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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
