regulatory requirement for bioequivalence

Regulatory Requirements
for BE
Nirmal Raj Marasine
Jaya pathak
8/26/2015 1Regulatory Requirements for BE

BIOAVAILABILITY
• According to Food and Drug Administration (FDA) guidance,
Bioavailability is defined as: ―the rate and extent to which
the active ingredient or active moiety is absorbed from a drug
product and becomes available at the site of action
• According to World Health Organization (WHO) guidelines,
Bioavailability is defined as: ―the rate and extent to which
the active drug ingredient or therapeutic moiety is absorbed
from a drug product and becomes available at the site of drug
action‖
8/26/2015 Regulatory Requirements for BE 2

BIOEQUIVALENCE
• According to Food and Drug Administration (FDA) Guidance,
bioequivalence is defined 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‖

• Bioequivalence requirement:A requirement imposed by the
FDA for in-vitro and/or in-vivo testing of specified drug
products, which must be satisfied as a condition for
marketing.
• Bioequivalent drug products. This term describes
pharmaceutical equivalent or pharmaceutical alternative
products that display comparable bioavailability when studied
under similar experimental conditions

• For systemically absorbed drugs, the test (generic) and
reference listed drug (brand-name) shall be considered
bioequivalent if:
(1) the rate and extent of absorption of the test drug do not
show a significant difference from the rate and extent of
absorption of the reference drug when administered at the
same molar dose of the therapeutic ingredient under similar
experimental conditions in either a single dose or multiple
doses

• (2) the extent of absorption of the test drug does not show a
significant difference from the extent of absorption of the
reference drug when administered at the same molar dose of
the therapeutic ingredient under similar experimental
conditions in either a single dose or multiple doses and the
difference from the reference drug in the rate of absorption of
the drug is intentional…..

, is reflected in its proposed labeling, is not essential to the
attainment of effective body drug concentrations on chronic
use, and is considered medically insignificant for the drug.
 When the above methods are not applicable (eg, for drug
products that are not intended to be absorbed into the
bloodstream), other in-vivo or in-vitro test methods to
demonstrate bioequivalence may be appropriate.

 Terms use in the Bioequivalence studies:
• Brand name. The trade name of the drug.
• This name is privately owned by the manufacturer or
distributor and is used to distinguish the specific drug product
from competitor's products (eg, Tylenol, McNeil Laboratories).
• Chemical name. The name used by organic chemists to
indicate the chemical structure of the drug (eg, N-acetyl-p-
aminophenol).

• Abbreviated New Drug Application (ANDA). Drug
manufacturers must file an ANDA for approval to market a
generic drug product. The generic manufacturer is not
required to perform clinical efficacy studies or nonclinical
toxicology studies for the ANDA.
• Drug product. The finished dosage form (eg, tablet, capsule,
or solution) that contains the active drug ingredient, generally,
but not necessarily, in association with inactive ingredients.

• Generic name. The established, nonproprietary, or common
name of the active drug in a drug product (eg,
acetaminophen).
• Generic substitution. The process of dispensing a different
brand or an unbranded drug product in place of the
prescribed drug product. The substituted drug product
contains the same active ingredient or therapeutic moiety as
the same salt or ester in the same dosage form but is made by
a different manufacturer.

 Pharmaceutical euqivalence:this term implies that two or
more drugs products are identical in strength quality
,purity,content uniformly and disintegration and dissolution
characteristics .
• They may, differ in containing different excipients.
 Therapeutics equivalance:this term indicates that two or
more drugs that contain the same therapeutically active
ingredient elicit identical pharmacological effects and can
control the disease to the same extent.

Reference Product
• A reference product is a pharmaceutical product with which
the new product isintended to be interchangeable in clinical
practice.
• The reference product would normally be the innovator
product for which efficacy, safety and quality have been
established.
• When the innovator product is not available the product
which is the market leader may be used as a reference
product, provided that it has been authorized for marketing
and its efficacy, safety and quality have been established and
documented8/26/2015 Regulatory Requirements for BE 12

• Generic products Products whose active pharmaceutical
ingredients, dosage form strengths and regimen are the same
as those of new products.
• Generic and new products should be the same in the
application area of dosage and their physiochemical
characteristics should be similar to those of new products.
• Bioequivalence range31 Acceptable range of bioequivalence is
generally 0.8% - 1.25% for the test or reference ratio of
average values, when the parameters are logarithmically
transformed.

• The acceptable range is generally ± 0.2 for the relative
difference in vivo parameters between reference and test
products, when the raw data are used

Bioequivalence: FDA Regulatory
Overview
• INDs-NDAs
• BE documentation may be useful during the IND-NDA period
to establish links between:
(i) early and late clinical trial formulations;
(ii) formulations used in clinical studies and stability studies, if
different; and
(iii) clinical trial formulations and the to-be-marketed drug
product. In each comparison, the new formulation or new
method of manufacture is the test product, and the prior
formulation or method of manufacture is the reference
product.

• It may not be possibl to conclude BE because the test product
produces higher or lower measures of rate and extent of
absorption or because the performance of the test or
reference is more variable.
• In some cases, “bioequivalence” is observed because of
inadequate numbers of subjects entered into the BE study
• ANDAs Sponsors of ANDAs are required to establish BE
between a pharmaceutically equivalent generic drug product
and the corresponding listed drug

• Postapproval Changes Information on the types of in vivo BE
studies and in vitro dissolution needed for postapproval
changes to drug products approved as either NDAs or ANDAs
are provided in FDA guidances
• In the presence of certain major changes in components and
composition, and/or method of manufacture after approval,
in vivo BE between pre- and postchange product may need to
be re established.

• Under such circumstances, for approved NDAs, the drug
product after change should be compared with the drug
product before change, whereas for approved ANDAs, the
drug product after change should be compared with the
reference listed drug
• TEST PROCEDURES
• Several in vivo and in vitro methods are appropriate to
document BA and BE

• In descending order of preference, the US regulations include
pharmacokinetic, pharmacodynamic, clinical, and in vitro
studies .
• . Willingness to rely on test procedures other than clinical
studies is based on the assumption that pharmacokinetic and
pharmacodynamic approaches and/or in vitro approaches,
along with appropriate goalposts, adequately reflect clinical
safety and efficacy outcomes

• Pharmacokinetic Studies
The statutory definition of BA and BE, expressed in rate and
extent of absorption of the active moiety or ingredient to the
site of action, emphasizes the use of pharmacokinetic
measures to indicate release of the drug substance from the
drug product with absorption into the systemic circulation.
This approach rests on an understanding that measurement of
the active moiety or ingredient at the site(s) of action is

generally not possible and that some predetermined
relationship exists between the drug concentration at the site
of action relative to that in the systemic circulation.
• A typical BE study is conducted as a crossover study, in which
clearance and physiologic variables (e.g., gastric emptying,
motility, and pH) are assumed to have less interoccasion
variability within an individual compared with variability
between individuals

• Where needed, a pilot study may be useful to validate
analytic methodology, to assess intra- and intersubject
variability in systemic exposure measures, and to optimize
sample collection times
• Although some authors have stated that multipledose studies
are useful in establishing BA and BE , singledose studies to
document BE may be preferred because they are generally
more sensitive in assessing in vivo release of the drug
substance from the drug product A goal in BA and BE studies
is to assess rate and extent of drug absorption.

• Extent of absorption is readily measured by AUC either to the
last sampled time point (AUC0-t) or following extrapolation to
time infinity (AUC0)
• Measurement of the true rate of absorption is difficult, given
that rate varies continuously over time . A recent FDA
guidance, therefore, has recommended that measures of
systemic exposure be used to reflect clinically important
differences between test and reference products in BA and BE
studies .

• These measures include (i) total exposure (AUC0-t or AUC0-
for single-dose studies and AUC0-t for steady-state studies),
(ii) peak exposure (Cmax), and (iii) early exposure (partial AUC
to peak time of the reference product for an immediate-
release drug product).
• Reliance on systemic exposure measures will reflect
comparable rate and extent of absorption, which in turn, will
achieve the underlying goal of assuring comparable
therapeutic effects

• Pharmacologic Effect (Pharmacodynamic) Studies
Locally acting drug products include oral inhalation drug
products, such as metered dose inhalers and dry powder
inhalers, and topically applied dermatologic drug products
such as creams and ointments.
• .These drug products deliver an active moiety or active
ingredient to local sites of action where they exert their
primary clinical effects. Pharmacokinetic studies measure
systemic exposure but are generally inappropriate to
document local delivery BA and BE.

• In such cases, BA may be measured, and BE may be
established, based on a pharmacodynamic (PD) study,
providing an appropriate PD endpoint is available, which can
be studied with sufficient accuracy, sensitivity, and
reproducibility.
• Bronchodilator drug products, such as albuterol metered dose
inhalers, produce relaxation of airway smooth muscle

• For these drug products, a PD endpoint, based either on
increase in forced expiratory volume in 1 s (FEV1) or on
measurement of PD20 or PC20 (the dose or concentration,
respectively, of a challenge agent) (17,18), is clinically relevant
and may be used for BA and BE studies
• An essential component of a BA or BE study based on a PD
response is documentation of a dose-response relationship

• The dose-response curve should be characterized as part of
the study. In the absence of other evidence, the commonly
used Emax model is assumed as the default model.
• To establish BE, the study is conducted in the sensitive region
of the dose-response curve .
• A BE study conducted near the plateau of response will be
insensitive to differences in drug delivery between the test
and reference products and will, thus, require increased
numbers of subjects to detect product differences.

• PD response measurements of the test and reference
products determined in the BE study may be converted to
estimates of delivered dose of the test and reference products
by using a dose-scale approach .
• The benefits of the dose-scale approach to BE assessment
arise from the translation of nonlinear PD measurements to
linear dose measurements

Comparative Clinical Trials
 In vitro bioequivalence studies :
• in viitro studies ,i.e dissolution studies can beused in ileu of in
vivo bioequivalence under certain circumstances called as
biowaivers (exemptions )-
1) the drugs product differs only in strength of the active
substances it contains ,provided all the following conditions
hold……..

• Pharmacokinetics are in linear
• The qualitative composition is the same
• The ratio between active substanceand the excipients is the
same ,or the ratio between the excipients is the sme
• Both products are produced by the same manufacturer at the
same production site.
• A bioavailability or bioequivalence study has been performed
with the original product .

• under the same test conditions ,the in vitro dissolution
rate is the same
2)The drugs product has been slightly reformulated or the
manufacturing method has been slightly modified by
the original manufacturer in ways that can
convincingly be agrued to be irrelevant for the
bioavailability.
3.The drugs product meets all of the following
requirements….
• The product is in the form of solution or solubilised
form (elixir ,syrup tincture ,etc).

• the product contains active ingredient in the
same concentration as the approved drug
product.
• The product contains no excipients known to
significantly affect absorption of the active
ingredient
4.An acceptable IVIVC and the invitro dissolution
ratte of the new product is equivalent with that
of the already approved medicinal product

More ever ,
• The product is intended for topical
administration (cream ,ointment,gel ,etc)for
local effect.
• The product is for oral administration but not
intended to be absorbed (antaacid or radio –
opaque medium)
• The product is administered by inhalation as a
gas or vapour

REFERENCES
• U.S. Food and Drug Administration, Title 21 CFR 21 CFR
314.50(d)(1)–(6), Office of Federal Register, National Archives
and Records Administration (2001).
• U.S. Food and Drug Administration, Title 21 CFR 314.94,
Office of Federal Register, National Archives and Records
Administration (2001).
• World Health Organization. Multisource (generic)
pharmaceutical products: guidelines on registration
requirements to establish interchangeability.

• Food and Drug Administration (FDA), Guidance for Industry:
Bioavailability and bioequivalence studies for orally
administered drug products general considerations. Informal
communication by the Center for Drug Evaluation and
Research (CDER), March 2003
• Rani S, Pargal A. Bioequivalence: An overview of statistical
concepts. Indian J Pharmacol. 2004;36:209–216

• Guideline for Bioequivalence Studies of Generic Products
(December,2006). National Institute of Health Sciences. Japan
NIHS. http://www.nihs.go.jp/drug/be-guide(e)/be2006e.pdf.
Accessed December 8, 2010.
• Bioequivalence Requirements Guidelines, Saudi Food and
Drug Authority Drug Sector. 2005, 5-8.

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