Presentation Outline. Introduction Sources of Challenge for BE study

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2 Presentation Outline Introduction Sources of Challenge for BE study Necessity of a BE Study? Study Design CRO Ethics Committee Regulatory Authority Sponsor (Personnel or Product) 1st MENA Regulatory Conference on BE/BIOWAI/BIOAN/DISS, , Amman Jordan 2

3 CRO In the middle of all Actions and Communications Regulatory Affairs Ethics Committee Science Based Regulations Regulatory Authority Science CRO BP-PK Statistics Pharmacology Pharm.Technology Medical Advice Documentation, Sponsor REG/CLIN/ BIAN/SCI Business Investigator - Other CRO s 3

4 Departments of a ponsor Pharmaceutical Company Science Business Science Based Regulatory 4

5 Innovative medicine Experimental data/ Literature Clinical data M mmmmmm (Module V) Preclinical data (Module IV) Bioequivalence bridging innovators and generics Generic medicine Multisource interchangeable BIOEQUIVALENCE Pharmaceutical data (Module III) Administrative and summarizing data (Modules I and II) incl. GMP 1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, , Amman Jordan 5

6 Sources of Challenges Necessity of a BE Study? Study Design CRO Ethics Committee Regulatory Authority Sponsor (Personnel or Product) 6

7 Necessity of a BE Study * Is it really necessary to perform BE study? * If yes, how many? Grandfather Drugs (FDA separates these drugs as that ones approved before 1938 and between ) Special Recommendations of Health Authorities ( ion/guidances/ucm htm) BCS (Memantine, Levofloxacine, Pregabalin) Bracketing for nonlinear pharmacokinetic showing Active Substances, for products showing deviation from proportional composition Local acting not absorbed drugs (Otilonium bromide in Turkey) MR Products how many studies (single unit, multiple unit products) 7

8 Source of Challenges Necessity of a BE Study? Study Design CRO Ethics Committee Regulatory Authority Sponsor (Personnel or Product) 8

9 Study Design Pharmacokinetic / Pharmacodynamic properties of Active Substance Intra-subject variability Choice of Reference Product Regulations Special Recommendations Pilot Studies Kind of Pivotal Studies Special Products 9

10 Golden standard study design Single dose, two-period, Crossover Healthy volunteers Reference (comparator)/ Test (generic) 1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, , Amman Jordan 10

11 1. Pharmacokinetic / Pharmacodynamic properties of Active Substance Intra-subject variability Tmax, Cmax, T1/2, AUC, Food effect, Linearity Blood sampling points Dose to be given - Wash-out period Inclusion Exclusion Criterion 11

12 1. Pharmacokinetic / Pharmacodynamic properties of Active Substance Intra-subject variability Biological Material Plasma, Urine, Serum or Whole Blood Analytical Method and Analytes to be measured (metabolite enantiomers) Study Design Intra-subject variability Number of Volunteers Cross-over, Replicate, Parallel, etc. 12

13 22. Choice of Reference Product Which is your target Market?? Choice of Reference Product Should be marketed in the EU? Which Country? If not available on EU markets? If registration in the US is also targeted Different batches different in vitro profiles of the reference??? 13

14 2. Choice of Reference Product Choice of Reference Product RLDs Listed in USA-FDA Orange book Lists of recommended reference / comparators products available on WHO website. Innovator product with established Q,S, and E sourced from well regulated market (ICH process countries). Other reference /comparator products must be justified. Recommended to consult WHO. 14

15 2. Regulations Special Recommendations Regulations Should be followed according to the target market Turkey follows EU regulations Special Recommendations Every country own recommendations FDA ( yinformation/guidances/ucm htm) 15

16 Regulatory Recommendations for MR products-ba/be Studies Type of MR Product Single Unit 3 studies (fasting, fed and Steady state/multiple dose) to the highest strength Multiple Unit Single dose fasting for each strength (or Bracketing) 3 studies (fasting, fed and steady state/multiple dose) to the highest strength 16

17 Pilot Studies As all we know 3 Especially important for MR products Very important not only to plan pivotal studies but also for post approval variations To be planned in both conditions (fasting and fed) Different test formulations to be used (IVIVC) 17

18 EXAMPLE : Pilot study T1-R in-vitro Study Code: IDE04206-TI05-PK

19 EXAMPLE : : Pilot study: Study Code: IDE04206-TI05PK301-1 Test 1 Test 3 Test 2 Reference T2-R in-vivo Study Code: IDE04206-TI05-PK

20 Statistical Results EXAMPLE : : Pilot study: Study Code: IDE04206-TI05-PK3011 Study Code: IDE04206-TI05-PK

21 Deconvolution Graph of in vivo Absorption EXAMPLE : : Pilot study: Study Code: IDE04206-TI05-PK3011 Study Code: IDE04206-TI05-PK

22 Test 2 Reference EXAMPLE : : Pilot study: Study Code: IDE04206-TI05-PK301-1 Positive pivotal study under fasting conditions Test 2 Reference Study Code: IDE04406-TI07-PK

23 EXAMPLE : : Pilot study: Test 2 Reference Study Code: IDE04206-TI05-PK301-1 Fed pivotal study failed Test 2 Reference Study Code: IDE04306-TI06-PK

24 EXAMPLE : : Pilot study: Study Code: IDE04206-TI05-PK301-1 Study Type Fasting Fed Pilot + - Pivotal + + (Failed) 24

25 3 Challenges of Pivotal Studies Metformin is adviced to be administered under fed conditions Standardized or high fat only breakfast Condition ( Fed Fasting) according to SmPC Composition of Meal according to SmPC 30 minutes after meal Timing of administration of the drug product in relation to food intake according to SmPC Multiple Dose Period Design Volunteer Number )ntrasubject Variability Replicate, Crossover, Parallel,

26 4 Special Products Endogenous Substances Factors that may influence the endogenous baseline levels should be controlled if possible (e.g. strict control of dietary intake) Administration of supra-therapeutic doses if possible Different doses should be studied in pilot or pivotal studies Baseline correction Attention to the wash-out period hard to see carry-over 26

27 4 Special Products Oral Dispersible Tablets BCS if no absorption in oral cavity BE study if absorption in oral cavity: With-out water if Reference used in both conditions With water if Reference used in only this condition 3 treatment, 3 period, 6 sequence design if the reference medicinal product is taken only in one way (e.g. only with water), and the test product is intended for additional ways of administration 27

28 4 Special Products Fixed Dose Combinations EU 2 way A+B Reference (A/B) Test combination Pharmacological Interaction should be investigated from literature or experimentally Turkey Like EU if literature data available. If no data available: 4 way A Reference B Reference A+B Reference (A/B) Test combination 28

29 4 Special Products Highly variable drugs or drug products Cmax ANOVA CV % 30 Replicate design(3 or 4 periods) Literature support AUC remains unchanged 80 % - 125% Cmax can be enlarged up to(69.84 % %) geometric mean ratio between 80 % % 29

30 Enlarged acceptance ranges according to EMA (L) (U) The extent of the widening is defined based upon the within-subject variability seen in the bioequivalence study using scaled-average-bioequivalence according to [U, L] = exp [±k swr] 30

31 Source of Challenges Necessity of a BE Study? Study Design CRO Ethics Committee Regulatory Authority Sponsor (Personnel or Product) 31

32 CRO The Guide of the Study Planning of the study study design Clinical Part Investigator and study team Human factor - volunteers Analytical Part Reporting Part support during marketing authorisation 32

33 CRO The Guide of the Clinical part Investigator and study team well experienced, know how to handle in problematic cases 33

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35 CRO The Guide of the Clinical part Observer, monitor for Human factors Volunteers/Human subjects-human factor Hard to control 35

36 EXAMPLE # 1: Volunteer didn t swallow the pantoprazole test product 36

37 EXAMPLE # 2:Volunteer took a double dose of Escitalopram 72 hours post test product 37

38 EXAMPLE # 3: Volunteer, most probably, vomitted after repaglinide administration but no records 38

39 Outlier Explanation for Example #3 In principle any reason for exclusion is valid provided it is specified in the protocol (vomiting, diarrhoea, concomitant medication) and the decision to exclude is made before bioanalysis. However the exclusion of data should be avoided, as the power of the study will be reduced and a minimum of 12 evaluable subjects is required. 39

40 Outlier Explanation for example #3 Exclusion of data cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons. alone. The exceptions to this are: A subject with lack of any measurable concentrations or only very low plasma concentrations for reference medicinal product. Subjects with carry-over effect. 40

41 EXAMPLE # 4: Volunteer vomited 1h 17min post Lisinopril administration Kusma ile ilgili örnek Reference Test 41

42 CRO The Guide for Reporting Very important if different markets are in target Report should be planned to cover all possible requests of all target market authorities Hard and soft copies of report and all related data CRO should continue consultancy during Marketing Authorisation Application 42

43 Source of Challenges Necessity of a BE Study? Study Design CRO Ethics Committee Regulatory Authority Sponsor (Personnel or Product) 43

44 Regulatory Authority and Ethics Committee Regulatory Authority Reviews CT Application - Quality, Safety, Efficacy/- Authorises trial - Continued oversight of ongoing trial/- Transparency - Reviews amendments/- Oversight of Safety - Up to end of trial/- Maintenance of safety and CT Databases/- Inspection/- Sanctions/- GMP Ethics Committee Reviews CT Application -Relevance of protocol and design/-anticipated benefit outweighs risk/-investigator staff and facilities/-information to subjects/recruitment/ Compensation/indemnity/insurance/-Cont nd oversight of ongoing trial/-reviews amendments, safety updates, new information to subjects/-up to end of trial 44

45 Ethics Committee and Regulatory Authority Ethics and Regulatory evaluation is very important but Time is the most important factor time is money for the sponsor. That s why the sponsor prefer countries where the approval procedures are faster. 45

46 Approval Procedures in Turkey Turkish BE Guideline is published Turkish Good Clinical Practice Guide is published 2009 New, ICH-GCP adopted Turkish Good Clinical Practice Guide is published A lot of burocratic problems arised since 2009 with the new ICH-GCP adopted regulations. Since August 2011 the problems are solved and with the new Turkish Drug and Medical Device Institution a section in the Clinical Trials Department is established for the examination for only BE studies. This has fasten the approval process: 1 week EC approval + 2 weeks MoH approval 46

47 Source of Challenges Necessity of a BE Study? Study Design CRO Ethics Committee Regulatory Authority Sponsor (Personnel or Product) 47

48 Sponsor Sponsor is the most important part of all kind of clinical trials including BE studies Personnel of the Sponsor should be well educated in terms of Regulations and Science Sponsor Total Quality should guarantee a good Quality and documentation over all the study 48

49 Summary Choice of an experienced CRO is the most important point for sponsor companies Choice of the type of pilot and pivotal studies should be evaluated carefully by sponsor companies on the advise of CRO Choice of the Country of the Clinical CRO may shorten the approval period and speed up the study Setting the needs according to the target Market(s) 49

50 1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, , Amman Jordan 50

51 1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, , Amman Jordan 51

52 Thank you for your attention! 52