Bioequivalence Studies for generic marketing application

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Bioequivalence studies have purpose to remove necessity for generic manufacturer to conduct own toxicological studies and full-scale clinical trials to prove that his product is of good quality, safe and effective. Instead, generic manufacturer proves that his product is equivalent to another product, for which clinical and non-clinical studies were performed, so those data apply to generic product. This way saves years of time and deal of money for generic manufacturer.

Everything starts with pharmaceutical development. There must be clearly explained choice of comparator product, whose non-clinical and clinical studies generic manufacturer is going to use. WHO guideline Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability describes a way to make that choice. Its presented on the next slide.

In order of preference: (i) to choose the innovator product for which quality, safety and efcacy has been established if this product has been granted a national marketing authorization (nationally authorized innovator); or (ii) to choose the WHO comparator product (for which marketing authorization has been granted, on the basis of quality, safety and efcacy) (WHO comparator product). The primary manufacturing site is indicated in the WHO comparator list (6), and the comparator is to be purchased in that country, or; (iii) to choose the innovator product for which a marketing authorization has been granted in a well-regulated country (ICH or associated country) on the basis of quality, safety and efcacy (ICH et al. innovator) and which is to be purchased from that market; or (iv) in the case that no innovator product can be identied within the context of (i)(iii) above, the choice of the comparator must be made carefully and must be comprehensively justied by the applicant. The most important selection criteria in order of preference are: approval in ICH- and associated countries; prequalied by WHO; extensive documented use in clinical trials reported in peerreviewed scientic journals; and long and unproblematic period of postmarket surveillance (well selected comparator). Additionally, well selected comparators must conform to compendial quality standards, where these exist. Note: a product that has been approved based on comparison with a non-domestic comparator product may or may not be interchangeable with currently marketed domestic products.

Pharmaceutical equivalence with comparator must be proved

same molar amount of the same active pharmaceutical ingredient(s) the same dosage form same routes of administration composition of excipients recommended to be close to comparator. Differences must be evaluated and discussed if they can affect biological equivalence of two products comparable quality standards. The simplest way is to compare release specification of comparator provided in his batch certificate with generic specification comparable impurity profiles of two products. Experimental data should be presented and discussed. As impurity levels generally associated with adverse reactions frequency it must be demonstrated that acceptance limits for generic manufacturer do not exceed comparators. There are possibilities in justification including pharmacopoeial impurity limits in specific product monograph and options presented in ICH Q3B Pharmaceutical performance comparison of two products: dissolution (for solids)

When pharmaceutical equivalence proved we come to biological equivalence

Possible ways to prove bioequivalence:

A. By pharmaceutical equivalence for these cases: (a) when the pharmaceutical product is to be administered parenterally (e.g. intravenously, subcutaneously or intramuscularly) as an aqueous solution containing the same API in the same molar concentration as the comparator product and the same or similar excipients in comparable concentrations as in the comparator product. Certain excipients (e.g. buffer, preservative and antioxidant) may be different provided it can be shown that the change(s) in these excipients would not affect the safety and/or efacy of the pharmaceutical product; (b) when pharmaceutically equivalent products are solutions for oral use (e.g. syrups, elixirs and tinctures), contain the API in the same molar concentration as the comparator product, and contain essentially the same excipients in comparable concentrations. Excipient(s) known to affect gastrointestinal (GI) transit, GI permeability and hence absorption or stability of the API in the GI tract should be critically reviewed; (c) when pharmaceutically equivalent products are in the form of powders for reconstitution as a solution and the resultant solution meets either criterion a or criterion b above; (d) when pharmaceutically equivalent products are gases;

(e) when pharmaceutically equivalent products are otic or ophthalmic products prepared as aqueous solutions and contain the same API(s) in the same molar concentration and essentially the same excipients in comparable concentrations. Certain excipients (e.g. preservative, buffer, substance to adjust tonicity or thickening agent) may be different provided their use is not expected to affect safety and/or efcacy of the product; (f) when pharmaceutically equivalent products are topical products prepared as aqueous solutions and contain the same API(s) in the same molar concentration and essentially the same excipients in comparable concentrations; (g) when pharmaceutically equivalent products are aqueous solutions for nebulizer inhalation products or nasal sprays, intended to be administered with essentially the same device, and contain the same API(s) in the same concentration and essentially the same excipients in comparable concentrations. The pharmaceutical product may include different excipients provided their use is not expected to affect safety and/or efcacy of the product.

B. Biowaiver (in vitro studies sufficient to prove bioequivalence) There are differences in use of biowaiver in different regions. Ukraine applies WHO approach described in guideline Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. USA FDA has more limits on biowaiver use. Biowaiver is possible for immediate-release solids if set of criteria met: For active ingredient compliance to Biopharmaceutics Classication System requirements: Solubility. High-solubility denition: when an API shows a dose:solubility ratio of 250 ml or lower at 37 C over a pH range of 1.26.8, it can be classied as highly soluble. Furthermore, the dose that is to be used for the calculation is the highest dose indicated in the Model List of Essential Medicines (EML). In some countries, products may be available at doses exceeding the highest dose on the EML. In such cases, the dose:solubility ratio and the permeability will have to be reassessed at the product dose. Permeability. High-permeability denition when of the orally administered API dose is absorbed in the small intestine to an extent of 85% or more, it is considered to be highly permeable. Permeability can be assessed by pharmacokinetic studies (for example, mass balance studies), or intestinal permeability methods, e.g. intestinal perfusion in humans, animal models, Caco 2 cell lines or other suitable, validated cell lines.

Immediate-release solids are eligible for biowaiver if API is:

Highly-permeable and highly-soluble (BCS Class I) Highly permeable and poorly soluble (BCS Class II) eligible only if the D:S is 250 ml or lower at pH 6.8 - Poorly permeable and highly soluble (BCS Class III) eligible if dosage form is very rapidly dissolving Dissolution of dosage form. For exemption from an in vivo pharmacokinetic bioequivalence study, an immediate-release multisource product should exhibit very rapid or rapid in vitro dissolution characteristics (see below), depending on the BCS properties of the API. In vitro data should also demonstrate the similarity of dissolution proles between the test and comparator products (usually by f250). Test conditions paddle apparatus at 75 rpm or a basket apparatus at 100 rpm in a volume of 900 ml or less in each of the following media: pH 1.2 HCl solution; a pH 4.5 acetate buffer; and a pH 6.8 phosphate buffer Definition of dosage form performance Very rapidly dissolving: no less than 85% of the labelled amount of the drug substance dissolves in 15 minutes Rapidly dissolving: no less than 85% of the labelled amount of the drug substance dissolves in 30 minutes

C. Pharmacokinetic comparative studies in vivo:

Comparison of concentrations of API or/and its metabolites in blood plasma, assuming that in the same subject an essentially similar plasma concentration time course will result in essentially similar concentrations at the site(s) of action and thus an essentially similar therapeutic outcome

D. Pharmacodynamic comparative studies in vivo:

Much more subjects needed to achieve sufficient statistical power of study and appropriate only if impossible to detect systemic exposure to API with sufcient accuracy and sensitivity. Usual for locally administered products: topical and for inhalation dosage forms

E. Comparative clinical studies

Huge numbers of subjects are required to achieve adequate statistical power. For example, it has been calculated that 8600 patients would be required to give adequate statistical power to detect a 20% improvement in response to the study drug compared with placebo. Worst-case and last choice if both systemic exposure measurement is impossible and meaningful pharmacodynamic parameters cannot be measured

Pharmacokinetic studies guidances

Pharmacokinetic studies is the most often case and well focus on it. Sources of guidance: - in Ukraine WHO guideline is legally binding, so this is central document: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (published as Annex 7 to WHO TRS 937 2006) - EMEA Guideline on investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1 (revised version of Note for guidance on the investigation of bioavailability and bioequivalence, in force from 1st August 2010) - EMEA Pharmacokinetic Studies in man - FDA Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations - FDA Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System - FDA Dissolution Testing of Immediate Release Solid Oral Dosage Forms - FDA Statistical Approaches to Establishing Bioequivalence - FDA Bioanalytical Method Validation - EMEA Validation of bionanalytical methods (draft guideline, final version is under development)

ICH E3 Structure and Content of Clinical Study Reports (essentially plays the same role as Notice to Applicants for Common Technical Document package) ICH E9 Statistical Principles for Clinical Trials ICH E6 (R1) Good Clinical Practice WHO Guidelines for good clinical practice (GCP) for trials on pharmaceutical products (in WHO TRS 850 1997) WHO Guidelines for organizations performing in vivo bioequivalence studies (in WHO TRS 937 2006, Annex 9) WHO Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products (in WHO TRS 902 2002) MHLW Guideline for bioequivalence studies of generic product EU-GMP Annex 13 Manufacture of Investigational Medicinal Products

Links for Your convenience: ICH Efficacy Guidelines EMEA Clinical efficacy and safety: Clinical pharmacology and pharmacokinetics FDA Biopharmaceutics Guidelines FDA Individual Product Bioequivalence Recommendations (designs proposed)