Asean guidelines for.doc

Adopted from the “NOTE FOR GUIDANCE ON THE INVESTIGATION OF BIOAVAILABILITY AND BIOEQUIVALENCE”(The European Agency for the Evaluation of Medicinal Products, London, 26 July 2001, CPMP/EWP/QWP /1401/98 ) with some adaptation for ASEAN application. 2.2 Pharmaceutical alternatives 2.3 Bioavailability 2.4 Bioequivalence 2.5 Essentially similar products 2.6 Therapeutic equivalence 3. DESIGN AND CONDUCT OF STUDIES 3.1 Design 3.2 Subjects 3.2.1 Selection of subjects 3.2.2 Standardisation of the study 3.2.3 Inclusion of patients 3.2.4 Genetic phenotyping 3.3 Characteristics to be investigated 3.4 Chemical analysis 3.5 Reference and test product 3.6.2 Acceptance range for pharmacokinetic parameters 3.6.3 Handling deviations from the study plan 3.6.4 A remark on individual and population bioequivalence 3.7 In vitro dissolution complementary to a bioequivalence study 3.8 Reporting of results APPL. FOR PRODUCTS CONTAINING NEW ACTIVE SUBSTANCES APPLICATIONS FOR PRODUCTS CONTAINING APPROVED ACTIVE SUBS TANCES 5.1. Bioequivalence studies 5.1.1. Oral Immediate Release Forms with Systemic Action 5.1.3.Non-Oral Immediate Release forms with systemic action 5.1.4.Modified Release and transdermal dosage forms 5.1.5.Fixed combinations products 5.1.6.Parenteral solutions 5.1.7. Gases 5.1.8. Locally applied products 5.2 In Vitro Dissolution 5.3 Variations 5.4 Dose proportionality i n immediate release oral dosage forms
Explanation of the symbols in paragraph 3.3
Dissolution testing

l : Clinical Laboratory Tests
ll: Reporting Format


To exert an optimal therapeutic action an active moiety should be delivered to
its site of action in an effective concentration for the desired period. To allow
reliable prediction of the therapeutic effect the performance of the dosage
form containing the active substance should be well characterised.
In the past, several therapeutic misadventures related to differences in bioavailability (e.g. digoxin, phenytoin, primidone) testify to the necessity of testing the performance of dosage forms in delivering the active substance to the systemic circulation and thereby to the site of action. Thus the bioavailability of an active substance from a pharmaceutical product should be known and reproducible. This is especially the case if one product containing one certain active substance is to be used instead of its innovator product. In that case the product should show the same therapeutic effect in the clinical situation. It is generally cumbersome to assess this by clinical studies. Comparison of therapeutic performances of two medicinal products containing the same active substance is a critical means of assessing the possibility of altenative use between the innovator and any essentially similar medicinal product. Ass uming that in the same subject an essentially similar plasma concentration time course will result in essentially similar concentrations 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. It is the objective of this guidance to define, for products with a systemic effect, when bioavailability or bioequivalence studies are necessary and to formulate requirements for their design, conduct, and evaluation. The possibility of using in vitro instead of in vivo studies with pharmacokinetic end points is also envisaged. This guideline should be read in conjunction with other pertinent elements outlined in current and future ASEAN, EU and ICH guidelines and regulations especially those on: • Modified Release Oral and Transdermal Dosage Forms: Section I (Pharmacokinetic and Clinical Evaluation) Modified Release Oral and Transdermal Dosage Forms: Section II (Quality) Investigation of Chiral Active Substances. Clinical Requirements for Locally Applied, Locally Acting Products Containing Known Constituents. Structure and Content of Clinical Study Reports (ICH topic E3) Good Clinical Practice: Consolidated Guideline (ICH topic E6) General Considerations for Clinical Trials (ICH topic E8) Statistical Principles for Clinical Trials (ICH topic E9) Choice of Control Group in Clinical Trials (ICH topic El 0) • Multisource(Generic) Pharmaceutical Products: Guidelines on registration Requirements to establish Interchangeability (WHO) For medicinal products not intended to be delivered into the general circulation the common systemic bioavailability approach cannot be applied. Under these conditions the (local) availability may be assessed, where necessary, by measurements quantitatively reflecting the presence of the active substance at the site of action using methods specially chosen for that combination of active substance and localisation (see section 5.1.8). In this case, as well as in others, alternative methods may be required such as studies using pharmacodynamic end points. Furthermore, where specific requirements for different types of products are needed, the appropriate exceptions are mentioned therein. This Guidelines does not explicitly apply to biological products. 2 . DEFINITIONS

Before defining bioavailability and related terminology some definitions
pertaining to dosage and chemical forms are given:
2.1 Pharmaceutical equiv alence
Medicinal products are pharmaceutically equivalent if they contain the same
amount of the same active substance(s) in the same dosage forms that
meet the same or comparable standards.
Pharmaceutical equivalence does not necessarily imply bioequivalence as
differences in the excipients and/or the manufacturing process can lead to
faster or slower dissolution and/or absorption.
2.2 Pharmaceutical alternatives

Medicinal products are pharmaceutical alternatives if they contain the same
active moiety but differ in chemical form (salt, ester, etc.) of that moiety or in
the dosage form or strength.

2.3 Bioavailability

Bioavailability means the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and bec omes available at the site of action. In the majority of cases substances are intended to exhibit a systemic therapeutic effect, and a more practical definition can then be given, taking into consideration that the substance in the general circulation is in exchange with the substance at the site of action: Bioavailability is understood to be the extent and the rate at which a substance or its active moiety is delivered from a pharmaceutical form and becomes available in the general circulation. It may be useful to distinguish between the "absolute bioavailability" of a given dosage form as compared with that (100%) following intravenous administration (e.g. oral solution vs. iv.), and the "relative bioavailability" as compared with another form administered by the same or another non intravenous route (e.g. tablets vs. oral solution). 2.4 Bioequivalence

Two medicinal products are bioequivalent if they are pharmaceutically
equivalent or pharmaceutical 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.
Alternatively to classical bioavailability studies using pharmacokinetic end
points to assess bioequivalence, other types of studies can be conducted,
e.g. human studies with clinical or pharmacodynamic end points, studies
using animal models or in vitro studies as long as they are appropriately
justified and/or validated.
Essentially similar products

"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 bioequiva lent unless it is apparent in the
light of scientific knowledge that it differs from the original original product as
regards safety and efficacy".
By extension, it is generally considered that for immediate release products
the concept of essential similarity also applies to different oral forms (tablets
and capsules) with the same active substance.
The need for a comparative bioavailability study to demonstrate bioequivalence is identified under 5.1. Concerns about differences in essentially similar medicinal products lie on the use of different excipients and methods of manufacture that ultimately might have an influence on safety and efficacy. A bioequivalence study is the widely accepted means of demonstrating that these differences have no impact on the performance of the formulation with respect to rate and extent of absorption, in the case of immediate release dosage forms. It is desirable that excipients must be devoid of any effect or their safe use is ensured by appropriate warning in the package label and not interfere with either the release or the absorption process. An essentially similar product can be used instead of its innovator product. An `innovator' product is a medicinal product authorised and marketed on the basis of a full dossier i.e. including chemical, biological, pharmaceutical, pharmacological-toxicological and clinical data. A 'Reference Product' must be an 'innovator' product . (see 3.5). If the innovator product is not available in the country, an alternative
comparator product approved by drug regulatory authority of the country can
be used.

2.6 Therapeutic equivalence
A medicinal product is therapeutically equivalent with another product if it
contains the same active substance or therapeutic moiety and, clinically,
shows the same efficacy and safety as that product, whose efficacy and
safety has been established.
In practice, demonstration of bioequivalence is generally the most
appropriate method of substantiating therapeutic equivalence between
medicinal products, which are pharmaceutically equivalent or
pharmaceutical alternatives, provided they contain excipients generally
recognised as not having an influence on safety and efficacy and comply
with labelling requirements with respect to excipients. (see 2.5).
However, in some cases where similar extent of absorption but different rates of absorption are observed the products can still be judged therapeutically equivalent if those differences are not of therapeutic relevance. A clinical study to prove that differences in absorption rate are not therapeutically relevant will probably be necessary. DESIGN AND CONDUCT OF STUDIES
In the following sections, requirements for the design and conduct of bioavailability or bioequivalence studies are formulated. It is assumed that the applicant is familiar with pharmacokinetic theories underlying bioavailability studies. The design should be based on a reasonable knowledge of the pharmacodynamics and/or the pharmacokinetics of the active substance in question. For the pharmacokinetic basis of these studies reference is made to the recommendation "Pharmacokinetic studies in man". The design and conduct of the study should follow ICH/ EU-regulations on Good Clinical Practice, including reference to an Ethics Committee. The rights, safety, and well-being of all trial subjects must always be respected and should be given special attention. A bioequivalence study is basically a comparative bioavailability study designed to establish equivalence between test and reference products. The following sections apply mainly to bioequivalence studies. Since bioavailability studies are comparative in nature, the contents of the following sections apply to these studies as well, with the necessary adaptations in accordance with the aim of each specific study. Where necessary, specific guidance concerning bioavailability studies will be given.
The methodology of bioequivalence studies can be used to assess
differences in the pharmacokinetic parameters in pharmacokinetic studies
such as drug-drug or food-drug interactions or to assess differences in
subsets of the population. In this case the relevant guidelines should be
followed and the selection of subjects, the design and the statistical analysis
should be adjusted accordingly.

3.1 Design
The study should be designed in such a way that the formulation effect can
be distinguished from other effects. If the number of formulations to be
compared is two, a two-period, two sequence crossover design is often
considered to be the design of choice.
However, under certain circumstances and provided the study design and
the statistical analyses are scientifically sound alternative well-established
designs could be considered such as parallel design for very long half-life
substances and replicate designs for substances with highly variable
In general, single dose studies will suffice, but there are situations in which steady-state studies • may be required, e.g. in the case of - dose- or time-dependent pharmacokinetics, - some modified release pro ducts (in addition to single dose - if problems of sensitivity preclude sufficiently precise plasma concentration measurements after single dose administration. - if the intra-individual variability in the plasma concentration or disposition precludes the possibility of demonstrating bioequivalence in a reasonably sized single dose study and this variability is reduced at steady state. In such steady-state studies the administration scheme should follow the usual d osage recommendations. The number of subjects required is determined by a) the error variance associated with the primary characteristic to be studied as estimated from a pilot experiment, from previous studies or from published data, the expected deviation from the reference product compatible with bioequivalence (delta , ie percentage difference from 100 %)and The clinical and analytical standards imposed may also influence the
statistically determined number of subjects. However, generally the
minimum number of subjects should be not smaller than 12 unless justified.
Washout Period
Subsequent treatments should be separated by periods long enough to
eliminate the previous dose before the next one (adequate wash out periods).
In steady-state studies wash out of the previous treatment last dose can
overlap with the build-up of the second treatment, provided the build-up
period is sufficiently long (at least three times the terminal half-life).
The sampling schedule should be planned to provide an adequate estimation
of Cmax and to cover the plasma concentration time curve long enough to
provide a reliable estimate of the extent of absorption. This is generally
achieved if the AUC derived from measurements is at least 80% of the AUC
extrapolated to infinity. If a reliable estimate of terminal half-life is necessary,
it should be obtained by collecting at least three to four samples during the
terminal log linear phase.
In order to study bioavailability under steady-state conditions when
differences between morning and evening or nightly dosing are known, (e.g. if
it is known that the circadian rhythm is known to have an influence on
bioavailability), sampling should be carried out over a full 24 hours cycle.
For drugs with a long half-life, relative bioavailability can be adequately
estimated using truncated AUC as long as the total collection period is
justified. In this case the sample collection time should be adequate to ensure
comparison of the absorption process.
3.2 Subjects
3.2.1 Selection of subjects
The subject population for bioequivalence studies should be selected with the
aim to minimise variability and permit detection of differences between
pharmaceutical products. Therefore, the studies should normally be
performed with healthy volunteers. The inclusion/exclusion criteria should be
clearly stated in the protocol.
Subjects could belong to either sex; however, the risk to women of
childbearing potential should be considered on an individual basis.
In general, subjects should be between 18 - 55 years old capable of giving informed consent and of weight within the normal range according to accepted normal values for the Body Mass Index (BMI) of 18-30 . Normally for ASIANs the recommended BMI is of 18-25. They should be screened for suitability by means of clinical laboratory tests, an extensive review of medical history, and a comprehensive medical examination. Depending on the drug's therapeutic class and safety profile special medical investigations may have to be carried out before, during and after the completion of the study. Subjects should preferably be non-smokers and without a history of alcohol or drug abuse. If moderate smokers are included (less than 10 cigarettes per day) they should be identified as such and the consequences for the study results should be discussed.
3.2.2 Standardisation of the study
The test conditions should be standardised in order to minimise the variability
of all factors involved except that of the products being tested. Therefore,
standardisation of the diet, fluid intake and exercise is recommended.
Subjects should preferably be fasting at least during the night prior to
administration of the products. If the Summary of Product Characteristics of
the reference product contains specific recommendations in relation with food
intake related to food interaction effects the study should be designed
The time of day for ingestion should be specified and as fluid intake may profoundly influence gastric passage for oral administration forms, the volume of fluid (at least 150 ml) should be constant. All meals and fluids taken after the treatment should also be standardised in regard to composition and time of administration during the sampling period. Prior to and during each study phase, (1) subjects should be allowed water as desired except for one hour before and after drug administration,(2) hot drink or juice may be provided after 3 hours of drug administration,(3) standard meals for each study periods can be provided no less than 4 hours after drug administration. One unit of the highest marketed strength or a clinical usual dose should generally be given. A higher dose which does not exceed the maximal dose of the dosage regime or labelled dose range may be employed when analytical difficulties exist. However, if the adverse events are too great or too risky, then the smaller dose unit is allowed. The subjects should not take other medicines during a suitable period before and during the study and should abstain from food and drinks, which may interact with circulatory, gastrointestinal, liver or renal function (e.g. alcoholic or xanthine-containing beverages or certain fruit juices). As the bioavailability of an active moiety from a dosage form could be dependent upon gastrointestinal transit times and regional blood flows, posture and physical activity may need to be standardised. 3.2.3 Inclusion of patients

If the investigated active substance is known to have adverse effects and the
pharmacological effects or risks are considered unacceptable for healthy
volunteers it may be necessary to use patients instead, under suitable
precautions and supervision. In this case the applicant should justify the
3.2.4. Genetic phenotyping
Phenotyping and/or genotyping of subjects should be considered for
exploratory bioavailability studies and all studies using parallel group design.
It may be considered as well in crossover studies (e.g. bioequivalence, dose
proportionality, food interaction studies etc.) for safety or pharmacokinetic
reasons. If a drug is known to be subject to major genetic polymorphism,
studies could be performed in panels of subjects of known phenotype or
genotype for the polymorphism in question.
3.3 Characteristics to be investigated
In most cases evaluation of bioavailability and bioequivalence will be based
upon the measured concentrations of the parent compound. In some
situations, however, measurements of an active or inactive metabolite may be
necessary instead of the parent compound. Such situations include cases
where the use of a metabolite may be advantageous to determine the extent
of drug input, e.g. if the concentration of the active substance is too low to be
accurately measured in the biological matrix (e.g. major difficulty in analytical
method, product unstable in the biological matrix or half-life of the parent
compound too short) thus giving rise to significant variability.
Bioequivalence determinations based on metabolites should be justified in
each case bearing in mind that the aim of a bioequivalence study is intended
to compare the in vivo performance of test and reference products. In
particular if metabolites significantly contribute to the net activity of an active
substance and the pharmacokinetic system is non -linear, it is necessary to
measure both parent drug and active metabolite plasma concentrations and
evaluate them separately.

In bioavailability studies, the shape of and the area under the plasma
concentration versus time curve s are mostly used to assess extent and rate
of absorption. The use of urine excretion data may be advantageous in
determining the extent of drug input in case of products predominately
excreted renally, but has to be justified when used to estimate the rate of
absorption. Sampling points or periods should be chosen, such that the time-
concentration profile is adequately defined so as to allow the estimation of
relevant parameters.
From the primary results, the bioavailability characteristics desired are
estimated, namely AUCt, AUC8 , Cmax, tmax, Aet, Ae 8 as appropriate, or any
other justifiable characteristics (cf Appendix I). The method of estimating
AUC-values should be specified. For additional information t 1/2 and MRT
can be estimated. For studies in steady state AUC t Cmax, Cmin and fluctuation
should be provided.
In bioequivalence studies the AUC t is the most reliable reflection of the extent
of absorption.
The exclusive use of compartmental based estimates are not recommended.
If pharmacodynamic effects are used as characteristics the measurements
should provide a sufficiently detailed time course, the initial values in each
period should be comparable and the complete effect curve should remain
below the maximum physiological response.
Specificity, accuracy and reproducibility of the methods should be sufficient.
The non-linear character of the dose/response relationship should be taken
into account and base line corrections should be considered during data
3.4 Chemical analysis
The bioanalytical part of bioequivalence trials should be conducted according
to the applicable principles of Good Laboratory Practice (GLP). (EMEA/OECD
The bioanalytical methods used to determine the active moiety and/or its
biotransformation product(s) in plasma, serum, blood or urine or any other
suitable matrix must be well characterised, fully validated and documented to
yield reliable results that can be satisfactorily interpreted. The main objective
of method validation is to demonstrate the reliability of a particular method for
the quantitative determination of an analyte(s) concentration in a specific
biological matrix. The characteristics of a bioanalytical method essential to
ensure the acceptability of the performance and the reliability of analytical
results are: (1) stability of the stock solutions and of the analyte(s) in the
biological matrix under processing conditions and during the entire period of
storage; (2) specificity; (3) accuracy; (4) precision (5) limit of quantification
and (6) response function.
The validation of a bioanalytical method should comprise two distinct phases:
(1) the prestudy phase in which the compliance of the assay with the six
characteristics listed above is verified and (2 ) the study phase itself in which
the validated bioanalytical method is applied to the actual analysis of samples
from the biostudy mainly in order to confirm the stability, accuracy and
A calibration curve should be generated for each analyze in each analytical
run and it should be used to calculate the concentration of the analyte in the
unknown samples in the 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. In addition, it is necessary to validate
the method of processing and handling the biological samples.
All procedures should be performed according to pre-established Standard
Operating Procedures (SOPs). All relevant procedures and formulae used to
validate the bioanalytical method should be submitted and discussed. Any
modification of the bioanalytical method before and during analysis of study
specimens may require adequate revalidation; all modifications should be
reported and the scope of revalidation justified.
According to the requirements of the note for guidance on the "Investigation
of Chiral Active Substances", bioequivalence studies supporting applications
for essentially similar medicinal products containing chiral active substances
should be based upon enantiomeric bio-analytical methods unless (1) both
products contain the same stable single enantiomer; (2) both products contain
the racemate and both enantiomers show linear pharmacokinetics.

3.5 Reference and test product
Test products in an application for a generic product are normally compared
with the corresponding dosage form of an innovator (see 2.5) medicinal
product (reference product). The choice of reference product should be
justified by the applicant and agreed upon by the regulatory authority .
If the innovator product is not available, an alternative comparator product
approved by drug regulatory authority of the coubtry can be used.
The test products used in the biostudy must be prepared in accordance with GMP-regulations. Batch control results of the test product should be reported. In the case of oral solid forms for systemic action the test product should
usually originate from a batch of at least 1/10 of production scale or 100 000
units, whichever is greater, unless otherwise justified. The production of
batches used should provide a high level of assurance that the product and
process will be feasible on an industrial scale; in case of production batch
smaller than 100 000 units, a full produc tion batch will be required. If the
product is subjected to further scale-up this should be properly validated.
Samples of the product from full production batches should be compared with
those of the test batch, and should show similar in vitro dissolution profiles
when employing suitable dissolution test conditions (see Appendix II).
The 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 whichever is longer to
allow re-testing, if it is requested by the authorities.
Reference and test product must be packed in an individual way for each
subject included in the bioequivalence trial. Every effort should be made to
allow a precise tracking of administration of the reference and test products to
the subjects, for instance by the use of labels with a tear-off portion.

3.6. Data analysis
The primary concern of bioequivalence assessment is to quantify the difference
in bioavailability between the reference and test products and to demonstrate
that any clinically important difference is unlikely.

3.6.1 Statistical analysis
The statistical method for testing relative bioavailability (e.g. bioequivalence) is
based upon the 90% confidence interval for the ratio of the population means
(Test/Reference), for the parameters under consideration.
This method is equivalent to the corresponding two one-sided test procedure
with the null hypothesis of bioinequivalence at the 5% significance level. The
statistical analysis (e.g. ANOVA) should take into account sources of variation
that can be reasonably assumed to have an effect on the response variable. A
statistically significant sequence effect should be handled appropriately.
Pharmacokinetic parameters derived from measures of concentration, e.g.
AUC, Cmax should be analysed using ANOVA. The data should be transformed
prior to analysis using a logarithmic transformation.
If appropiate to the evaluation the analysis technique for tmax should be non-
parametric and should be applied to untransformed data. For all
pharmacokinetic parameters of interest in addition to the appropriate 90%
confidence intervals for the comparison of the two formulations, summary
statistics such as median, minimum and maximum should be given.

3.6.2 Acceptance range for pharmacokinetic parameters
The pharmacokinetic parameters to be tested, the procedure for testing and
the acceptance ranges should be stated beforehand in the protocol.
In studies to determine average bioequivalence the acceptance intervals for
the main characteristics are detailed as follows:
The 90% confidence interval for this measure of relative bioavailability should lie within an acceptance interval of 0.80-1.25. In specific cases of a narrow therapeutic range the acceptance interval may need to be tightened. In rare cases a wider acceptance range may be acceptable if it is based on sound clinical Cmax-ratio The 90% confidence interval fo r this measure of relative bioavailability should lie within an acceptance interval of 0.80-1.25. In specific cases of a narrow therapeutic range the acceptance interval may need to be tightened. In certain cases a wider interval may be acceptable. The interval must be prospectively defined e.g. 0.75-1.33 and justified addressing in particular any safety or efficacy concerns for patients switched between formulations. Statistical evaluation of tmax only makes sense if there is a clinically relevant
claim for rapid release or action or signs related to adverse effects. The non-
parameterc 90% confidence interval for this measure of relative
bioavailability should lie within a clinically determined range.
For other (see 3.3) pharmacokinetic parameters in comparison relative
bioavailability (e.g. Cmin, Fluctuation, t12, etc.) considerations analogous to
those for AUC, Cmax or tmax apply, taking into consideration the use of log-
transformed or untransformed data, respectively.

3.6.3 Handling deviations from the study plan

The method of analysis should be planned in the protocol. The protocol
should also specify methods for handling drop-outs and for identifying
biologically implausible outliers. Post hoc exclusion of outliers is generally
not accepted. The outliers could not be omitted, if there is no strong reason
on technical fault reason. Data analysis should be done both with and/
without these data and the impact to the final result should be discussed.
Medical or pharmacokinetic explanation is needed for such observations.

3.6.4 A remark on individual and population bioequivalence
To date, most bioequivalence studies are designed to evaluate average
bioequivalence. Experience with population and individual bioequivalence
studies is limited. Therefore, no specific recommendation is given on this

3.7 In vitro dissolution complementary to a bioequivalence study
The results of "in vitro" dissolution tests, obtained with the batches of test
and reference products that were used in the bioequivalence study should
be reported. The results should be reported as profiles of percent of labelled
amount dissolved versus time.
The specifications for the in vitro dissolution of the product should be
derived from the dissolution profile of the batch that was found to be
bioequivalent to the reference product and would be expected to be similar
to those of the reference product (see Appendix 11).
For immediate release products, if the dissolution profile of the test product
is dissimilar compared to that of the reference product and the in vivo data
remain acceptable the dissolution test method should be re-evaluated and
optimised. In case that no discriminatory test method can be developed which
reflects in vivo bioequivalence a different dissolution specification for the test
product could be set.
3.8 Reporting of results
The report of a bioavailability or a bioequivalence study should give the
complete documentation of its protocol, conduct and evaluation complying
with GCP-rules and related EU and ICH E3 guidelines. This implies that the
authenticity of the whole of the report is attested by the signature of the
principal investigator. The responsible investigator(s), if any, should sign for
their respective sections of the report.
Names and affiliations of the responsible investigator (s), site of the study and period of its execution should be stated. The names and batch numbers of the products used in the study as well as the composition(s), finished product specifications and comparative dissolution profiles should be provided. In addition, the applicant should submit a signed statement confirming that the test product is the same as the one that is submitted for marketing authorisation. All results should be clearly presented and should include data from subjects who eventually dropped-out. Drop-out and withdrawal of subjects should be fully documented and accounted for. The method used to derive the pharmacokinetic parameters from the raw data should be specified. The data used to estimate AUC should be reported. If pharmacokinetic models are used to evaluate the parameters the model and computing procedure used should be justified. Deletion of data should be justified. All individual subject data should be given and individual plasma concentration/time curves presented in linear/linear and log/linear scale. The analytical report should include the results for all standard and quality control samples as well. A representative number of chromatograms or other raw data should be included covering the whole concentration range for all, standard and quality control samples as well as the specimens analysed. The analytical validation report should be submitted as well. The statistical report should be sufficiently detailed to enable the statistical analysis to be repeated, e.g. randomisation scheme, demographic data, values of pharmacokinetic parameters for each subject, descriptive statistics for each formulation and period. A detailed ANOVA and/or non-parameterc analysis, the point estimates and c orresponding confidence intervals including the method of their estimation should also be included. APPLICATIONS FOR PRODUCTS CONTAINING NEW ACTIVE

4.1 Bioavailability
In the case of new active substances (new chemical entities) intended for
systemic action, the pharmacokinetic characterisation will have to include the
determination of the systemic availability of the substance in its intended
pharmaceutical form in comparison with intravenous administration. If this is
not possible (e.g. not technically feasible or for safety reasons) the
bioavailability relative to a suitable oral solution or suspension should be
determined. In the case of a prodrug the intravenous reference solution
should preferably be made of the active moiety.

4.2 Bioequivalence

During development bioequivalence studies are necessary as bridging
studies between (i) pivotal and early clinical trial formulations; (ii) pivotal
clinical trial formulations, especially those used in the dose finding studies,
and the to -be-marketed medicinal product; (iii) other
comparisons depending on the situation. Such studies may be exempted if the absence of differences in the in vivo performance can be justified by satisfactory in vitro data (see 5.1.1 and 5.2). APPLICATIONS FOR PRODUCTS CONTAINING APPROVED

5.1 Bioequivalence studies
In vivo bioequivalence studies are needed when there is a risk that possible
differences in bioavailability may result in therapeutic inequivalence.
The kind of studies to be performed may vary with the type of product, as
5.1.1. Oral Immediate Release Forms with Systemic Action
This section pertains to dosage forms such as tablets, capsules and oral
suspensions and takes into consideration criteria derived from the concepts
underlying the Biopharmaceutics Classification System, i.e. high solubility,
high permeability for the active substance and high dissolution rate for the
medicinal product. These criteria, along with a non-critical therapeutic range
should be primarily cons idered; therefore the following characteristics have
to be taken into account in order to justify the request for exemption from in
vivo bioequivalence studies. Hence data must be supplied to justify the
absence of such studies.
Characteristics related to the active substance: i - risk of therapeutic failure or adverse drug reactions : this risk depends on the requirements of special precautions with respect to precision and accuracy of dosing of the active substance, e.g. the need for critical plasma concentrations; evidence of bioavailability problems or bioinequivalence exists for some specific active substances; When the active substance is highly water soluble, the product could be in general exempted from bioquivalence studies unless, considering the other characteristics, the exemption could entail a potential risk. Polymorphism and particle size are major determinants of dissolution rate and special attention should be paid to these characteristics. An active substance is considered highly water soluble if the amount contained in the highest dose strength of an immediate release product is dissolved in 250 ml of each of three buffers within the range of pH 1 -8 at 37°C (preferably at or about pH 1.0, 4.6, 6.8); linear and complete absorption indicating high permeability reduces the possibility of an immediate release dosage form influencing the bioavailability. b) Characteristics related to the medicinal produc t: in case of exemption from bioequivalence studies, in vitro data should demonstrate the similarity of dissolution profile between the test product and the reference product in each of three buffers within the range of pH 1-8 at 37°C (preferably at or about pH 1.0, 4.6, 6.8). However, in cases where more than 85% of the active substance are dissolved within 15 minutes, the similarity of dissolution profiles may be accepted as demonstrated (see appendix II); the excipie nts included in the composition of the medicinal product are well established and no interaction with the pharmacokinetics of the active substance is expected. In case of atypically large amounts of known excipients or new excipients being used, additional documentation has to be submitted; the method of manufacture of the finished product in relation with critical physicochemical properties of the active substance (e.g. particle size, polymorphism) should be adequately addressed and documented in the development pharmaceutics section of the dossier. 5.1.2 Oral solutions
If the product is an aqueous oral solution at time of administration and
contains an active substance in the same concentration as an oral solution
currently approved as a medicinal product, no bioequivalence study is
required, provided the excipients contained in it do not affect gastrointestinal transit, absorption or in vivo stability of the active substance. In those cases where an oral solution has to be tested against an oral immediate release formulation a comparative bioavailability study will be required unless an exemption can be justified (see 5. 1. 1). 5.1.3 Non-Oral Immediate Release forms with systemic action
In general bioequivalence studies are required.

5.1.4 Modified Release and transdermal dosage forms

Requirements for bioequivalence studies in accordance with the specific
5.1.5 Fixed combinations products
Combination products should in general be assessed with respect to
bioavailability and bioequivalence of individual active substances either
separately (in the case of a new combination) or as an existing combination.
Criteria under 5.1.1 will apply to individual components. The study in case of
a new combination should be designed in such a way that the possibility of a
pharmacokinetic drug-drug interaction could be detected.
5.1.6 Parenteral solutions
The applicant is not required to submit a bioequivalence study if the product is to be administered as an aqueous intravenous solution contain ing the same active substance in the same concentration as the currently authorised product. In the case of other parenteral routes, e.g. intramuscular or subcutaneous, if the product is of the same type of solution (aqueous or oily), contains the same concentration of the same active substance and the same or comparable excipients as the medicinal product currently approved, then bioequivalence testing is not required. 5.1.7 Gases

If the product is a gas for inhalation a bioequivalence study is not required.
5.1.8 Locally applied products
For products for local use (after oral, nasal, inhalation, ocular, dermal, rectal, vaginal etc. administration) intended to act without systemic absorption the approach to determine bioequivalence based on systemic measurements is not applicable and pharmacodynamic or comparative clinical studies are in principle required. The lack of them should be justified (see specific Note for Guidance). Whenever systemic exposure resulting from locally applied, locally acting medicinal products entails a risk of systemic adverse reactions, systemic exposure should be measured. For locally applied products with systemic action a bioequivalence study is always required. 5.2 In Vitro Dissolution

Dissolution studies are always necessary and consequently required. . In vitro
dissolution testing forms a part of the assessment of a bioequivalence waiver
request based on criteria as described in section 5.1. Dissolution studies must
follow the guidance as laid out in Appendix II.
5.3 Variations
If a product has been reformulated 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 required, unless otherwise justified. Any justification presented should be based upon general considerations, e.g. as per 5.1.1, or on whether an acceptable in vivo / in vitro correlation has been established. In cases where the bioavailability of the product undergoing change has been investigated and an acceptable correlation between in vivo performance and in vitro dissolution has been established, the requirements for in vivo demonstration of bioequivalence can be waived if the dissolution rate in vitro of the new product is similar to that of the already approved medicinal product under the same test conditions as used to establish the correlation (see Appendix II) In all other cases bioequivalence studies have to be performed. For variations of the innovator product the reference product for use in bioequivalence and dissolution studies is usually that authorised under the current formula, manufacturing method, packaging etc. and the product
manufactured in line with th e proposed changes is tested against this.
When variations to an essentially similar product are made the reference
product for the bioequivalence study should be the innovator product.
5.4 Dose proportionality in immediate release oral dosage forms
If a new application concerns several strengths of the active substance a
bioequivalence study investigating only one strength may be acceptable.
However the choice of the strength used should be justified on analytical,
pharmacokmetic and safety grounds. Furthermore -all of the following
conditions should be fulfilled:
§ the pharmaceutical products are manufactured by the same manufacturer
§ the drug input has been shown to be linear over the therapeutic dose range (if this is not the case the stre ngths where the sensitivity is largest to identify differences in the two products should be used); § the qualitative composition of the different strengths is the same; except § the ratio between amounts of active substance and excipients is the same, or, in the case of preparations containing a low concentration of the active substance (less than 5%), the ratio between the amounts of excipients is similar; § the dissolution profile should be similar under identical conditions for the additional strengths and the strength of the batch used in the bioequivalence study.
If a new strength (within the approved dose range) is applied for on the basis
of an already approved medicinal product and all of the stated conditions hold
then a bioequivalence study is not necessary.

5.5 Suprabioavailability
If suprabioavailability is found, i.e. if the new product displays an extent of
absorption appreciably larger than the approved product, reformulation to a
lower dosage strength s hould be considered. In this case, the
biopharmaceutical development should be reported and a final comparative
bioavailability study of the reformulated new product with the old approved
product should be submitted.
In case reformulation is not carried out the dosage recommendations for the
suprabioavailable product will have to be supported by clinical studies. Such a
pharmaceutical product should not be accepted as therapeutically equivalent
to the existing reference product. If marketing authorisation is obtained, the
new product may be considered as a new medicinal product.
To avoid confusion for both prescribers and patients, it is recommended that
the name of suprabioavailable product precludes confusion with the older
approved product
Suprabioavailable products cannot claim "essential similarity" (see section
2.5) with the innovator/comparator product.

Explanation of the symbols in paragraph 3.3

Cmax: maximal plasma concentration;
Cmin: minimal plasma concentration;
Cav: average plasma concentration; tmax: time passed since administration at which the plasma concentration maximum occurs; area under the plasma concentration curve from administration to last observed concentration at time t. AUCco: area under the plasma concentration curve extrapolated to AUCt: AUC during a dosage interval in steady state; Aet: cumulative urinary excretion from administration until time t; Ae8: cumulative urinary excretion extrapolated to infinite time; APPENDIX II
Disolution testing
A medicinal product is composed of drug substance and excipients and the proportion between them, the type of excipients and the manufacturing method of the final product are chosen based on the content, the physicochemical and the bulk properties of the drug and on its absorption properties. Taken as a whole this gives each product certain dissolution characteristics. During the development of a medicinal product a dissolution test is used as a tool to identify formulation factors that are influencing and may have a crucial effect on the bioavailability of the drug. As soon as the composition and the manufacturing process are defined a dissolution test is used in the quality control of scale-up and of production batches to ensure both batch to-batch consistency and that the dissolution profiles remain similar to those of pivotal clinical trial batches. Furthermore, a dissolution test can be used to support the bioavailability of a new drug product, the bioequivalence of an essentially similar product or variations. Therefore, dissolution studies can serve several purposes: i- Quality assurance § To get information on the test batches used in bioavailability / bioequivalence studies and pivotal clinical studies to support specifications for quality control. § To be used as a tool in quality control to demonstrate consistency in § To get information on the reference product used in bioavailability/bioequivalence studies and pivotal clinical studies § To demonstrate similarity between reference products from different § To demonstrate similarity between different formulations of an active substance (variations and new, essentially similar products included) and the reference medicinal product § To collect information on batch to batch consistency of the products (test and refere nce) to be used as basis for the selection of appropriate batches for the in vivo study.
The test methodology should be in accordance with pharmacopoeial
requirements unless those requirements are shown to be unsatisfactory.
Alternative methods can be considered when justified that these are
discriminatory and able to differentiate between batches with acceptable and
non-acceptable performance of the product in vivo.
If an active substance is considered highly soluble, it is reasonable to expect
that it will not cause any bioavailability problems if, in addition, the dosage
system is rapidly dissolved in the physiological pH-interval expected after
product administration. A bioequivalence study may in those situations be
waived based on case history and similarity of dissolution profiles which are
based on discriminatory testing, provided that the other exemption criteria in
5.1.1 are met. The similarity should be justified by dissolution profiles,
covering at least three time points, attained at three different buffers (normally
pH range 1-6.8; in cases where it is considered necessary pH range 1-8).
In the case of a drug or excipients that are insensitive to pH, profiles from only
two buffer systems are required.
If an active substance is considered to have a low solubility and a high
permeability, the rate limiting step for absorption may be dosage form
dissolution. This is also the case when one or more of the excipients are
controlling the release and subsequent dissolution step of the active
substanc e. In those cases a variety of test conditions is recommended and
adequate sampling should be performed until either 90% of the drug is
dissolved or an asymptote is reached. Knowledge of dissolution properties
under different conditions e.g. pH, agitation, ionic strength, surfactants,
viscosity, osmotic pressure is important since the behaviour of the solid
system in vivo may be critical for the drug dissolution independent of the
physico-chemical properties of the active substance. An appropriate
experimental statistical design may be used to investigate the critical
parameters and for the optimisation of such conditions.
Any methods to prove similarity of dissolution profiles are accepted as long as
they are justified.
The similarity may be compared by model-independent or model-dependent
methods e.g. by linear regression of the percentage dissolved at specified
time points, by statistical comparison of the parameters of the Weibull
function or by calculating a similarity factor e.g the one defined below:
n In this equation f 2 is the similarity factor, n is the number of tim e points, R (t) is the mean percent drug dissolved of e.g. a reference product, and T(t) is the mean percent drug dissolved of e.g. a test product. The evaluation of similarity is based on the conditions of § A minimum of three time points (zero excluded) § 12 individual values for every time point for each § not more than one mean value of > 85% dissolved for each formulation § that the standard deviation of the mean of any product should be less than An f2 value between 50 and 100 suggests that the two dissolution profiles are similar. In cases where more than 85% of the drug are dissolved within 15 minutes, dissolution profiles may be accepted as similar without further mathematical evaluation. SUPPLEMENT l
Suggested Clinical Laboratory Tests For Bioequivalence Study SUPPLEMENT lI
Study tittle Name of sponsor Name and address of clinical laboratory Name and address of analytical laboratory Dates of clinical study (start, completion) Signature Page Name of Principal and Clinical Investigator(s) List of other study personnel Study Protocol Reference and Test Product Information Name, Batch Number, Batch size (test product), formulation, active ingredient, amount of active ingredient and expiry date, finished product specifications, comparative dissolution profiles Clinical and Safety Records Assay Methodology and Validation Statistical Analyses Results and discussion Conclusions Appendices Letter of Approval of Institutional Review Board/Independent Ethics Committee


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