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ARGOM Appendix 1: Guidelines on efficacy and safety aspects of OTC applications

Version 1.0

12 October 2012

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2. Literature-based submissions

In circumstances where the sponsor lacks supportive data of their own but considers available published scientific literature to be supportive, it may be appropriate to submit a ‘literature-based submission’. This option may be appropriate for applications such as changes to indications or directions for use or less commonly for new product applications. The supporting literature must be appropriately relevant to the application - for example the information should generally relate closely to the formulation, dosage regimen and indications of the proposed product.

A literature-based submission should represent a comprehensive and unbiased review of the available literature in relation to the application using a medical/scientific database such as Medline. For older medicines or where relevant reports are few, the search may need to include all records in Medline and/or other databases such as Embase. To enable critical analysis or duplication of the search by the TGA, details of the search strategy and search output should be included (electronically on CD/DVD, as well as hard copy) in the application. The search output should be annotated to include those papers selected for inclusion in the submission and cross-referenced to the overview. A list or table of reports which have been excluded from consideration should be presented together with reasons for exclusion. All submitted data/papers etc. should be page numbered.

Published reports of clinical trials should only be included in the submission where:

  • the trials are conducted using the same active ingredient(s) with the same dosage concentration, a similar dosage regimen, dosage form, route of administration and indications to the product proposed for registration;
  • the trials are reported in sufficient detail to allow an independent assessment of the results (including methods and a statistical analysis of the results) in relation to the safety and efficacy of the product proposed for registration.

Trials should be excluded if they are not consistent with the above, or if they are poorly conducted or reported, or not of sufficient power to produce statistically significant results. All relevant, well-conducted and reported trials should be included regardless of whether the findings are adverse to the product proposed for registration. For relevant trials which are reported in a language other than English, a certified translation should be provided.

Well conducted, published reviews may be of assistance as supporting material and should be included where relevant.

2.1 Overview and summary of reports

A literature-based submission must include an overview, which includes a critical appraisal of all the papers submitted. In the Common Technical Document (CTD) format this overview effectively forms module 2.5 for clinical data (in the “old European format” this overview would include the expert report).

The overview should include the reasons for selecting and excluding retrieved published papers and refer to the selection criteria used. Issues such as publication bias and potential duplication of data from the same subjects in different papers should be discussed where relevant.

The overview should also include a comprehensive appraisal of the quality of all the papers submitted, the quality of the clinical trials reported in those papers, and the quality of the data generated. Studies considered to be pivotal should be identified and a rationale provided. Data from randomised, double blind, controlled studies would be expected to be given greater weight than data from non-randomised, uncontrolled or open studies. The papers need to be discussed individually and collectively in terms of the weight of evidence they provide. Implications of any differences in formulation used in the literature reports should be discussed.

A table should also be included giving summary details of all reports which are present in the submission including:

  • abbreviated publication details (author(s) and journal reference) where relevant;
  • the type of study or report (e.g. double blind, randomised, multi-centre, cross-over trial);
  • the number of subjects included in the trial;
  • treatment details, including details of the dosage form, formulation, dosage schedule and treatment duration;
  • parameters studied; and
  • summary of results in relation to efficacy and safety.

With regard to safety data, there should be tabulation and analysis of all adverse events (including abnormal laboratory values, medicine interactions etc.) for all documented clinical studies and any adverse events which have been reported to the sponsor. Further guidance on literature-based submissions may be found on the TGA website.

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