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Considerations for Effective Clinical Overviews for Regulatory Submissions

31 Oct 2023
The Clinical Overview is an integral component of Module 2.5 of the Common Technical Document (CTD) for prospective clinical studies conducted by the product innovator. The Clinical Overview succinctly presents crucial and extensive data from drug development presented in other CTD modules and facilitates the critical review of a drug's benefit-risk profile. This summarized document is, therefore, a pivotal part of drug approval submission to regulatory agencies like the FDA or EMA. It enables the health authorities (HAs) to make an informed decision on the approval of a product for marketing through a document that summarizes the extensive detail provided in other sections of the CTD.
Authoring Clinical Overviews presents several challenges due to the complexity of the drug development process, the vast data available for analysis and presentation, and the stringent regulatory requirements, including but not limited to:
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:
Carefully considering various clinical endpoints, adverse events, and patient populations.
Balancing potential benefits against risks with expertise and thorough analysis.
Regulatory compliance:
Awareness of the changes to regulatory requirements.
Adherence to market-specific regulatory guidelines 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.
The information presented in a Clinical Overview determines the fate of the product in the market – be it an outright rejection of marketing authorization for the product, drug withdrawals on account of concerns over a drug's safety profile, or questions being raised on the efficacy of the drug in the intended indication and/or population.
Taking into consideration the criticality of the Clinical Overview, it becomes imperative to focus on adopting best practices. Focusing on the key areas, listed below, during the development of Clinical Overviews, can increase the probability that the submission is well received by HAs, ultimately minimizing the need for back-and-forth communication with the HA.
Planning and Collaboration:
Start Early: Begin the clinical overview preparation early in the drug development process to allow ample time for data compilation, analysis, and review.
Pre-Submission Meeting: 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: 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: 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 regulatory expectations and standards.
Content and Flow:
Compliance: 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: 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: 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: 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.
Comprehensive Literature Review: Include relevant references and citations that support the key message of the submission with emphasis on populations or geographies of interest. Ensure that cited studies are credible and peer-reviewed.
Language: 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 submission.
Consistent Messaging: Ensure consistency in key messaging between the Clinical Overview and other submission sections, including the clinical summaries in Module 2.7, Module 3 (Quality), Module 4 (Nonclinical) in the CTD. And Module 5 (Clinical study reports).
Quality Control: Perform thorough quality control checks to identify and correct any content and typographical errors, inconsistencies, or formatting issues.
Regulatory Awareness:
Being Aware: 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: Keep abreast with 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 submissions 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.

Author

Vladimir Penkrat
Vladimir Penkrat
Dr. Aditi Nadkarni
Dr. Aditi Nadkarni

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