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. The suggested headings of the template are given below, although not all will apply for all products.

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     Effect of food on bioavailability

       2.3     Comparative bioavailability/bioequivalence

                    2.4.1     Commercial vs clinical trial formulations

                    2.4.2     Comparison with reference product

                    2.4.3     Dosage strength proportionality

                    2.4.4     (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     Local tolerability

       5.6     Tolerability profile

                    5.6.1     Incidence of adverse reactions

                    5.6.2     Important adverse reactions and/or related groups of these

                    5.6.3     Therapeutic class effects

       5.7     Use in special situations

                    5.7.1     Pregnancy

                    5.7.2     Lactation

                    5.7.3     Elderly

                    5.7.4     Children

                    5.7.5     Hepatic impairment

                    5.7.6     Renal impairment

                    5.7.7     (Other)

       5.8     Potential for drug abuse, dependency and rebound phenomenon

       5.9     Effects on ability to drive/operate machinery

       5.10   Overdose

6     Benefits and Risks Conclusions   (about 5-10 pages)

       6.1     Therapeutic context

                    6.1.1     Disease or condition

                    6.1.2     Current therapies

       6.2     Benefits

       6.3     Risks

       6.4     Benefit-risk assessment

       6.5     Appendix (detailed methods and results of benefit-risk assessment)

7     Literature References   (donít include in page count)

      Annex   (justification of absent studies in Module 5.3)

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