Transcript 36pt Trebuchet MS Bold

Study Design and Execution of the Bioequivalence
Studies - Module 5
Hafrún Friðriksdóttir
VP R&D Actavis Group hf
1. Introduction
Comparision of the therapeutic performances of two
medicinal produts containing the same active substance is a
critical means of assessing the possibility of alternative use
between the innovator and any essentially similar medicinal
product.
“A medicinal product is essentially similar to an
original product where it satisfies the criteria of having the
same qualitative and quantitative composition in terms of
active substances, of having the same pharmaceutical form
and of being bioequivalent unless it is apparent in the light of
scientific knowledge that it differs from the original product
as regards safety and efficacy
1. Introduction
Assuming that in the same subject an essentially
similar plasma concentration time course will
result in essentially similar conc at the site of
action and thus in an essentially similar effect,
pharmacokinetic data instead of therapeutic
results may be used to establish
equivalence:bioequivalence
1. Introduction
• To define, for product with a systemic effect,
when bioavailability or bioequivalence studies
are necessary and to formulate requirement for
their design, conduct and evaluation,
•
the possiblility of using in vitro instead of
invivo studies with pharmacokinetic end points is
also envisaged
1. Introduction
• For medicinal products not intened to be
delivered into the general circulation the
common systemic bioavailability approach cannot
be applied
• Then clinical studies can be requered, using
pharmacodynamic end points.
2. Definations
2.3 Bioavailability
•
The rate and extent to which the
active igredient or active moiety is
absorbed from a pharmaceutical form and
becomes available at the site of action
2.Defination
2.4 Bioequivalence
•
Two medicinal products are bioequivalent if
they are pharmaceutically equivalent or
pharmaceutically alternatives and if their
bioavailabilities after administration in the same
molar dose are similar to such degree that their
effects, with respect to both efficacy and safety
will be essentially the same.
3. Design and conduct
of studies
Informations required to design a study
• Drug conserned
• Pharmacokinetic evaluation
• Pharmacodynamic evaluation
• EU Guidance note on:
• Pharmacokinetic in man
• Good Clinical Practice
3.1 Design
• Healthy volunteers
• Number of subjects depends on clinical and
analytival standards imposed , but not less than
12. Unwritten rule in Europe is not less than 24
subjects.
• Number depends on the required power
• Number depends on intrasubject variability
3.1 Design cont.
 Typically, a cross over design
 Balanced sequence of administration
 Number of treatment periods=number of
formulations tested
Other designs acceptable if statistically
sound
• Parallel design for long half-life drugs
• Replicate design for highly variable drugs
3.1 Design cont.
Usually a single dose study
However, multiple doses study (steady state) is
nessesary if:
 Dose or time- dependent pharmacokinetic
 High intra-individual variablilty
 Inadequate sensitivitiy of analysis of
concentration
 For modified release products (in addition to a
singel dose investigation)
3.1 Design cont.
 Caution with washout period between
treatments
 Usually 10 half-lives if short half-lives drug
(sometimes 5 half-lives if very long half-lives
drug)
 Can be 3 in steady state studies where the
washout of the previous treatment can overlap
with build up of the next treatment if build up
time is sufficietnly long.
3.1 Design cont.
Sampling points and duration
 Must allow determination of Cmax of the
pharmacologically active moiety
 To provide an adequate estimation of Cmax and to cover
the plasma-conc curve long enough to provide a reliable
estimate of extent of absorbtion (AUC)
 AUC0-t should not be less than 80% of AUCinf. AUC0t/AUCinf > 80%
 The sampling should be collected at least 3-4 times the
half-live
 For steady-state sampling should be carried out over a full
24 hours cycle
3.2.1 Selection of Subject
 The subject population for bioequivalence study should
be selected with the aim to minimise variability and permit
detection of differneces between pharmaceutical products
 Healthy volunteers
 Inclusion/exclusion criteria stated in the protocol
 Subjects could belong to either sex, the risk of
childbearing potential should be considered on an
individial basis
 Age of 18-55 years
 Weight within the Body Mass Index normal values
 Screening before and after the study for safety issue
 Should preferably be non-smokers and without history of
alcohol or drug abuse. If moderate smokers (less than 10
cigarettes per day)
3.2.2 Standardisation
of the study
 Standardisation of the diet and exercise
recommended.
 Preferably be fasting during the night prior to
administration of the products.
 If SPC of the reference product contains specific
recommendation in relation with food intake
related to food interactions effect the study
should be desgined accordingly.
 At least 150 ml of fluid with drug intake.
 Intake of other drug is forbidden.
3.3 Characteristics to be
investigated
Usually parent compound measurement
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However, in certain cases, active or inactive metabloite
measurement may be necessary instead of the parent
compound
If rapid metabolism leading to very low conc of the parent
drug
If the parent product is very unstable
If the concentration too low in biological matrix of interest.
If metabolite contributes significantly to net activity of the
drug then it is necessary to measure both, and evaluate
separately
3.3 Characteristics to be
investigated
Fixed Combination Products
 Measure both components
 Each component goes into analysis and
assessment of bioequivalence
 For new combinaitons, consider the
possiblility of drug-drug interaction
between the two components
3.3 Characteristics to be
investigated
Parameters of Interest in single dose studies
Cmax
Maximum plasma concentration
Tmax
Time to Cmax
T1/2
Plasma half-life
AUC0-t
AUC to last observation point
AUCinf
AUC extrapolated to infinity
Ae(t)
Cumulative urinary excretion to time
Ae(alpha) Cumulative urinary excretion
extrapolated to infinity
3.3 Characteristics to be
investigated
Parameters of Interest in steady state studies
Cmax
Maximum plasma concentration
Cmin
Minimum plasma concentration
Fluctation: (Cmax-Cmin)/Cave
AUCτ
AUC during a dosing interval at
steady state
3.4 Chemical analysis
The bioanalytical part of the BE trial
should be conducted according to the
applicable principles of Good Laboratory
Practice (GLP)
3.4 Chemical analysis
Validation
1. Stability of the stock solutions and of the analyte
in the biological matrix under processing
conditions and during the entire period of
storage
2. Specificity
3. Accuracy
4. Precision
5. Limit of Quantification
6. Linearity
3.4 Chemical analysis
A calibration curve should be generated for
each analyte in each analytical run
A number of separately prepared Quality control
samples should be analysed with processed test
samples at intervals based on the total number
of samples
All procedures should be performed according
to to pre-established SOPs.
3.5 Reference and test product
Choice of Reference Product
 Dose forms must correspond; Reference/Test
 The choice of Reference (innovator) product should be
justified by the Sponsor
“For abridged application claming essential similarity to a reference
product, application to numerious Member State based on
bioequivalence with a reference product form one Member Statne can be
made”
“unless there is a significat difference between the reference products
originating from the same maufacturer in terms of qualitive and
quantative composition in excipients”
3.5 Reference and test product
Choice of Reference Product
Concerned Member State may request
information from the first member state on the
reference product in term of
-Composition
-Manufacturing Process
-Finished product Specification
If there are significant differences, separate
study may be required using the reference
product in the Concerned Member State
3.5 Reference and test product
Test product used in a biostudy must be
prepared in accordance with GMP-regulations.
Batch control results of the test porduct should
be reported
Batch size of the biobatch should be 1/10 of the
production size or at least 100 000 units
(tablets, capsules) otherwheis justified.
Samples from full production batches should be
compared with those of test batch, and should
show similar in vitro dissolution profiles when
employng suitable dissolution test conditions.
3.5 Reference and test product
Study sponsor will have to retain a
sufficient number of all investigational
product samples in the study for one year
in excess of the accepted shelf life or two
years after completion of the trial or until
approval whihever is longer to allow retesting, if it is requested by the
authorities.
3.6 Data analysis
Primary objectives is to:
-Quantify differences in bioavailability
-Demonstrate that clinically
significant differences are unlikely
3.6.1 Statistical analysis
The statistical method for testing the relative
biovalability is based upon the 90% Confidence
interval of ratio (T/R) of population mean for the
parameters under consideations.
Log transformed data for AUC and Cmax
Untransformed data for Tmax
Also include details of:
Median, minimum and maximum values for each
parameter for each formulation
3.6.1 Statistical analysis
Bioequivalece is established if 90% Confidence
interval of ratio of population of means
For AUC 80-125%
For Cmax 80-125%
Wider interval as an example 75-133%
can be acceptable if predifined and
justified adressing in particular
any safety or efficacy concerns
for patients switched between
formulations
3.7 In vitro dissolution
complementary to a BE study
The results of “in vitro” dissolution test,
obtained with the batches of test and
reference produch that were used in the
BE study should be reported
The dissolution profiles would be
expected to be similar to those of the
reference product otherwheis justified
3.8 Reporting of results
Complete documetation of its protocol, conduct
and evaluation complying with GCP rules and
releated EU and ICH E3 Guideline.
Final report content:
-Summary
-Clinical
-Pharmacokinetic calculations
-Statistical calculations
-Analytical and Validation report
-Case report Form
3.8 Reporting of results
• Reporting of results
Data from subjects who
dropped-out included in the
results
4. Applications for products containing
approved active substances
Oral solutions
If the product is an aqueous oral solution at the
time of administration and contains an active
substance in the same conentration as an oral
solution currently approved a bioequivalence
study is NOT required
Provided the excipient contained in it do not
affect gastrointestinal transit, absorption or in
vivo stablity of the active substance
4. Applications for products containing
approved active substances
Bioequivalece studies NOT required for
 Parenteral products
(aqueous intravenous solutions, intramuscular
of sucutaneous)
 Locally applied products without systemic
absorption-Clincal study needed
(Oral nasal, inhalation, ocular, dermal,rectal,
vaginal)
 Gases (for inhalation)
4. Applications for products containing
approved active substances
Bioequivalence study required for locally
applied products with systemic action
4. Applications for products containing
approved active substances
• BE studies required for MR products:
• Delayed-release
same as for IR, but SD fed mandatory
• SR
• Single unit formulations (matrix)
• SD fasting on each strength
• SD fed with the same strength as those of the pivotal BE
studies
• SS on the highest strength only, if
→ waiver
• multiple unit formulations (pelets)
• SD fasting on the highest strength only, if
• Pk-linear
• Dose-proportional
• Similar dissolution profiles
• Contain identical beads or pellets
5.3 Variations
If a product has been re-formulated from the
formulation initially approved or the
manufacturing method has been modified by the
manufacturer in ways that could be considered
to impact on the bioavailability, a bioequivalence
study is requiered unless otherwise justified
By
-Scientific argument (section 5.1.1)
-In vivo-In vitro correlation (Appendix II)
5.3 Variations
• Waivers of BE studies
If a new application concerns several strengths of the active
substance a BE study investigating only one strength can be
acceptable when all of the following conditions are fulfilled:
According to the ICH guidance it is possible to use whate ever
strengths ( it is the highest, the lowest or the middle strength) if
following criteria are fulfilled!
• Same manufacturer and –process
• Pk-linearity
(if this is not the case the strength where the sensitivity is largest to
identify differences in the two products should be used)
• Same qualitative composition
• The ratio of the amount of active and excipients is the same or in the
case of active conc. < 5%, the ratio between the amount of excipients is
similar
• Similar dissolution profiles
MODULE 5 :
CLINICAL STUDY REPORTS*
• Content that relates to biostudy is listed
under 5.3.1 (Clinical expert report)
5.3.1 Reports of Biopharmaceutic Studies
5.3.1.1 Bioavailability (BA) Study Reports
5.3.1.2 Comparative BA and Bioequivalence (BE) Study
Reports
5.3.1.3 In vitro-In vivo Correlation Study Reports
5.3.1.4 Reports of Bioanalytical and Analytical Methods for
Human Studies
MODULE 5 :
CLINICAL STUDY REPORTS *
• Content that relates to publically available
literature is listed under 5.3.2 -5.3.7
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using
Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.4 Reports of Human Pharmacodynamic (PD) Studies
5.3.5 Reports of Efficacy and Safety Studies
5.3.6 Reports of Post-Marketing Experience
5.3.7 Case Report Forms and Individual Patient
Listings
MODULE 5 :
CLINICAL STUDY REPORTS*
• Our module writer experts understands
the above index as suggestion and uses his
own headings
• No comments from the authorities so far