Advisory Committee for
Pharmaceutical Science Meeting
Topic: Research for Generics - Bioequivalence of Topical Products
Prepared by:
Date:
Bioequivalence
of Topical Products
Problem Statement
Despite tremendous efforts by industry, FDA, and academia for the past decade, a cost-effective, scientifically sound system to evaluate the therapeutic equivalence of topical products is still unavailable. For example, the bioequivalence demonstration of many topical products relies on clinical trials that may require hundreds of patients (due to high variability of the patient population). These studies can also require a long time and complex statistical analysis. All these factors combine to render the study design expensive. Due to the limited knowledge and experience of sponsors, these costly studies may have to be repeated to meet the confidence interval criteria to demonstrate bioequivalence. The lack of a bioequivalence method has limited the availability of generic products as well as the ability of innovator companies to make post-approval formulation or process changes.
Background
The
agency has been evaluating topical product equivalence issues using Dermatopharmacokinetic
(DPK) techniques such as
skin-stripping for more than a decade. In 1998, the agency issued a draft
Guidance for Industry titled “Topical
Dermatological Drug Product NDA’s and ANDA’s—In Vivo Bioavailability, Bioequivalence and In Vitro
Release”. Subsequently in 2000, two definitive equivalence studies were
conducted in humans using tretinoin gel 0.25%, based
on the skin-stripping methodology described in the Guidance. The studies were
conducted at two different locations by two expert researchers: Dr. Lynn
Pershing of the University of
The
Committee also expressed concern that the guidance covered all topical products
including those that are delivered to areas of skin without healthy stratum corneum (SC).
For
drugs treating target sites that are not the SC, the DPK method may not
accurately reflect therapeutic effectiveness if penetration through another
pathway (e.g., hair follicles) is important. Similarly, because healthy SC is
absent in many skin diseases, therapeutic effectiveness could be unrelated to
SC penetration.
At
the
To
move forward the FDA is working to develop improved DPK methods for a focused
product class (topical anti-fungals) and to design a
framework for physical characterization of topical products.
Improved Dermatopharmacokinetic
methods
To
develop an improved DPK method FDA is first considering topical anti-fungal
products. These products target the stratum corneum itself,
thus skin-stripping directly measures the delivery of the drug to its site of
action. Experience from these products can then be generalized to other topical
products.
Some
of the problems with the previous skin stripping trials have been identified.
The withdrawn guidance mandated removing the same number of strips from each
subject irrespective of the amount of stratum corneum
removed. However both the thickness of the stratum corneum
and the amount of skin removed by each strip varies between individuals and so
each individual would have a different and uncontrolled fraction of the stratum
corneum removed. Mathematical modeling shows that
removing the same fraction of the stratum corneum
from each individual is important for reproducible measurement. The withdrawn guidance was not specific about
the protocol for drug application and stripping and it is likely that different
control of the drug application area and stripping area contributed to the
contradictory results observed in the past.
In the
new method there will be precise specification of the drug application area and
stripping area. The thickness of the stratum corneum
and the thickness removed will be measured so that for each subject it is
assured that a sufficient fraction of the stratum corneum
has been removed. Mathematical modeling of diffusion through the stratum corneum will allow the choice of application strategies and
stripping times to minimize variability in the method.
Introduction to the Q3
concept
Working Definition of the Q3
concept: Q1
means qualitative similarity between generic and reference listed products,
while Q2 represents quantitative similarity of composition. Q3 is a newly
defined term that describes structural similarity and refers to the arrangement
of matter and state of aggregation of the product. Examples of products that
are Q1 and Q2 similar to each other, but differ in Q3 would be a solid dosage
forms that differ only in crystal structure or suspensions or emulsions that
differ only in particle size distribution or gels that differ only in the
extent of cross-linking.
For
pharmaceutical dosage forms that are in thermodynamic equilibrium,
such as solutions of small molecules, specification of Q2 and the
conditions of temperature and pressure uniquely determine Q3. For the many
dosage forms that are not in thermodynamic equilibrium, including most topical
formulations, their Q3 or arrangement of matter depends on their history which
includes the manufacturing processes and the conditions of storage. Differences
in Q3 could manifest themselves as differences in physical properties such as rheology or in dissolution rate.
Historically,
for solid oral dosage forms FDA has not been concerned with Q3 identity because
in vivo bioequivalence methods were readily available. For example, two tablet
formulations that have different particle sizes but still provide the same rate
and extent of drug delivery to the blood would be considered bioequivalent even
though they were not Q3 to each other. Where the Q3 concept is especially
important is for products that are locally acting and do not have demonstrated
in vivo bioequivalence methods such as topical products.
For
topical products FDA is investigating how to characterize Q3 for different
dosage forms and how to demonstrate the validity of Q3 to bioequivalence
determinations.
Measurement of Q3: The nomenclature for
topical products is confusing as discussed at a previous advisory committee
meeting. An FDA working group is developing an improved classification tree
that defines the different dosage forms (suspension, lotion, paste, gel, cream,
ointment) based on measurable physical properties. The appropriate Q3 methods
would be different for each category of products and it would be designed for
the specific physical chemistry in each dosage form.
FDA
envisions that the primary Q3 characterization of topical dosage forms would be
determination of particle/droplet size distributions and characterization of
the rheology. The size distribution would directly
indicate the distribution of matter, while the rheology
is very sensitive to how the dispersed material interacts with each other. As
an example two suspensions with the same particle size distribution may have
vastly different rheology if the surface chemistry of
the particles is not identical. Rheological
characterizations should not be limited to the viscosity alone but should
recognize that most topical dosage forms are non-Newtonian (viscosity depends
on shear rate) and may also posses yield stresses (the material is solid-like
or liquid-like depending on the applied stress). The rheological
data that should be supplied for both products being compared is a plot of
shear stress versus strain rate, a plot of the linear viscoelastic
response (G’ and G’’ versus frequency), and a determination of the yield
stress. The stress-strain plot will indicate the degree of non-Newtonian
behavior present, linear viscoelasticity will
characterize the relaxation times of the material, and the yield stress is part
of the distinction between different dosage forms.
An
important issue in the characterization of Q3 is to recognize that methods to
measure the particle size distribution often involve modification of the
product (dilution to use dynamic light scattering or evaporation of solvent to
use microscopy). While these issues do not limit characterization by the
product manufacturers, for the comparison of generic and innovator products
only the final innovator product is available. There is concern that
modification of the product will invalidate the particle size measurement, thus
FDA is interested in methods for particle size determination that can be used
in situ.
Q3 validation: Q3 must be demonstrated to
be related to therapeutic equivalence of generic topical products. Existing
markers such as drug release can be used to verify the Q3 identity is
associated with drug product performance. Techniques of drug release using
different apparatus and methods will be evaluated for this role. Improved DPK
methods could also serve to validate the role of Q3. It will also be valuable
to identify critical manufacturing variables that are associated with variation
in Q3.
Questions for the Committee:
DPK
What
type of studies should be conducted to validate the DPK method?
Q3
What
type of data is needed to demonstrate that two products are Q3 equivalent?
How
should the Q3 concept be validated or demonstrated?
· Demonstration that we can
detect changes in manufacturing processes?
· Demonstration that we can
detect formulations with known differences?
· Demonstration that drug
release rates are identical?
Bioequivalence for topical
products
What
role should Q3 and DPK play in the demonstration of bioequivalence for topical
products?
· Under what circumstances
should Q3 equivalence be sufficient to justify a wavier of in vivo
bioequivalence tests?
· Under what circumstances
should Q3 equivalence and a DPK method in healthy subjects be sufficient to
determine bioequivalence?