Regulation documentation requirements Saila Antila, PhD WHO consultant Training workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence, Kiev 3.-7.10.2005

Guidelines WHO: Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products / Regulatory Support Series, No 5 (WHO/DMP/RGS/98.5) continues

Guidelines (continues) EMEA (EU) Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98 Note for Guidance on Modified Release Oral and Transdermal Dosage Forms: Section II (Pharmacokinetic and Clinical Evaluation) CPMP/EWP/280/96 continues

Guideline (continues) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations (FDA, March 2003) Guidance for Industry: Bioequivalence Guidance (FDA, October 9, 2002) Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations Used for Systemic Effects (Canada, 1992)

Immediate release product Preparations showing a release of the active substance(s) which is not deliberately modified by a special formulation design and/or manufacturing method tablets capsules

Immediate release product usually a single dose study in fasting state is adequate if the application contains several strengths of the active substance, bioequivalence study only with one strength may be acceptable dissolution profiles with each strength if food enhances or interferes with drug absorption, a bioequivalence study in fed state should be performed

Immediate release product if label indicates ’should be administered in fed or fasting state’ then bioequivalence study should be performed accordingly a single dose study at a higher than approved dose may be appropiate for certain drugs ( difficulties in bioanalytics)

The amount of bioequivalence studies with preparations containing several strengths if the application contains several strengths of a immediate release oral dosage form bioequivalence study only with one strength may be acceptable. The following conditions should be fulfilled: the products are manufactured by the same manufacturer and process qualitative composition of the different strength is the same continues

The amount of bioequivalence studies with preparations containing several strengths ratio between amounts of active substance and excipients is the same (or in case of preparations containing low concentration of the active substance; <5 %; the ratio between amount of excipients is similar) the dissolution profiles of the test products are similar the drug input should be linear over the therapeutic dose range

Modified release formulations EMEA Prolonged release formulations Delayed release formulations WHO, FDA Extended (controlled, prolonged, sustained) release tablets, capsules, granules, pellets or suspension

Modified release formulations single dose, non-replicate cross-over study in fasting conditions bioequivalence study under fed conditions (to ensure absence of dose dumping) multiple dose study

Modified release forms (Prolonged and delayed release formulations) Food effect As different modified release preparations may differ with respect to food, the influence of food should be investigated (the effects on efficacy and safety) Predefined high fat meal immediately before dosing

Modified release forms Food effect (EMEA) Food affects absorption-> should perform a 2-way randomized single-dose study after fasting with food Food has no affect-> should perform a 2-way randomized single-dose study

Modified release formulations essentially similar to a marketed one if two products differ in their release controlling excipients or mechanism but show similar in vitro dissolution profiles these products can be considered belonging to same category of pharmaceutical form and are considered essentially similar after showing bioequivalence if the products differ in their release controlling excipients or mechanism and show different dissolution profiles then clinical trials should be considered

Prolonged release formulations (essentially similar to a marketed one) Single and multiple dose studies the test formulation exhibits the claimed prolonged release characteristics of the reference the active drug substance is not released unexpectantly from the test formulation (dose dumping) performance of the test and reference product is equivalent after single dose and at steady state continues

Prolonged release formulations (essentially similar to a marketed one) (continues) food effect is comparable for both formulations after high fat meal

Prolonged release formulation: (essentially similar to a marketed one) Many strengths Single unit: single dose study in fasting conditions with each strength multiple dose study with the highest strength if the pharmacokinetics is linear, the quality of the products is the same etc.

Prolonged release formulation (essentially similar to a marketed one) Many strengths Multiple unit: linear pharmacokinetics and the composition of the lower strengths are proportional to that of the highest strength, the formulation contains identical beads or pellets and dissolution profiles are acceptable single dose study under fasting conditions with the highest strength

Modified release formulation vs. immediate release formulation new indications  clinical studies bioavailability should be investigated (rate and extend of absorption, fluctuations, variability, dose proportionality, risk of unexpected release characteristics) rate and extend of absorption from a modified release formulation should be evaluated with an immediate release formulation (reference product) following single and repeated dosing

Modified release formulation vs. immediate release formulation AUC, Cmax, Cmin, fluctuation inter-individual variability of modified release formulation should not exceed variability of immediate release formulation

Modified release formulation vs. immediate release formulation dose proportionally linear pharmacokinetics: modified release formulation and immediate release formulation at one dose level following multiple dose administration non-linear pharmacokinetics: modified release formulation and immediate release formulation at the highest and lowest dose level following multiple administration

Delayed release formulation Gastro-resistant formulations (entero-coated formulations) post-prandial bioequivalence studies are necessary similar statistical procedures as for immediate release formulations

Oral solution bioequivalence study is not required if the product is in aqueous solution and contains active substance in the same concentration as an oral solution currently approved and the excipients in the product do not affect gastrointestinal transit, absorption and in vivo stability of the active substance if the solution has to be tested against immediate release formulation, a comparative bioavailability study is required

Fixed combination products bioequivalence should be assessed of individual active substance separately (new combination) or as existing combinations design a way that drug-drug interactions should be detected

Bioequivalence study is not needed The product is a parenteral solution aqueous intravenous solution containing same active substance in the same concentration aqueous or oily intramuscular or subcutaneous solution containing same active substance and same comparable excipients gas for inhalation

Bioequivalence study is not needed locally applied product (oral, nasal, inhalation, ocular, dermal, rectal vaginal etc) without systemic absorption  pharmacodynamic or clinical studies are required (note: if the product has systemic effects a BE study is required)

Immediate release form Bioequivalence study is needed, in vitro dissolution is not enough: Properties of the active substance: narrow therapeutic index absorption is not complete and/or small bioavailability poor water solubility of the drug risk of bioinequivalence risk of therapeutic failure or adverse drug reaction

Transdermal drug delivery system bioequivalence should be assessed after single dose and after multiple dose administration the site of application should be the same body area for both test and reference product multiple strengths-> bioequivalence study with the highest strength proportionality in the formulation there is an acceptable in vitro test continues

Transdermal drug delivery system (continues) intraindividual variability should be assessed (replicate design) if products with different release mechanism are compared, a replicate design is required (formulation interaction) the products should have the same or less degree of local irritation, adhesiveness to skin, phototoxicity, sensitization and similar systemic adverse event profile compared to the reference drug

Non-linear pharmacokinetics if pharmacokinetics is non-linear, extrapolating the results from one bioequivalence study to other strengths is not possible drugs that exhibit nonlinear pharmacokinetics at steady state (saturable metabolism, active secretion) -->multiple dose study if the pharmacokinetic system is non-linear, plasma concentrations of the parent drug and the metabolite should be measured and analysed separately

Narrow therapeutic window examples of narrow therapeutic drugs: digoxin, litium, warfarin, theophylline drug concentrations or pharmacodynamics are monitored Cmax and AUC confidence intervals 80-125 % unless otherwise justified the applicant should consider additional tests and controls to ensure interchangeability of the products (Ctox/Cther < 5)

Highly variable drugs drugs and drug products exhibiting intra-subject variability greater than 30 % CV for AUC and Cmax (CV=coefficient of variation) number of subjects required for a study with highly variable drugs is higher than normally ethical concerns of exposing large number of healthy volunteers to the studies continues

Highly variable drugs (continues) replicate designs often used to reduce the sample size sample size may reduce up to 50 % takes longer time to finalize the study drop-outs may increase group sequence design useful when uncertainty about the estimates of variability continues

Highly variable drugs (continues) no regulatory definition for these drugs ICH has not accepted bioequivalence as a topic several proposals in the literature continues

Highly variable drugs (continues) Regulatory approaches in different regions: EMEA: Cmax in certain cases e.g. 75-133 % provided that there is no safety concerns South Africa: CI 75-133 % for Cmax except for narrow therapeutic drugs Canada: a limit is placed only on the means (point estimate) for Cmax. The sponsor may add more subjects, if random variation or a larger than expected relative difference continues

Highly variable drugs (continues) Japan: wider limits allowed for less potent drugs dissolution rates should be equivalent, log AUC and Cmax log(0.9)-log(1.11), total number of subjects 20 or pooled sample size 30 USA: CI 80-125 %

Test product (oral) test product used in bioequivalence studies should be indentical to the projected commercial pharmaceutical product composition and quality characteristics (including stability) should be the same manufacturing methods should be the same test product should preferably be from the industial scale

Test product (oral) pilot or production batches may be used provided that they are not smaller than 1/10 of the expected full production batch EMEA (EU): batch size at least 100000 units or 1/10 of the production batch whichever is higher (unless otherwise justified)

Test product (oral) certificate of analysis of the test product should be included in the documentation batch numbers and expiry dates should be provided in the bioequivalence study documentation

Test product (oral) the content of the active drug substances between the test and reference product should not differ more than ±5 %

Reference product innovator product (full chemical, biological, pharmaceutical, pharmacological, toxicological and clinical data) EMEA (EU): the innovator product must be from a EU country

Reference product WHO: the innovator product should be obtained from a well regulated market (such as Australia, Canada, European Union member states, Japan, USA, Switzerland) a generic product should not be used as an innovator

Reference product WHO: when the innovator product is not available, the market leader may be used as reference product provided its efficacy, safety and and quality has been established

Reference product galenic development: innovator products are not exactly the same as those with full quality, safety and efficacy -> should still used as reference product fixed dose combinations should not be used as comparators unless full clinical trials establishing the safety and efficacy of the product