Writing an accelerated submission
A submission dossier that normally takes months sometimes has to be written in weeks. Neither longer hours nor more writers make that possible by themselves; it turns on preparation that starts before the data exist, lean authoring with disciplined review and quality control, and a team organised to keep the documents consistent.
A normal timeline and an accelerated one
Accelerated regulatory submissions pose major challenges even to the most experienced medical writers. A regulatory submission dossier is a major undertaking that requires thousands of hours of work and usually takes several months. Project teams typically need four months to deliver the clinical documents, such as the pivotal clinical study report (CSR) and the high-level documents, which include the CTD Module 2.7 summaries and the Module 2.5 clinical overview. Four months may seem a reasonable time, but most authoring teams find the experience stressful. The sheer volume of work, combined with challenges in data interpretation and the complexity of the documents, can overwhelm an inexperienced team.
Some applicants use programmatic methods to detect adverse drug reactions, but the process cannot be fully automated, because it requires careful review by safety physicians and risk-management experts. Mistakes in it can have disastrous consequences for patients, healthcare professionals and health authorities, as well as legal and financial consequences for the applicant. Identifying adverse drug reactions is therefore a crucial process that cannot be rushed.
Project teams nevertheless often find themselves under pressure to accelerate submissions, and the pressure can come from company management, from health authorities or from both. In the COVID-19 pandemic, when tens of thousands of people were hospitalised and entire countries went into lockdown, every day counted.
Accelerated submissions may force teams to cut document production timelines drastically, from four months to four weeks in cases of hyper-acceleration. Working longer hours is not sufficient to meet such timelines, since there are still only 24 hours in a day. Stress, fatigue and sleep deprivation can lead to errors and poor document quality. Allocating more resources to the submission is not sufficient either. Experience shows that resource requirements increase exponentially as timelines shorten. For a four-week submission, the applicant may need 20 writers or more, depending on the complexity of the dossier.
In a typical submission the team writes the pivotal CSR before the high-level documents, because that staggered process makes content easier to reuse. In an accelerated submission this staggered approach is not always possible, and several documents may be authored in parallel. Keeping the documents consistent with each other then becomes a major challenge for the team. Coordinating writers who work on different documents is an issue, and frequent team meetings further reduce the time available for authoring. Teams may find that they can devote quality time to their documents only at weekends.
Unexpected clinical findings or feedback from health authorities can force the applicant to conduct unforeseen post-hoc analyses or even change the regulatory strategy. In some cases, major comments from senior stakeholders can trigger a rewrite of some sections or of whole documents.
A high-quality dossier is nevertheless possible even under hyper-accelerated timelines. Preparation and process optimisation are essential to it, and medical writers should drive them.
Preparation before the data exist
Teams should start preparing for a submission well in advance, several months before database lock of the pivotal studies. The first step is a kick-off meeting at which all submission-related activities are discussed. The team must devise a clear plan for those activities, with timelines for data-independent and data-dependent writing of the clinical documents. Data-independent writing can start shortly after the meeting.
Teams should also consider preparing a storyboard, a concise, high-level distillation of all aspects of the clinical submission story. The storyboard is used to secure cross-functional alignment on the dossier's key messages and stakeholders' endorsement of the submission strategy. The advantages of a well-developed storyboard are numerous, and they include an early focus on the desired label, clarity on the submission's scope and purpose, and identification of major scientific issues, gaps and potential regulatory hurdles. It has to be revised once the pivotal data become available.
During preparation, teams may populate the data-dependent sections of the clinical documents with shell or dummy tables. This helps to ensure that the programmed tables and figures are adequate to support the key messages, and it helps to identify gaps in the statistical analyses. Writing complete clinical documents on dummy data can prove risky, because it may give teams a false sense of security. Once the real data arrive, simply replacing the dummy numbers with real ones often proves insufficient, especially in the high-level documents, which must analyse the findings critically as well as summarise the data. Placeholder text must be rewritten with that in mind.
One medical writing team, whose work did not pause during the pandemic, often preplans global submissions by starting its documents much earlier, even before the final clinical trial is complete, with region-specific background text and assumed successful outcomes. In that team's view, adding more automation and technology to such early writing can help to reduce the writers' time and effort, and it may reduce rework in the later stages of document development.
In the five years before 2022, the FDA introduced initiatives that affect the regulatory writer. Real-Time Oncology Review and the Assessment Aid aim to increase the speed of information for regulatory review, and they require meticulous planning and focused reporting of complex, approval-supporting data with quality. Parallel review initiatives such as the FDA's Project Orbis require new approaches to working concurrently, and with speed, with several participating countries.
Data interpretation and authoring
In the interest of time, some teams want to shorten data interpretation meetings or skip them altogether and rely on the medical writers to interpret the data. One experienced regulatory writer does not recommend this, because it is counterproductive. Even in the fastest submission, the team must find time to analyse the data and reach cross-functional alignment on the key messages. Early stakeholder buy-in is also important to reduce the risk of major comments during document review.
During data-dependent authoring, medical writers should follow lean authoring principles and avoid repetition in the high-level documents. Rather than repeat information available elsewhere in the dossier, the documents should link to the relevant CTD sections.
Review and quality control
Document review and quality control (QC) can be as challenging as authoring in a fast-paced submission. Reviewer discipline is always important, and it becomes critical when timelines are squeezed. Both the number of reviews and their duration are then reduced. One experienced regulatory writer usually recommends two review rounds for each document, and a single round may be sufficient if the reviewers are relatively few, between 10 and 20. In large companies the number of reviewers can be much higher, and a single document can draw hundreds of comments. In such cases, the team can consider holding a team review first and a stakeholder and management review after it. Reviewers should be encouraged to conduct strategic, substantive review, and medical writers have an important role in educating them in good review practice. Comments should be specific, directive and based on facts rather than personal preferences.
Accelerated submissions do not always allow time for a separate QC step, so QC can run in parallel with the last review round. A final QC should be done once all comments are addressed, and it focuses only on the changes made since the last draft. Medical writers should keep redline copies so that QC specialists can find those changes easily. Teams should avoid amending documents after the final QC, because last-minute changes can result in discrepancies and lead to other quality issues.
The submission team
Effective teamwork is essential in accelerated submissions. The whole submission team must work as a well-oiled machine, with efficient processes, well-defined roles and responsibilities and clear lines of communication. Any duplication of work should be avoided, content should be reused as much as possible, and teams should refrain from rewriting text that has been reviewed and approved.
Every team of medical writers needs a submission lead, and in an accelerated submission the lead does not always have time to author documents. The rule of thumb is at least one person in charge of coordination for every ten writers, so a team of 22 writers requires at least two full-time coordinators. A team that large should consider preparing a charter so that everyone is aware of their roles and responsibilities. It may also help to set up sub-teams, with sub-team leads reporting to the submission lead, to make coordination and communication easier. Regular meetings are a necessity, but teams should find the right balance between attending meetings and working on documents. Submission leads and coordinators should attend all meetings relevant to the submission, and writers of individual documents only the most important ones, such as data interpretation meetings.
Consistency across the dossier
Maintaining consistency throughout the dossier is a major challenge in accelerated submissions. The submission lead has a key role in it, but a single person does not always have time to review every document in detail. Writers should also review each other's documents to help alignment. The authors of the efficacy, safety and pharmacology summaries, for example, should review the corresponding sections of the clinical overview. Ensuring consistent safety messaging between the CSRs, the summary of clinical safety, the clinical overview and the risk management plan is also critical.
What an accelerated submission offers the team
Delivering a submission dossier in record time often seems a daunting task, but great challenges bring equally great opportunities. Successful accelerated submissions foster a spirit of cooperation and camaraderie that can last for years and benefit the team in many ways. They are also an opportunity to innovate and optimise company processes. Finally, they are an excellent opportunity for professional development for every member of the submission team.