Those who have worked in clinical research and drug development for a decade or more (or even several decades) will attest to the evolving nature of regulatory documents, particularly regarding their length and complexity. If you have ever wondered if clinical study reports (CSRs) are getting much longer – no, it is not a figment of your imagination. We at Niche Science & Technology Ltd have been asking ourselves about the reasons behind this shift, some of which may be attributed to changes in regulatory requirements and the expanding length and complexity of clinical protocols.
Evolution of Clinical Trial Protocols
Until the late 1980s, early phase CSRs were often 20 to 30 pages in length. Today, CSR synopses alone approach or surpass that length. We recently worked on a CSR for a relatively standard Phase II trial that had a synopsis of over 20 pages and the report itself had a total page count of over 150 pages (excluding the post-text tables and appendices). When it comes to Phase III CSRs, they routinely span 250 pages or more (again, without factoring in the appendices). While many of the changes in clinical trials since the 1990s have been positive, it is important that CSRs do not become excessively large and unwieldy. Shorter technical reports are known to enhance clarity and user engagement, whereas lengthy reports often include extraneous information that can obscure your key findings [1, 2]. Authors need to consider how they can avoid the downsides of longer documents, and conversely, glean the benefits of shorter ones.
In addressing these concerns, medical writers and other CSR stakeholders can be empowered to make decisions on whether or not to include certain information. In terms of trial reporting, recent years have seen a tendency towards risk avoidance, leading to the inclusion of every detail from the methods documentation (protocol and statistical analysis plan) and all data from the tables, figures and listings (TFLs) within the main body of the CSR. Considering past tragedies that have hit clinical development with the TeGenero and BIAL incidents [3, 4], it is only natural to take a low-risk approach. However, the concern remains that leaving out information – no matter how minor – could open the door to potential criticism from senior reviewers and regulatory authorities. While including everything seems like the safest option, medical writers equipped with advanced training and experience can guide study teams on determining the appropriate level of detail and identify noncritical information that can be excluded. This approach enhances clarity without compromising regulatory compliance or transparency.
In addition to the concerns about inadvertently leaving out something important, another reason for the increasing length of CSRs is the growing complexity of trial designs and the subsequent expansion in clinical trial protocol length. Since the 1980s, there has been a consistent rise in trial complexity (e.g., number of trial endpoints, number of participant groups). This rise is illustrated in a 2023 publication [5] that analysed more than 180 Phase I–III protocols. In Phase II and III trials conducted between 2009 and 2020, several trial design factors demonstrated growth, including:
The authors attributed these changes largely to an increase in customised drug development strategies aimed at addressing challenging disease targets, particularly in therapeutic areas like oncology and rare diseases [6]. In another study of more than 16,000 trials, a machine learning algorithm was used to evaluate trial features such as number of endpoints, number of eligibility criteria, and number of trial arms [7]. A complexity score was assigned to each of the evaluated trials and showed substantial increases across all trial phases over the period 2011 to 2022, with the average score increasing by more than 10 percentage points in that time. The COVID-19 pandemic further accelerated this growth in trial complexity, with adaptive trial designs increasingly being implemented to allow flexibility of study conduct in an uncertain environment [8]. For example, the adaptive design of the Randomised Evaluation of COVid‑19 thERapY (RECOVERY) trial allowed the inclusion of numerous different treatment arms, which could be rapidly closed if a treatment was shown to be ineffective (or effective) in patients with COVID-19. This flexibility allowed results to be disseminated quickly, in the case of emergent dexamethasone intervention, this approach most likely saved the lives of many patients [9, 10].
Another consequence of increasing trial design complexity is a higher number of protocol amendments. A recent study of 950 trials conducted between 2015 and 2022 showed that the percentage of Phase I–IV protocols with at least one amendment increased from 57% to 76% and the mean number of amendments increased by 60%, from 2.1 to 3.3 amendments per protocol. This increase in amendments was particularly apparent during the COVID-19 pandemic [6]. The increased frequency in amendments was attributed partially to recruitment difficulties in challenging therapy areas (such as oncology) or rare patient populations. For example, a study of 249 oncology and 701 non-oncology protocols showed that a larger proportion of oncology trials had at least one amendment compared with non-oncology trials (91.1% vs. 72.1%) [11].
Clinical Study Report Development
Although the bulk of any CSR is based on the most recent version of the protocol, the CSR also needs to summarise the changes introduced in each protocol amendment as per the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, E3 guideline on structure and content of CSRs (ICH E3), impacting on CSR length [12].
For trials that do not fit easily within the ICH E3 guidance (e.g., pharmacokinetic trials or trials with quality of life outcomes), strict adherence to the template can lead to repetition and poor presentation. Authors should adapt their document to better fit the needs of their particular trial; indeed, the ICH E3 Questions and Answers document states that “ICH E3 is a guideline, not a set of rigid requirements or a template, and flexibility is inherent in its use. […] Modifications and adaptations to the structure presented in the guideline that lead to better display and communication of information are encouraged” [9]. Thus, sections that are not relevant can be deleted and new sections may be added. The CORE Reference Manual for CSRs retains the Level 1 heading hierarchy of ICH E3 but beyond that, suggests that the CSR authors may use their discretion to decide on the most appropriate CSR structure [13].
Concise documents are always more desirable (where possible) as they focus on the important trial findings without distracting the reader with unnecessary details. Appropriately structuring CSRs and cross-referencing ensures that additional information is easily accessible in the post-text tables and appendices, which also include all protocol versions, the full statistical analysis plan, and all of the data. For further tips on CSR development, see our ‘Insider’s Insight into Clinical Study Reports’ (https://www.niche.org.uk/resource_insiders_insight.html). When writing documents, it is good to look for opportunities to keep things concise. Areas that can be targeted include:
A medical writer following the principles of lean CSR writing focuses on the key messages of a clinical trial and steers clear of duplication within the document. This ensures straightforward, clear, streamlined writing, and avoids repetitive text. In the methods sections, cross-references to the protocol and statistical analysis plan can be included rather than providing lengthy explanations. In the results, reference can be made to other sections, tables and appendices to avoid repetition of the data. In the demography, rather than re-stating the summary data from the source table, the text should pick out any differences between groups that might affect data interpretation. For efficacy, where statistical analyses have been conducted, a lean CSR focuses on the interpretation of the statistical findings rather than presenting detailed in-text displays of all the summary statistics. In the safety results, cut-offs can be used for adverse event data by only including adverse events reported in a certain percentage of participants (e.g., ≥5%) in the in-text tables, rather than all events. For laboratory data and vital signs, the description of any clinically significant results should be prioritised, along with findings that were reported as adverse events. In conjunction with the review team, an experienced medical writer can use their knowledge and judgement to summarise very large amounts of clinical trial data concisely, meaningfully, and in a readable and accessible format, without omitting any important findings. By streamlining and focusing on the most relevant information, this approach directly supports the ultimate goal of the development programme: assisting regulators in their review and assessment of regulatory documents, which could increase the likelihood of obtaining approval and help bring new medicines to patients more quickly.
The new ICH M11 protocol template is expected to be adopted in Autumn 2025 [15]. The guideline places a renewed focus on quality and the introduction of specific protocol headings. The advantages of ICH M11 include the introduction of internationally harmonised protocol structure and content, along with efficiencies in most steps of trial conduct (e.g., trial design, investigator on-boarding, trial setup, trial reporting, and review). Once adopted, this template will greatly help report authors in locating relevant information to include in CSR Section 9.6 (Quality Assurance).
An additional consideration impacting on clinical research teams stems from the current industry landscape, where compounds are frequently bought and sold during the course of their development. This often leads to high rates of staff turnover, requiring new team members to familiarise themselves with (increasing) volumes of data midway through the development process. It is becoming increasingly rare for team members to be involved in a project from the beginning. This dynamic can result in potential misunderstandings and requests for clarification (sometimes from senior staff members), leading to detail being included in CSRs that might otherwise not have been contemplated.
When considering the CSR’s results, opportunities exist to reduce the size of the document. It is not necessary to re-iterate information already present in the in-text tables and figures; rather, important data can be highlighted in the text, along with a reference to the relevant display. Concerns often arise that regulators may miss important points if they are not ‘hammered home’, but in reality, a clear and concise presentation can assist the reader’s comprehension. Further, there is no need to present each post-text table and figure as an individual in-text display. Instead, the decision can be made to only include key tables and figures in the main body and cross-reference others with a short descriptive paragraph. The medical writer and the CSR review team must draw upon their experience and confidence to discern between essential and non-essential information. Nevertheless, writers must remember to briefly describe (or at the very least, refer to) each one of the source tables and figures within the main body, even if a decision has been made not to include them as in-text displays.
In the current clinical research environment, CSRs will realistically continue to be longer than they used to be. Nevertheless, continuing to look for opportunities to keep documents concise, where feasible, will bring its own rewards and aligns with the current drive towards good trial design and heightened data quality, as exemplified in the concept of ‘quality by design’ (ICH E8) [16]. In addition, fostering critical thinking, open dialogue and stakeholder engagement in trial designs, including patient engagement initiatives, will likely improve the quality of CSRs as a natural outcome of better clinical trial protocol designs. These concepts are reinforced in the recent update to the Declaration of Helsinki, which states “Meaningful engagement with potential and enrolled participants and their communities should occur before, during, and following medical research” [17]. While efforts to streamline CSR content can enhance clarity and focus, a CSR is fundamentally only as good as the protocol and underlying source data, making the collaboration between medical writer and trial teams essential to producing high-quality reports.
References
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