Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same. The first generation of biological drugs, which have introduced many revolutionary treatments to life threatening and rare illnesses, is currently facing patent expiration. As a result, research-based and generics pharmaceutical companies alike are pursuing the opportunity to develop “generic” substitutes to original biologics, which are also known as biosimilars.

1. Bio-equivalence and Bio-
similarity studies of Drugs
TRAINING
on
ORION
Presented By:
MD. ZAKARIA FARUKI
ORION Pharma Ltd.

2. Bioequivalence is a term used when comparing brand name
and generic drugs. Before a generic drug can be sold, the
manufacturer must prove that it has the same strength as
the brand name medication, and affects people the same
way within the same time frame. If a generic passes these
tests, it is said to be bioequivalent to the original drug.
Equivalence studies are necessary in two cases:
1. For the formulation and manufacture of generic medicines. Logically
regulatory bodies require that the therapeutic quality elicited by the
generic formulation is identical to that of the originator formulation. The patient
must experience the same efficacy from the generic and the originator
formulation: interchangeability.
2. For formulation changes by the originator. A good example of the latter is
the replacement of CFC‘s in MDI‘s (metered dose inhalers) by the ozone-
friendly HFA-propellants. Such major change of a formulation must incur
no change in the therapeutic quality, which must be proven by the
manufacturer. In other words, an equivalence study is obligatory.
Bioequivalence & Bio-similarity ORION

3. Bioequivalence & Bio-similarity
Biosimilar means “high similar” to Pioneer not withstanding
minor differences in clinically inactive components; and no
clinically meaningful differences with Pioneer in terms of safety,
purity and potency. Biosimilars or Follow-on biologics are terms
used to describe officially-approved subsequent versions of
innovator biopharmaceutical products made by a different sponsor
following patent and exclusivity expiry on the innovator product.
There are unique and inherent characteristics of biologics that must be
considered as FDA establishes a regulatory pathway for biosimilars:
Biologics are manufactured using live cells and biologics, such as monoclonal
antibodies manufactured by MedImmune, are larger and more complex than
small molecule drugs.
Biologics are more difficult to characterize using laboratory techniques and
have a more complex manufacturing process.
Every biologic is different - even slight differences between biosimilars and
innovator biologics, including their manufacturing processes, can result in
meaningful differences in the safety and efficacy profile of the products.
ORION

4. Executive Summary:
A) Bio-equivalence
Bioequivalence is a term in pharmacokinetics used to assess the expected
in vivo biological equivalence of two proprietary preparations of a drug. If two
products are said to be bioequivalent it means that they would be expected to
be, for all intents and purposes, the same.
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.
The United States Food and Drug Administration (FDA) has defined bioequivalence
as, "the absence of a significant difference in the rate and extent to which the active
ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives
becomes available at the site of drug action when administered at the same molar dose
under similar conditions in an appropriately designed study." (FDA, 2003)
ORION

5. The first generation of biological drugs, which
have introduced many revolutionary treatments to life threatening and
rare illnesses, is currently facing patent expiration. As a result,
research-based and generics pharmaceutical companies alike are
pursuing the opportunity to develop “generic” substitutes to original
biologics, which are also known as biosimilars.
B) Bio-similarity
Yet the field of biosimilars presents several important challenges
– safety, regulatory, legal and economic – which are the topic of
discussion across the globe. Most of these discussions stem from the
idea that, unlike the relatively straightforward process of introducing a
generic equivalent to an original drug based on a new chemical entity
(NCE), the process of introducing a biosimilar to an original biological
drug is far more complex. With this in mind, the purpose of this paper
is to examine the various challenges that biosimilars raise, particularly
with regards to the regulatory framework, commercial opportunities,
intellectual property rights (IPRs) and most importantly of all, to public
safety.
ORION

6. The FDA considers two products bioequivalent if the 90% CI of the relative
mean Cmax, AUC (0-t) and AUC (0-∞) of the test (e.g. generic formulation) to reference (e.g.
innovator brand formulation) should be within 80.00% to 125.00% in the fasting state.
Although there are a few exceptions, generally a bioequivalent comparison of Test to
Reference formulations also requires administration after an appropriate meal at a
specified time before taking the drug, a so-called "fed" or "food-effect" study. A food-
effect study requires the same statistical evaluation as the fasting study, described
above.
In general, the FDA considers two products to be "therapeutic equivalents" if they each meet the
following criteria:
1.They are pharmaceutical equivalents,
2.They are bioequivalent (demonstrated either by a bioavailability measurement or an in vitro
standard),
3.They are in compliance with compendial standards for strength, quality, purity and identity,
4.They are adequately labelled, and
5.They have been manufactured in compliance with Good Manufacturing Practices as established
by the FDA.
In Australia, the Therapeutics Goods Administration (TGA) considers preparations to
be bioequivalent if the 90% confidence intervals (90% CI) of the transformed natural
log ratios, between the two preparations, of Cmax and AUC lie in the range 0.80-1.25.
Tmax should also be similar between the products. (Birkett2003)
ORION

7. Bioequivalence Trial
Bioequivalence trial is the Clinical study to compare a new formulation and current
formulation of drug product. Its Objective is to demonstrate bioequivalence (BE) of
pharmacokinetic (PK) profile
PK - drug concentration in the blood
Surrogate for efficacy and safety
PK measures: AUC and Cmax
Bioequivalence trial is conducted to gain market access for new formulation.
The first intimations of bioequivalence problems with multi-source drug products
were given by early investigations of the availability of vitamins, aspirin, tetracycline, and
tolbutamide. In 1974, after an extensive review of the bioavailability of drugs, Koch-
Weser concluded that “. . . among drugs thus far tested bioinequivalence of different
drug products has been far more common than bioequivalence". Of particular note were
the studies involving digoxin; the findings of these investigations sparked the discussion
about bioequivalence assessment that still continues today.
Similar reports of bioinequivalence and therapeutic inequivalence appeared for other drugs as
well, including phenytoin, phenylbutazone, chloramphenicol, tolbutamide and thyroid. The clinical
significance of these reported differences in bioavailability relates to the therapeutic index of the
drug, the dose of the drug and the nature of the disease. In 1973 the Ad Hoc Committee on Drug
Product Selection of the American Pharmaceutical Association published a list of drugs with a
potential for therapeutic inequivalence based on reported evidence of bioinequivalence. The drugs
fall in three categories: "high," "moderate “or” low risk" based on the clinical implications:
ORION

8. Drugs with various risk potential for in
equivalence
High Risk Potential Moderate Risk Potential Low/Negligible Risk Potential
 Aminophylline
 Aspirin (when used in
high dose
 Levels)
 Bishydroxycoumarin
 Digoxin
 Dipheylhydantoin
(phenytoin)
 Para-aminosalicylic acid
 Prednisolone
 Prednisone
 Quinidine
 Warfarin
 Amphetamines
 (sustained-release)
 Ampicillin
 Chloramphenicol
 Chlorpromazine
 Digitoxin
 Erythromycin
 Griseofulvin
 Oxytetracycline
 Penicillin g (buffered)
 Pentobarbital
 Phenylbutazone
 Phenacetin
 Potassium chloride (solid
dosage
 Forms)
 Salicylamide
 Secobarbital
 Sulfadiazine
 Tetracycline
 Tolbutamide
 Acetaminophen
 Codeine
 Ferrous sulfate
 Hydrochlorothiazide
 Ephedrine
 Isoniazid
 Meprobamate
 Penicillin VK
 Sulfisoxazole
ORION

9. In 1977, the FDA implemented a series of bioavailability and
bioequivalence regulations which formed the basis of
subsequent discussion, if not controversy, of therapeutic
equivalency of drug products. The regulations are divided into
two separate regulations; Subpart B - Procedures for
Determining the Bioavailability of Drug Products and Subpart C
- Bioequivalence Requirements.
Key provisions for bioavailability regulations
Defines bioavailability in terms of both the rate and extent of drug absorption.
Describes procedures for determining the bioavailability of drug products.
Sets forth requirements for submission of in vivo bioavailability data.
Sets forth criteria for waiver of human in vivo bioavailability studies.
Provides general guidelines for the conduct of in vivo bioavailability studies.
Imposes a requirement for filing an Investigational New Drug Application.
ORION

10. The FDA will waive the requirement for submission of in-vivo evidence of bioavailability or bioequivalence if the
drug product meets one of the following criteria:-
1.The drug product is a solution intended solely for intravenous administration, and contains the active drug
ingredient in the same solvent and concentration as an intravenous solution that is the subject of an approved
full New Drug Application (NDA).
2.The drug product is a topically applied preparation intended for local therapeutic effect.
3.The drug product is an oral dosage form that is not intended to be absorbed, e.g., an antacid.
4.The drug product is administered by inhalation and contains the active drug ingredient in the same dosage
form as a drug product that is the subject of an approved full NDA.
5.The drug product is an oral solution, elixir, syrup, tincture or other similar soluble form, that contains an active
drug ingredient in the same concentration as a drug product that is the subject of an approved full NDA and
contains no inactive ingredient that is known to significantly affect absorption of the active drug ingredient.
6.The drug product is a solid oral dosage form (other than enteric-coated or controlled-release) that has been
determined to be effective for at least one indication in a Drug Efficacy Study Implementation (DESI) notice and
is not included in the FDA list of drugs for which in vivo bioequivalence testing is required.
7.The drug product is a parenteral drug product that is determined to be effective for at least one indication in a
DESI notice and shown to be identical in both active and inactive ingredients formulation, with a drug product
that is currently approved in an NDA. (Excluded from the waiver provision are parenteral suspensions and
sodium phenytoin powder for injection).
Criteria for waiver of evidence of in-vivo bioavailability
Although a human in-vivo test is considered to be preferable to other
approaches for the most accurate determination of bioequivalence,
there is a provision in the 1977 regulations for waiver of an in-vivo
bioequivalence study under certain circumstances. For some drug
products, the in-vivo bioavailability of the drug may be self-evident or
unimportant to the achievement of the product's intended purposes.
ORION

11. 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
disposition 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 products (in addition to single dose investigations),
 or can be considered, e.g.
oIf problems of sensitivity preclude sufficiently precise plasma concentration
measurements after single dose administration.
oIf 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.
i. the error variance associated with the primary characteristic to be studied as estimated
from a pilot experiment, from previous studies or from published data,
ii. the significance level desired,
iii. the expected deviation from the reference product compatible with bioequivalence (delta ,
ie percentage difference from 100 %)and
iv. the required power.
ORION

12. ORION
The test conditions should be standardized in order to minimize the variability of all factors involved
except that of the products being tested. Therefore, standardization 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 accordingly.
Selection of subjects
The subject population for bioequivalence studies should be selected with the aim to minimize
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.

13. 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.
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.
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 alternative.
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.
ORION

14. ORION
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.
The bioanalytical part of bioequivalence trials should be conducted according to the applicable
principles of Good Laboratory Practice (GLP).
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 characterized,
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:
a) Stability of the stock solutions and of the analyte(s) in the biological matrix under processing conditions and
during the entire period of storage;
b) Specificity; c) Accuracy; d) Precision , e) Limit of quantification and f) Response function.
The validation of a bioanalytical method should comprise two distinct phases:
I. The prestudy phase in which the compliance of the assay with the six characteristics listed above is
verified and
II. 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 precision.

15. ORION
Test products in an application for a generic product are normally compared with the
corresponding dosage form of an innovator 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 country 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 000units, 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 production 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.
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.

16. ORIONIn order for different formulations of the same drug substance to be considered bioequivalent,
they must be equivalent with respect to the rate and extent of drug absorption. Thus, the two
predominant issues involved in the assessment of bioequivalence are: the pharmacokinetic parameters that best
characterize the rate and extent of absorption and, the most appropriate method of statistical analysis of the data.
Statistical criteria
After a bioequivalence study is conducted and the appropriate parameters are determined, the pharmacokinetic
data must be examined according to a set of predetermined criteria to confirm or refute the bioequivalency of the
test and reference formulations. That is, one must determine whether the test and reference products differ within
a predefined level of statistical significance. Since the statistical outcome of a bioequivalence study is the primary
basis of the decision for or against therapeutic equivalence of two products, it is critically important that the
experimental data be analyzed by an appropriate statistical test.
The current FDA guidelines are that two formulations whose rate and extent of absorption differ by -20%/+25% or
less are generally considered bioequivalent. In order to verify that the -20%/+25% rule is satisfied, the two one-
sided statistical tests are carried out: one test verifies that the bioavailability of the test product is not too low and
the other to show that it is not too high. The current practice is to carry out the two one-sided tests at the 0.05 level
of significance.
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 appropriate 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.

17. 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:
AUC-ratio
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 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 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.
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 16 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.
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 matter.
ORION

18. • 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 labeled 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.
• 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 optimized. 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.
Evaluation of data from several bioequivalence studies
If the application contains some studies which demonstrate bioequivalence and others
that do not, the documentation must be considered as a whole. The existence of a
positive study does not mean that negative studies can be ignored.
In this situation the interpretation of the overall documentation is not straightforward but
there are three distinct situations which can be considered:
If after the failed trial or trials, some well justified modifications have been made to the
product that address the deficiencies that were revealed, then a subsequent
bioequivalence study can be assessed ithout reference to the previous results. A positive
study in this situation is not downgraded by the previous negative results.
ORION

19. If the failed trial was ambiguous e.g. the confidence intervals were wide
and were consistent with both possible bioequivalence and lack of
bioequivalence, then a subsequent positive study can be convincing. This is
because the new study does not contradict the previous study, but it provides
additional information that allows us to be confident that the previous failure
was because of lack of information rather than lack of bioequivalence. It is
not acceptable to pool together two ambiguous studies to reach a positive
conclusion.
If the failed study(s) clearly shows that the test product is bioinequivalent with the reference, a
subsequent positive trial will then be a contradictory finding. In this situation, additional study(s) will
be needed until the evidence for bioequivalence clearly outweighs the evidence against, indicating
that the failed study(s) were simply unlucky chance findings. It is not acceptable to pool together
positive and negative studies in a meta-analysis.
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.
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.
ORION

20. Decisiontreeonmeasurementof
parentcompoundormetabolite
ORION

21. ORION
Equivalency & Similarity of Medicinal Product
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.
Nowadays bioequivalence & similarity studies of the drugs are a pivotal part of registration
dossiers. These studies measure the bioavailability of two (or more) formulations of the same
active ingredient. The purpose of the study is that the bioavailability of the formulations under
investigation is shown to be equal. Based on that conclusion, one may subsequently claim
that the therapeutic quality of these formulations is identical. The latter means that both the
beneficial and side effects are identical and hence the formulations are truly interchangeable
Using plasma concentration-time profiles to claim therapeutic equivalence
When a major formulation change occurs or a generic equivalent of an originator formulation
desires market approval, a clinical comparative study in patients is the most obvious route to show
therapeutic equivalence. In such a study, one simply compares the pharmacodynamics or the
therapeutic effects of the two formulations (and/or other relevant clinical endpoint1 like side
effects). W hen both beneficial effects and side effects are the same, the formulations are
interchangeable.
Frequently this proves to be a very (or even too) difficult task. Clinical comparative studies are
often hampered by a lack of clearly defined and measurable endpoints. Take
antidepressants for example: the measurement of the severity of a depression is a science in itself
and a consensus on the best measurement method often does not exist.

22. The basic assumption underlying the kinetic approach of bioequivalence studies is that when the
same number of drug molecules occupy the same number of receptors, identical
pharmacodynamic effects will be elicited. So the problem of showing identical clinical effects is now
replaced by showing that identical numbers of drug molecules are present on the receptors
at any time point, irrespective the formulation used to deliver the molecules. Now within the same
subject the numbers of receptors is of course stable, so any difference in therapeutic effect is
caused by differences in the number of drug molecules delivered to the receptor.
The Drug Receptor Interaction
Having defined bio-equivalence as proving that the
same number of drug molecules occupy the
receptors, one can further simplify the problem
by looking at the parameters which influence the
number of drug molecules at the receptor. The
systemic circulation delivers the drug molecules
to the receptor, so the number of molecules in
the systemic circulation is a measure for the
number at the receptor.
The parameters governing the plasma
concentration of a drug are absorption, distribution,
metabolism and elimination of the active drug. So
when these parameters are measured and shown
to be equal, the numbers of drug molecules which
reach the receptors are equal. As a result one can
only conclude that the therapeutic effects must be
equal too.
ORION

23. Basic to this approach is that the human body handles a specific
drug in a specific way, i.e. absorption, distribution, metabolism and
elimination of a drug molecule is of course always the same, irrespective
the source of the drug. Whether it is administered using formulation A or B, does not
matter: the chemical nature of the drug determines the pharmacokinetic handling
by the body. The latter may show inter-individual differences but these are of no
interest at all, because the basic goal of bioequivalence testing is to show
interchangeability in the individual patient (only intra-individual variability counts).
ORION

24. Earlier it was argued that a bioequivalence study is a check on the similarity of the
release characteristics of formulation A and B. The amount of drug molecules
released and the speed of the release are therefore the most important parameters. Rephrased:
the rate and extent of the release. In the in-vivo bioequivalence study these characteristics
are determined by measuring the following parameters:
1. The area under the plasma concentration-time curve (AUC), because it describes the total
number of molecules present in plasma, thereby informing the researchers on the extent of the
release;
2. The maximum plasma concentration (Cm a x) because it is linked to the speed of the release;
3. The time at which the maximum plasma concentration is reached (Tm a x) because it is linked to
the speed of the release;
4. The elimination half life T1 /2 , because it is linked to the elimination of the drug (see later). T1 /2
is obtained by calculation of Kel, the elimination constant.
Fig. 4 is a typical example of a
plasma concentration-time profile of
a drug in a volunteer. One can
distinguish an absorption and
elimination phase. W hen the mass
absorbed equals the mass
eliminated, Cm a x is present.
Before Cm a x is reached (before
Tm a x) the absorption is higher
than the elimination, after Tm a x
the situation is reversed.
ORION

25. Frequently elimination is a so-called first order process, which means that per
unit of time a percentage of the mass present in the blood disappears from it.
So for example every hours 5% of the mass present in the blood
disappears, which means that as the plasma concentration declines, the
eliminated mass per time unit also declines.
When elimination is a
true first order process,
a log transformation of
the measured plasma
concentrations will render
a straight line during the
elimination phase, which
we shall use later to
calculate the elimination
half-life.
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 bioequivalent unless it is apparent in the light of scientific knowledge that it differs from the 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.
ORION

26. BIOSIMILAR DRUGS
The name given to drugs showing similarity to a licensed biological reference drug. The
active substances of biosimilar products are drugs similar to the related biological reference
drugs. Biosimilar and biological reference drugs are generally used at the same strength to treat
the same disease. Biosimilar drugs are only different from biological reference drugs based on trade name,
appearance and packaging features.
The identification of biological drugs is generally more difficult than the identification of chemically
derived products. In addition, there is molecular complexity interval between the various products in this
group (recombinant DNA, blood or plasma products, immunological products, gene and cell therapy, etc.).
Furthermore, post-translation modifications such as three dimensional structure, acid-base variants
amount or glycolization profile, may change significantly with changes which may be considered “minor”
at the beginning of the production process. In this context the safety and efficacy profiles of the said
products depends on them being sufficient in terms of quality and monitoring. Within this scope:
Standard generic approach (evidencing bioequivalence with reference medicinal product by using appropriate
bioavailability studies) is normally applied to chemically produced products. Depending on the complexity of the
biological/biotechnological products a generic approach is not appropriate in biosimilar products. In this case comparability
studies have to be made in terms of quality safety and efficacy.
In terms of the data regarding the evidencing of quality, efficacy and safety the biosimilar product should meet all
requirements identified in Appendix 1 of the Medicinal Products for Human Use and also meet technical requirements
included in the Monographs of the European Pharmacopeia and any additional requirement identified in the CHMP
(Committee for Medicinal Products for Human Use) and ICH current guides related to general and products.
 The active substance of a biosimilar product should show molecular and biological similarity to the active substance of
the reference medicinal product.
 The pharmaceutical form, strength and route of administration of the biosimilar medicinal product should be same with
the reference product.
 In case the pharmaceutical form, strength and route of administration are not the same additional data should be
presented within the scope of comparability studies.
 Any difference between the biosimilar medicinal product and the reference medicinal product should be evaluated with
appropriate studies per case.
BASIC PRINCIPLES & REGISTRATION CRITERIA OF BIOSIMILAR MEDICINAL PRODUCTS
ORION

27. 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.
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.
ORION

28. Controversies and Concerns in Bioequivalence
The design, performance and evaluation of bioequivalence studies have received a
great deal of attention over the past decade from academia, the pharmaceutical
industry and regulatory agencies. A number of concerns and questions have been raised
about the conduct of bioequivalence studies as well as the guidelines and criteria used to
determine bioequivalence. Many of these concerns were triggered by the passage of the
Drug Price Competition and Patent Term Restoration Act (The Waxman-Hatch
Amendments) by Congress in 1984. This Act provided for an expedited approval by the
FDA of generic drugs, thereby expanding the potential generic market for prescription
generic drugs. Shortly after the passage of this Act, numerous published reports appeared
in the scientific literature questioning the FDA's ability to ensure that generic drugs were
equivalent to the brand name drugs they were copying. Most of the concerns of the
scientific community centered around adequate standards for evaluation of bioequivalence
and correlation between bioequivalence and therapeutic equivalence.
Issues and Concerns regarding bioequivalence
Correct analysis of drugs in biological fluids
Appropriate choice of pharmacokinetic parameters to assess bioequivalence
Generalizing results obtained in healthy volunteers to patients
Problems involved in extrapolating from single-dose studies to steady-state
Importance of evaluating active metabolites
Inadequate statistical criteria to evaluate bioequivalency
Bioequivalence does not always ensure therapeutic equivalence
Lack of clear guidelines for evaluation of bioequivalence
Statistically, the power approach and the 75/75 rule were shown to have poor performance
characteristics and bioequivalence evaluation based on these methods was discontinued by the
FDA in 1986. In their place, the Agency currently employs the two one-sided tests procedure, as
previously discussed.
ORION

29. Critical Therapeutic Categories of Drugs
Category Example
Cardiovascular drugs
Anticonvulsants
Bronchodilating agents
Oral anticoagulants
Digoxin
Phenytoin
Theophylline
Warfarin
In general, the choice of the appropriate
bioequivalence range should be done on clinical
grounds; for a drug with a narrow therapeutic
range, more stringent limits should be
considered. On the other hand, the current
requirements for Cmax for some drugs may be
too stringent, considering the difficulty in
accurately estimating this value. For example, it
has been suggested that the acceptable
bioequivalence range for Cmax for fast-
releasing nifedipine formulations should be 70%
to 130%, rather than the usual 80% to 125%. In
light of this, many, including the Pharmaceutical
Research and Manufacturers of America
(formerly the Pharmaceutical Manufacturers
Association [PMA]), feel that the FDA should
repudiate its -20%/+25% rule and develop drug-
by- drug bioequivalence criteria.
Biosimilar Drug Therapies
Millions of Americans depend on biologic therapies and
advances being made in the field of biotechnology. The
field of biotechnology holds great promise for the
development of many new biologic products to treat
such serious diseases as cancer, multiple sclerosis,
anemia and rheumatoid arthritis. Biologics are certain to
play an increasingly important role in the country’s
health care system – both in terms of scientific
improvements in the treatment of disease and increased
drug costs.
Safe alternatives to some biologic drugs have existed for more than 20 years, but no regulatory pathway for
FDA approval of these products currently exists. In anticipation of the expiration of patents for older biologic
products and the new biologic products that are expected to come to market and in recognition of the fact that
these products are often prohibitively expensive, it is imperative that Congress address this issue. The
Academy believes that the federal government needs to provide incentives that will encourage both innovator
companies to pursue the development of safe and effective biologics and other companies to develop
competing, lower-cost biosimilar products that are comparable to the innovator and which can reach the
market expeditiously.
ORION

30. The Academy supports granting FDA authority to establish an expedited
review process for biosimilar products, one that would be similar to
the process that is used for approval for generic drugs under the Hatch-
Waxman law, but one which recognizes that there are potentially
significant differences between a biosimilar and a generic drug. The
Academy specifically supports the following legislative initiatives related
to biosimilars:
Congress should enact legislation that authorizes the FDA to use an expedited marketing
approval process for biosimilars.
 The legislation should provide that applicants seeking approval of biosimilars be required to
conduct clinical studies as part of the approval process if the FDA determines on a case-by-case
basis that such studies are necessary.
The legislation should provide that applicants seeking approval of biosimilar products be required
to conduct post-market studies as a pre-condition for approval if the FDA determines on a case-by-
case basis that such studies are necessary.
The legislation should grant the FDA authority to determine whether or not an approved biosimilar
is interchangeable with the innovator drug.
The legislation should provide that the manufacturer of an approved biosimilar be allowed to use
the same government approved name as the innovator product.
The legislation should provide an incentive for the development of new biologics in the form of a
period of market exclusivity that allows a manufacturer to recoup its investment in the research and
development of its product plus realize an appropriate profit; however, the specific time period
should take into account the importance of encouraging biosimilar competition in order ensure a
robust marketplace in terms of value for the dollar and effective control of costs and be based upon
an independent, objective, evidence-based recommendation made by a nationally recognized
organization.
ORION

31. Biosimilars – Extending the Paradigm
Over time, as regulators, payers, physicians, and patients adapt, markets
for biosimilars may evolve to more closely resemble the intensely competitive markets for
generic chemical entities. Initially, however, innovative biologics will be more able to
compete effectively after patent expiration, perhaps even more so than such “complex”
small molecules, where generics are rated as interchangeable. Since biologics are typically
highly complex to manufacture, and difficult to characterize and replicate, at least initially
many biosimilars may be approved by the FDA on the basis of “similarity” rather than
“interchangeability.”
ORION

32. ORION
Statistical methods for assessment of biosimilarity using biomarker data
The problem for assessing biosimilarity between biologic products is studied. For approval
of follow-on biologic products, the U.S. Food and Drug Administration (FDA) indicated that
the follow-on biologic products can be approved under an abbreviated new drug application
(ANDA) if the innovator products are approved under a new drug application (NDA). However, for biologic
products that are licensed under a BLA, there exists no abbreviated BLA in current Codes of Federal
Regulations (CFR). In this case, draft guidance for assessment of biosimilarity is being prepared. As
indicated in Chow and Liu (2008), the assessment of bioequivalence for drug products is performed under
a so-called fundamental bioequivalence assumption, which uses pharmacokinetic responses as the
surrogate endpoint for clinical endpoint for evaluation of the safety and efficacy of the drug products.
Following a similar idea, in this article, statistical methods for assessment of biosimilarity between a follow-
on biologic product and an innovator product are derived under a fundamental biosimilar assumption and a
probability-based criterion for biosimilarity using biomarker data, assuming that the biomarker is predictive
of the clinical outcome of the biologic product.
Regulatory considerations for biosimilars
Currently there is considerable interest in the legislative debate around generic biological drugs or "biosimilars" in
the EU and US due to the large, lucrative market that it offers to the industry. While some countries have issued a
few regulatory guidelines as well as product specific requirements, there is no general consensus as to a single,
simple mechanism similar to the bioequivalence determination that leads to approval of generic small molecules
all over the world. The inherent complex nature of the molecules, along with complicated manufacturing and
analytical techniques to characterize them make it difficult to rely on a single human pharmacokinetic study for
assurance of safety and efficacy. In general, the concept of comparability has been used for evaluation of the
currently approved "similar" biological where a step by step assessment on the quality, preclinical and clinical
aspects is made. In India, the focus is primarily on the availability and affordability of life-saving drugs. In this
context every product needs to be evaluated on its own merit irrespective of the innovator brand. The formation of
the National Biotechnology Regulatory Authority may provide a step in the right direction for regulation of these
complex molecules. However, in order to have an efficient machinery for initial approval and ongoing oversight
with a country-specific focus, cooperation with international authorities for granting approvals and continuous risk-
benefit review is essential. Several steps are still needed for India to be perceived as a country that leads the
world in providing quality biological products.

33. The authorisation of biosimilarsThe authorisation of Biosimilars
Biosimilars, in contrast to chemical substances, can be authorised only through the central
procedures administered by the EMEA, the European Medicines Agency, which is based in London.
In order for the efficacy, safety and quality of biosimilars to be demonstrated, the EMEA has set up a
system of hierarchically structured, mandatory guidelines (Figure 3). The basic guideline defines the
concept of biosimilars and stipulates general requirements with regard to authorisation. The
conditions for demonstrating the quality of biosimilars are set out in a second guideline. This
guideline contains criteria that must be observed in the production of biosimilars, plus rules
concerning the analytical methods that are used to demonstrate the physical/chemical properties,
biological activity, degree of purity and possible contaminants.
Depending on the indication, the
number of patents can, on
occasion, reach several hundred
or thousands. Within the
framework provided by the
general guidelines, there are
further, product-specific
guidelines. The product-specific
guidelines that have been drawn
up so far are those for
recombinant G-CSF (filgrastim),
recombinant erythropoietin,
recombinant insulin and
recombinant human growth
hormone (HGH). Further
product-specific guidelines are in
the pipeline.
Figure – The hierarchical structure of the EMEA-guidelines
ORION

34. Problem statement
The term biosimilar product is a new European term which came-up with the review of the EU
legislation called Review 2004 . Biosimilar products can be regarded as a generic version of
biologically or biotechnologically derived products situated in-between the pure generic approach and a full new
application. The generic approach showing simply bioequivalence to a branded product is not considered being
sufficient for this kind of products neither in the USA nor in the EU. While the FDA is still quarreling with an
adequatepathway and the kind and amount of data needed for such application, the EU separated the term
essentially similar into generic and biosimilar and published some essential guidelines laying down the
requirements on the quality, pre-clinical and clinical part of the dossier. Furthermore, there are already four
product-specific guidelines, one draft guideline is released for consultation and more are likely to follow.
Figure: Skills & barriers required to develop Biosimilars
ORION

35. Evolution of Bio-similar medicine
• As the biological reference medicine has been authorized for several years, there
is available information, which does not need to be reproduced. The legislation
defines the studies that need to be carried out to show that the bio similar
medicine is similar and as safe and effective as the biological reference medicine.
Due to the complex method of production of biological medicines, the active
substance may differ slightly between the biological reference and the bio similar
medicine.
Therefore, studies comparing the two medicines have to be carried out. These studies involve a step-
by-step process starting with a comparison of the quality and the consistency of the medicinal product
and of the manufacturing process. Studies are also conducted to compare the safety and efficacy of the
medicines. These studies should demonstrate that there are no meaningful differences between the
biosimilar and the biological reference medicines in terms of safety or efficacy. When the biological
reference medicine is used to treat different diseases, the efficacy and safety of the biosimilar medicine
may also have to be assessed using specific tests or studies for each disease.
Biosimilar medicines are manufactured following the same quality standards as for all other medicines.
Regulatory authorities also perform periodic inspections of the manufacturing site(s) as for all other
medicines.
Safety of biosimilar medicines
Pre-approval safety data should be obtained in a sufficient number of patients to characterize the safety
profile of the biosimilar products. The safety of all medicines, including biosimilar medicines, is also
monitored after authorisation. Each company marketing a new medicinal product is required to set up a
system to monitor the safety of the products that it markets, including any immunological responses to
the administration of biological products. The regulatory authorities may also perform an inspection of
this system. If there are specific precautions to be considered when taking the reference medicine, the
biosimilar medicine will require in general the same safeguards
ORION

36. Strategic options and implications
As described, biosimilars will evolve to an interesting market in the coming
years and with its very specific dynamics, this market will differ significantly
from those for originator products and for ‘classic’ generics. In general, biosimilars will
be a higher-risk but also higher-rewarded business than compared to classic generic
drugs. The dynamic developments will put pressure both on originator companies and
generics firms to meet these challenges and to develop a position in this new
environment. Based on the analyzed trends, Accenture sees the following likely
strategic options:
1: Generics firms enter successfully into the biosimilars market
The development of biosimilars represents a significant opportunity for generic firms interested in
entering the marketplaces for biotechnologically produced drugs. Without the necessity of
undertaking costly full-scale R&D activities, they can master the manufacturing and marketing of
recombinant proteins. In the long run it is possible they themselves gain the expertise and
resources needed to modify and improve biopharmaceuticals and bring innovative biologics to the
market, as the core competencies for production, development and approval needed for both
biologic or biosimilar are largely the same.
2: Pharmaceutical companies expand their biologics business and enter
biosimilars market opportunistically
For manufacturers of biologics the challenge is to define defense and pushback strategies. On the
one hand, this can include the development of improved second generation biologics with better
protein stability and efficacy.
3: New types of cooperation between Pharma, Biotech or Generics
As a third option, new forms of cooperation between relevant players, Pharma, Biotech or
Generics could evolve.
ORION

37. Key Success Factors to enter Biosimilar Market
The development of the biosimilar market will bring a new dynamic into the Pharma
world. Despite the described risks and challenges it will open up very interesting
opportunities for both Pharma and generic companies. The dynamics in the biosimilar market will
be more challenging than in the classic generic market requiring greater investments and risks,
forcing the producers to make careful selection on protein classes, building up new competencies
and developing new models for cooperation. In general, the main differentiator for players in the
biosimilars market will be safety, efficacy and convenience of their products; and to a lesser extent
the price of their drugs.
Fig. : Key Success Factors for Biosimilars
ORION

38. Biosimilarity Question 1: Determining whether a product is “highly similar”
 Side-by-side analytical comparison should occur for active protein molecules and
for formulated drug products
 Structural requirements for identity should be stringent
 Use of multiple orthogonal analytical methods is essential
 Other manufacturing & quality aspects of the biosimilar should also be assessed in relation to what
is publicly known about the reference product.
 Proof of biosimilarity should also be demonstrated by comparative nonclinical and clinical studies
 The scope of clinical studies depends on factors including the findings and limitations of analytical
studies, nonclinical studies, and state of public knowledge about product structure and function.
Biosimilarity Question 4: Acceptable range of structural differences
Biosimilar products must have the same amino acid sequence
Biosimilar products must have highly similar secondary and tertiary structure, bioactivity, and binding
Any structural difference that alters the amount of drug administered would be unacceptable as this
reflects a change in pharmacokinetics or in vivo bioactivity
Differences in charge variants and glycosylation have to be justified
Biosimilarity Question 5: Necessity of animal and clinical studies
 Animal PK and/or toxicity studies are necessary, and should be comparative, unless no
pharmacologically relevant species is available
study/studies are necessary, and should be comparative
ORION
Biosimilarity Question 3: Clinical Studies
Clinical studies are necessary
Immunogenicity must be assessed in clinical studies
Potency of biosimilar must be similar to that of reference
Clinical PK assessments should be maintained

39. Key questions for regulators
Biosimilar authorization poses a number of substantial scientific and regulatory
challenges for regulatory authorities. These include:
01. Reference product: Against what innovative product(s) may a biosimilar be
compared to support its authorisation?
02. Quality: What data must a biosimilar application include and what showing
must be made to demonstrate that a biosimilar’s quality is sufficiently
comparable to that of the reference product?
03. Non-clinical data: What type and amount of non-clinical data (including
data comparing a biosimilar to its reference product) are needed, and what
showing must be made, to support biosimilar authorisation?
04. Clinical trials: Under what circumstances is clinical data (including data
comparing a biosimilar to its reference product) needed to support a
biosimilar’s authorisation? What type of data is needed (such as,
pharmacokinetic, pharmacodynamic, efficacy, safety or immunogenicity)?
05. Extrapolation of indications: Under what circumstances (if any) may a
biosimilar receive authorisation for an indication of the reference product
based on data that evaluate, and show comparable safety and efficacy of, the
biosimilar for a different indication of the reference product?
ORION

40. ORION
Scientific & Regulatory Challenges Contd…
06. Naming: What proprietary and/or non-proprietary names should be permitted
(or required) for biosimilars so that physicians may select among medications and dictate
the specific product dispensed, and so that manufacturers and regulators may distinguish among
biologics for pharmacovigilance purposes?
07. Labelling: How will biosimilars be labelled? For example, what information from the reference
product’s label may or must appear in the biosimilar’s labelling? Must a biosimilar’s labelling indicate
that the product is a biosimilar?
08. Pharmacovigilance and risk management: What (if any) post-marketing monitoring and safety-
related requirements should be imposed on biosimilar applicants (such as, special requirements related
to safety reporting, post-marketing studies, or information that must appear in labelling for physicians or
patients)?
09. Interchangeability and substitution: What data must be provided and what showing must be
made for a regulatory authority to conclude that a biosimilar is interchangeable with its reference
product (that is, to determine that the two products have acceptably similar therapeutic results and
safety risks such that one can be used in place of the other in a given patient, or a given patient can
switch back and forth between them, and the same clinical outcome can be expected)? As a legal or
policy matter, under what circumstances (if any) can automatic substitution take place (that is, when
can, or must, a pharmacist dispense a biosimilar in place of the biologic medicine prescribed by a
physician, without the consent of the physician or patient)?
10. Data protection: To help innovators recoup their investment and to encourage continued medical
innovation, should innovators be afforded a period of time during which a biosimilar applicant cannot
rely on the innovator’s proprietary data to support authorisation of the biosimilar? If so, what length of
data protection should be provided?

41. FDA Guidance for Bio similarity
In contrast to non-biological small molecule drugs, an applicant that wants to
develop a biosimilar product cannot completely copy all aspects of the approved
product's data. Studies of the biosimilar product will have to be performed to show
safety, purity, and potency since the biosimilar product is not an exact copy. The
legislation provides that an application for approval of a biosimilar product shall
include that-
1. The biological product is biosimilar to a reference product (the FDA approved and licensed
product) based upon data derived from—
a) Analytical studies demonstrating that the product is highly similar notwithstanding
clinically in active components;
b) Animal studies (including toxicity); and
c) Clinical studies (including immunogenicity and pharmacokinetics) to demonstrate
safety, purity, and potency;
2. Utilizes the same mechanism of action for the condition of use;
3. same conditions of use approved for reference product;
4. Route of administration, dosage form, and strength of product are the same as the
reference product; and
5. he facility of manufacture meets FDA standards.
Must be available for public comment-
Not required to approve Biosimilar application
Can be product or product class-specific
FDA can determine that “science and experience” do not allow approval of
Biosimilar/Interchangeable for product or product class (but not for recombinant proteins)
ORION

42. The issues that FDA will need to address include:
a) What analytical data are necessary to show that a biosimilar is highly similar to its reference product
(notwithstanding minor differences in clinically inactive components) and what constitute minor
differences.
b) What type and how much non-clinical and clinical data it requires in applications.
c) Whether and when it will permit extrapolation from one reference product indication to another.
d) Whether and when it will exercise the discretion to permit omission of data otherwise required in
biosimilar applications.
e) Whether it will exercise its option, granted by statute, to declare that certain products or product
classes are not yet suitable for biosimilar applications.
f) How biosimilars will be labelled, including whether and how the labelling will indicate that a product is
a biosimilar and whether a biosimilar’s labelling will be permitted or required to include information
from clinical studies of the reference product conducted by (or for) the reference product sponsor.
g) What data or other showing is necessary for a biosimilar to be found interchangeable with its
reference product.
h) Whether biosimilars should have non-proprietary names that are distinct from the non-proprietary
names of the reference products on which they are based.
i) Whether and when information concerning a reference product could lead the agency to take action to
revoke or suspend the authorization of products biosimilar to that reference product.
“Sameness” test developed for uncharacterized large molecule drug requires
equivalence showing for:
• Physical and chemical properties
• Source material
• Methods of processing of source material
• Nature and arrangement of components that constitute the drug
• Laboratory measurements of drug activity
• Certain aspects of the drug’s effect in humans
ORION

43. 1.Legislation should require a baseline scientific evaluation of the original drug and the biosimilar.
Thisassessment should establish that key similarities exist between the two (for example, in the
active substance, pharmaceutical form, strength and route of administration) and then determine any
differences.
2.Following on from the first, the legislation should identify the level of clinical data that will be needed
to evaluate and approve the biosimilar. This requirement should be twofold. First, product class-
specific guidelines should identify a baseline level of clinical testing for various product types. This
should take into account the level of existing knowledge about the original biologic and the illness the
medicine seeks to treat. Second, the legislation should mandate that more specific clinical
requirements be determined based on the differences identified in the scientific comparison with the
original biologic described above (for instance, related to the host cell, secondary agents and the
development and manufacturing process).
3.Legislation should call for post-marketing safety studies in order to monitor any potential differences
in safety and efficacy between the biosimilar and original drug that become apparent once a
biosimilar enters the market. This should take into account any health-related issues identified during
the development stage (i.e. related to differences in quality between the biosimilar and original drug
or the manufacturing process), as well health elements that are associated with the original biologic.
The entry of biosimilars presents several unique policy dilemmas. Forming a
pathway for approval that addresses the safety and IP challenges has shown to be a
thorny process, particularly when political and commercial interests come into play, as
they have in the US. In order to ensure public safety and to preserve sufficient incentives
for future biomedical innovation, the best practices gleaned from existing pathways
demonstrate that approval pathways for biosimilars should seek to uphold the following
five principles.
ORIONPOLICY CONSIDERATION

44. 4.Legislation should define the standard and criteria for interchangeability of
the biosimilar with the original drug. The legislation should clarify if marketing approval
indicates that automatic substitution is permissible (from a pharmacological, as opposed
to a reimbursement/cost containment point of view), or if the decision on substitution
should be left to more immediate health authorities or physicians. If central health
authorities are given a mandate to determine interchangeability, the legislation should also
fix the criteria they should use. The criteria should be well-defined – it should require that
the biosimilar produce the same clinical effect as the original drug – and should be tailored
to product classes or even individual products. Furthermore, it should prioritize public
safety considerations over cost-containment objectives.
4.Legislation should provide sufficient incentives to research-based companies via IP
protection. It should ensure that patent protection is not eroded with the entry of
biosimilars. Importantly, it should recognize the possibility that gaps in patent protection
could result from biosimilars designing around patents of the original drug. One way of
resolving this is by extending the term of data exclusivity to cover fully or in part the
potential gaps. Whatever the data exclusivity term that is deemed appropriate by
individual countries, it should as much as is possible, within reason, attempt to off-set
the disincentives to investment resulting from potential weakening of patent protection.
Legislation should also prevent the erosion of patent protection by making certain that a
patent resolution system does not involve asymmetrical patent disclosure (i.e. only by
the patent holder). In addition, policymakers should consider to what extent drug
authorities will increase their reliance on data belonging to the original drug in order to
evaluate biosimilars, as well as the extent to which this may dampen the incentives to
develop new drugs. If appropriate, the term of data exclusivity can be extended
accordingly.
ORIONPOLICY CONSIDERATION Contd…

45. ORION
CONCLUSION
Finally it can be said that a number of problems remain in the
bioequivalence process which should be addressed. FDA scientists themselves
have readily acknowledged the existence of shortcoming in the
bioequivalence testing program. However, a great deal of progress has been
made in this area in the last twenty years. The improved design of the studies,
the interpretation of the data, the increased scientific rigor of the acceptance
criteria, as well as the more rigorous auditing and inspection program have
made bioequivalence data an appropriate and valid means of proving generic
drug products.
As new, innovative biologics and biosimilars enter the marketplace. To ensure
patient safety and product efficacy are of utmost importance. As a result, we
support the development of a regulatory pathway for biosimilars that is based
on patient safety, product efficacy and incentives for innovation. We will
continue to monitor policy discussions and proposed regulations as the FDA
moves forward in establishing a biosimilars pathway, and share our expertise
and views where appropriate.
Biosimilars present considerable opportunities – whether for growth in the
healthcare sector or for treating patients – especially over the long-term.
Concurrently, however, policymakers must ensure that high standards of
public safety are maintained to protect patients and that the right IP
framework is in place to incentivise innovators. If so, then we can reasonably
expect favourable results from the greater use of biosimilars improving
healthcare standards in both the developed and developing world.

46. ORION