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

Version 1.0

29 November 2015

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6. 'Generic' products

An 'originator' product (sometimes referred to as the 'innovator' product) is a medicine that has been approved for marketing in Australia on the basis of a full dossier which may include chemical, biological, pharmaceutical, pharmacological-toxicological and clinical data. A 'generic' product is a medicine that, in comparison to the originator product:

  • has the same quantitative composition of therapeutically active substances, being substances of similar quality to those in the originator product; and
  • has the same pharmaceutical form; and
  • is bioequivalent (or for topical products, is considered to be therapeutically equivalent - see 'Section 6.2 Therapeutic equivalence data - topical products'); and
  • have the same safety and efficacy properties.

Regarding point 2 above, the various immediate-release oral dosage forms (e.g. tablets, capsules, oral liquids or suspensions) can be considered to be one and the same pharmaceutical form (see 'Section 8 Products with a 'new' dosage form').

The TGA will accept applications to register ‘generic’ products without further safety and efficacy data where the proposed indications and dosage regimen are the same as those of the originator product and where the safety and efficacy data provided with the originator product are not ‘protected’ (Section 25A of the Therapeutic Goods Act 1989 refers). In some cases however, data will be required to demonstrate that the proposed ‘generic’ is bioequivalent to the originator product (i.e. that it qualifies as a ‘generic’; see 'Section 6.1 Bioequivalence data'). For some proposed topical products, where the formulation may have a significant impact on efficacy and/or safety, data may be required to establish therapeutic equivalence with the originator product (see 'Section 6.2 Therapeutic equivalence data - topical products').

Where bioequivalence [or therapeutic equivalence for a topical product - see 'Section 6.2 Therapeutic equivalence data - topical products') is a requirement, a generic medicine must be shown to be bioequivalent (or therapeutically equivalent) to the corresponding strength of a leading brand (normally the originator product) as marketed in Australia. However, in some circumstances the TGA may accept bioequivalence (or therapeutic equivalence) studies carried out using samples of the originator product obtained from outside Australia, provided the sponsor can support this with evidence that the formulation of this product is the same as the formulation marketed in Australia. Details of the evidence required for oral products in this case can be found in the Australian Regulatory Guideline for Prescription Medicines (ARGPM) - Appendix 15 Biopharmaceutic Studies.

6.1 Bioequivalence data

Detailed information on TGA requirements for biopharmaceutic studies can be found in the Australian Regulatory Guideline for Prescription Medicines (ARGPM) - Appendix 15 Biopharmaceutic Studies and the European Union (EU) guideline, Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1), which has been adopted by the TGA with annotations.

In most cases, bioequivalence data are not required for OTC medicines, but for some products, particularly those containing more recently approved or down-scheduled active ingredients, bioequivalence data may be required.

Bioequivalence data, or a justification for not providing bioequivalence data, are generally required for oral ‘generic’ products except in the following circumstances:

  • where there are other oral ‘generic’ products on the register that have been approved without either bioequivalence data (not including clones of the originator product) or a justification for not providing bioequivalence data. A large number of OTC products will fall into this category - see 'Section 11 Active ingredients for which bioequivalence data are generally not required' or contact the TGA if unsure;
  • products that are aqueous oral solutions at the time of administration and contain an active substance in the same concentration as an oral solution currently approved as a medicinal product, provided the excipients contained in them do not affect gastrointestinal transit, absorption or in vivo stability of the active substance, for example gastric pH changes; or
  • products which contain active ingredients that are not absorbed (e.g. barium sulphate, simethicone, alginic acid).

For OTC oral immediate release tablets, capsules and suspensions containing active substances with high solubility and high permeability and where the medicinal product has a high dissolution rate, bioequivalence data will not be required if an acceptable justification for not providing such data can be provided (see also 'Section 8 Products with a new dosage form').

Justifications for not providing bioequivalence data should address at least the following issues where applicable:

  • the nature of the dosage form
  • the solubility of the active ingredient(s)
  • the comparative dissolution profiles across the physiological pH range (1-7.5) of the products being considered
  • the pharmacokinetic characteristics of the active ingredient(s), such as permeability (or absolute bioavailability), linearity or otherwise, first pass effect (if any) and its significance
  • the clinical consequences of any potential differences in bioavailabilities of the products under consideration (e.g. increased dose leading to toxicity or decreased dose leading to lack of efficacy)
  • the width of the margin between the minimum effective and minimum toxic plasma concentrationsthe similarities of, or differences between, the formulations being considered.

More details regarding justifications for not providing bioequivalence data can be found in Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1): Section 5.1, which has been adopted by the TGA with annotations, and as outlined in ARGPM Appendix 15 Biopharmaceutic Studies.

Copies of any cited literature should be provided. If the justification is considered inadequate by the TGA, the sponsor will be required to provide bioequivalence or other clinical data for the application to proceed.

To assist the evaluator(s) in identifying the studies to be assessed and locating the relevant information, sponsors submitting biopharmaceutic data are strongly encouraged to complete, for each study, the optional Summary of a Bioavailability or Bioequivalence Study form. For applications submitted in CTD format, completed summary forms should be included as part of Module 1.

Products for topical use intended to act without systemic absorption do not generally require bioequivalence data (i.e. using systemic measurements), but therapeutic equivalence data may be required - see 'Section 6.2 Therapeutic equivalence data - topical products'.

6.2 Therapeutic equivalence data - topical products

Some topical OTC medicines have a long history of use in many different formulations and their efficacy is well accepted (e.g. salicylic acid for treatment of warts). Efficacy and safety data are generally not required to support the registration of such generic products.

Where the efficacy of the product is likely to be formulation dependent (see below for examples), the efficacy of the particular formulation proposed for registration will need to be established.

The TGA has identified certain topical products where the efficacy and/or safety of the product are influenced by the formulation. In these cases, differences in non-active ingredients may affect the extent of penetration of the active substance and therefore efficacy and/or safety data are usually required before the product is approved for registration. As OTC medicines are so diverse, the TGA has adopted a flexible approach in which the need for data to support registration of generic topical products should be determined on a case-by-case basis.

The following ingredients or product categories have been identified as being formulation-dependent in terms of efficacy and/or safety:

  • Head lice preparations
  • Aciclovir for treatment of cold sores
  • Minoxidil
  • NSAIDs
  • Antiseptics/skin disinfectants [See ARGOM Appendix 6 Antiseptics/skin disinfectants (still to be finalised)]
    Note: Antiseptics guideline is under a review at the TGA.
  • Antidandruff shampoos containing imidazole antifungals as active ingredients
  • Dithranol preparations
  • Corticosteroids (except hydrocortisone) (see 'Section 7.1 Nasal corticosteroid sprays')
  • Products containing glyceryl trinitrate (see 'Section 7.5 Oral nitrate products')

The above list is not exhaustive and the absence of any ingredient does not necessarily indicate that safety or efficacy are considered to be independent of formulation – the ingredient may simply not have been considered by the TGA in this regard (e.g. for recently down-scheduled ingredients). The TGA will endeavour to update the list as new categories are identified as being formulation dependent.

In some cases the TGA may seek advice from the Advisory Committee on Non-prescription Medicines (ACNM) regarding data requirements for a particular product (e.g. for topical products containing active ingredients that have been down-scheduled from prescription to OTC). In most instances, the ACNM has advised that data from clinical trials would be required to support the application of formulation-dependent topical products.

For guidance on data requirements for locally applied/acting products, refer to the EU document Clinical requirements for locally applied, locally acting products containing known constituents (pp. 193 - 198 of Rules 1998 (3C) - 3CC12a).

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