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Module 4 - Bioequivalence Study Design and Protocol Elements

The document outlines the essential elements and design of a bioequivalence study protocol, including objectives, study design, population, and statistical evaluation. It details the necessary components such as screening parameters, study treatments, sampling time points, and analytical methodologies. Additionally, it emphasizes the importance of clinical safety measures and bioequivalence criteria for regulatory compliance.

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Uma Maheshwari
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127 views18 pages

Module 4 - Bioequivalence Study Design and Protocol Elements

The document outlines the essential elements and design of a bioequivalence study protocol, including objectives, study design, population, and statistical evaluation. It details the necessary components such as screening parameters, study treatments, sampling time points, and analytical methodologies. Additionally, it emphasizes the importance of clinical safety measures and bioequivalence criteria for regulatory compliance.

Uploaded by

Uma Maheshwari
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PPTX, PDF, TXT or read online on Scribd
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Bioequivalence Study Design

and Protocol Elements


Bioequivalence Study Protocol
Protocol: A document that describes the
objective(s), design, methodology, statistical
considerations, and organization of a trial. The
protocol usually also gives the background and
rationale for the trial, but these could be
provided in other protocol referenced
documents. Throughout the ICH GCP Guideline
the term protocol refers to protocol and protocol
amendments.

Protocol Amendment: A written description of


a change(s) to or formal clarification of a
protocol.
Bioequivalence Study Protocol
• Title/Objectives
• Study Design
• Study Population (healthy/patients)
• No. of Study Subjects
• Screening Parameters
• Housing period
• Study Treatments
• Dosage administration
Bioequivalence Study Protocol
• Sampling time points
• Volume of blood if Blood is collected
• Sample processing and storage
• Clinical Safety Parameters
• Analytical Methodology
• Pharmacokinetic Parameters
• Statistical Evaluation and Parameters
• Bioequivalence Criteria
Title and Objectives
• AN OPEN-LABEL, BALANCED, RANDOMIZED, TWO-
TREATMENT, TWO PERIOD,TWO-SEQUENCE, SINGLE DOSE,
CROSSOVER, COMPARATIVE ORAL BIOAVAILABILITY STUDY OF
XXXXXXXXXXXXXXXX and XXXXXXXXXXX IN HEALTHY, ADULT,
HUMAN, MALE SUBJECTS ADMINISTERED WITH APPLE SAUCE
UNDER FASTING CONDITIONS

• To assess Bioequivalence
• To assess the safety of test product
Study Designs, Population and Sample Size

• Designs
• Population – Healthy males, females, mixed
population, special population, patients
• Sample Size – Intra Subject Variability and
Formulation ratio
US FDA table
Screening Parameters
• Healthy Subjects
• Haematology, Biochamistry, urine
examinations, drugs of abuse test, alcohol
breath test and other special investigations if
any.
• Housing period
Depends on the blood draw time points
Study Treatments
• Test Product (s)
• Reference Product (s)
• Dose selection
• Placebo?? No.
• GMP
• COA
• Administration procedures for fasting, fed and
multiple dose study
Dose Selection
• Usually highest dose

Some examples where US FDA recommended be studies on lower strengths


for safety reasons

• Topiramate tablets (Antiepileptic drug) 25*, 100, 200 mg

• Glimiperide tablets (Antidiabetic drug) 1*, 2, 4 mg

• Olanzepine tablets (Antiepileptic drug) 2.5, 5*, 7.5, 10, 15, 20 mg

• Risperidone tablets (Antipsychotic drug) 0.25, 0.5, 1*, 2, 3, 4 mg

• Lamotrigine tablets (Antiepileptic drug) 25*, 100, 150 , 200 mg


Sampling Time Points and Sample
Processing
• Sampling time points selection (Thalf and Tmax based)
• At lest 3 half life covered for collection
• Frequent sampling around Tmax
• One non Cmax time point before Cmax
• Pre dose sample
• Post dose samples
• To cover ADME
• Long half life drugs – Ambulatory collections
• Centrifugation, rpm, temperature
• Anticoagulant, blood draw procedure
• Storage at Deep Freezers
10
Clinical Safety Measures
• Pre study safety
Screening
• Study safety
Vitals monitoring, ECG etc.
• Post Study Safety
Lab Evaluations
Medical officers, ICUs, Ambulance, Hospital
collaborations, Medical experts etc.
Wash Out Period
• Depends on
Drug molecule and product
Study Design
Half life of drugs determines wash out
At least 5 Half lifes to covered
If not sufficient, pre-dose concentrations at Period II
• Long half life drugs
Truncated AUC approach
Parallel Study Designs
Wash Out Period
• Cefuroxime axetil tablets : t1/2 = 1.2 to 1.3 hours
Wash out period - At least 3 days

• Fexofenadine tablets : t1/2 = 15 hours


Washout period - At least 7 days

• Fluoxetine capsules : t1/2 = 190 Hours (Analyte:


Norfluoxetine)
Washout period – At least 75 days

13
Analytical Methodology
• Drug, Parent/metabolite - analytes
• LC/MS/MS detections
• HPLC-UV, Fluorescense detection
• Gas Chromatography
• Extraction Techniques
Solid phase extraction
Liquid-Liquid extraction
Precipitation methods
Pharmacokinetic Parameters
• Primary parameters
Cmax
AUC 0-t
AUC 0-inf
• Secondary parameters
Tmax
Thalf
Kel
Calculated by validated software like WinNonlin and Kinetica
Statistical Parameters
• Summary Statistics (mean, SD, interCV, min, median,
max)
• Geometric mean of T and R
• Geometric mean Ratio (T/R)
• Intra Subject CV
• Power
• 90% Confidence Intervals (upper and lower limits)
• Calculated by SAS software
Bioequivalence Criteria
• 90% CI should be with in the limits of 80-125%
US FDA – Parent should be with in limits and
metabolite (if any) support data
EU – Both parent and active metabolite should
be in limits
Narrow therapeutic index drugs – Cmax 90-
110%
MCC – for Cmax 75-133%
Wish You Good Luck!

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