Submissions for Generic Topical Drugs

Contact: BPS Enquiries - Bureau of Pharmaceutical Sciences

Policy Issues From the Drugs Directorate

September 24, 1990
900924.EXT

The policy outlined below has been developed to assist manufacturers in the preparation of New Drug Submissions (NDS) for generic topical preparations.

Generic topical drug products considered to be new drugs are subject to the requirements of Division 8 of Part C of the Food and Drug Regulations. NDSs for these preparations are required to contain evidence of safety and efficacy under the proposed conditions of use in conformity with sections C.O8.002 and C.O8.005.1 of the Regulations.

Definitions

Topically applied drug products may be classified into three categories based on their intended site of action:

• dermal-topical drug products, that is, those applied on the skin for the purposes of achieving localized effects, for example anti-acne preparations;
• regional-topical drug products, that is, those applied on the skin for the purposes of treating diseases or alleviating disease symptoms in tissues underlying the site of application, for example certain anti-inflammatory drug preparations; and
• transdermal drug products, that is, those intended for systemic activity, for example estrogen patches.

This policy deals only with products in the first class

Category I: products of simple formulation, such as solutions containing the drug substance in which the solvent does not include non-medicinal ingredients that may affect the penetration/absorption of the drug through the skin.

Products of simple formulation may not require clinical trials. In place of these trials, extensive testing of the physico-chemical parameters in comparison to the innovator's product may be accepted as providing sufficient evidence of the safety and efficacy of the generic product.

Category II: products of complex formulation, such as emulsions, suspensions, ointments, pastes, foams, gels, sprays, and medical adhesive systems.

Because of the complexity of these formulations, extensive testing of the physico-chemical parameters will not suffice to demonstrate safety and efficacy. Direct evidence of safety and efficacy through clinical trials or via surrogate models must be provided for these products.

In view of the particular considerations that may apply to these products, a written opinion on special requirements for individual products will be provided on request, upon submission of chemistry and manufacturing data, and proposed labelling.

General requirements

A New Drug Submission (see Guidelines for Preparing and Filing New Drug Submissions) must be prepared including:

• complete chemistry, manufacturing and quality control data;
• in vitro and in vivo animal studies and clinical trials establishing safety and effectiveness of the drug substance and the finished product. Data in the public domain may be acceptable as fulfilling all or part of this requirement;
• dermal irritation studies on abraded and non-abraded skin, and eye irritation studies. (See Toxicology Guidelines);
• fully annotated Product Monograph, accompanied by appropriate documents cited in the annotations; and
• labels and any other labelling material required for the product.

Pharmaceutical Considerations - In addition to the general requirements as outlined in the guidelines for preparation of the Chemistry and Manufacturing part of an NDS, a generic product may have to undergo extensive physico-chemical testing in comparison to the innovator's product. This may involve tests such as in vitro dissolution/release and rheological properties.

Clinical Considerations - In general, well-controlled clinical trials are required to establish safety and efficacy of the generic preparation. As the state of the art develops and more predictive in vitro and/or in vivo models prove to be of value in comparing the test product to that of the innovator, such test(s) may be considered in lieu of clinical studies in certain cases. At the present time there is only one surrogate model which could be used in place of or to supplement clinical trials. This is the Vasoconstrictor Assay, which was developed by McKenzie and Stoughton, has proved to be the most useful method to compare steroid products. However, problems may be faced in applying this method for bioequivalence testing since there is great variation in subject response and it is critical that it be carried out by experienced investigators.

E. Somers