First UNGAP meeting Food-Drug Interactions Regulatory Aspects

Size: px
Start display at page:

Download "First UNGAP meeting Food-Drug Interactions Regulatory Aspects"

Transcription

1 First UNGAP meeting Food-Drug Interactions Regulatory Aspects Leuven, 09 March 2018 Dr. Henrike Potthast HPt COST meeting, Leuven, BE 09 March 2018 Page 1

2 Disclaimer The presentation reflects the personal opinion of the author and not necessarily the official policy of the agency. HPt COST meeting, Leuven, BE 09 March 2018 Page 2

3 Guidelines 1/2 EMA Note for Guidance on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98/ Rev. 1 Corr** Product specific guidelines on bioequivalence (see EMA website) EMA Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms EMA/CPMP/EWP/280/96/ Corr1 HPt COST meeting, Leuven, BE 09 March 2018 Page 3

4 Guidelines 2/2 Guideline on the investigation of drug interactions CPMP/EWP/560/95/Rev. 1 Corr. 2** EMA Guideline on equivalence for products that are locally applied, locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied, locally acting products containing known constituents. EMA/CPMP/EWP/239/95 Rev.1 others include certain information HPt COST meeting, Leuven, BE 09 March 2018 Page 4

5 The Starting Point Drug substance substance related food effects, e.g. via solubility Drug product formulation related food effects (various types) Patient s situation Tolerability / safety, efficacy, quality concerns timing of intake; usual food intake healthy volunteers vs pediatrics vs aged patients vs cancer patients vs. HPt COST meeting, Leuven, BE 09 March 2018 Page 5

6 New Drug Developments 1/4 Comprehensive investigations expected which should consider Feasibility and / or need of fasted intake (e.g. stability, solubility / absorption (rate and extent characteristics)...) Feasibility and / or need of fed state intake (e.g., see above plus type / volume of food; timing of food intake before or after ) Investigating / defining the clinical relevance of food interactions (ideally before Phase 3) Implementation of drug-food interaction into the labeling (SmPC, and patient leaflet) HPt COST meeting, Leuven, BE 09 March 2018 Page 6

7 New Drug Development 2/4 Excerpt from DDI guideline section 5.1: The effect of food intake on the rate and extent of absorption of an orally administered investigational drug should be investigated as early as possible during drug development to optimize dose finding and to ensure optimal food recommendations in the phase III clinical studies and drug labeling. In general, recommendations regarding timing of drug intake in relation to food should aim at minimizing variability and obtaining optimal exposure If the pharmacokinetics are nonlinear with less than dose-proportional increases in AUC when increasing the dose, it is recommended to investigate the effect of food on the highest and lowest doses of the therapeutic range. If the nonlinearity give rise to larger than dose-proportional increases, studying the dose giving rise to the most marked saturation, usually the highest dose, may be sufficient.if a clinically significant effect of food is found and the medicinal product therefore will have a specific recommendation regarding time of administration in relation to food-intake, further food-drug interaction studies are recommended. HPt COST meeting, Leuven, BE 09 March 2018 Page 7

8 New Drug Development 3/4 Possible further investigations on, e.g.,: Biotransformation in the presence of grapefruit Sprinkling / suspending the product Complexation, e.g., with Ca in case of milk diet Alcohol (?) HPt COST meeting, Leuven, BE 09 March 2018 Page 8

9 New Drug Development 4/4 Excerpt from MR guideline section 4.1: If there is a clinically relevant food effect on the MR formulation, additional study(ies) with an oral solution can be considered, to evaluate if the food effect is related to the formulation or to the drug substance. In this situation, a single dose 4 way crossover study; MR fed and fasted versus oral solution (or immediate release (IR) formulation if a solution is not feasible) fed and fasted can be conducted. HPt COST meeting, Leuven, BE 09 March 2018 Page 9

10 Labeling A (recent) real example of an IR tablet with a low solubility drug substance: should be taken in the morning and in the evening with meals, chewed or unchewed, preferably with a little liquid. For a better absorption of active ingredients, a fat-containing diet is recommended for the period of treatment. This should be as solid as possible and contain over 40 g of fat per meal. Some patients, especially young children, may have difficulty swallowing the tablets as a whole and should stop chewing the tablets with a little water. Alternatively, the tablets can be crushed. Question: What has been investigated? What may be required for a generic? HPt COST meeting, Leuven, BE 09 March 2018 Page 10

11 New MR Developments with Reference to an IR Dosage Form 1/3 Excerpt from guideline on modified release (MR) products 280/96: Factors affecting the performance of a modified drug formulation. influence of food on the bioavailability of oral modified release formulations must be investigated in a single dose study high-fat highcalorie meal immediately before dosing....for the assessment of food effect besides AUC and Cmax, it may also be valuable to compare the modified release characteristics by verifying that the shape of the concentration time profiles are not significantly altered. HPt COST meeting, Leuven, BE 09 March 2018 Page 11

12 New MR Developments with reference to an IR dosage form 2/3 Excerpt from guideline on modified release (MR) products 280/96: Further from Factors affecting the performance of a modified drug formulation: The clinical relevance of the effect of food should be discussed both from an efficacy and a safety perspective.... Different type of administration: The labeling of certain multiple unit formulations can recommend that the product can be opened and the pellets/beads can e.g. be sprinkled on soft foods, dispersed in a glass of noncarbonated water and swallowed without chewing or administered through a gastric tube. additional stability and in vitro dissolution testing showing equivalence between the closed and the opened formulation is necessary. The absence of BE studies.. should be justified.. HPt COST meeting, Leuven, BE 09 March 2018 Page 12

13 New MR Developments with reference to an IR dosage form 3/3 Reg: additional stability and in vitro dissolution testing showing equivalence between the closed and the opened formulation is necessary. The absence of BE studies.. should be justified.. What can be investigated by means of in vitro data? HPt COST meeting, Leuven, BE 09 March 2018 Page 13

14 Generic IR applications 1/5 Immediate release (IR) dosage forms (see Bioequivalence guideline 1401/98) In general, a bioequivalence study should be conducted under fasting conditions as this is considered to be the most sensitive condition to detect a potential difference between formulations. For products where the SmPC recommends intake of the reference medicinal product only in fed state, the bioequivalence study should generally be conducted under fed conditions. However, for products with specific formulation characteristics (e.g. microemulsions, solid dispersions), bioequivalence studies performed under both fasted and fed conditions are required unless the product must be taken only in the fasted state or only in the fed state. HPt COST meeting, Leuven, BE 09 March 2018 Page 14

15 Generic IR applications 2/5 Defining specific formulation characteristics for IR products some real examples E.g., a generic employs the solid dispersion to keep a highly soluble drug substance in the amorphous state (the originator uses the crystalline form, patent protected) E.g., a generic employs galenic technology, i.e. specific excipients including bi-carbonate in order to substantially increase in-vitro as well as in-vivo dissolution rate for a pain killer. Reduced rate of bioavailability in the fed state for the originator who recommends the fed state intake only for GI tract sensitive patients. The generic claims almost no food effect. Questions: Which study would be the most sensitive case? Is there a need for two studies (like the US-FDA is requesting it)? HPt COST meeting, Leuven, BE 09 March 2018 Page 15

16 Generic IR applications 3/5 Defining specific formulation characteristics for IR products Example of diclofenac (ph-dependent low solubility drug substance) /WC pdf.Therefore as Diclofenac epolamine tablets and the reference product dicloclofenac epolamine granules for solution are different oral pharmaceutical formulations, and because literature data show that the food effect on Cmax of diclofenac is not only dependent on the drug substance but also on the formulation, in this case, bioequivalence can only be concluded if bioequivalence is shown under fed as well as fasted conditions. The CHMP endorsed the PKWP s advice.. In contrast to Ibuprofen! HPt COST meeting, Leuven, BE 09 March 2018 Page 16

17 Generic IR applications 4/5 Implications of specific formulation characteristics for IR products Example of tadalafil e/2018/02/wc pdf. The reference product can be taken with or without food according to the SmPC. Since the specific formulation (e.g. particle size and excipients) is known to be critical to the performance of the formulation in fed conditions, it cannot be assumed that the impact of food will be the same regardless of formulation. Therefore, following the requirements for specific formulation characteristics described in the Guideline on Investigation of Bioequivalence, both fasted and fed state comparisons of test to reference formulations are required... Main PK characteristics: 90% confidence interval: % for AUC0-72h and Cmax. Comparable median and range for Tmax. HPt COST meeting, Leuven, BE 09 March 2018 Page 17

18 Generic IR applications 5/5 Implications of specific formulation characteristics for IR products E.g., example of everolimus pdf. Fasted and fed for the intact tablet, fasted for the suspension of tablet, and fasted and fed for dispersible tablets. Background: The reference product (tablets - either intact or as a suspension or dispersible tablets) should be consistently taken with or without food according to the SmPC. Since the specific formulation (e.g., particle size and excipients) is known to be critical to the performance of the formulation in fed conditions, it cannot be assumed that the impact of food will be the same regardless of formulation. Differences have also been detected depending on the mode of administration, i.e., intact or suspended tablet.... HPt COST meeting, Leuven, BE 09 March 2018 Page 18

19 Generic MR applications 1/4 Modified release (MR) dosage forms (see guideline for MR dosage forms 280/96) Like with IR products this is about similarity of test and reference food effect, i.e. demonstrating the same robustness, rather than investigating particular food-effects. Of note: Differentiation of single unit and multiple unit products HPt COST meeting, Leuven, BE 09 March 2018 Page 19

20 Generic MR applications 2/4 General requirements The test formulation exhibits the claimed prolonged release characteristics of the reference The active substance is not released unexpectedly from the test formulation (no dose dumping) Performance of the test and the reference formulation is equivalent after single dose and at steady-state The effect of food on the in vivo performance is comparable for both formulations when a single dose study is conducted Of note: fed studies are generally required for MR formulations in contrast to IR HPt COST meeting, Leuven, BE 09 March 2018 Page 20

21 Generic MR applications 3/4 Multiple-unit formulations vs Single-unit formulations Fed / fasting studies depending on SmPC recommendations For MR formulations it s a matter of robustness => additonal fed study is always required single unit formulations vs multiple unit formulations One only sufficient if dose proportional plus shape and extremes (bracketing) One with the highest strength is generally sufficient HPt COST meeting, Leuven, BE 09 March 2018 Page 21

22 Generic MR applications 4/4 Multiple Unit vs Single Unit Formulations For multiple unit formulations with multiple strengths, a single dose study under fasting (*) conditions on the highest strength is sufficient, provided that the compositions are proportional, the formulations contain identical beads or pellets and the dissolution profiles are acceptable. (*) or fed depending on SmPC recommendations Cave: Define most sensitive strength HPt COST meeting, Leuven, BE 09 March 2018 Page 22

23 Generic Delayed Release Products 1/2 Additional challenges in case of single unit formulations Identifying the proportionality and/or extremes including shape and gastroresistant coating layer thickness (should stay the same and not proportional to the core weight)! How to handle variability in fed state bioequivalence studies appropriately? HPt COST meeting, Leuven, BE 09 March 2018 Page 23

24 Generic Delayed Release Products 2/2 Additional challenges in case of single unit formulations ctd Excerpt MR guideline, sect Gastric emptying of. (e.g. enteric coated tablets) may be prolonged and highly erratic. The consequences of this effect on the enteric coating of delayed release formulations are largely unpredictable. If the incidence of this outlier behaviour is observed with a comparable frequency in both, test and reference product, data can be excluded from statistical analysis provided that it has been pre-specified. If the percentage of excluded subjects exceeds 20% for a particular study, the validity of the study may need to be discussed.. release of the active substance may be considerably delayed..the sampling period should be designed such that measurable concentrations are obtained, taking into consideration not only the half-life of the active substance but the possible occurrence of this effect as well. HPt COST meeting, Leuven, BE 09 March 2018 Page 24

25 Generic Applications for Oral Drugs, locally applied, locally acting in the GI Tract Section in the draft Products acting locally in the intestine.some degree of systemic bioavailability is observed, bioequivalence studies based on plasma levels usually in fed and fasting state could be used as a surrogate of equivalence in efficacy and systemic safety because the sites of action is the site of absorption for drugs acting inside the gastrointestinal membrane. For drugs acting in the lumen or the luminal side of the membrane bioequivalence studies based on plasma levels usually in fasting and fed state could also be used as a surrogate of equivalence, if absorption is not saturated (demonstrated e.g. by means of a dose-proportionality study). When the rate and extent of absorption of the drug is comparable, distribution of drug within the different zones of the intestine are expected to be comparable. Bioequivalence studies in fasting and fed state are usually required, even for products that are recommended to be taken in fasting state only, because locally acting drugs generally have low permeability and remain in the intestinal lumen for a prolonged period. Therefore, they are expected to interact with food during their intestinal transit. " HPt COST meeting, Leuven, BE 09 March 2018 Page 25

26 Some questions on the regulatory requirements Is there any alternative for the fed study using the high fat / calorie meal for an IR product? Would it be desirable to require additional fed BE studies for all low solubility drugs (like, e.g., US FDA)? Timing vs. food information generally still limited despite DDI guideline requirements! How to deal adequately with recommendations for pediatric patients, e.g., open the capsule and sprinkle the content on soft food? What can be investigated in vitro, e.g., by means of stirred burger? Are ph changes due to proton pump inhibitors and a fed study interchangeable? HPt COST meeting, Leuven, BE 09 March 2018 Page 26

27 Thank you very much for your attention! Contact Federal Institute for Drugs and Medical Devices Division 5 Kurt-Georg-Kiesinger-Allee 3 D Bonn Person to contact: Dr. Henrike Potthast H enrike.potthast@bfarm.de Tel. +49 (0) HPt COST meeting, Leuven, BE 09 March 2018 Page 27