Track 9-1 Designing of bioequivalence studies of anticancer products Protocol Issues F2
- 1. 3rd World Congress on BA/BE Hyderabad 28 Mar, 2012 Vikas Kumar 1
- 2. Disclaimer: The views and opinions expressed in this presentation belong to the speaker only and should not be attributed to OMICS group and/or Fresenius Kabi Oncology Limited or employees related to these organizations
- 3. Bioequivalence Studies: Overview Bioequivalence studies of Anticancer Drug Products: Overview Bioequivalence studies of Anticancer Drug Products: Challenges Scientific Challenges Operational Challenges Regulatory Challenges Case studies References
- 4. BE studies are comparative Bioavailability (BA) studies Definition: “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study” BE approach depends largely on the formulation under evaluation
- 5. BE studies of anticancer products may or may not be feasible in healthy population Limited understanding and options: PhM Patient recruitment challenges Ethical Concerns Inclusion/Exclusion criteria’s Lack of interest from Investigator
- 6. Key challenges in designing of bioequivalence studies are A: Scientific B: Operational C: Regulatory 1. Study Population 2. Study Design 3. Safety Aspect
- 7. Key challenges in designing of bioequivalence studies are A: Scientific B: Operational C: Regulatory 1. Study Population 2. Study Design 3. Safety Aspect Studies in targeted patient population: Capecitabine Lack of homogeneity in the study population To enroll the patients without modifying of the established Regime Concomitant medications: Complex Bioanalytical Exercise Limited appropriate patients population High dropout rates: Number of patients to be enrolled in study need to properly defined in protocols Criteria for withdrawal/dropout need to be clearly defined Widening of age window (18-55 years): Ex. Doxorubicin upper age limit 75 years (Non binding recommendations)
- 8. Key challenges in designing of bioequivalence studies are A: Scientific B: Operational C: Regulatory 1. Study Population 2. Study Design (I) 3. Safety Aspect Cross over designs v/s Parallel designs Parallel design preferred in case of long half drugs but this is not feasible in case of oncology drug Ethical concerns: Patients can not be deprived of therapy Available Option: Steady state design
- 9. Key challenges in designing of bioequivalence studies are A: Scientific B: Operational C: Regulatory 1. Study Population 2. Study Design (II) 3. Safety Aspect Steady state design: Required in case of continuous dosing Potential difference in AUC at steady state Problem in analysis: Sensitivity Single dose studies not feasible in patients Difficulty in maintaining protocol compliance for longer duration: HIGH COSTS
- 10. Key challenges in designing of bioequivalence studies are A: Scientific B: Operational C: Regulatory 1. Study Population 2. Study Design (III) 3. Safety Aspect SAMPLE SIZE No/Limited data available on Intra subject %CV EU guidance recommends use of Two Stage design to determine appropriate sample size: Intra subject %CV in part I of study can be used ? Some Anticancer drugs have Narrow therapeutic Index: Narrowing of the BE CI limit (90-110) example; Everolimus Anticancer drugs with high variability (> 30%): Reference scaled approach
- 11. Key challenges in designing of bioequivalence studies are A: Scientific B: Operational C: Regulatory 1. Study Population 2. Study Design 3. Safety Aspect Patients are on several concomitant medications: Difficult to compare safety of test and reference drugs Long patients follow up time for safety monitoring Administration of IMP: Very high dose Large number of adverse events
- 12. Key challenges in designing of bioequivalence studies are A: Scientific B: Operational C: Regulatory 1. Study Population 2. Study Design 3. Safety Aspect Limited Investigator sites with required Infrastructure and facilities Sample Pre-processing at Investigator sites PK sample handling: Collection & Transportation Flow of activities: Activity Site Challenge Sample Collection Preprocessing Sample Analysis Investigator Central Bioanalytical Site Timing + Expertise Shipment in Batches MD/MV Investigator/CRO
- 13. Key challenges in designing of bioequivalence studies are A: Scientific B: Operational C: Regulatory 1. Study Population 2. Study Design 3. Safety Aspect Lack of homogeneity within regulatory recommendations for BE studies of anticancer products Some regulatory bodies require studies in local population example; Russia, China Regulatory agencies may require BE studies with Local RLD Patients prone to several SAE which may or may not be due to study drugs Difficulty in finding suitable CRO for conducting patients based BE studies in region All these issues will casus increase in the project costs, unnecessary duplication of generated data, long project timelines
- 14. Two case studies related to designing of BE studies for oncology products I: II:
- 15. Two case studies related to designing of BE studies for oncology products I: Capecitabine Reference Product: ? 150 mg or 500 mg: 500 mg ?? Dose: 1250 mg/m2 twice daily so 4×500 mg tablets Study Population: ? Healthy or Patients: Patients with advanced colorectal cancer Study Design: Highly variable (32%), large patients pool required > 50 Need to measure active Metabolites 5’DFCR, 5’DFUR II: Imatinib
- 16. Two case studies related to designing of BE studies for oncology products I: Capecitabine II: Imatinib Reference Product: • 100 mg or 400 mg: 400 mg • Dose: 400 mg daily to 800 mg Study Population: • Healthy or Patients: Patients in whom titration away from the 400 mg dose is unlikely (USFDA) • Studies being conducted by the manufactures in healthy subjects
- 17. S.No. Study Type Number of Subjects (Male/Females) Dose/Route Important Inclusion Criteria 1. Bioequivalence study 3* 22 (All Male) 400 mg (Single dose fasting study)/Oral Age: 18 to 55 years BMI: 18.5 TO 30 Kg/m2 2. Metabolism and Disposition 4 4 (All Male) 239 mg (14C- labeled)/Oral Demography: Caucasian Age: 41 to 55 years Body Weight: 61.8 to 85.7 kg 3. Bioequivalence5 30 (All Male) 400 mg (Single dose fasting)/Oral Demography: South American (Uruguayan) Age: 27.8 years ± 6.5 Weight: 71.2 kg ± 9.8 4. Absolute Bioavailability 6 12 400 mg (Oral) or 100 mg (I.V) Demography: Caucasian Age: 40 to 58 years Body Weight: 62 to 88 kg 5. Pharmacokinetics 7 12 (6/6) 400 mg day 1 and 14 (Oral) Age: 20-51 years
- 18. 1. USFDA Guidance for Industry 2. EMA Guidance 3. Ghannam M, Jawhari D and Alswisi M, Bioavailability of a New Generic Formulation of Imatinib Mesylate 400mg Tablets Versus Glivec in Healthy Male Adult Volunteers, Journal of Bioequivalence & Bioavailability, Volume 3(7): 2011; 161-164 4. Gschwind et al, Metabolism And Disposition Of Imatinib Mesylate In Healthy Volunteers, Drug Metabolism And Disposition, 33: 2005; 1503–1512 5. Campiglia et al, Bioequivalence of two film-coated tablets of imatinib mesylate 400 mg: A randomized, open-label, single-dose, fasting, two-period, two-sequence crossover comparison in healthy male South American volunteers, Clinical Therapeutics, (31); 2009, 2224-2232 6. Peng et al, Absolute Bioavailability of Imatinib (Glivec®) Orally versus Intravenous Infusion, Journal of Clinical Pharmacology, 44(2); 2004, 158-162. 7. Frye et al, Effect of St John's Wort on imatinib mesylate pharmacokinetics, Clinical Pharmacology & Therapeutics, 76, 323-329
- 19. Thanks for your kind attention!