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Bioequivalence of Topical Dermatological Drug Products
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, 3001 Mercer
University Drive, Mercer University, Atlanta, GA 30341
*To whom correspondence should be addressed:
Topical dosage forms are liquid or semisolid dosage forms, which are not intended for
systemic absorption. These dosage forms comprise solutions, lotions, gels, ointments,
patches, and foams; that are applied onto the skin either to elicit therapeutic effect within the
The Code of Federal Regulations: 21 CFR § 320.1 has the following definitions:
a) Drug product means a finished dosage form, e.g., tablet, capsule, or solution, that
contains the active drug ingredient, generally, but not necessarily, in association with
b) Bioavailability (BA) is 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. For drug
products that are not intended to be absorbed into the bloodstream, BA may be assessed
by measurements intended to reflect the rate and extent to which the active ingredient or
active moiety becomes available at the site of action.
c) Pharmaceutical equivalents (PE) means drug products in identical dosage forms that
contain identical amounts of the identical active drug ingredient, i.e., the same salt or
ester of the same therapeutic moiety, or, in the case of modified release dosage forms that
require a reservoir or overage or such forms as prefilled syringes where residual volume
may vary, that deliver identical amounts of the active drug ingredient over the identical
dosing period; do not necessarily contain the same inactive ingredients; and meet the
identical compendial or other applicable standard of identity, strength, quality, and
purity, including potency and, where applicable, content uniformity, disintegration times,
d) Pharmaceutical alternatives (PA) means drug products that contain the identical
therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage
form or as the same salt or ester. Each such drug product individually meets either the
identical or its own respective compendial or other applicable standard of identity,
strength, quality, and purity, including potency and, where applicable, content
uniformity, disintegration times and/or dissolution rates.
e) Bioequivalence (BE) is the absence of a significant difference in the rate and extent to
which the active ingredient or active moiety in pharmaceutical equivalents (PE) or
pharmaceutical alternatives (PA) becomes available at the site of drug action when
administered at the same molar dose under similar conditions in an appropriately
Establishing BE for Topical Dermatological Drug Products has been a topic of discussion for
many years between scientific community and the regulatory agency. Despite great advances
in addressing the issues related to topical bioequivalence, many challenges remain due to the
complexity of drug transport through the skin from different formulations and lack of
harmonized guidance documents. Siewert et al
. (2003) have acknowledged that no single test
procedure would be suitable for the development, biopharmaceutical characterization, and
quality control of all semi-solid topical dosage forms.
The FDA’s current approval strategy for most of the topical drug products (New Drug
Application/Abbreviated New Drug Application) is based on clinical studies. Clinical trials
to prove BE often lack sensitivity and require large and costly trials (FDA’s Critical Path
Initiative § 4.3.3, 2004; Narkar, 2010). It may not be cost effective for generic manufacturers
to conduct large clinical trials. Several surrogate methods have been in development to
address this issue as summarized in this review. However, adoption by industry is limited.
The reason could be less competition for a relatively smaller market of topical dosage forms
when compared to other dosage forms. The Federal Trade Commission (FTC) has put
conditions on Novartis AG's Acquisition of Fougera Holdings, Inc.
in order to protect the
competition in the skin care market for certain products.
The scope of this review is to summarize different methods that can facilitate establishing BE
of Topical Dermatological Drug Products.
2. Regulations Governing Bioequivalence in USA
The Code of Federal Regulation (CFR), Title 21, describes how the Food and Drug
Administration (FDA) regulates food, drugs, cosmetics, biologics, tobacco products,
veterinary products, radiation emitting products, and medical devices in the US. As part of
Department of Health and Human Services (DHHS), the FDA’s mandate is to protect and
promote public health. There have been significant amendments to the Food, Drug and
Cosmetics legislation ever since the Sulfanilamide Elixir tragedy in 1937 (Skelly, 2009;
Table 1). The US enacted the Drug Price Competition and Patent Term Restoration Act of
1984 (DPCA 1984), widely known as the Hatch-Waxman Act, to lower the raising costs of
prescription drugs by increasing the competition among manufacturers. The generic industry
has flourished by the virtue of this legislation. However, due to lack of reliable alternative
methods, clinical studies are required to establish BE of Topical Dermatological Drug
Products (FDA’s Critical Path Initiative § 4.3.3, 2004). Topical BE has been a topic of much
discussion among researchers, industry, and agency (Table 1).
Regulatory information pertaining to BE of Topical Dermatological Drug Products1
The Federal Food, Drug, and Cosmetic Act (FD&C Act) – required evidence of safety for market approval of new drug products
The Kefauver-Harris Amendments established drug safety and effectiveness requirement from the manufacturers
The Drug Price Competition and Patent Term Restoration Act of 1984 – Title I: Abbreviated New Drug Application; Title II: Patent Extension (Hatch-Waxman Act)
Interim Guidance, Topical Corticosteroids: In Vivo BE and In Vitro Methods
The FDA’s Guidance for Industry: Nonsterile Semisolid Dosage Forms Scale-Up and Post Approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and Bioequivalence (SUPAC-SS)
The FDA’s Draft Guidance-Not for Implementation, Topical Dermatological Drug Product NDAs and ANDAs — In Vivo Bioavailability, Bioequivalence, In Vitro Release, and Associated Studies
FDA Draft guidance on the Skin stripping method withdrawn due to contradictory results from two independent laboratories
FDA’s Critical Path Initiative: To drive innovation in the scientific processes
through which medical products are developed, evaluated, and manufactured.
FDA Guidance recommends in vivo bioequivalence of topical dermatologic corticosteroids based on pharmacodynamics approach (Stoughton-McKenzie vasoconstrictor assay)
FDA’s Critical Path Opportunities for Generic Drugs: 4.3.3 BE of Topical
3Mar 13 Workshop on the evaluation of Topical Drug Products Development and
1http://www.fda.gov/RegulatoryInformation/default.htm 2Described DPK methodology for establishing BE for topical products 3Expected date; organized by Product Quality Research Institute (PQRI)
3. BE of Topical Dermatological Drug Products
In order to get an approval to market a generic copy of “pioneer or innovator drug product”
must demonstrate bioequivalence to the Reference Listed Drug (RLD) in compliance with
DPCA 1984. Simple solutions or liquid dosage forms may be exempted from this
The new drug application relies on already existing safety and/or efficacy data of
already approved drug product, but must demonstrate non-inferiority to the RLD,
for example, seeking approval of cream dosage form to the RLD (ointment or
3.1.2. Abbreviated New Drug Application (ANDA)
The new drug products intended for approval through the § 505(j) of DPCA 1984 (Table
“Same drug product formulation
means the formulation of the drug product submitted for
approval and any formulations that have minor differences in composition or method of
manufacture from the formulation submitted for approval, but are similar enough to be
relevant to the agency's determination of bioequivalence” (21 CFR § 320.1). In the case of
any changes to the already approved product (same drug formulation), the NDA or ANDA
holder may document BE with respect to unchanged formulation. The FDA’s Guidance for
Industry: Nonsterile Semisolid Dosage Forms Scale-Up and Post Approval Changes:
Chemistry, Manufacturing, and Controls; In Vitro Release Testing and Bioequivalence
(SUPAC-SS, 1997) provides recommendations for pharmaceutical sponsors. The guidance
defines “(1) the levels of change; (2) recommended chemistry, manufacturing, and controls
(CMC) tests to support each level of change; (3) recommended in vitro release tests and/or in
vivo bioequivalence tests to support each level of change; and (4) documentation to support
4. Demonstration of BE for Topical Dermatological Drug Products
Demonstration of PE and BE for Topical Dermatological Drug Products must be based on
the intuitive choice from several available techniques. As envisaged by Franz (2011), a
systematic approach for selecting an appropriate surrogate test can be adapted to establish BE
(Figure 1). The choice primarily depends on the therapeutic target and secondly the type of
vehicle in which drug is formulated with emphasis on Q3 equivalence (Lionberger, 2004).
Skin being the largest organ of the body, has several biologically and chemically distinct
layers. To simplify the structure of skin with respect to partitioning of drugs, the outermost
layer (stratum corneum) is lipophilic and protects the underlying dermis, which is
hydrophilic. Thus, drug release from various vehicles (creams, lotions, gels, ointments, and
foams) and diffusion into or through the skin is complex.
Systematic approach to selecting an appropriate surrogate test to establish
Bioequivalence of Topical Dermatological Drug Products (Franz TJ, AAPS Annual Meeting,
October 2011); IVRT: In Vitro Release Testing, TEWL: Trans Epidermal Water Loss, IVPT: In
Vitro Permeation Testing
Lionberger (2004) has classified the pharmaceutical equivalence of semisolid dosage
Q1 equivalence qualitative similar components as RLD
Q2 equivalence quantitatively similar components as RLD
Q3 equivalence Q1 and Q2 with structural similarity as RLD
IVRT utilizes widely accepted Franz diffusion cells to estimate rate of drug release from
drug products. It involves the application of a drug product on to a membrane (synthetic
membrane, excised animal skin, or excised human skin) that separates the donor and
receiver chambers. The receiver chamber simulates sink conditions in vivo. The rate of
delivery obtained from these studies is assumed to be similar to the in vivo situation. The
method has been widely employed in discovery research for screening formulations and
understanding mechanism of cutaneous drug transport (Narkar, 2010). However, it is not
recognized as a surrogate for in vivo BA/BE of new drug products (SUPAC-SS, 1997).
However, Franz et al.
(2009) have reported substantial evidence of in vitro – in vivo
correlation (maximum rate of absorption, total absorption, and time to maximum rate of
absorption) using dermatomed cadaver human trunk skin (0.5 – 0.9 mm; finite dose
model) for glucocorticoids and retinoid dosage forms of different vehicles when
compared to respective RLD. (Glucocorticoid formulations: Alclometasone dipropionate
cream and ointment 0.05%, Halobetasol cream and ointment 0.05%, Mometasone
ointment 0.1%; Retinoid formulations: Tretinoin gels 0.01%, 0.025%) It is important to
note that in vitro excised human skin model provided discriminatory evidence across
different vehicles (Alclometasone dipropionate cream versus Ointment; Betamethasone
valerate foam versus lotion) in contrast to non-discriminatory vasoconstriction assay
(Franz TJ et al
., 2009). In addition, Lehman et al
., in their recent evaluation of literature,
have concluded that using excised human skin would establish better in vitro – in vivo
correlation, provided the study protocols are harmonized.
SUPACSS (1997) provides a detailed description of the method along with
recommended instructions in the event of any changes to the already approved drug
Tape stripping provides information on drug uptake, apparent steady-state levels, and
drug elimination from the stratum corneum based on a stratum corneum concentration-
time curve (FDA’s Draft Guidance, 1998). This method is also known as the
dermatopharmacokinetic (DPK) approach similar to blood, plasma, and urine analysis
for drug concentrations as a function of time.
Though the draft guidance document was withdrawn in 2002, the FDA has
recommended it as surrogate method for certain class of drugs, for example antifungals
that target the stratum corneum itself (Narkar, 2010). However, Au et al
. (2010) have
illustrated the potential of standardized TS methods; demonstrating the BE of two 0.05%
clobetasol propionate cream formulations and bio-inequivalence of cream and ointment
formulations. Pershing et al.
(2003) have shown direct correlation between DPK
parameters in healthy patients and clinical safety/efficacy of tretinoin gel products in
Microdialysis is a continuous sampling technique in which the molecule of interest is
collected from the target tissue; thus providing insight into the time course of drug action
or biochemical monitoring of the tissue. The technique can be imagined as an artificial
capillary, in which a hollow semipermeable probe is carefully inserted into the site of
interest: brain, muscle, eye, and skin. Therefore, it provides valuable information of
unbound drug concentrations or biomarkers at the site closer to the pharmacological
action compared to the conventional plasma/blood drug concentration versus time.
Though it was developed for neurological research, it has gained acceptance in other
areas of research. Stenken et al.
in their quest to answer, “how minimally
invasive is microdialysis in human skin,” have concluded that “probe insertion in the
skin leads to inflammatory responses, both acute and chronic, and an immunological
probe rejection response, all of which have the potential to affect experimental
microdialysis in different ways.” However, with respect to sampling of drug molecules
from the skin, perturbation of blood flow to the local tissue is critical which would
recover to normal in approximately two hours. The technique has been successfully
adopted and demonstrated for dermatological research as well as for demonstrating the
BE of topical dosage forms (Narkar, 2010, Stenken et al.,
2010). The technique has
shown promise in published and unpublished research in our laboratories for monitoring
intradermal and subcutaneous tissue drug concentrations after application of transdermal
drug formulations (Chaturvedula et al.,
2005; Katikaneni et al.
, 2011; Paturi et al
Benfeldt et al.
(2007) have estimated, based on the variability component of dermal
microdialysis of Lidocaine cream and ointment products, the number of subjects as 27
for demonstrating BE with 90% CI and 80 –125% BE limits using two probes in each
test area, or 18 subjects using three probes per formulation application site. The required
number of subjects using dermal microdialysis is relatively smaller compared to
traditional clinical efficacy trials requiring as many as 300 patients for demonstrating BE
Dermal microdialysis technique is appealing, however, faces many limitations; such as
technical difficulties, protein binding, variability associated with the recovery, and tissue
Various spectroscopic methods, including ATR-FTIR, NIR, and Raman, have been
investigated for non-invasive measurement of the drug in the skin. Not all molecules can
have quantifiable spectral features, which can be used to distinguish from the stratum
corneum (Narkar, 2010). NIR has been widely explored as one of the process analytical
technology tools in the pharmaceutical industry. The promising feature of NIR is
relatively rapid data acquisition and in vivo applicability.
4.6. Pharmacological Response to Demonstrate BE
Pharmacodynamic approaches based on pharmacological response are more appropriate
for dosage forms intended for local action at the site of application. Topical
glucocorticoids (TG) are formulated in various vehicles to treat atopic dermatitis and
psoriasis (Wiedersberg S, 2008). FDA Guidance recommends demonstrating in vivo BE
of topical dermatologic corticosteroids based on the pharmacodynamics approach,
Stoughton-McKenzie vasoconstrictor assay (Table 1). This test is based on the
chromameter readings of skin blanching effect resulting from vasoconstrictive action of
Several other tests were reported in the literature, for example, laser Doppler flow meter
for measuring the blood flow to assess topical NSAIDs; Trans Epidermal Water Loss
(TEWL) to evaluate absorption of retinoids; skin temperature increase by nicotinic acid
esters (Narkar, 2010; Wiedersberg et al.
The intricacy of cutaneous drug delivery is very well addressed in the literature.
Nevertheless, there is a knowledge gap between industry and regulatory agencies. It will not
be possible to have a single step solution for demonstrating the BE of all Topical
Dermatological Drug Products. However, FDA’s Guidance documents on surrogate methods
could not only reduce US healthcare costs by encouraging competition among companies,
but also increase the emphasis on product quality, in particular Q3 equivalence.
Please refer the following references for detailed information.
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(2010) 13(1):11-20. Benfeldt E, Hansen SH, Vølund A, Menné T, Shah VP. Bioequivalence of topical formulations in humans: evaluation by dermal microdialysis sampling and the dermatopharmacokinetic method. J Invest Dermatol
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(2005) 22:1313-1319. Chen ML, Shah V, Patnaik R, Adams W, Hussain A, Conner D, Mehta M, Malinowski H, Lazor J, Huang SM, Hare D, Lesko L, Sporn D, Williams R. Bioavailability and bioequivalence: an FDA regulatory overview. Pharm Res.
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CFR Code of Federal Regulation, Title 21: Food and Drugs, Chapter I Food and Drug
Administration Department of Health and Human Services, Subchapter D Drugs for human
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