Common Deficiences in Bioequivalence Studies and Biowaiver Requests submitted to the JFDA

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Mercy Cross
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1 Common Deficiences in Bioequivalence Studies and Biowaiver Requests submitted to the JFDA DIMA S. SHAHIN, M.SC. MEMBER OF THE BIOEQUIVALENCE STUDIES TECHNICAL COMMITTEE REGISTRATION DEPARTMENT, DRUG DIRECTORATE- JORDAN FOOD AND DRUG ADMINISTRATION (JFDA) 2 ND MENA REGULATORY CONFERENCE ON BIOEQUIVALENCE, BIOWAIVERS, BIOANALYSIS, DISSOLUTION AND BIOSIMILARS

2 Topics for Discussion Why to request BE studies for generic drugs? Statistics for BE studies \ BW requests submitted in 2013 Common deficiencies in BE\BW submissions Case studies Recommendations for better BE and Bio-waivers submissions

3 Why to request BE studies for generic drugs? A generic product must meet the standards established by Jordan Food and Drug Administration (JFDA) to be approved for marketing in Jordan. JFDA approves a generic product for marketing if it is proved to be therapeutically equivalent to the reference product. Therapeutic Equivalence = Pharmaceutical Equivalence / Alternative + Bioequivalence Same safety and efficacy profiles after administration of same dose A therapeutically equivalent generic product is interchangeable with the RLD.

4 Why to request BE studies for generic drugs? Establishing Equivalence Comparative pharmacokinetic studies In vivo comparative bioavailability studies Comparison of performance of FPPs based rate and extent of absorption of API from each formulation Area under the concentration-time curve (AUC) Maximal concentration (Cmax) Time to maximal concentration (Tmax) Comparative pharmacodynamic studies Comparative clinical trials Comparative in vitro methods Biopharmaceutics Classification System (BCS)-based biowaivers Additional strengths biowaivers

5 Statistics for BE studies \ BW requests submitted in 2013 A total of 61 (36.75%) Bioequivalence Studies and 105 (63.25%) Bio-waiver requests were submitted in 2013 Results of the review process within the past 2 years (till the end of August 2015) All (61) submitted BE Studies have been evaluated Only 4 of the submitted (105) BW requests have not been Discussed / Waiting for BE Approvals

$Statistics for BE studies \ BW requests submitted in 2013 Total BE Studies$

6 Statistics for BE studies \ BW requests submitted in 2013 Total BE Studies Submitted in 2013 (61 BE Studies) 7% 6% Accepted Pending / Deficiencies 87% Rejected

7 Statistics for BE studies \ BW requests submitted in % Accepted BE Studies relative to no. of BE Committee sessions 85.25% 80.00% 70.00% 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% 0.00% 13.11% 1.64% st 2nd 3 or more 13.11% 57.14% 80.95% Accepted 85.25% 36.73% 19.05% Pending / Deficiencies 1.64% 6.12% 0.00% Rejected

$\ BW requests submitted$ in 2013 Total Biowaivers

8 Statistics for BE studies \ BW requests submitted in 2013 Total Biowaivers Submitted in 2013 (105 BW requests) 4% 15% Accepted Pending / Deficiencies 15% 66% Rejected Not Discussed / Waiting for BE Approvals

9 Statistics for BE studies \ BW requests submitted in % 60.00% 50.00% 40.00% Accepted BW Requests relative to no. of BE Committee sessions 60.00% 38.89% 30.00% 20.00% 10.00% 0.00% 9.90% st 2nd 3 or more 9.90% 60.00% 38.89% Accepted 82.18% 36.00% 47.22% Pending / Deficiencies 7.92% 4.00% 13.89% Rejected

10 Common deficiencies in BE submissions 1. Poorly-organized files or Not filled out completely (can be avoided). BE reviewers take longer to review poorly organized submissions 2. No information on batch size/type (Pilot or production scale) & source of the API of test product 3. GCP\GLP Certificates for the clinical \ bioanalytical sites of the study, and IRB approvals are not submitted 4. Typo errors in Batch numbers, Test/Reference products names 5. Study start & end dates 6. Certificates of Analysis (COAs) of test batch &/or Reference product are not submitted 7. Composition formula of the test product 8. 20% of subjects chromatograms

11 Common deficiencies in BE submissions (continued) 9. Pharmacokinetic and statistical calculations not submitted 10. Detailed description of study design not submitted 11. Unjustified exclusion of subjects: Subjects are excluded from statistical analysis without proper justification / Dropping subjects who are assumed outliers from statistical analysis without adequate justification. 12. Individual pharmacokinetic parameters not submitted 13. Pharmacokinetic (PK) repeats / the criteria for selection of samples for re-analysis 14. Bioanalytical SOPs used in the application were not submitted. 15. Inadequate validation data of bioanalytical method 16. Long-term storage stability: the long-term frozen storage stability data were not submitted or not enough to cover the whole biological sample storage time period.

12 Common deficiencies in BW submissions Dissolution specification: the in vitro dissolution testing specifications were not proposed or not as recommended. Dissolution method: the dissolution method used in the application is not optimal or not as recommended. High variability in dissolution data. Failure to submit individual dissolution data for each of the 12 units of test and reference products. Improperly calculated F2 values / improper selection of dissolution time points. RSD values not submitted, or not justified. Incomplete dissolution testing (for example, lacking dissolution data in multimedia for extended release products and alcohol dose dumping data for certain products). Proof of dose proportionality, - linear PK over dosage range, Failure to provide information on dissolution testing date and site address In-vitro dissolution profiles not submitted for test product / for reference product (Different batches??) for different strengths of the same product

13 Case Studies

14 1. Mefenamic Acid (50mg/5ml) Suspension

15 1. Mefenamic Acid (50mg/5ml) Suspension

16 1. Mefenamic Acid (50mg/5ml) Suspension Fasting or Fed???

17 2. Celecoxib 100mg Capsule Biowaiver request based on approval of BE study for the higher strength (200mg) BE study of Celecoxib 200mg Capsule vs. Celebrex 200mg Capsule. Product composition/formula is provided for both strengths: Celecoxib 200mg and 100mg Capsules are dose proportional (Ratio of API & Excipients is 2:1). Size of the biobatch is Capsules, and for the 100mg strength is Capsules. COAs (Assay%, Dissolution test, ) of both T & R are not provided. Comparative dissolution: 12 units, 1000ml, apparatus II, 75rpm, time points (10, 15, 20, 30, 45, & 60 minutes), 3 dissolution media (ph 6.8 phosphate buffer, ph 4.5 acetate buffer, & 0.1N HCl) with / 1% SLS & 0.15% Pepsin Calculated F2 values (all >50): (ph 6.8; 77.2), (ph 4.5; 54.8), (0.1N HCl; 90.5)

18 2. Celecoxib 100mg Capsule Biowaiver request based on approval of BE study for the higher strength (200mg)

19 2. Celecoxib 100mg Capsule Biowaiver request based on approval of BE study for the higher strength (200mg)

20 Typo error??? 2. Celecoxib 100mg Capsule Biowaiver request based on approval of BE study for the higher strength (200mg)

21 2. Celecoxib 100mg Capsule Biowaiver request based on approval of BE study for the higher strength (200mg)

22 2. Celecoxib 100mg Capsule Biowaiver request based on approval of BE study for the higher strength (200mg) In the analytical method validation report, concentration of the filtered samples? (LLOQ, HLOQ)??

23 3. Erlotinib 100mg Film Coated Tablet Biowaiver request based on approval of BE study for the higher strength (150mg)

RSD values??? COAs of T & R??? Erlotinib 100mg vs.

?? Size of the T product batch is 30000 FCT Addition of 1%

24 Erlotinib 100mg Film Coated Tablet Biowaiver request based on approval of BE study for the higher strength (150mg) RSD values??? COAs of T & R??? Erlotinib 100mg vs. Erotinib 150mg (Biobatch)??? Size of the T product batch is FCT Addition of 1% SLS to the 3 dissolution media??? (same deficiencies apply to the dissolution profile In other media)

25 Risperidone 4mg Tablet BE study under fasting conditions 1. No IRB signature. 2. Study was conducted on 4mg concentration and for safety reasons it must be conducted on the 1mg strength. 3. GLP dated 2006 / year of study 2003.**The bioanalytical part of bioequivalence trials should be performed in accordance with the principles of Good Laboratory Practice (GLP) 4. GMP for manufacturer dated 2008 / biobatch manufactured in 2003.

26 Glimepiride 1 mg Film Coated Tablet BE study under fasting conditions 1. Assay difference between T (99%) and R (106%) > 5%.** assayed content of the batch used as test product should not differ more than 5% from that of the batch used as reference product..emea CPMP/QWP/EWP/1401/98 Rev Long term stability for samples in matrix did not cover period of storage and analysis.

27 Recommendations for Better BE Submissions Complete data filling at time of submission According to the CTD format Check the New JFDA Guidelines in 30/9/2010, and their latest updates Check the recommended dissolution methods listed in Dissolution Database for comparison to different method applicant may propose ( Check the periodically updated BE Recommendations Databases (In form of draft or final guidance) (

28 Thank you for your kind attention

BIOEQUIVALENCE TRIAL INFORMATION FORM (Medicines and Allied Substances Act [No. 3] of 2013 Part V Section 39)

ZAMRA BTIF BIOEQUIVALENCE TRIAL INFORMATION FORM (Medicines and Allied Substances Act [No. 3] of 2013 Part V Section 39) The Guidelines on Bioequivalence Studies to be consulted in completing this form.