Demystifying CTD Module 2.4 and 2.5: Writing Effective Overviews for Generic Applications
Introduction
In the Common Technical Document (CTD), Module 2 acts as the bridge between detailed data (Modules 3–5) and the regulatory reviewer’s first impression.
While generic applications often focus on bioequivalence and quality, Modules 2.4 (Non-clinical Overview) and 2.5 (Clinical Overview) remain critical components.
They demonstrate scientific justification, regulatory compliance, and a coherent story of equivalence to the reference product.
At RGInsight LLP, we frequently support clients in preparing and reviewing these modules to ensure their dossiers meet EMA and ICH standards — minimizing post-submission queries.
1. Understanding the Purpose
Both overviews summarize and interpret the underlying data, but their focus differs:
Module 2.4 – Non-clinical Overview:
Summarizes published data and toxicological profiles to justify product safety.
For generics, this often means referencing literature rather than conducting new studies.Module 2.5 – Clinical Overview:
Provides the clinical rationale for bioequivalence, safety, and efficacy, explaining how the generic mirrors the reference product in clinical performance.
Even though no new pre-clinical or clinical trials are usually conducted for generics, these sections demonstrate scientific understanding and regulatory alignment.
2. Module 2.4 – Non-Clinical Overview: What to Include
A strong Module 2.4 should:
Justify omission of new animal studies (in line with ethical principles and ICH M3(R2)).
Summarize available literature on pharmacology, pharmacokinetics, and toxicology.
Address impurities and excipients, comparing them with the reference product.
Discuss safety margins, genotoxicity potential, and cumulative exposure data.
Provide references from credible scientific journals or databases.
End with an expert conclusion confirming that no new non-clinical concerns exist.
📘 Tip: Ensure that your toxicology narrative aligns with the impurity data discussed in Module 3 (Quality section). This cross-consistency is a frequent focus of EU reviewers.
3. Module 2.5 – Clinical Overview: Key Elements
This section transforms raw data into a regulatory narrative.
For generic applications, it should:
Summarize the bioequivalence (BE) study design — including fasting/fed conditions, strength selection, and justification for waiver of additional strengths.
Interpret statistical results (Cmax, AUC, 90% CI) and confirm compliance with EMA bioequivalence limits.
Discuss safety and tolerability — summarizing adverse events from BE trials.
Justify the absence of new efficacy or safety studies.
Address excipient or formulation differences, if any, that could impact clinical performance.
Ensure alignment with SmPC and PIL — a common reason for queries if mismatched.
📊 Tip: Use clear tables comparing test vs. reference parameters; EMA reviewers appreciate concise visual summaries.
4. Common Queries from EU Health Authorities
Even well-prepared dossiers may attract clarification requests.
Some of the frequent queries seen in generic applications include:
Insufficient justification for omission of non-clinical studies.
Lack of alignment between Module 2.5 and Module 5 (BE report).
Missing discussion on excipient differences.
Unclear explanation of statistical methods or acceptance criteria.
SmPC/PL discrepancies with Module 2.5 clinical interpretation.
Anticipating these points during drafting or internal QC can prevent delays.
5. Best Practices Before Submission
To ensure dossier readiness:
✅ Use a reviewer’s self-audit checklist (like RGInsight’s internal QC tool) to confirm completeness.
✅ Maintain cross-module consistency — product name, strength, BE design, and references must align.
✅ Have the expert sign and date both overviews with their CV attached in Module 1.4.
✅ Ensure compliance with EMA “Notice to Applicants” Volume 2B format and numbering.
6. Conclusion
Even though Modules 2.4 and 2.5 are concise in generic dossiers, they play a decisive role in regulatory evaluation.
A well-written, scientifically justified overview conveys confidence, minimizes deficiencies, and supports smooth assessment by EU authorities
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