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Impact Story: Developing New Ways to Evaluate Bioequivalence for Topical Drugs

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The proportion of prescribed medications that are generic drugs has continued to grow in recent years, resulting in substantial savings for patients. To further support the availability of safe and effective generic drugs in all product categories, FDA conducts regulatory science research to identify new tools for evaluating the bioequivalence of brand name and generic drugs.

Demonstrating the bioequivalence of a generic drug product means showing that it can deliver the same amount of the same drug to the site(s) of therapeutic action at the same rate and to the same extent as the brand name product. For many systemically acting drug products, evaluating bioequivalence involves administering the product (e.g., a tablet taken by mouth) and then drawing blood at scheduled times to measure the amount of the drug in the circulation at each point.

Plot illustrating that the pharmacokinetic profiles of a brand name and generic drug are not the same.Figure 1. Bioequivalence is established by showing that a generic drug product and the brand name version are similar in terms of their concentrations over time at the site of action.  Note: The curves depicted here do not appear to match and would not necessarily be bioequivalent.

A plot illustrating how the resulting drug concentration in the blood increases and decreases over time is called a pharmacokinetic profile. If the brand name and generic drug products exhibit the same profiles, then the rate and extent to which the drug becomes available at the relevant site(s) of action are the same, and the safety and efficacy of the generic drug product will be the same as that of the brand name drug product. Alternatively, if the pharmacokinetic profiles do not match (as depicted in Figure 1), then the drug products cannot be considered equally safe and efficacious.

This pharmacokinetic approach is one of the most accurate, sensitive, and reproducible ways to evaluate bioequivalence. It is also relatively efficient and has been used to establish bioequivalence and support the approval of most systemically acting generic drug products.

The Scientific Challenge

Although it is possible to repeatedly and harmlessly take small samples of circulating blood from people enrolled in a pharmacokinetic study, sampling drug concentrations in this manner within a solid tissue like the skin was not considered feasible until recently, so the pharmacokinetic approach to evaluating bioequivalence was not typically considered applicable to locally acting, topical dermatological drug products. Instead, investigators relied on two other approaches to demonstrate bioequivalence for many topical creams, lotions, and ointments.

One of these approaches, involving a vasoconstrictor study, is reasonably efficient, although its utility is limited to steroid (glucocorticoid) drug products.

A second, more broadly applicable approach relies on a comparative clinical endpoint bioequivalence study, which involves treating populations of patients with either the brand name drug product, the prospective generic drug product, or a placebo product (with no drug) and monitoring the changes in the patient's skin condition. These studies are very expensive, often requiring thousands of patients with the disease (compared with several dozen normal subjects in pharmacokinetic or vasoconstrictor studies) and lasting months. Because of the significant hurdles, this approach has been used for only a small proportion of topical dermatological drug products, so few generics are available for those drug products, even though patents and exclusivities may have long since expired.

FDA's Research to Develop Innovative Bioequivalence Methodologies

To help make more generic topical dermatological drug products available, FDA undertook a major research initiative to develop a pharmacokinetic study methodology that could work in the skin.

open-flow microperfusion method for monitoring the amount of a topical drug in the skin showing liquid being sent through a 0.5 millimeter tubeFigure 2. Dermal open-flow microperfusion allows investigators to measure the concentration of drugs in the skin. Source: Bodenlenz et al. (2017).

FDA collaborated with international researchers to evaluate a new method for monitoring the amount of a topical drug in the dermis. In a procedure called dermal open-flow microperfusion (dOFM), a thin, hollow tube is inserted just under the skin surface, running through a section of the skin a few inches wide and then exiting. A liquid similar to body fluid is injected into the tubing; a portion of the tube under the skin is porous, so any drug that has been applied and absorbed through the skin's outer layer enters the flowing liquid, which is then collected for analysis.

This approach was developed in a clinical study that evaluated whether dOFM could reliably measure the changing amounts of drug in the skin after topical application of a dermatological drug product. Investigators applied a U.S. brand name acyclovir cream to two locations and a European acyclovir cream that had a different formulation to a third location (the assignment of application locations was randomized). Before dosing, the dOFM tubing was inserted under these three areas, and the concentration of acyclovir in the collected fluid was measured over 36 hours. The results were analyzed in the conventional manner, using both the area under the curve (AUC) and maximum concentration (Cmax) of the pharmacokinetic profile.

The study demonstrated that the dOFM pharmacokinetic approach could accurately and reproducibly confirm that the U.S. brand name product was bioequivalent to itself at different anatomical sites. Furthermore, the dOFM approach was sufficiently sensitive to discriminate between the pharmacokinetics of the U.S. and European versions of the creams, which were—as expected—confirmed not to be bioequivalent. Additional studies are being developed to determine whether dOFM may be broadly applicable to other topical dermatological drugs with different chemical characteristics.

How does this research advance the development of generic drugs?

The innovative method for measuring the concentration of drugs in the skin that was assessed in this study can help drug developers determine whether proposed generic versions of drugs applied to the skin perform as well as their brand name equivalents.

Other FDA Research Initiatives for Providing Safe, Effective Generic Versions of Topical Dermatological Products

FDA has undertaken other major research initiatives to help ensure that high-quality, safe, effective topical dermatological drug products become available. Historically, generic drug products did not necessarily contain the same inactive ingredients as the brand name drug products. For instance, a generic cream could have had a slightly different appearance and feel than the brand name cream. However, clinical testing was routinely required to ensure that the differences between the generic and brand name drug products did not affect the rate and extent of drug delivery. For topical dermatological drug products, the clinical testing was so challenging that many generics were never developed.

To address this issue, one of FDA's major research initiatives focuses on complex generic topical dermatological drug products designed to contain all the same ingredients in the same proportions, with essentially the same chemical, physical, and structural properties (e.g., pH, viscosity, drug crystal form, globule size distribution), as the brand name drug products. A generic drug product would be fundamentally identical to the brand name drug product, as close as the brand name drug product is to itself from batch to batch. Instead of expensive, time-consuming clinical studies, more efficient tests could ensure that these closely matched generic drug products perform the same way as the brand name drug product. Research to stimulate the development of generic topical dermatological drug products by making it more efficient has resulted in fascinating new tools for product characterization, providing important new insights into drug products. For topical dermatological products, the FDA-initiated research has indicated that bioequivalence may also be demonstrated by a novel, efficient cutaneous pharmacokinetic approach in which excised human skin is mounted in a diffusion cell. Read the Office of Generic Drugs Fiscal Year 2016 Regulatory Science Research Report to learn more.

FDA's Pursuit of Science to Benefit the Public Health

This development of novel, accurate, sensitive, reproducible, and efficient pharmacokinetic approaches to evaluating bioequivalence for topical dermatological drug products illustrates FDA's commitment and unique capabilities to identify potential barriers to generic drug development and to overcome them by collaborating with researchers in industry and academia. The methods and tools that result from this research become valuable resources for the medical, pharmaceutical, and regulatory communities to advance drug development, as well as providing more certainty in regulatory decision making.

For more information, please visit the Office of Generic Drugs.

Related Publication

Bodenlenz, M, KI Tiffner, R Raml, et al., 2017, Open flow microperfusion as a dermal pharmacokinetic approach to evaluate topical bioequivalence disclaimer icon, Clin Pharmacokinet, 56:91-98, doi:10.1007/s40262-016-0442-z.

Related Guidance

Draft Guidance on Acyclovir (PDF - 247KB): Product-specific guidance for generic products referencing Zovirax® (acyclovir) cream, 5% as the reference listed drug product. Recommended December 2014; revised December 2016.

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