study design and execution of the bioequivalence studies - module 5 hafrún friðriksdóttir vp...

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


It is a grate honour for me to serve here as a speeker to day in this big conferance. It is of course grate honour for Actavis too. I would like to start with thanking the organizers for making that happend.I will mainly base me speach on the biovailability and bioequivalence guidance. My presentation is set up on a similar way as the guidance and is mainly aimd for further discussion.


similar form it means one can f. ex. compare tablets to Capsules

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


the guidance are ment to de

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 designBalanced sequence of administrationNumber 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. AUC0-t/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

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


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


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


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)


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


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”


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


Test product used in a biostudy must be prepared in accordance with GMP-regulations. Batch control results of the test porduct should be reportedBatch 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.


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 re-testing, 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 meansFor 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 resultsData 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


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)


Bioequivalence study required for locally applied products with systemic action


• 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 studiesIf 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) Studies5.3.4 Reports of Human Pharmacodynamic (PD) Studies5.3.5 Reports of Efficacy and Safety Studies5.3.6 Reports of Post-Marketing Experience5.3.7 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