BIOEQUIVALENCE OE TOPICAL CORTICOSTEROIDS: A REGULATORY PERSPECTIVE ROGER L. WILLIAMS, M.D.
Abstract After reviewing the history of generic drug substitution policy in the United States, this paper discusses issues of equivalence as they apply to topical drug products. Documentation of bioequivalence of topical products has been problematic, and current methods are being re-evaluated by the Food and Drug Administration. The FDA is currently evaluating various extensions of the basic methodology of the Stoughton-McKenzie vasoconstrictor assay, in order to develop a more comprehensive pharmacodynamic methodology for documenting topical drug bioequivalence. A modern pharmacodynamic model is described, based on nonlinear dose-response relationship, a baseline effect, and a maximum or plateau effect. The Agency's goal is a bioequivalent methodology that will be simple, readily performed, and based on more objective methods of measuring the vasoconstrictor response. Authority to approve generic copies of innovator new drugs resides with the Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA). The Office's current methods for approving generic copies of innovator compounds have evolved over many years. Historically, premarketing approval of all new drugs began with the 1938 amendments to the 1906 Food, Drug, and Cosmetics Act. With those amendments, drug manufacturers were required to submit safety data to obtain market access. Evidence of efficacy was not required for new drug approval until the 1962 Kefauver-Harris Amendments to the Food, Drug, and Cosmetics Act. After passage of the 1962 amendments, the agency created the Drug Efficacy Study Implementation (DESI) program to establish retrospectively the efficacy of innovator compounds that had previously been approved solely on the basis of safety data. As part of this effort, panels of experts were convened to assess evidence of efficacy and provide recommendations to the agency as to whether the evidence was sufficient to document a specific therapeutic claim.
From the Office of Generic Drugs, Food and Drug Administration, Rockville, Maryland. Address for correspondence: Roger L. Williams, M.D., Director, Office of Generic Drugs, Food and Drug Administration, MPN #2, HFD-600, 7500 Standish Place, Rockville, MD 20855.
Between 1938 and 1962, thousands of drug products were introduced into the American market that were identical, similar, or related to innovator new drugs that were approved during this period. These generic drugs were allowed to remain on the market, and new generic copies were accepted through an abbreviated application mechanism if the manufacturers could demonstrate bioequivalence to the relevant pioneer product. Eor some of those products, bioequivalence could be documented on the basis of in vitro data. There remained, however, no clear regulatory mechanism to approve generic copies of new drugs that were introduced after 1962. A partial mechanism, termed the "paper" NDA, was created, which allowed generic manufacturers to submit acceptable evidence from published literature that the originator product was safe and effective. This information, coupled with information documenting bioequivalence, was sufficient for approval of a generic copy of a post-1962 new drug. That mechanism was not widely used and resulted in the approval of only a handful of new generic products. The Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman) amended the Eood, Drug, and Cosmetics Act to allow a clear regulatory path for approval of generic copies of post1962 pioneer drugs. According to these 1984 amendments, generic copies of post-1962 pioneer new drugs could be marketed, after expiration of patent or exclusivity protection, if satisfactory bioequivalence, labeling, chemistry, manufacturing, and manufacturing controls data were submitted to the Eood and Drug Administration. This general history of generic drug substitution in the United States is also specifically applicable to generic topical products (Table 1). Eor similar, identical, or related generic topical products approved before 1962, bioequivalence has usually been documented through in vitro studies, while evidence of in vivo bioequivalence has almost always been required for generic topical products introduced after 1962. To meet quality control requirements, both innovator and generic manufacturers must document that their products behave in a consistent, predictable manner over many years of manufacture, taking into consideration potentially numerous manufacturing and formulation changes. Under these circumstances, the challenge of documenting equivalence is one that applies to both innovator as well as to a generic manufacturer.
A Regulatory Perspective Williams
Table 1. Topical Products: Regulatory History and Requirements • Pre-1938 No data • 1938-1962 Safety data • 1962-1984 (pre Hatch-Waxman) Safety and efficacy data All topical products approved before 1962: 1. Pioneer: efficacy (DESI) and bioavailability (1977) 2. Generic (identical, similar or related): in vitro bioequivalence Generic topical products approved after 1962: 1. "Paper" NDA 2. In vivo bioequivalence • 1984-Present (post Hatch-Waxman) All topical generic products: 1. In vivo bioequivalence 2. No "paper" NDA
TOPICAL PRODUCTS: PHARMACEUTICAL AND THERAPEUTIC EQUIVALENCE
Generic topical products must be pharmaceutically equivalent to the corresponding pioneer product (the listed drug) before an Abbreviated New Drug Application (ANDA) can be accepted in the Office of Generic Drugs. To be pharmaceutically equivalent to its innovator counterpart, any generic drug must contain the same active ingredietit, in the same concentration, be intended for the same route of administration, and have comparable (though not necessarily identical) labeling (Table 2). Eor a topical generic product, the vehicle (cream, ointment, lotion, or gel) in which the drug is suspended or dissolved should be the same as that of the innovator product. If a pharmaceutically equivalent topical product can be shown to be bioequivalent to the pioneer product to the satisfaction of the FDA, the generic product is approved for marketing in the United States and will receive an AB rating in an FDA document entitled Approved Drug Products With Therapeutic Equivalence Ratings (the Orange Book).' With this designa-
Table 2. Topical Products: Pharmaceutical and Therapeutic Equivalence Pharmaceutical Equivalence Same active ingredient:Yes Same strength (concentration):Yes Same vehicle (cream, ointment, lotion, gel):Yes Same route of administration:Yes Gomparable labeling:Yes Bioequivalence [In vivo measurement of active moiety (moieties) in biologic fluid] In vivo pharmacodynamic comparison In vivo clinical comparison tn vitro comparison If all of the above are met, then there is therapeutic equivalence.
tion, the public is notified that the agency believes that the product is therapeutically equivalent to, and hence substitutable for, the corresponding pioneer product. At FDA, the preferred method for assessing bioequivalence is to compare concentrations of the active moiety or moieties of a drug in an accessible biologic fluid such as blood or urine after administration of the generic and innovator products on separate occasions. When administration of a drug does not produce concentrations in the body sufficiently high for measurement, other methods to measure bioequivalence, in descending order of preference, include: (a) an in vivo pharmacodynamic study; (b) a comparative clinical trial; (c) a comparative blood level study in animals; (d) an in vitro study; atid (e) any other method the agency believes to be acceptable to document bioequivalence. These methods frequently are not optimal, and, in the case of a comparative clinical trial, tend to subvert the intent of the 1984 Fiatch-Waxman legislation, which was, iti part, designed to elimitiate the requirements for clinical studies. TOPICAL PRODUCTS: CURRENT REGULATORY REQUIREMENTS
Eor topical drug products, documentation of bioequivalence is frequently problematic, because application of a drug topically does not produce sufficiently high concentrations of drug in blood or urine for measurement. Even if there were a reliable method to apply an agent to the skin and measure levels in blood, the method would not account for excipient effects that may contribute to safety and efficacy effects of the topical product. Because pharmacokinetic and/or pharmacodynamic methods are not adequate to determine bioequivalence of many topical products, the agency has turned to comparative clinical trials as a means of assessing bioequivalence. Eor example, according to draft agency guidelines, documentation of topical and vaginal antifungal generic preparations must now be based on comparative clinical trials. In these studies, the test formulation must be compared with both the reference innovator preparation and a vehicle without drug. Guidelines for bioequivalence testing of generic anti-acne products are not presently available. Topical generic formulations of corticosteroids are now approved at the agency based on the observation that topically applied corticosteroids produce skin blanching, or vasoconstriction. Termed the StoughtonMcKenzie assay, the application of this pharmacodynamic observation requires visual estimation of blanching 16 hours after application of a topical corticosteroid to the skin of healthy subjects.^ This general methodology is being re-evaluated now at the agency because of published reports suggesting inequivalence between marketed formulations of topical corticosteroids containing the same drug in the same vehicle.^-''
International Journal of Dermatology Supplement 1 October 1992
Linear Model 100
Concentration Log-linear Model
.• .%:^, .:•.
: - ,
,.
:,
0
Log-linear Model
10
2 0
3 0
4 0
Concentration Figure 1. Pharmacodynamic relationships: linear, log-linear, maximum effect are desirable. PHARMACODYNAMIC RELATIONSHIPS
McKenzie and Stoughton's 1962 report of a pharmacodynamic method to assess bioequivalence anticipated the application of modern pharmacodynamic methods in drug development by many years. Scientists in the fields of pharmacology and pharmacokinetics have recently emphasized the relationship between drug dose and a pharmacologic effect of interest. In the late 1970s, clinical pharmacologic research began emphasizing the relationship between drug concentration and effect, as opposed to drug dose and effect. As part of this effort, models were evaluated to define the relationship between drug dose or concentration and drug effect under usual clinical conditions (Fig. 1). Because of the potentially wide concentration range allowed in a specific study, animal or in vitro pharmacology studies sometimes emphasize a log-linear relationship between dose/concentration and effect. Application of a log-linear model can obscure clinically important information, namely, the baseline effect when concentration is zero, as well as the maximum effect beyond which increments in concentration produce essentially
x. Baseline effect and
no increment in effect. More modern models thus emphasize a nonlinear relationship between dose/concentration and effect that allows for both a baseline and a maximum effect relative to dose.^ One model now applied for many dose/concentration response relationships is the E,ni,x model, represented by the following equation: V •C E = Eo +
ECso + C
:.-''-
-
'
- -•
In this equation, Emax is the maximum effect attributable to the drug, ECso is the drug concentration that produces 50% of Emax, and Eo is the baseline effect in the absence of drug. This equation can also be expressed in terms of dose (D) rather than concentration (C).
PHARMACODYNAMICS AND BIOEQUIVALENCE OF TOPICAL PRODUCTS
At the FDA, application of modern pharmacodynamic methods is being assessed to determine the bioequivalence of drugs that do not produce measurable concen-
A Regulatory Perspective Williams
trations of drug or active metabolite in an accessible biologic fluid. These methods may be particularly applicable to topically applied corticosteroid products, utilizing the primary Stoughton-McKenzie methodology. In a sense, application of pharmacodynamic methodology will be based on achievement of a bioassay based on corticosteroid skin vasoconstriction, and success will be achieved to the extent that validation of the bioassay is possible. One important point in this validation is to document the relationship between dose of corticosteroid applied and the vasoconstriction response observed. If an Emax relationship is documented, then assessment of bioequivalence must be documented at doses of the topical corticosteroid that produce less than maximum response. Just as an MPLC assay loses sensitivity at amounts of drug delivered in excess of the capacity of its detector to respond, so too does a bioassay of a topical corticosteroid lose sensitivity at concentrations in excess of the capacity of the skin to vasoconstrict. Development of a dose-response relationship may be difficult for any drug product because of the requirement to deliver a number of doses over a sufficiently wide range to generate a reasonable doseresponse curve. Fortunately, there are several ways to deliver varying doses of a topical corticosteroid to the skin, including dilution down from a strength eliciting a maximal response, application of the same strength to different surface areas, and application of the same strength for different periods of time. Documentation of sensitivity is only one aspect of the challenge of developing a vasoconstrictor bioassay to assess bioequivalence of topical products. The rate of onset and offset of the vasoconstrictor effect is also of interest because of the statutory requirement to document equivalence between rate and extent of absorption between pioneer and generic products. This assessment is also important to ascertain that the maximum effect at any given dose of the topical corticosteroid has been attained. Additional validation of the vasoconstrictor bioassay may also be necessary, as with any analytical method. Once the vasoconstrictor bioassay is developed and validated, statistical methodology must be applied to compare parameters of the pharmacodynamic relationship, such as Emax> EC50, and Eo, just as peak concentrations and area under the curve are compared in blood-level studies of orally administered drugs.
CONCLUSIONS
Studies are now in progress at the FDA to assess the validity of various extensions of the basic methodology of the Stoughton-McKenzie vasoconstrictor assay. These studies are beginning to point the way toward a more comprehensive pharmacodynamic methodology to assess bioequivalence of topical corticosteroid products. This methodology might be based on a validated vasoconstrictor bioassay that would not be excessively cumbersome or difficult to perform. In addition, more objective methods of measuring the vasoconstrictor response to a topically applied corticosteroid are required, and fortunately these more objective methods are becoming available. Both generic and innovator manufacturers of topical drug products might be interested in the generic methodology, because both are concerned with testing bioequivalence of approved drug products over many years of manufacture. Despite the challenges, application of the primary vasoconstrictor methodology, as developed by Stoughton and McKenzie, offers the reasonable possibility that a simple, readily performed pharmacodynamic method may be used to document bioequivalence between different formulations of topical corticosteroids.
REFERENCES
1.
2.
3.
4.
5.
Approved Drug Products With Therapeutic Equivalence Evaluations. 11th Ed. Rockville, MD: Department of Health and Human Services, Public Health Service, Food and Drug Administration, 1991, McKenzie AW, Stoughton RB, Methods for comparing percutaneous absorption of steroids. Arch Dermatol 1962; 86:608-610. Stoughton RB. Are generic formulations equivalent to trade name topical glucocorticoids.-' Arch Dermatol 1987; 123:1312-1314, Shah VP, Peck CC, Skelly JP. 'Vasoconstriction'—skin blanching—assay for glucocorticoids—a critique. Arch Dermatol 1989; 125:1558-1561, Holford NHG, Sheiner LB, Understanding the doseeffect relationship: clinical application of pharmacokinetic-pharmacodynamic models, Clin Pharmacokinet 1981; 6:429-453,
The views expressed are solely those of the author and do not necessarily represent the views or the policies of the Food and Drug Administration.
Abstract After reviewing the history of generic drug substitution policy in the United States, this paper discusses issues of equivalence as they apply to topical drug products. Documentation of bioequivalence of topical products has been problematic, and current methods are being re-evaluated by the Food and Drug Administration. The FDA is currently evaluating various extensions of the basic methodology of the Stoughton-McKenzie vasoconstrictor assay, in order to develop a more comprehensive pharmacodynamic methodology for documenting topical drug bioequivalence. A modern pharmacodynamic model is described, based on nonlinear dose-response relationship, a baseline effect, and a maximum or plateau effect. The Agency's goal is a bioequivalent methodology that will be simple, readily performed, and based on more objective methods of measuring the vasoconstrictor response. Authority to approve generic copies of innovator new drugs resides with the Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA). The Office's current methods for approving generic copies of innovator compounds have evolved over many years. Historically, premarketing approval of all new drugs began with the 1938 amendments to the 1906 Food, Drug, and Cosmetics Act. With those amendments, drug manufacturers were required to submit safety data to obtain market access. Evidence of efficacy was not required for new drug approval until the 1962 Kefauver-Harris Amendments to the Food, Drug, and Cosmetics Act. After passage of the 1962 amendments, the agency created the Drug Efficacy Study Implementation (DESI) program to establish retrospectively the efficacy of innovator compounds that had previously been approved solely on the basis of safety data. As part of this effort, panels of experts were convened to assess evidence of efficacy and provide recommendations to the agency as to whether the evidence was sufficient to document a specific therapeutic claim.
From the Office of Generic Drugs, Food and Drug Administration, Rockville, Maryland. Address for correspondence: Roger L. Williams, M.D., Director, Office of Generic Drugs, Food and Drug Administration, MPN #2, HFD-600, 7500 Standish Place, Rockville, MD 20855.
Between 1938 and 1962, thousands of drug products were introduced into the American market that were identical, similar, or related to innovator new drugs that were approved during this period. These generic drugs were allowed to remain on the market, and new generic copies were accepted through an abbreviated application mechanism if the manufacturers could demonstrate bioequivalence to the relevant pioneer product. Eor some of those products, bioequivalence could be documented on the basis of in vitro data. There remained, however, no clear regulatory mechanism to approve generic copies of new drugs that were introduced after 1962. A partial mechanism, termed the "paper" NDA, was created, which allowed generic manufacturers to submit acceptable evidence from published literature that the originator product was safe and effective. This information, coupled with information documenting bioequivalence, was sufficient for approval of a generic copy of a post-1962 new drug. That mechanism was not widely used and resulted in the approval of only a handful of new generic products. The Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman) amended the Eood, Drug, and Cosmetics Act to allow a clear regulatory path for approval of generic copies of post1962 pioneer drugs. According to these 1984 amendments, generic copies of post-1962 pioneer new drugs could be marketed, after expiration of patent or exclusivity protection, if satisfactory bioequivalence, labeling, chemistry, manufacturing, and manufacturing controls data were submitted to the Eood and Drug Administration. This general history of generic drug substitution in the United States is also specifically applicable to generic topical products (Table 1). Eor similar, identical, or related generic topical products approved before 1962, bioequivalence has usually been documented through in vitro studies, while evidence of in vivo bioequivalence has almost always been required for generic topical products introduced after 1962. To meet quality control requirements, both innovator and generic manufacturers must document that their products behave in a consistent, predictable manner over many years of manufacture, taking into consideration potentially numerous manufacturing and formulation changes. Under these circumstances, the challenge of documenting equivalence is one that applies to both innovator as well as to a generic manufacturer.
A Regulatory Perspective Williams
Table 1. Topical Products: Regulatory History and Requirements • Pre-1938 No data • 1938-1962 Safety data • 1962-1984 (pre Hatch-Waxman) Safety and efficacy data All topical products approved before 1962: 1. Pioneer: efficacy (DESI) and bioavailability (1977) 2. Generic (identical, similar or related): in vitro bioequivalence Generic topical products approved after 1962: 1. "Paper" NDA 2. In vivo bioequivalence • 1984-Present (post Hatch-Waxman) All topical generic products: 1. In vivo bioequivalence 2. No "paper" NDA
TOPICAL PRODUCTS: PHARMACEUTICAL AND THERAPEUTIC EQUIVALENCE
Generic topical products must be pharmaceutically equivalent to the corresponding pioneer product (the listed drug) before an Abbreviated New Drug Application (ANDA) can be accepted in the Office of Generic Drugs. To be pharmaceutically equivalent to its innovator counterpart, any generic drug must contain the same active ingredietit, in the same concentration, be intended for the same route of administration, and have comparable (though not necessarily identical) labeling (Table 2). Eor a topical generic product, the vehicle (cream, ointment, lotion, or gel) in which the drug is suspended or dissolved should be the same as that of the innovator product. If a pharmaceutically equivalent topical product can be shown to be bioequivalent to the pioneer product to the satisfaction of the FDA, the generic product is approved for marketing in the United States and will receive an AB rating in an FDA document entitled Approved Drug Products With Therapeutic Equivalence Ratings (the Orange Book).' With this designa-
Table 2. Topical Products: Pharmaceutical and Therapeutic Equivalence Pharmaceutical Equivalence Same active ingredient:Yes Same strength (concentration):Yes Same vehicle (cream, ointment, lotion, gel):Yes Same route of administration:Yes Gomparable labeling:Yes Bioequivalence [In vivo measurement of active moiety (moieties) in biologic fluid] In vivo pharmacodynamic comparison In vivo clinical comparison tn vitro comparison If all of the above are met, then there is therapeutic equivalence.
tion, the public is notified that the agency believes that the product is therapeutically equivalent to, and hence substitutable for, the corresponding pioneer product. At FDA, the preferred method for assessing bioequivalence is to compare concentrations of the active moiety or moieties of a drug in an accessible biologic fluid such as blood or urine after administration of the generic and innovator products on separate occasions. When administration of a drug does not produce concentrations in the body sufficiently high for measurement, other methods to measure bioequivalence, in descending order of preference, include: (a) an in vivo pharmacodynamic study; (b) a comparative clinical trial; (c) a comparative blood level study in animals; (d) an in vitro study; atid (e) any other method the agency believes to be acceptable to document bioequivalence. These methods frequently are not optimal, and, in the case of a comparative clinical trial, tend to subvert the intent of the 1984 Fiatch-Waxman legislation, which was, iti part, designed to elimitiate the requirements for clinical studies. TOPICAL PRODUCTS: CURRENT REGULATORY REQUIREMENTS
Eor topical drug products, documentation of bioequivalence is frequently problematic, because application of a drug topically does not produce sufficiently high concentrations of drug in blood or urine for measurement. Even if there were a reliable method to apply an agent to the skin and measure levels in blood, the method would not account for excipient effects that may contribute to safety and efficacy effects of the topical product. Because pharmacokinetic and/or pharmacodynamic methods are not adequate to determine bioequivalence of many topical products, the agency has turned to comparative clinical trials as a means of assessing bioequivalence. Eor example, according to draft agency guidelines, documentation of topical and vaginal antifungal generic preparations must now be based on comparative clinical trials. In these studies, the test formulation must be compared with both the reference innovator preparation and a vehicle without drug. Guidelines for bioequivalence testing of generic anti-acne products are not presently available. Topical generic formulations of corticosteroids are now approved at the agency based on the observation that topically applied corticosteroids produce skin blanching, or vasoconstriction. Termed the StoughtonMcKenzie assay, the application of this pharmacodynamic observation requires visual estimation of blanching 16 hours after application of a topical corticosteroid to the skin of healthy subjects.^ This general methodology is being re-evaluated now at the agency because of published reports suggesting inequivalence between marketed formulations of topical corticosteroids containing the same drug in the same vehicle.^-''
International Journal of Dermatology Supplement 1 October 1992
Linear Model 100
Concentration Log-linear Model
.• .%:^, .:•.
: - ,
,.
:,
0
Log-linear Model
10
2 0
3 0
4 0
Concentration Figure 1. Pharmacodynamic relationships: linear, log-linear, maximum effect are desirable. PHARMACODYNAMIC RELATIONSHIPS
McKenzie and Stoughton's 1962 report of a pharmacodynamic method to assess bioequivalence anticipated the application of modern pharmacodynamic methods in drug development by many years. Scientists in the fields of pharmacology and pharmacokinetics have recently emphasized the relationship between drug dose and a pharmacologic effect of interest. In the late 1970s, clinical pharmacologic research began emphasizing the relationship between drug concentration and effect, as opposed to drug dose and effect. As part of this effort, models were evaluated to define the relationship between drug dose or concentration and drug effect under usual clinical conditions (Fig. 1). Because of the potentially wide concentration range allowed in a specific study, animal or in vitro pharmacology studies sometimes emphasize a log-linear relationship between dose/concentration and effect. Application of a log-linear model can obscure clinically important information, namely, the baseline effect when concentration is zero, as well as the maximum effect beyond which increments in concentration produce essentially
x. Baseline effect and
no increment in effect. More modern models thus emphasize a nonlinear relationship between dose/concentration and effect that allows for both a baseline and a maximum effect relative to dose.^ One model now applied for many dose/concentration response relationships is the E,ni,x model, represented by the following equation: V •C E = Eo +
ECso + C
:.-''-
-
'
- -•
In this equation, Emax is the maximum effect attributable to the drug, ECso is the drug concentration that produces 50% of Emax, and Eo is the baseline effect in the absence of drug. This equation can also be expressed in terms of dose (D) rather than concentration (C).
PHARMACODYNAMICS AND BIOEQUIVALENCE OF TOPICAL PRODUCTS
At the FDA, application of modern pharmacodynamic methods is being assessed to determine the bioequivalence of drugs that do not produce measurable concen-
A Regulatory Perspective Williams
trations of drug or active metabolite in an accessible biologic fluid. These methods may be particularly applicable to topically applied corticosteroid products, utilizing the primary Stoughton-McKenzie methodology. In a sense, application of pharmacodynamic methodology will be based on achievement of a bioassay based on corticosteroid skin vasoconstriction, and success will be achieved to the extent that validation of the bioassay is possible. One important point in this validation is to document the relationship between dose of corticosteroid applied and the vasoconstriction response observed. If an Emax relationship is documented, then assessment of bioequivalence must be documented at doses of the topical corticosteroid that produce less than maximum response. Just as an MPLC assay loses sensitivity at amounts of drug delivered in excess of the capacity of its detector to respond, so too does a bioassay of a topical corticosteroid lose sensitivity at concentrations in excess of the capacity of the skin to vasoconstrict. Development of a dose-response relationship may be difficult for any drug product because of the requirement to deliver a number of doses over a sufficiently wide range to generate a reasonable doseresponse curve. Fortunately, there are several ways to deliver varying doses of a topical corticosteroid to the skin, including dilution down from a strength eliciting a maximal response, application of the same strength to different surface areas, and application of the same strength for different periods of time. Documentation of sensitivity is only one aspect of the challenge of developing a vasoconstrictor bioassay to assess bioequivalence of topical products. The rate of onset and offset of the vasoconstrictor effect is also of interest because of the statutory requirement to document equivalence between rate and extent of absorption between pioneer and generic products. This assessment is also important to ascertain that the maximum effect at any given dose of the topical corticosteroid has been attained. Additional validation of the vasoconstrictor bioassay may also be necessary, as with any analytical method. Once the vasoconstrictor bioassay is developed and validated, statistical methodology must be applied to compare parameters of the pharmacodynamic relationship, such as Emax> EC50, and Eo, just as peak concentrations and area under the curve are compared in blood-level studies of orally administered drugs.
CONCLUSIONS
Studies are now in progress at the FDA to assess the validity of various extensions of the basic methodology of the Stoughton-McKenzie vasoconstrictor assay. These studies are beginning to point the way toward a more comprehensive pharmacodynamic methodology to assess bioequivalence of topical corticosteroid products. This methodology might be based on a validated vasoconstrictor bioassay that would not be excessively cumbersome or difficult to perform. In addition, more objective methods of measuring the vasoconstrictor response to a topically applied corticosteroid are required, and fortunately these more objective methods are becoming available. Both generic and innovator manufacturers of topical drug products might be interested in the generic methodology, because both are concerned with testing bioequivalence of approved drug products over many years of manufacture. Despite the challenges, application of the primary vasoconstrictor methodology, as developed by Stoughton and McKenzie, offers the reasonable possibility that a simple, readily performed pharmacodynamic method may be used to document bioequivalence between different formulations of topical corticosteroids.
REFERENCES
1.
2.
3.
4.
5.
Approved Drug Products With Therapeutic Equivalence Evaluations. 11th Ed. Rockville, MD: Department of Health and Human Services, Public Health Service, Food and Drug Administration, 1991, McKenzie AW, Stoughton RB, Methods for comparing percutaneous absorption of steroids. Arch Dermatol 1962; 86:608-610. Stoughton RB. Are generic formulations equivalent to trade name topical glucocorticoids.-' Arch Dermatol 1987; 123:1312-1314, Shah VP, Peck CC, Skelly JP. 'Vasoconstriction'—skin blanching—assay for glucocorticoids—a critique. Arch Dermatol 1989; 125:1558-1561, Holford NHG, Sheiner LB, Understanding the doseeffect relationship: clinical application of pharmacokinetic-pharmacodynamic models, Clin Pharmacokinet 1981; 6:429-453,
The views expressed are solely those of the author and do not necessarily represent the views or the policies of the Food and Drug Administration.
