditional approvals. Its risks were a competitive landscape that was a significant concern, multiple overlapping documents to meet the timeline and the sponsor's exponential growth in a short time. The contract research organisation assembled the documents and facilitated the reviews, while the sponsor's employees and consultants oversaw and managed timelines and risks and the interactions with internal and external stakeholders.
Because of the time constraints, the project used live data reviews, in which the contract research organisation's writer worked directly with stakeholders early in drafting, allowing real-time drafting and consensus building and reducing draft cycles. Their success depended on the right attendees being available and endorsing this change from traditional iterative authoring and review. Where the first project used a small core team with targeted reviewers to reach consensus, this one used a larger review team, management included, to increase functional alignment at approval, which worked largely because of trust at every level.
PleaseReview was used for a stepwise review, comment reconciliation and closeout workflow under highly prescriptive procedures. The procedures did not let the internal writers and the consultants, who had only reviewer licences, review live copies of fundamentally relevant documents, such as in-development study reports or summary modules alongside the in-development clinical overview. The review system allowed reference documents to be attached, but those documents were changing at the same time, so attaching them was ineffective. A system was needed to finalise the document with the key subject matter experts after team review. A first attempt to use SharePoint for this failed for lack of prospective access management and because internal sites restricted guest accounts for external consultants and writers, so the writer and the subject matter expert resolved the outstanding issues by email.
As a lesson from other submissions on the same programme, and in line with sprint-style methods, the writing team attended specific key meetings, which let it communicate about the submission and gave it more time to complete action items. The sponsor's head of medical writing attended general and contract research organisation meetings, the external consultants divided the contract organisation's and other internal meetings among themselves, and all external consultants and contract organisation writers attended most document roundtables and stand-up meetings. Those who did not attend could read the meeting information in a Teams chat, an email or a OneNote summary.
The regulatory and quality requirements were met and the submission was filed on time, with observations for future process improvement. The regulatory writing provider was engaged late in the project's planning and may have been able to influence the project management approach had it been involved earlier.
The third was a two-week amendment to an early-phase protocol in a non-COVID-19 indication, under an IND that had been open for some time with one other completed early-phase study. The sponsor, described both as a medium-sized pharmaceutical company and as a small company with limited resources, had no established medical writing department, and the amendment was written by external consultants. The team was tasked with finding a way to add necessary flexibility to the study because of the evolving COVID-19 closures in the first half of 2020. The stakeholders were global regulators, among them several US bodies, institutional review boards and independent ethics committees, the internal team and management, the study sites and the contract research organisation. The protocol had been finalised around the time the first COVID-19 cases were reported in the United States, and the study was in start-up when the work began, as sites across the country restricted access under infectious disease procedures. As cases rose globally, the sponsor grew concerned about the likely impact on enrolment and on the ability to ensure proper safety follow-up of any patients enrolled.
The amendment was planned to allow alternate assessments and to reduce patients' travel burden and chance of COVID-19 exposure. It added home sample collection, select phone visits, alternative media for patient-reported outcomes and consent, and, as a last resort because of its high cost, home nursing for safety assessments and drug accountability and dispensation. FDA guidance on conducting studies during the pandemic was issued several weeks into the work and informed several key planned mitigations. When it was issued the pandemic was evolving, and the agency had judged prior public participation not feasible or appropriate, so early guidance was open to some interpretation. The FDA's questions and answers on that guidance were issued and updated while the amendment was being written. Implementing the mitigations required active discussion with contract research organisation partners and subcontracted vendors to ensure they were properly described and executed, and the mitigations might not succeed and came at a high price.
The core authoring team was limited to the writer, the operations associate, the clinician, the clinical trial manager, the regulatory strategist, the programme manager and the drug supply and chemistry, manufacturing and controls manager. Having each function involved kept the protocol updated efficiently and accurately as conversations with the contract organisation and other vendors progressed in daily, focused, one-hour working meetings. Authoring was in Teams, with access managed by a full-time employee on the core team. The document had a single round of management review in the sponsor's PleaseReview, which the writer initiated and managed and in which reviewers mostly used the commenting feature. The team vetted management comments together, the core authors aligned with their line management outside the review, and all authors and the management reviewers attended the roundtables.
Limiting the team to line-function representatives, meeting regularly and using authoring and review tools that promote transparency let the team use multiple minor draft sprints to take in information and reach consensus as it became available between meetings with stakeholders and partners. The amendment aligned with the emerging guidance while mitigating the impact of COVID-19 on enrolment, study feasibility and participant safety.
Agile practices within a controlled process
Each regulatory writing project has its own budget, collaborators, timelines, risks and gaps, and the regulatory writer and regulatory project manager must discuss how a project links to department and company goals and decide which project management principles to apply. The provider concluded that the strategies that best balanced a controlled process with adaptability in these projects came from agile project management, particularly its scrum framework. The method, often used in software development, is employed when the requirements the software must meet change over time because of competitive intelligence or other factors, and it uses continuous planning to identify and implement change rapidly. In all three projects, microdrafts were produced in short sprints between other milestones such as internal and stakeholder meetings, continuously delivering a work product informed by feedback at every stage. Early and frequent delivery of microdrafts maintains momentum and reduces both the amount of work done late in the process and the chance that late-breaking information jeopardises quality or on-time delivery. Producing high-quality microdrafts required the authoring team to stay in regular contact to self-regulate, agree the tasks to be done, check progress and correct course as needed. The method's focus on optimal technical quality and design is aligned with the rigour regulatory documentation requires and with the need to position it for its intended audience, and its approach to simplicity is aligned with the latest lean authoring trends in regulatory writing.
Any methodology must be paired with the best tools, systems and practices. Setting expectations for how the team would work together, outlining roles and responsibilities and scheduling regular checkpoints were critical success factors in every project. Managing systems access and training proactively, with a dedicated IT business partner to triage technical problems, made authoring more efficient in some of the projects, even remotely. No system is perfect, and telling reviewers a system's limits may help avoid pitfalls, such as a sponsor's SharePoint set up to keep only a certain number of versions, or contractors who may not have compatible versions of Microsoft Office for coauthoring. Archiving the comments and decisions produced in any system requires the writer's discipline and should follow best practices and sponsor procedures so that the rigour of regulatory documentation is met.
Project management software was critical to every project, and some of its features that regulatory writers seldom use have become critical for assessing the available resource pool. For example, the project utilisation feature, which shows the exact hours a writer will be dedicated to a project between a task's start and stop dates, had been underused by the provider. As the pandemic progressed and project complexity grew, the provider implemented the software's enterprise resourcing function, giving automatic initial notification of project plan updates between regular checkpoints. After its analysis, the provider also invested in Power BI business intelligence software to visualise data from several enterprise applications, including project management and customer relationship management software, which let its leadership track resource allocation efficiently and other details, including the funds remaining on work orders at both client and contractor level.
Communication was paramount in completing each document, and although the teams came to different conclusions about meetings, each decided in advance how often and how to interact. Setting such expectations at the start of a project both increases the odds of its technical success and manages the potential for over-accessibility and burnout. A team that cannot pull away from its digital tools because of an inundation of competing requests cannot get the work done. One sponsor acknowledged a history of exactly this problem and successfully addressed it by dividing meeting attendance. Several agile principles, including the preference for face-to-face interaction, a sustainable pace and leaving the team to produce the deliverable, therefore need to be balanced.
What the agile approach costs
Agile assumes that workers' time is retained, mostly available and free of other distractions so that they can pivot. Regulatory writing resources, however, often cover several deliverables across several programmes, so properly resourcing agile projects may raise a department's overall budget. The chance of reaching the market sooner may outweigh that burden. The approach may not be how every regulatory writer wants to work, and it works best when a team wants to innovate rapidly in its own way. Making it routine could increase the risk of burnout and make workers lose faith in the prioritisation, trust, teamwork and problem-solving that are core to the method. The method may also need writers experienced enough to pivot as needed. Experienced writers are a finite part of the workforce and demand for this way of working may increase, so this could leave a large gap in the available resource pool that leadership in the regulatory writing field needs to address urgently.