BIO EQUIVALENCE

STUDY IN CLINICAL RESEARCH

1
RUSHALI PATEL JUNE-JULY 2015 AHMEDABAD INTERNATIONAL SCHOOL
 PRESENTATION OVERVIEW
BIO EQUIVALENCE STUDY IN CLINICAL RESEARCH

INTRODUCTION PRACTICES PROTOCOL AND DEPARTMENTS BABE STUDY:

TO THE STUDY FOLLOWED BY PROCEDURES INVOLVED IN AS IT
THE STUDY THE STUDY HAPPENED IN
REAL LIFE

09:30 10:00
10:00 10:30

BABE STUDY. 2
 INTRODUCTION
BIO EQUIVALENCE STUDY IN CLINICAL RESEARCH

WHAT IS THE STUDY ABOUT

01 BABE: Study of Bio Availability and Bio Equivalence

WHO HAS REQUESTED THE STUDY AND FOR WHAT

02 Sponsor: An individual, institution or company that takes the responsibility to initiate, manage or finance a clinical trial, but
does not actually conduct the investigation.
Sponsor wants Drug B in the market so wants the study to prove Drug B’s Bio equivalence to Drug A

WHO CARRIES IT OUT

03 Contract Research Organization (CRO): An organization that provides support to the pharmaceutical,
biotechnology, and medical device industries in the form of research services outsourced on a contract basis

ON WHOM
04 The study involves healthy volunteers in which the objective is to compare the two formulations of different
manufacturers or two different batches of same manufacturers to determine its BABE

BABE STUDY. 3
PRACTICES FOLLOWED
 PRACTICES FOLLOWED
BIO EQUIVALENCE STUDY IN CLINICAL RESEARCH
ICH
1 International Conference
on Harmonization
Project that brings together the regulatory
authorities of Europe, Japan and the
United States and experts from the
pharmaceutical industry to discuss
scientific and technical aspects of
pharmaceutical product registration
Purpose:
More economical use of human, animal
and material resources
To eliminate unnecessary delays in
availability of new medicines
To produce a single set of technical
requirements for the registration of new
drug products to streamline development
BABE STUDY.
GCP
2 Good Clinical Practice
Quality Standard provided by ICH,
Schedule Y, Indian GCP to regulate clinical
trials involving human subjects
Purpose:
Enforce tight guidelines on ethical aspects
of a clinical study
Guidelines include protection of human
rights for the subjects and volunteers in a
clinical trial
Provides assurance of the safety and
efficacy of the newly developed
compounds
Key Players:
Investigators, Ethics Committee, Sponsor,
QA)
GLP
3 Good Laboratory Practice
A set of principles that provide a
framework within which laboratory studies
are planned, performed, monitored,
reported and archived.
Given by OECD, WHO, 21 CFR part 58,
Schedule L1
Purpose:
Help improve quality of data and reports
and increases the confidence in validity of
test reports.
Key players:
Management, Study Director, QA,
Personnel
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 INDEPENDENT ETHICS COMMITTEE
BIO EQUIVALENCE STUDY IN CLINICAL RESEARCH

COMPOSITION
An independent body (a review board or a committee: institutional, regional,
national or supranational) constituted of medical professionals and non
medical members

RESPONSIBILITIES
Ensure protection of rights, safety and week being of human subjects
involved in a trial
Provide public assurance of that protection by reviewing and approving/
providing favorable opinion on trial protocol
Ensure suitability of investigator, facilities and methods, and material to be
used in obtaining and documenting informed consent of trial subjects.

BABE STUDY. 6
 IHC-GCP Principles
BIO EQUIVALENCE STUDY IN CLINICAL RESEARCH

1 Conduct trials according to GCP 8 Use qualified support staff

Weighs Risks vs. Benefits Obtain informed consent

2 9
Right, safety and well being of the Record information appropriately
3 subjects
10
4 Have adequate information to justify trial 11 Protect confidentiality

Write a sound protocol Handle investigational products

5 12 appropriately

Receive IRB/IEC approval Implement quality systems

6 13
Medical care given to subjects should
7 always be the responsibility of qualified
physicians

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DEPARTMENTS INVOLVED
 DEPARTMENTS INVOLVED
BIO EQUIVALENCE STUDY IN CLINICAL RESEARCH

MEDICAL WRITING DEPARTMENT

Protocol and Document Preparation and Review

QA/QC DEPARTMENT
Compliance, Quality Improvement and Staff Training

BIOMETRICS DEPARTMENT
Pharmacokinetic and Statistical Analysis, Bio Equivalence Established

BIO ANALYTICAL LAB

Method Development, Method Validation, Sample Analysis

CLINIC
Cannulation, Feeding Subjects, Dosing, Blood Collection, Centrifugation

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 CLINIC
BIO EQUIVALENCE STUDY: DEPARMENTS INVOLVED

FOLLOWS GCP RESPONSIBLE FOR COLLECT BLOOD CENTRIFUGRATIO

N & STORAGE
Clinic Follows Good Clinical Patient protection Blood Samples collected Centrifugation of blood
Practice (GCP) Quality of data here at previously decided samples to separate blood
Dermatological studies time points from plasma
ICU
Sample Collect

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 BIO ANALYTICAL LAB
BIO EQUIVALENCE STUDY: DEPARMENTS INVOLVED

METHOD EXTRACTION SAMPLE ANALYSIS

DEVELOPMENT
Method development, Yellow light for drugs are not Blood samples previously
validation, subject sample stable in normal light collected are analyzed using
analysis methods to get quantitative
Centrifugation to separate
results of the concentration of
plasma and serum
the drug:
Cleaning Area
Liquid Chromatography
Labeling/ Measuring of
Mass Spectrometry
Plasma Samples
Column Chromatography
Balance Room

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 BIOMETRICS DEPARTMENT
BIO EQUIVALENCE STUDY: DEPARMENTS INVOLVED

PHARMACOKINETIC
S (OR BIOMETRY)
Branch of pharmacology
dedicated to determining the
fate of substances
administered externally to a
living organism
Involves Absorption,
Distribution, Metabolism and
Excretion
BABE STUDY.
BIOSTATISTICS
Application of statistics to a
wide range of topics in
biology.
Design of biological
experiments, especially in
medicine, pharmacy,
agriculture and fishery
Collection, summarization,
and analysis of data from
those
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 QUALITY ASSURANCE/QUALITY CONTROL
BIO EQUIVALENCE STUDY: DEPARMENTS INVOLVED

COMPLIANCE IMPROVEMENT &

TRAINING
Assures Compliance to: Acts as a catalyst for quality
Study Protocol improvement
Standard Operating Helps to train clinical
Procedures (SOPs) research staff
Good Clinical/Laboratory
Practices (GCP/GLP)
Regulatory Requirements

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 ARCHIVE DEPARTMENT
BIO EQUIVALENCE STUDY: DEPARMENTS INVOLVED

ARCHIVAL

After completion of study and submission of data

to Sponsor and regulatory bodies, documents and
samples involved in the study are archived for a
time period according to regulatory requirements

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 MEDICAL WRITING DEPARMENT
BIO EQUIVALENCE STUDY: DEPARMENTS INVOLVED

MEDICAL WRITING

Prepares Protocol first

Prepares Informed Consent Document (ICD)
Prepares Case report form prepared (CRF)
Gets documents reviewed by departments involved with the project
Sponsor reviews the documents
Independent Ethics Committee (IEC) Reviews

BABE STUDY. 15
BABE STUDY
AS IT HAPPENED
IN REAL LIFE
 BABE STUDY
AS IT HAPPENED IN REAL LIFE

STEP 6
REPORTING

STEP 5
STATISTICAL

STEP 4
ANALYTICAL
STEP 3
CLINICAL
STEP 2
CHECKIN
STEP 1
SCREENING

BABE STUDY. 17
 SCREENING
BABE STUDY: AS IT HAPPENED IN REAL LIFE

HEALTHY VOLUNTEERS WALK ENROLLMENT CONSENT

01 IN 02 To enroll data into database e.g. personal details
DOCUMENT
such as height, weight, BMI etc.

SCREENING CONSENT SCREENING PROCESS

03
SUBJECT DEEMED FIT OR UNFIT
05 Investigator analyzes test results to declare
volunteer fit or unfit for study
04 ECG, X: Ray, Blood Collection for
Hematology Tests (RBC, WBC, Hemoglobin),
Urine Sample Collection (To test for drug
abuse), Alcohol Test (Breathalyzer) , Subject
History

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 CHECKIN PROCESS
BABE STUDY: AS IT HAPPENED IN REAL LIFE

ATTENDANCE

1. CHECKIN STARTS
Attendance taken
(Documented in Subject
Arrival Record) ICF

2. INFORMED CONSENT
FORM
ICF issued and subjects
given ample time to read it
PROTOCOL

3. PROTOCOL PRESENTATION
Details about expected
Blood loss and
compensation provided
TRIAL CONSENT

4. TRIAL CONSENT
TAKEN taken
Trial consent
(Video recording of
Consent)
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 ALCHOHOL
TEST
5. ALCHOHOL TEST
Digital Alcohol Detector/
Breathalyzer
DRUG ABUSE
TEST
6. DRUG ABUSE TEST
Detector Urine Test to
check for Drug Abuse
VITALS
CHECKED
7. MEDICAL EXAM
Vital Stats, Blood
pressure etc. checked)
COMPLIANCE
CHECK
8. COMPLIANCE CHECK
Basic questions asked to
subject to ensure
compliance

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 NUMBER ALLOTED

9. SUBJECT NUMBER
ALLOTED

FINAL CHECKIN

10. BAGGAGE ROOM

Body and Baggage
Room to change into
uniform and to leave all
baggage in lockers
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 CLINICAL PROCESS
BABE STUDY: AS IT HAPPENED IN REAL LIFE

01 CANNULATION is done in order to minimize punctures and pain to subject at each time of blood
collection. A tube (cannula) is placed inside a vein to provide venous access. (takes place 75
minutes before dosing)

02 FOOD PROVIDED depending upon whether fasting or fat study. Meals are provided in order of
number allocated to subjects. Necessary to ensure that all the food provided is completed as fat
study. Subjects which are unable to digest the food and vomit are discontinued. They are
replaced with extra subjects.

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 CLINICAL PROCESS
BABE STUDY: AS IT HAPPENED IN REAL LIFE

03 INVESTIGATIONAL PRODUCT (IP) ADMINISTRATION/ DOSING

• Occurs 30 minutes after breakfast for each subject. There is a 2 minute interval between each subject during dosing.
• Subject card and ID cards are compared to ensure the correct subject is given the IP
• Instructions as to how dosing will take place are given to the subject
• Trained personnel then put the IP in the mouth of subject and 240 ml of water is given to the subject
• Mouth and hands of the subject are checked

04 BLOOD COLLECTION After cannulation is over, blood collection starts in the same order. 2 minute interval between the blood
collection of each subject. 0.5 ml of heparinized blood is discarded prior to the collection of each blood sample. Blood sample is
collected and placed into appropriately labeled vacuette.

05 CENTRIFUGATION of the blood samples is then carried out to separate plasma from the blood as the drug is present in the
plasma. Centrifugation is carried out at 3000 revolutions per minute for 15 minutes and at 4 degrees Celsius. A pipette is then
used to transfer the separated plasma from the vacuettes to appropriately labeled RIA vials. Placed into 2 duplicate RIA vials (1 is
for backup).

BABE STUDY. 23
 ANALYTICAL PROCESS
BABE STUDY: AS IT HAPPENED IN REAL LIFE

01 METHOD DEVELOPMENT A specific extraction and instrument process is decided and planned for each specific molecule (drug)
to be analyzed.

02 METHOD VALIDATION To ensure that the method developed produces accurate and precise results. A lot of parameters are
validated: Accuracy, Precision, Selectivity , Stability , Matrix Effect

03 SUBJECT SAMPLE ANALYSIS

• CC: A calibration standard is a standard with a known amount of analyte concentration which is added to a biological matrix and
used to construct a calibration curve. From this CC, values of instrument response are extrapolated to provide the analyze
concentration.
• IS: Internal Standards: A same concentration of Internal Standards is added in same quantity to all samples and hence by finding
the change in concentration of IS, the estimation and nullification of any variation in the analyte concentration can be done.
• QC: A sample with a known amount of analyte concentration is added to a biological matrix to establish precision and percentage
bias.
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 INSTRUMENTS USED IN ANALYTICAL
PROCESS
BABE STUDY: AS IT HAPPENED IN REAL LIFE

ANALYTICAL BALANCE FUME HOOD

01 Used for precise weighing of reference
standards, metabolites, Internal standards
02
and small amount of reagents.
Continuous air draft is maintained in a
particular direction to guide the flow of gases,
vapors and fumes in the direction of air.

PIPPETTES LIQUID
03 A lab tool commonly used in the lab to
transport a measured volume of liquid often
04 Used for the separation of molecules present
CHROMATOGRAPHY
in plasma
as a media dispenser.

EVAPORATORS MASS SPECTROSCOPY

05 Help provide simultaneous evaporation of
multiple samples.
06 Molecules are separated according to
differences in their mass.

BABE STUDY. 25
 STATISTICAL PROCESS
BABE STUDY: AS IT HAPPENED IN REAL LIFE

Biometrics (Pharmacokinetics and Biostatistics):

Graphs plotted here, mean, median, standard deviation
found

01 Drug concentration from blood samples is obtained by

chromatographic analysis in bio analytical lab

02 Drug concentration used to create drug behavior profile of every

subject. Pharmacokinetic and statistical analysis takes place.
• Mean: Sum of sampled values divided by #of items in sample
• Median: Middle value of a set of values
• Standard Deviation: Measure that is used to quantify amount
of variation or dispersion of a set of data values.

03 Bio equivalence is then established by comparing graphs, cmax,

tmax and AUC.
• Cmax: The maximum concentration of the drug which is
reached in the body.
• Tmax: The time at which the maximum concentration is
reached.
• AUC: The area under the curve obtained (Concentration vs
time)
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 REPORTING PROCESS
BABE STUDY: AS IT HAPPENED IN REAL LIFE
STUDY REPORT
Results of each study
involving an IP are
summarized and described in
an integrated study report
containing clinical data and
statistical descriptions,
presentations and analysis
BABE STUDY.
CRC GROUP
Central Report Compilation
(CRC) IS group responsible
for regular communication
and coordination with
sponsor.
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 GLOSSARY OF TERMS
BABE STUDY: AS IT HAPPENED IN REAL LIFE

CRO: Contract Research Organization BAC: Blood Alcohol Concentration SAE: Serious Adverse Event

IEC: Independent Ethics Committee IP: Investigational Product CFR: Court of Federal Regulation

SOP: Standard operating procedure QA: Quality Assurance CRC: Central Report Compilation

CRF: Case Report Form QC: Quality Control IS: Internal Standards

GCP: Good clinical Practice AP: Analytical Procedure ULOQ: Upper Limit of Quantitation

GLP: Good Laboratory Practice ICH: International Conference on Harmonization LLOQ: Lower Limit of Quantitation

MSR: Medical Screening Record IRB: Institutional Review Board BLQ: Below limit of Quantitation

ECG: Electro Cardiogram LAR: Legally Acceptable Representative ALQ: Above Limit of Quantitation

ICF: Informed Consent Form ICMR: Indian Council for medical research CC: Calibration Curve

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