'Femi Fajimi

Writing Clinical Overviews and Clinical Summaries in Regulatory Submissions: A Regulatory Writing Walkthrough with Oncometherin 

By Femi Fajimi | 26 July 2025 

(Educational content. Oncometherin is a fictional investigational product.) 

Introduction: Clinical Modules at the Heart of Regulatory Submissions 

Regulatory medical writers play a pivotal role in preparing the documentation that supports new medicine applications. Among the most essential deliverables in a Common Technical Document (CTD) submission are Module 2.5 (Clinical Overview) and Module 2.7 (Clinical Summary). These documents serve as the reviewer’s guide to the entire clinical dataset and must be scientifically sound, logically structured, and compliant with ICH guidelines (notably ICH E3 and M4E(R2)). 

While Module 2.7 summarises the detailed data from clinical study reports (found in Module 5), Module 2.5 interprets these findings from a high-level clinical and regulatory perspective. Together, they form the analytical core of a Marketing Authorisation Application (MAA) or New Drug Application (NDA). 

In this post, I’ll walk through both modules using a fictional anticancer drug, Oncometherin, a novel small-molecule tyrosine kinase inhibitor (TKIs) being developed for advanced non-small cell lung cancer (NSCLC). Though imaginary, this case study is designed to mirror real-world regulatory writing practice and highlight the critical thinking, scientific synthesis, and cross-functional input required to create effective clinical documents. 

About the Fictional Drug: Oncometherin 

Oncometherin (ONM-21) is an oral selective tyrosine kinase inhibitor designed to target EGFR and ALK mutations in advanced NSCLC. Phase I and II trials have been completed in patients who failed at least one prior line of therapy. The sponsor is preparing an MAA submission to the EMA, supported by pivotal Phase II data and additional supportive studies. 

The Clinical Overview and Clinical Summary are now being written to compile, interpret, and contextualise the clinical findings for regulators. 

Module 2.5: The Clinical Overview – Framing the Story 

The Clinical Overview (as defined by ICH M4E(R2)) is a concise, integrated review of the clinical information in the submission. It provides the scientific rationale and benefit–risk assessment for the medicinal product. It is typically authored or heavily supported by medical writers, often in collaboration with clinical, pharmacovigilance, and regulatory leads. 

Structure of the Clinical Overview: 

1. Product Development Rationale and Overview 

2. Clinical Pharmacology 

3. Efficacy 

4. Safety 

5. Integrated Benefit–Risk Conclusion 

Example from Oncometherin: 

1. Product Development Rationale and Overview: 

“Oncometherin (ONM-21) was developed to address the unmet clinical need in EGFR-positive and ALK-rearranged NSCLC patients resistant to first-line TKIs. Preclinical models demonstrated potent dual inhibition of EGFR and ALK pathways, which justified its selection for clinical evaluation. A total of six studies were conducted, including one first-in-human trial, two dose-escalation studies, and a pivotal open-label Phase II trial enrolling 147 patients with advanced NSCLC.” 

2. Clinical Pharmacology: 

This section covers pharmacokinetics (PK), pharmacodynamics (PD), and exposure–response data. The writer must clearly interpret how the clinical pharmacology profile supports dose selection and safety monitoring. 

“Oncometherin exhibited linear PK across the 50–200 mg once-daily dose range. Steady-state was reached by Day 5. Mean C_max at the 150 mg dose was 320 ng/mL, exceeding the preclinical IC₅₀ values for EGFR inhibition. No significant food effects or clinically relevant QT prolongation were observed. Based on exposure–response modelling, the 150 mg dose was selected for Phase II trials.” 

3. Efficacy: 

A concise synthesis of key efficacy findings across trials. Often structured around population, endpoints, results, and clinical interpretation. 

“In the pivotal Phase II study (ONM-202), the ORR was 42.5% (95% CI: 34.1–51.3) and median PFS was 5.9 months in patients with prior TKI failure. Response was consistent across EGFR and ALK subgroups. Durable responses were observed in 28% of patients, with a median DoR of 7.2 months.” 

4. Safety: 

A high-level summary of safety signals, adverse events, serious adverse events (SAEs), and discontinuations. Medical writers must ensure consistency with the Clinical Summary and reference tables/appendices. 

“Across 412 patients, the most common treatment-emergent AEs were rash (34.5%), diarrhoea (29.1%), and fatigue (21.3%). Grade ≥3 AEs occurred in 18.2%, with transaminase elevations being the most frequent laboratory abnormality. Four patients (1.0%) discontinued due to hepatotoxicity. There were no treatment-related deaths.” 

Adverse Event (AE) Grading (CTCAE Standard) 

Grade	Severity Level	Definition (Simplified)	Example (Common in Oncology)
Grade 1	Mild	Asymptomatic or mild symptoms; no intervention needed	Mild rash, slight fatigue
Grade 2	Moderate	Some impact on daily activities; minimal intervention required	Moderate diarrhoea, low appetite
Grade 3	Severe	Limits self-care and daily activities; hospitalisation may be needed	Severe nausea, elevated liver enzymes
Grade 4	Life-threatening	Urgent intervention required; immediate risk to life	Severe neutropenia with fever
Grade 5	Death	Death related to the adverse event	Fatal anaphylaxis or cardiac arrest

5. Benefit–Risk Assessment: 

The culmination of the overview, articulating a reasoned conclusion based on the preceding sections. 

“The benefit–risk profile of Oncometherin is favourable in patients with advanced NSCLC after first-line TKI failure. The observed response rates and progression-free survival outcomes compare well with historical controls, and the safety profile is manageable with routine monitoring. The data support approval of Oncometherin 150 mg once daily for this indication.” 

What the Medical Writer Does in Module 2.5: 

• Synthesises complex trial results into a coherent narrative 

• Collaborates with clinical and pharmacovigilance teams to align safety and efficacy narratives 

• Ensures the overview is consistent with source documents (e.g. Clinical Study Reports, Protocols, SmPC drafts) 

• Applies scientific judgment and regulatory awareness to present findings with clarity 

• Formats content according to ICH M4E(R2) and agency preferences 

Module 2.7: The Clinical Summary – Distilling the Evidence 

If Module 2.5 tells the story, Module 2.7 delivers the evidence. The Clinical Summary provides detailed yet synthesised data on all clinical studies conducted with the investigational product. It is structured into five subsections (2.7.1–2.7.5), each corresponding to a specific area of clinical development, and closely reflects the structure of the complete study reports in Module 5. 

This section requires the writer to summarise and tabulate key data, extract trends, and present numerical evidence without interpretation. It must be factually exact, consistently formatted, and supported by clear referencing to CSR tables, appendices, and raw datasets. 

Structure of the Clinical Summary (ICH M4E): 

• 2.7.1 Summary of Biopharmaceutics and Associated Analytical Methods 

• 2.7.2 Summary of Clinical Pharmacology 

• 2.7.3 Summary of Clinical Efficacy 

• 2.7.4 Summary of Clinical Safety 

• 2.7.5 Synopses of Individual Studies 

Oncometherin Clinical Summary Highlights: 

2.7.1 Biopharmaceutics and Analytical Methods 

Oncometherin is formulated as a 150 mg immediate-release oral tablet. Relative bioavailability was evaluated in a crossover study comparing capsules vs tablets (Study ONM-106), which showed 97.8% bioequivalence (90% CI: 93.1–102.2). Food effect studies (Study ONM-108) demonstrated no clinically relevant impact of a high-fat meal on C_max or AUC. 

Bioanalytical methods for PK plasma concentrations were validated using LC-MS/MS with a lower limit of quantification of 0.5 ng/mL. Inter-batch precision and accuracy met EMA and FDA guidelines across all studies. 

2.7.2 Clinical Pharmacology Summary 

This section aligns closely with the content of the Clinical Overview, but now requires precise tabular and numerical details. 

Six clinical pharmacology studies were conducted, including first-in-human (ONM-101), food effect (ONM-108), drug–drug interaction (ONM-110), and renal impairment studies (ONM-112). Oncometherin showed dose-proportional PK over 50–200 mg. No significant accumulation was observed with once-daily dosing. 

Oncometherin did not inhibit or induce major CYP enzymes in vitro. In ONM-110, co-administration with midazolam (CYP3A4 substrate) did not alter its PK profile significantly (GMR for AUC: 1.08; 90% CI: 0.92–1.18). 

The pharmacodynamic marker (phospho-EGFR inhibition in skin biopsies) showed a dose-dependent decrease, with >60% inhibition at 150 mg, correlating with plasma concentrations above 200 ng/mL. 

2.7.3 Clinical Efficacy Summary 

A substantial portion of the Clinical Summary. It covers each study individually and also presents pooled data when appropriate. 

Efficacy was evaluated in three key studies: ONM-201 (dose-finding), ONM-202 (pivotal Phase II), and ONM-204 (Japanese bridging study). The primary endpoint in ONM-202 was objective response rate (ORR) assessed by RECIST v1.1. 

Table – Key Efficacy Results (Study ONM-202): 

Endpoint	Result	95% CI
ORR (%)	42.5%	34.1–51.3
Disease Control Rate	68.7%	60.3–76.1
Median PFS (months)	5.9	4.4–7.1
Median DoR (months)	7.2	5.3–8.4

Subgroup analyses revealed consistent response across patients with EGFR (ORR: 43.8%) and ALK mutations (ORR: 40.9%). Exploratory endpoints included QoL (EORTC QLQ-C30), where improvements in physical and role functioning were observed in 28.6% of patients. 

2.7.4 Clinical Safety Summary 

This section must comprehensively report AEs, lab abnormalities, deaths, discontinuations, and any emerging safety concerns, ideally tabulated and explained with consistent terms (e.g., MedDRA). 

A total of 412 patients were exposed to Oncometherin across all studies. Median duration of exposure was 5.1 months. 

Table – Common Treatment-Emergent Adverse Events (≥10% incidence): 

Adverse Event	All Grades (%)	Grade ≥3 (%)
Rash	34.5	2.1
Diarrhoea	29.1	1.6
Fatigue	21.3	0.8
ALT increase	11.8	1.5
Nausea	14.9	0.2

SAEs were reported in 9.7% of patients, with the most common being pneumonia (1.2%) and elevated liver enzymes (1.0%)—12 patients discontinued due to AEs, including 4 cases of hepatotoxicity. 

There were 3 deaths deemed unrelated to study treatment. No Hy’s Law cases were observed. 

No pattern of QT prolongation was detected. ECG abnormalities were transient and not clinically significant. 

2.7.5 Synopses of Individual Studies 

A series of 1–2 page synopses per study is provided here, following the structure defined in ICH E3. These typically cover study title, design, objectives, methods, results, and conclusions. 

Example: 

Study ONM-202: A Phase II, Open-label Study of Oncometherin in Patients with Advanced NSCLC After First-Line TKI Failure 

Design: Multicentre, single-arm, 147 patients 

Primary Endpoint: ORR (RECIST 1.1) 

Result: 42.5% ORR; 5.9 mo median PFS 

Conclusion: Oncometherin showed clinically meaningful activity with a manageable safety profile 

What the Medical Writer Does in Module 2.7: 

• Extracts and compiles clinical data from multiple CSRs 

• Formats summary tables and ensures accuracy in referencing 

• Aligns content with the Clinical Overview and SmPC 

• Highlights patterns and trends while maintaining objectivity 

• Verifies consistency across study summaries and pooled data 

• Follows the structure defined by ICH M4E and E3 guidelines 

Abbreviations and Definitions 

Abbreviation	Full Term	Definition (for beginner readers)	Where in Post
CTD	Common Technical Document	A standardised format for regulatory submissions to health authorities, including modules on quality, nonclinical, and clinical data.	Introduction
MAA	Marketing Authorisation Application	The formal request to the EMA to approve a medicine for use in the European Union.	Introduction
NDA	New Drug Application	The equivalent of an MAA submitted to the US FDA.	Introduction
ICH	International Council for Harmonisation	An organisation that creates guidelines for drug development across regions (e.g. ICH E3, ICH M4E).	Introduction
NSCLC	Non-Small Cell Lung Cancer	A common type of lung cancer for which Oncometherin is being developed.	About the Fictional Drug
TKI	Tyrosine Kinase Inhibitor	A class of drugs that blocks enzymes (tyrosine kinases) involved in cancer growth.	About the Fictional Drug
PK	Pharmacokinetics	The study of how a drug is absorbed, distributed, metabolised, and excreted in the body.	Clinical Pharmacology (Module 2.5 & 2.7.2)
PD	Pharmacodynamics	The study of the drug’s effects on the body, including mechanism of action.	Clinical Pharmacology (Module 2.5 & 2.7.2)
ORR	Objective Response Rate	The percentage of patients whose tumours shrink (partial response) or disappear (complete response).	Clinical Efficacy (Module 2.5 & 2.7.3)
PFS	Progression-Free Survival	The length of time during which a patient lives without the disease worsening.	Clinical Efficacy (Module 2.5 & 2.7.3)
DoR	Duration of Response	How long the tumour continues to respond to treatment before growing again.	Clinical Efficacy (Module 2.5 & 2.7.3)
AE	Adverse Event	Any undesirable experience associated with the use of a drug.	Safety (Module 2.5 & 2.7.4)
SAE	Serious Adverse Event	A more severe type of adverse event that may be life-threatening or require hospitalisation.	Safety (Module 2.5 & 2.7.4)
CSR	Clinical Study Report	A detailed report describing the methods and results of a clinical trial.	Clinical Summary (Module 2.7, esp. 2.7.5)
SmPC	Summary of Product Characteristics	A document describing how to use the medicine safely and effectively, submitted as part of the regulatory application.	Clinical Overview & Clinical Summary
RECIST	Response Evaluation Criteria in Solid Tumours	A standardised set of rules for measuring tumour response in cancer trials.	Efficacy (Module 2.7.3)
Cmax	Maximum Plasma Concentration	The highest concentration of drug in the bloodstream after dosing.	Clinical Pharmacology (Module 2.5 & 2.7.2)
AUC	Area Under the Curve	A measure of the total drug exposure over time.	Clinical Pharmacology (Module 2.5 & 2.7.2)
LC-MS/MS	Liquid Chromatography–Tandem Mass Spectrometry	A lab technique used to measure drug levels in biological samples.	Biopharmaceutics (Module 2.7.1)
EORTC QLQ-C30	European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire	A questionnaire used to assess quality of life in cancer patients.	Clinical Efficacy (Module 2.7.3)

Final Thoughts 

Writing Modules 2.5 and 2.7 require more than simply restating study results. It demands clinical understanding, narrative skill, attention to structure, and an eye for accuracy. As regulatory writers, our job is to help regulators make well-informed decisions by making complex data comprehensible and well-organised. 

Using Oncometherin as a fictional but realistic case study, I’ve illustrated how these critical documents are constructed from strategic interpretation (Module 2.5) to data distillation (Module 2.7). Each has its purpose, but both must speak in a unified voice, echoing the science, safety, and benefit–risk profile of the product. 

References 

1. ICH M4E(R2) – Common Technical Document for the Registration of Pharmaceuticals for Human Use: Efficacy – Structure and Content of Clinical Overview and Clinical Summary. URL: https://database.ich.org/sites/default/files/M4E_R2__Guideline.pdf 

2. ICH E3 – Structure and Content of Clinical Study Reports. URL: https://database.ich.org/sites/default/files/E3_Guideline.pdf 

3. European Medicines Agency (EMA) – Guideline on the Evaluation of Anticancer Medicinal Products in Man. 

4. FDA (2018) – Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics: Guidance for Industry. URL: https://www.fda.gov/media/71195/download 

5. Eisenhauer EA, et al. (2009) – New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European Journal of Cancer, 45(2), 228–247. DOI: https://doi.org/10.1016/j.ejca.2008.10.026