The Clinical Overview is a pivotal component of the Common Technical Document (CTD) that provides a critical analysis of the clinical data supporting a marketing application. This whitepaper outlines its purpose and structure, highlighting the need for a clear interpretation of clinical findings rather than mere data recapitulation. It covers essential elements like clinical development strategy, benefit-risk assessment, and regulatory compliance. The paper addresses common challenges in drafting Clinical Overviews, including maintaining consistency, ensuring data integrity, and effective interdisciplinary collaboration. It offers practical advice for creating concise, accurate, and compliant Clinical Overviews to support successful regulatory submissions and drug approvals.
Introduction
The Clinical Overview is intended to provide a critical analysis of the clinical data in the Common Technical Document (CTD). The Clinical Overview will necessarily refer to application data provided in the comprehensive Clinical Summary, the individual clinical study reports (ICH E3), and other relevant reports; but it should primarily present the conclusions and implications of those data and should not recapitulate them. Specifically, the Clinical Summary should provide a detailed factual summarization of the clinical information in the CTD, and the Clinical Overview should provide a succinct discussion and interpretation of these findings together with any other relevant information (e.g., pertinent animal data or product quality issues that may have clinical implications).
The Clinical Overview is primarily intended for use by regulatory agencies in the review of the clinical section of a marketing application. It should also be a useful reference to the overall clinical findings for regulatory agency staff involved in the review of other sections of the marketing application. The Clinical Overview should present the strengths and limitations of the development program and study results, analyze the benefits and risks of the medicinal product in its intended use, and describe how the study results support critical parts of the prescribing information.
To achieve these objectives, the Clinical Overview should:
- Describe and explain the overall approach to the clinical development of a medicinal product, including critical study design decisions
- Assess the quality of the design and performance of the studies and include a statement regarding good clinical practice (GCP) compliance
- Provide a brief overview of the clinical findings, including important limitations (e.g., lack of comparisons with an especially relevant active comparator; absence of information on some patient populations, on pertinent endpoints, or on use in combination therapy)
- Provide an evaluation of benefits and risks based on the conclusions of the relevant clinical studies, including an interpretation of how the efficacy and safety findings support the proposed dose and target indication and an evaluation of how prescribing information and other approaches will optimize benefits and manage risks
- Address particular efficacy or safety issues encountered in development and how they have been evaluated and resolved
- Explore unresolved issues, explain why they should not be considered barriers to approval, and describe plans to resolve them
- Explain the basis for important or unusual aspects of the prescribing information
The Clinical Overview should generally be a relatively short document (about 30 pages). The length, however, will depend on the complexity of the application. The use of graphs and concise tables in the body of the text is encouraged for brevity and to facilitate understanding. It is not intended that material presented fully elsewhere be repeated in the Clinical Overview; cross-referencing to more detailed presentations provided in the Clinical Summary or in Module 5 is encouraged.
Because of the intricacy of the drug development process, the abundance of data available for analysis and presentation, and the strict regulatory requirements, writing Clinical Overviews can be difficult in a number of ways. These issues involve, among other things:
Maintaining consistency and clarity:
- Ensuring consistency of key messaging across the different modules.
- Effectively conveying complex scientific concepts in an understandable manner.
- Striking a balance between scientific accuracy and accessibility. For example, presenting accurate clinical evidence while addressing any ambiguities arising from patients discontinuing a clinical study prematurely.
Planning and coordination:
- Planning of the modules and coordination between the medical writers and the cross-functional teams, including clinicians, statisticians, pharmacologists, and regulatory professionals, so as to align with submission timelines.
- Integrating expertise to create a coherent and accurate overview, such as in the case of Biopharmaceutics and BA/BE information versus Pharmacology and PK/PD information.
Benefit-risk assessment in clinical trials
Carefully considering various clinical endpoints, adverse events, and patient populations.
Balancing potential benefits against risks with expertise and thorough analysis.
Regulatory compliance in clinical trial operations
- Awareness of the changes to regulatory requirements.
- Adherence to market-specific Regulatory guidelines for clinical trials and standards to meet HA expectations.
- For example, as it relates to the benefit-risk profile, there is significant update toward a structured approach and framework for B-R assessments, including the recent Prescription Drug User Fee Act (PDUFA) VII and goals related to structured BR and patient preferences, the formal qualification from the EMA Committee for Medicinal Products for Human Use (CHMP) in May 2022 of the Patient Preferences in Benefit-Risk Assessments during the Drug Life Cycle (PREFER) project framework on benefits risk and the upcoming thinking in 2023 from CIOMS XII Working Group on BR balance of medical products.
Planning and Collaboration for clinical operations
Start Early:Â Begin the clinical overview preparation early in the drug development process to allow ample time for data compilation, analysis, and review.
Pre-Submission Meeting:Â Collaborate with regulatory colleagues and consider requesting a pre-submission meeting between the regulatory authority and the core subject matter experts (SMEs) from safety, medical, clinical, pharmacology, statistics, and epidemiology to discuss the content, format, and any potential concerns, based on initial data analyses, regarding the clinical overview as well as timelines for submission.
Meet Regularly:Â Schedule a kick-off meeting and a regular series of meetings for the team to stay connected and aligned on timelines for authoring, review cycles, the flow of content and style, awareness of dependencies, or any potential delays that can be communicated in real-time.
Plan Well:Â Draft realistic timelines, factor in buffer time, and identify rate-limiting bottlenecks that may arise during Clinical Overview development and require truncating of timelines. Identify the sequence of development of the various CTD components calling out interdependencies. Explore the best approach feasible to work smart – the possibility of adopting a follow-the-sun model to make the best possible use of time. Align the writing team with the creation of a document shell/outline with clear instructions so that the resultant Clinical Overview contains the right amount of well-organized data adhering to the 30-page limit recommendation per regulatory guidelines. Write different sections as and when data becomes available, and do rolling reviews to save reviewer time and catch any needed changes early. Plan review slots for all reviewers, especially when the same team is working on multiple documents.
Team Work Prevails: Engage experts from various disciplines, such as safety, clinicians, statisticians, pharmacologists, and regulatory affairs professionals, to ensure comprehensive and accurate content. Engage with the regulatory affairs team to ensure the Clinical Overview meets the standards from a regulatory perspective.
Content and Flow for clinical overview
Compliance:Â Follow the CTD format for the Clinical Overview. Provide clear headings, subheadings, and a logical flow to facilitate the regulatory review process. Adhere to formatting requirements specified in the CTD with accurate cross-referencing and linking to appropriate modules, such as the list of literature references cited in the Clinical Overview or the clinical study reports in Module 5 of the CTD. Finalize the style guide to ensure consistency in fonts, styles, and headings for a professional and organized presentation.
Transparency/Accurate Data Presentation:Â Present clinical trial data accurately and objectively while avoiding selective reporting. Ensure the accuracy, integrity, and traceability of the data presented. Maintain detailed records of all data sources and analyses.
Lean Writing:Â Adopt a deductive writing style with the key message/inference presented upfront followed by supporting evidence. Organize content as bullet points, tabular summaries, and short, focused paragraphs that would facilitate the provision of easy-to-read relevant information to the target audience, improve comprehension, and avoid misinterpretation. Do not repeat data across sections in the Clinical Overview or across related CTD modules. Instead, adopt effective cross-referencing and bookmarking, such as cross-referring inferences and key messages in the Clinical Overview with relevant data from the summary documents, which contain data at the study level.
Realistic Interpretations:Â Avoid overly optimistic or speculative interpretations of data that could misrepresent the drug’s profile, and address both positive and negative findings transparently while discussing data limitations or challenges encountered during the study conduct or data collation. Base conclusions on solid evidence and statistical analyses. Clearly describe adverse events and serious adverse events, providing context and potential implications.
Realistic Interpretations:Â Avoid overly optimistic or speculative interpretations of data that could misrepresent the drug’s profile, and address both positive and negative findings transparently while discussing data limitations or challenges encountered during the study conduct or data collation. Base conclusions on solid evidence and statistical analyses. Clearly describe adverse events and serious adverse events, providing context and potential implications.
Language:Â Maintain a scientific and non-promotional tone throughout the clinical overview. Use clear and concise language to convey complex scientific concepts while adopting a direct form of writing with the use of active voice, strong subject-verb object patterning, and sparing use of hedging (appears/seems to be/may/probably/unlikely), qualifiers or modifiers (quite/very/less/rather/indeed/basically/somewhat/slightly/generally) or redundant terms (past medical history/end result/combined together).
Data Integrity and Quality
Data Validation: Subject the Clinical Overview to rigorous internal review by experts from various disciplines, including safety, clinical, statistics, pharmacology, chemistry, manufacturing, and controls, toxicology, and regulatory affairs to ensure data accuracy with clear messaging. Address all feedback and ensure accuracy before Clinical Overview Submission.
Consistent Messaging:Â Ensure consistency in key messaging between the Clinical Overview and other submission sections, including the clinical summaries in Module 2.7, Module 3 (Quality), and Module 4 (Nonclinical) in the CTD. And Module 5 (Clinical study reports).
Quality Control:Â Perform thorough quality control checks to identify and correct any content and typographical errors, inconsistencies, or formatting issues.
Regulatory Awareness
Being Aware:Â Understand the unique requirements of each regulatory authority based on regulatory guidelines for clinical overview preparation. Ensure that relevant components of the submission are included, such as Form 1.4.3, signed by a licensed clinical or medical expert, and included in the submission along with a curriculum vitae for a new product registration.
Stay Updated:Â Keep abreast of any changes or updates to the regulatory guidelines. Ensure data from clinical trials or published literature specific to populations of interest are provided.
In summary, authoring Clinical Overviews for CTD regulatory submission involves navigating complex data, regulatory requirements, interdisciplinary collaboration, and effective communication. Overcoming these challenges is essential to creating accurate, compliant, and transparent documents that facilitate successful regulatory reviews and drug approvals.
