Designing of Bioequivalence Studies

of Anticancer products: Protocol

Issues

3rd World Congress on BA/BE

Hyderabad
28 Mar, 2012
Vikas Kumar

1
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
Contents
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
Bioequivalence (BE) Studies: Overview
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
Bioequivalence (BE) studies of
Anticancer Drug Products: Overview
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 criterias
Lack of interest from Investigator
Bioequivalence studies of Anticancer
Drug Products: Challenges
Key challenges in designing of bioequivalence studies are

A: Scientific

1. Study Population
2. Study Design
3. Safety Aspect

B: Operational

C: Regulatory
Bioequivalence studies of Anticancer
Drug Products: Challenges
Key challenges in designing of bioequivalence studies are
Studies in targeted patient population: Capecitabine

A: Scientific Lack of homogeneity in the study population

To enroll the patients without modifying of the

established Regime
1. Study Population
Concomitant medications: Complex Bioanalytical Exercise
2. Study Design
3. Safety Aspect Limited appropriate patients population

High dropout rates: Number of patients to be enrolled in

B: Operational study need to properly defined in protocols

Criteria for withdrawal/dropout need to be clearly defined

C: Regulatory
Widening of age window (18-55 years): Ex. Doxorubicin

upper age limit 75 years (Non binding recommendations)

Bioequivalence studies of Anticancer
Drug Products: Challenges
Key challenges in designing of bioequivalence studies are

Cross over designs v/s Parallel designs

A: Scientific
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

1. Study Population
2. Study Design (I) Available Option:
3. Safety Aspect
Steady state design

B: Operational

C: Regulatory
Bioequivalence studies of Anticancer
Drug Products: Challenges
Key challenges in designing of bioequivalence studies are

Steady state design:

A: Scientific
Required in case of continuous dosing

Potential difference in AUC at steady state

Problem in analysis: Sensitivity

1. Study Population
2. Study Design (II) Single dose studies not feasible in patients
3. Safety Aspect
Difficulty in maintaining protocol compliance for

longer duration: HIGH COSTS

B: Operational

C: Regulatory
Bioequivalence studies of Anticancer
Drug Products: Challenges
Key challenges in designing of bioequivalence studies are

A: Scientific SAMPLE SIZE

No/Limited data available on Intra subject %CV

EU guidance recommends use of Two Stage design to

1. Study Population determine appropriate sample size: Intra subject %CV in

2. Study Design (III)
3. Safety Aspect part I of study can be used ?

Some Anticancer drugs have Narrow therapeutic Index:

B: Operational Narrowing of the BE CI limit (90-110) example; Everolimus

Anticancer drugs with high variability (> 30%): Reference

C: Regulatory scaled approach

Bioequivalence studies of Anticancer
Drug Products: Challenges
Key challenges in designing of bioequivalence studies are

Patients are on several concomitant medications: Difficult

A: Scientific
to compare safety of test and reference drugs

Long patients follow up time for safety monitoring

Administration of IMP: Very high dose

1. Study Population
2. Study Design Large number of adverse events
3. Safety Aspect

B: Operational

C: Regulatory
Bioequivalence studies of Anticancer
Drug Products: Challenges
Key challenges in designing of bioequivalence studies are
Limited Investigator sites with required
A: Scientific
Infrastructure and facilities

Sample Pre-processing at Investigator sites

PK sample handling: Collection & Transportation

1. Study Population
2. Study Design
Flow of activities:
3. Safety Aspect

Activity Site Challenge

B: Operational
Sample Timing +
Investigator
Collection Expertise

C: Regulatory Investigator/CR Shipment in

Preprocessing
O Batches

Central
Sample Bioanalytical MD/MV
Analysis Site
Bioequivalence studies of Anticancer
Drug Products: Challenges
Key challenges in designing of bioequivalence studies are
Lack of homogeneity within regulatory recommendations

A: Scientific for BE studies of anticancer products

Some regulatory bodies require studies in local

population example; Russia, China

1. Study Population
Regulatory agencies may require BE studies with Local
2. Study Design
3. Safety Aspect RLD

Patients prone to several SAE which may or may not be

B: Operational due to study drugs

Difficulty in finding suitable CRO for conducting patients

C: Regulatory
based BE studies in region

All these issues will casus increase in the project costs,

unnecessary duplication of generated data, long project
timelines
Case Studies
Two case studies related to designing of BE studies for oncology products

I:

II:
Case Studies
Two case studies related to designing of BE studies for oncology products
Reference Product:

I: Capecitabine ? 150 mg or 500 mg: 500 mg

?? Dose: 1250 mg/m2 twice daily so 4500 mg tablets

Study Population:

? Healthy or Patients: Patients with advanced colorectal

II: Imatinib
cancer

Study Design:

Highly variable (32%), large patients pool required >

50

Need to measure active Metabolites 5DFCR, 5DFUR

Case Studies
Two case studies related to designing of BE studies for oncology products
Reference Product:
I: Capecitabine
100 mg or 400 mg: 400 mg

Dose: 400 mg daily to 800 mg

Study Population:
II: Imatinib
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
Imatinib BE in healthy subjects
S.No. Study Type Number of Dose/Route Important Inclusion
Subjects Criteria
(Male/Females)
1. Bioequivalence 22 (All Male) 400 mg Age: 18 to 55 years
study 3* (Single dose BMI: 18.5 TO 30 Kg/m2
fasting
study)/Oral
2. Metabolism and 4 (All Male) 239 mg (14C- Demography: Caucasian
Disposition 4 labeled)/Oral Age: 41 to 55 years
Body Weight: 61.8 to 85.7
kg
3. Bioequivalence5 30 (All Male) 400 mg Demography: South
(Single dose American (Uruguayan)
fasting)/Oral Age: 27.8 years 6.5
Weight: 71.2 kg 9.8
4. Absolute 12 400 mg (Oral) Demography: Caucasian
Bioavailability 6
or 100 mg Age: 40 to 58 years
(I.V)
Body Weight: 62 to 88 kg
5. Pharmacokinetics 7
12 (6/6) 400 mg day 1 Age: 20-51 years
and 14 (Oral)
References
1.U SFDA Guidance for Industry

2.E MA 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.G schwind et al, Metabolism And Disposition Of Imatinib Mesylate In Healthy Volunteers, Drug Metabolism And

Disposition, 33: 2005; 15031512

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.P eng et al, Absolute Bioavailability of Imatinib (Glivec) Orally versus Intravenous Infusion, Journal of Clinical

Pharmacology, 44(2); 2004, 158-162.

7.F rye et al, Effect of St John's Wort on imatinib mesylate pharmacokinetics, Clinical Pharmacology & Therapeutics, 76,

323-329
Thanks for your kind attention!
Any Questions please?