1st MENA Regulatory Conference on Bioequivalence, Biowaivers, Bioanalysis and Dissolution Jordan September 23 24, 2013 Revised European Guideline on PK and Clinical Evaluation of Modified Release Dosage Forms José A. Guimarães Morais Faculdade de Farmácia, Universidade de Lisboa INFARMED Portuguese Medicines agency EMA European Medicines Agency 1
Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms (EMA/CPMP/EWP/280/96 Corr1) Draft XXIII Draft Agreed by Pharmacokinetics Working Party October 2012 Adoption by CHMP for release for consultation 21 February 2013 End of consultation (deadline for comments) 31 August 2013 This guideline replaces Guideline on Modified Release Oral and Transdermal Dosage Forms Section II (Pharmacokinetic and Clinical Evaluation (EMA/CPMP/EWP/280/96 Corr1) Comments should be provided using this template. The completed comments form should be sent to PKWPsecretariat@ema.europa.eu. Keywords Modified release, prolonged release, delayed release, transdermal drug delivery systems (TDDS), bioequivalence, pharmacokinetics, biowaiver, in vitro dissolution, generics 2
3 Outline Modified Release Dosage Forms (MRDF) covered in the Guideline: Which are they? Structure of the Modified Release Dosage Forms Guideline (PK and Clinical evaluation) 1. Introduction (background) 1.1. Types of Modified release and dosage forms 1.2. Rationale for Development 2. Scope 1.2.1. The clinical rationale 1.2.2. Considerations for use and posology 3. Legal basis and relevant guidelines 4. Applications for modified release dosage forms of new chemical entities 5. Applications for a modified release formulation of a substance that is authorized as an immediate release formulation 6. Abridged application for modified release forms referring to a marketed modified release form Definitions Appendix I (sensitization and irritation test for transdermal products) Appendix II (In vitro in vivo correlation): Appendix III: Summary of study recommendations for abridged applications:
Modified Release Dosage Forms Modified release dosage forms are formulations where the rate and/or site of release of the active ingredient(s) is different from that of the immediate release dosage form administered by the same route. This deliberate modification is achieved by special formulation design and/or manufacturing methods. Modified release dosage forms covered by this guideline include orally, intramuscularly, subcutaneously administered modified release and transdermal dosage forms. 4
Modified Release Dosage Forms Modified release dosage forms covered by this guideline include Prolonged release Delayed release Multiphasic release Multiple/single unit Intramuscular/subcutaneous Depot formulations Transdermal drug delivery systems (TDDS) 5
Prolonged Release Dosage Forms Prolonged release dosage forms are modified release dosage forms showing a slower release than that of an immediate release dosage form administered by the same route. 6
Prolonged Release Dosage Forms These drug products allow (1) reduction in dosing frequency and (2) reduce fluctuations in plasma concentrations. They can be in the form of capsules, tablets, granules, pellets and suspensions 7
Delayed Release Dosage Forms The release of the active substance from such dosage forms is delayed for a certain period after administration or application of the dosage. The subsequent release is similar to that of an immediate release dosage form. 2000 1500 1000 500 0 0.0 2.0 4.0 6.0 8.0 10.0 12.0 Typically gastro-resistant coatings are intended to delay the release of the drug substance either to 8 protect the stomach from drug local undesired action or to protect the drug from the acidic medium in the stomach, or to achieve targeted release in a defined segment of the intestine
Multiphasic Release Dosage Forms Biphasic Release: The first phase of drug release is determined by the immediate release dose fraction providing a therapeutic drug level shortly after administration. The second extended release phase provides the dose fraction required to maintain an effective therapeutic level for a prolonged period. Pulsatile Release: Pulsatile drug release is intended to deliver a burst of drug release at specific time interval 9
Modified Release Dosage Forms Multiple-unit: A multiple unit dosage form contains a plurality of units e.g. pellets or beads each containing release controlling excipients, e.g. in a gelatin capsule or compressed in a tablet Single-unit: The single-unit dosage forms consist of only one unit, e.g. matrix or osmotic tablet 10
Modified Release Dosage Forms Intramuscular/subcutaneous Depot formulations: A depot injection is usually a subcutaneous or intramuscular product which releases its active compound continuously over a certain period of time. Subcutaneous depot formulations include implants. Transdermal drug delivery systems (TDDS): A TDDS or transdermal patch is a flexible pharmaceutical preparation of varying size containing one or more active substance(s) to be applied on the intact skin for systemic availability. 11
Transdermal Drug Delivery Systems (TDDS) and Intramuscular/subcutaneous Depot formulations (ISDF) Pharmacokinetic Studies required for TDDS and ISDF of a new chemical entity (it applies to a substance already in an IR form as well sections 4 & 5) Besides clinical trials, studies should be conducted to evaluate drug transport characteristics and the rate limiting step that determines systemic availability i.e. drug release and/or other formulation related particularities. Pharmacokinetic investigations should comprise single-dose and multiple-dose investigations application site-dependent absorption fluctuation lag-times. IVIVC is advisable. In case of several dose strengths, dose proportionality issues should be adequately addressed. for Transdermal Drug Delivery Systems skin irritation, sensitization (see also appendix 1), phototoxicity, patch adhesion 12
Transdermal Drug Delivery Systems (TDDS) and Intramuscular/subcutaneous Depot formulations (ISDF) Pharmacokinetic Studies required for TDDS referring to a marketed modified release form (generic section 6) A generic TDDS is defined by having the same amount of active substance released per unit time as compared to the reference TDDS skin irritation, sensitization, phototoxicity, patch adhesion non-inferiority trial prior to BE In case of several dose strengths, dose proportionality issues should be adequately addressed., including bracketing approach Pharmacokinetic Studies required for ISDF referring to a marketed modified release form (generic section 6) Single dose comparison test multiple-dose comparison test, unless low extent of accumulation: cut-off AUC single dose covers 90% of AUC multiple dose 13
5. Application for a prolonged release formulation of a substance that is authorized as an immediate release formulation 5.1. Pharmacokinetic studies 5.1.1. Rate and extent of absorption, fluctuation 5.1.2. Variability 5.1.3. Dose proportionality 5.1.4. Factors affecting the performance of a modified drug formulation Food GI function: interaction with e.g. opioids, ph and motility modifiers Dose dumping Effect of alcohol: in vitro, in vivo 5.2. Therapeutic studies 5.2.1. Waiving of therapeutic studies mimicking of immediate release (pulsatile, delayed release) BE for C max, C min and AUC at steady state (different shape, no clinical effect) C max, C min below therapeutic interval with IR 5.2.2. How to design clinical studies 14 Clinical benefit throughout 24 hours
6. Abridged application for modified release forms referring to a marketed modified release form 15 6.1. Prolonged release formulations for oral administration 6.1.1. Strength(s) to be evaluated 6.2. Delayed release formulations 6.2.1. Strength(s) to be evaluated 6.2.2. Prolonged residence time in the stomach 6.3. Multiphasic modified release products 6.4. Intramuscular/Subcutaneous Depot Formulations 6.4.1. Strength to be evaluated 6.5. Transdermal Drug Delivery Systems (TDDS) 6.5.1. Strength to be evaluated 6.6. Bracketing approach 6.7. New strength for an already approved MR product 6.8. Evaluation 6.8.1. Parameters to be analysed 6.8.2. Acceptance criteria 6.9. Effects of alcohol 6.10. Further points to consider for bioequivalence studies
Multiphasic modified release products This Guideline also applies to the assessment of bioequivalence for biphasic- / pulsatile-release designed to achieve sequential release combining immediate and modified characteristics If one of the release phases is prolonged, the type of studies required are those described in section 6.1. For multiphasic modified release products additional parameters to be determined include partial AUC, C max and t max in all phases. The time point for truncating the partial AUC (cut-off) should be based on the PK profile for the IR and the MR parts respectively and should be justified and pre-specified in the study protocol based on PD 16 considerations as well.
5. Application for a modified release formulation of a substance that is authorized as an immediate release formulation Next few slides condense requirements on MRDF for Multiple or single unit Dosage Forms concerning Single dose & multiple dose Different strengths Fed and fasting studies 17
Prolonged release single unit formulation study requirements Current requirement Strength Single dose fasting Single dose fed Steady-state high yes yes yes middle yes * waiver low yes * waiver * Fed study to be conducted at the same strength as pivotal BE study SmPC recommends intake under fasting or fasting and fed conditions Strength Single dose fasting* Single dose fed Multiple dose high yes yes yes SmPC recommends intake under fed conditions Strength Single dose fasting Single dose fed* Multiple dose high yes yes yes middle yes waiver waiver middle waiver yes waiver low yes waiver waiver low waiver yes waiver * bracketing approach possible if criteria are met 18
Prolonged release multiple unit formulation study requirements Current requirement Strength fasting fed Steady-state* high yes yes yes middle waiver waiver waiver low waiver waiver waiver SmPC recommends intake under fasting or fasting and fed conditions Strength Single dose fasting Single dose fed Multiple dose * high yes yes yes middle waiver waiver waiver low waiver waiver waiver SmPC recommends intake under fed conditions Strength Single dose fasting Single dose fed Multiple dose * high yes yes yes middle waiver waiver waiver low waiver waiver waiver 19 * see criteria for necessity in section 6.1
Delayed release single unit formulation study requirements Only Single Dose Studies required Current requirement Strength fasting fed Steady-state high yes yes waiver middle waiver waiver waiver low waiver waiver waiver SmPC recommends intake under fasting or fasting and fed conditions Strength Fasting* Fed high yes yes middle yes waiver low Yes waiver SmPC recommends intake under fed conditions Strength Fasting Fed * high Yes yes middle waiver yes low waiver yes 20 * bracketing approach possible if criteria are met
Delayed release multiple unit formulation Single dose Only Single Dose Studies required Current requirement Strength fasting fed Steady-state high yes yes waiver middle waiver waiver waiver low waiver waiver waiver SmPC recommends intake under fasting or fasting and fed conditions Strength Fasting Fed high yes yes middle waiver waiver low waiver waiver SmPC recommends intake under fed conditions Strength Fasting Fed high yes yes middle waiver waiver low waiver waiver 21
Safety concerns prevent the Company from conducting single dose studies of higher strengths in healthy volunteers and that ethical constraints prevent the Company from conducting single dose studies in patients. Strength (mg) Single Dose Fasting Single Dose Fed Steady State 0.26 / 0.375 x 0.52 / 0.75 x 1.05 / 1.5 x 1.57 / 2.25 x 2.1 / 3.0 x 2.62 / 3.75 x 3.15 / 4.5 x x x Strength (mg) Single Dose Fasting Single Dose Fed Steady State 0.26 / 0.375 x 0.52 / 0.75 x 1.05 / 1.5 x 1.57 / 2.25 x 2.1 / 3.0 x 2.62 / 3.75 x 3.15 / 4.5 x* * fasted and fed Strength (mg) Single Dose Fasting Single Dose Fed Steady State 0.26 / 0.375 x x 0.52 / 0.75 1.05 / 1.5 1.57 / 2.25 2.1 / 3.0 x 2.62 / 3.75 3.15 / 4.5 x* 22
Further points to consider for bioequivalence studies Same as in BE GL Test and reference product Subjects Study conduct Statistical evaluation of primary endpoints Parent compound or metabolites Enantiomers Endogenous substances Narrow therapeutic index drugs (in addition narrowing of the acceptance criteria of C might be necessary) Highly variable drugs or drug products Linearity 23
IS THERE A NEED FOR MULTIPLE DOSE STUDIES IN MODIFIED RELEASE DOSAGE FORMS? FDA Because single dose studies are considered more sensitive in addressing the primary question of BE (i.e., release of the drug substance from the drug product into the systemic circulation), steadystate studies are not generally recommended, even in instances where nonlinear kinetics are present. Health Canada EMA For formulations that are likely to accumulate (i.e., AUCx/AUCinf < 0.8) safety requires that steady-state studies be performed in addition to single-dose studies Multiple-dose comparison test required unless low extent of accumulation: cut-off AUC single dose covers 90% of AUC Under discussion 29-09-2013 24
IS THERE A NEED FOR MULTIPLE DOSE STUDIES IN MODIFIED RELEASE DOSAGE FORMS? 70.00 60.00 50.00 40.00 30.00 20.00 10.00 C = C min 0.00 29-09-2013 25 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76
IS THERE A NEED FOR MULTIPLE DOSE STUDIES IN MODIFIED RELEASE DOSAGE FORMS? 70.00 Multiple dose plots: 60.00 50.00 40.00 30.00 20.00 C 10.00 C C min 0.00 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 29-09-2013 26-10.00
IS THERE A NEED FOR MULTIPLE DOSE STUDIES IN MODIFIED RELEASE DOSAGE FORMS? The EMA MR GL states A multiple dose study is needed unless a single dose study has been performed with the highest strength which has demonstrated that the mean AUC 0- after the first dose covers more than 90% of mean AUC 0- for both test and reference, and consequently a low extent of accumulation is expected. 29-09-2013 27
IS THERE A NEED FOR MULTIPLE DOSE STUDIES IN MODIFIED RELEASE DOSAGE FORMS? 29-09-2013 28
IS THERE A NEED FOR MULTIPLE DOSE STUDIES IN MODIFIED RELEASE DOSAGE FORMS? 29-09-2013 29
IS THERE A NEED FOR MULTIPLE DOSE STUDIES IN MODIFIED RELEASE DOSAGE FORMS? The simulations presented in this paper show that the inclusion of additional steady-state PK parameters increases the ability to identify differences between formulations. The extra benefit over single dose PK parameters does not compensate the extra effort expended. However the benefit obtained from performing multiple-dose studies is too small to compensate the extra effort expended. By using C max, AUC 0 t and additionally C, the evaluation of bioequivalence between two ER formulations can be made simply by using single dose data, with similar discriminatory characteristics of the current EMA requirements without the need of a multiple-dose study Reduction in the number of studies and volunteers is possible without loss of discriminative power. 29-09-2013 30
IS THERE A NEED FOR MULTIPLE DOSE STUDIES IN MODIFIED RELEASE DOSAGE FORMS? 29-09-2013 31
IS THERE A NEED FOR MULTIPLE DOSE STUDIES IN MODIFIED RELEASE DOSAGE FORMS? As a result of this discussion the following note was added The discussion of the opportunity of using equivalence in C in single dose studies as basis for waiving the multiple dose study has been recognized. However, there is not considered to be sufficient scientific evidence at the moment to encourage this approach. 29-09-2013 32
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