Clinical Overview

The Clinical Overview is an important part of the Common Technical Document (CTD), especially in the EU. If written well, it should provide an invaluable resource for Medical Assessors to familiarise themselves with the scope of, the Applicantís rationale for, and the critical issues in the clinical development programme. However, it is not easy to write a truly critical, yet appropriately supportive, assessment of the data that often also has to justify the proposed Summary of Product Characteristics (SmPC), especially if an indigestible, over-long document is to be avoided.

Based on official guidance, the experience of Dr Hession since 2001 in writing and reviewing Clinical Overviews for both full and abridged applications, and feedback from regulators, Mediplex has developed a structural template for Clinical Overviews that is more detailed than that provided in the CTD guidance. This template is designed as a reminder of the scope of issues that should be addressed in the document and to help organise the data in a logical way in order to facilitate comprehension. The suggested headings of the template are given below. Notes on the contents of each section can be found in an article by Dr Hession published in Regulatory Rapporteur February 2007; 4(2): 6-11.

Main Headings of Clinical Overview (Module 2.5)

Structural Template for Clinical Overview

       Contents   (donít include in page count)

       Abbreviations   (donít include in page count)


1     Product Development Rationale   (about 5-10 pages)

       1.1    Pharmacological class

       1.2    Targeted indication

       1.3    Rationale for developing product

       1.4    Clinical development programme

       1.5    Concordance with current research practice

2     Overview of Biopharmaceutics   (about 2-3 pages)

       2.1     Overview of different formulations

       2.2     Dosage-form proportionality

       2.3     Effect of food on bioavailability

       2.4     Comparative bioavailability/bioequivalence

                    2.4.1     Commercial vs clinical trial formulations

                    2.4.2     Comparison with reference product

                    2.4.3     (Other)

3     Overview of Clinical Pharmacology   (about 10-15 pages)

       3.1     Pharmacokinetics

                    3.1.1     Overview of studies

                    3.1.2     Absorption

                    3.1.3     Distribution

                    3.1.4     Metabolism

                    3.1.5     Excretion

                    3.1.6     Variations due to intrinsic factors

                    3.1.7     Variations due to extrinsic factors

       3.2     Pharmacodynamics

                    3.2.1     Overview of studies

                    3.2.2     Mode of action

                    3.2.3     Primary clinical pharmacodynamics

                    3.2.4     Secondary pharmacodynamics

       3.3     Pharmacokinetic-pharmacodynamic relationships

       3.4     Interactions

                    3.4.1     Pharmacodynamic interactions

                    3.4.2     Pharmacokinetic interactions

                    3.4.3     Interactions of uncertain type

4     Overview of Efficacy   (about 10-15 pages per indication)

       4.1     Overview of studies

       4.2     Methods of assessing efficacy

       4.3     Patient demographics and disease stage

       4.4     Efficacy results

                    4.4.1     Study 1/Group of similar studies

                    4.4.2     Study 2/Group of similar studies

                    4.4.3     Meta-analyses

        4.5     Conclusions

5     Overview of Safety   (about 10-20 pages)

       5.1     Extent of exposure

       5.2     Methods of assessing tolerability

       5.3     Patient demographics and disease stage

       5.4     Comparative tolerability

                    5.4.1     Introduction

                    5.4.2     Adverse events

                    5.4.3     Serious adverse events

                    5.4.4     Other significant adverse events

                    5.4.5     Laboratory and physiological findings

                    5.4.6     Compliance

                    5.4.7     Conclusions

       5.5     Tolerability profile

                    5.5.1     Incidence of adverse reactions

                    5.5.2     Important adverse reactions and/or related groups of these

                    5.5.3     Therapeutic class effects

                    5.5.4     Adverse effects of excipients

       5.6     Use in special situations

                    5.6.1     Pregnancy

                    5.6.2     Lactation

                    5.6.3     Elderly

                    5.6.4     Children

                    5.6.5     Hepatic impairment

                    5.6.6     Renal impairment

                    5.6.7     (Other)

       5.7     Potential for drug abuse, dependency and rebound phenomenon

       5.8     Effects on ability to drive/operate machinery

       5.9     Overdose

6     Benefits and Risks Conclusions   (about 2-3 pages)

       6.1     Efficacy summary

       6.2     Safety summary

       6.3     Justification of dosing recommendations

       6.4     Appropriateness of product information

       6.5     (Review of any special justifications)

       6.6     (Any plans for development in children)

       6.7     (Any risks to other people)

       6.8     Benefit-risk ratio

       6.9     Conclusion

7     Literature References   (donít include in page count)

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