Shifting views on the safety of drug substances at FDA are not uncommon with the advent of new scientific findings or upon better understanding of physiological processes or disease states. With time, these shifting views may manifest as differences in policies or requirements for drug approval. The most obvious cases highlighting changes in Agency thinking are reflected in new guidances or regulations, but these changes in perspective can also be reflected in more subtle ways, including the requirement for additional postmarketing commitments.

In the regulatory case that is the focus of this blog post, azelaic acid is used to highlight the changing views of the Dermatology review division of FDA related to the safety of products containing this active ingredient over the last 20 years, as well as what could be viewed as an overall shift in the Division’s perspective; with a trend towards more stringent requirements for dermal carcinogenicity testing of topical products.

Azelaic acid, a naturally occurring saturated dicarboxylic acid found in wheat, rye, and barley, possesses antimicrobial activity, affects keratin production, and reduces inflammation. Azelaic acid was first approved as a new molecular entity by FDA in 1995 as a topical cream (20%) produced by Allergan (Azelex^®; NDA 020428). As a topical product, Azelex was approved by the Division of Dermatologic and Dental Drug Products (now referred to as the Division of Dermatology and Dental Products or DDDP) at FDA. According to the Division’s website, the mission of this DDDP is to regulate Investigational New Drug Applications, New Drug Applications, and Biologics Licensing Applications for drugs and biologics intended for the prevention and treatment of dermatology and dental conditions including:

• Acne
• Actinic keratosis
• Aesthetic indications (facial lines, subcutaneous fat, scarring, etc.)
• Atopic dermatitis
• Condyloma acuminate (genital warts)
• Dental caries
• Gingivitis
• Psoriasis
• Rosacea
• Superficial basal cell carcinoma
• Wound healing/ulcers
• Xerostomia (dry mouth)

Azelex is FDA-approved for the following indication: topical treatment of mild-to-moderate inflammatory acne vulgaris. Clinical trials for Azelex were performed for approval, although the details are not provided in the approved product labeling. Adverse effects associated with the use of Azelex are generally mild and transient, with the most common effects occurring locally. Azelex is a Pregnancy Category B product, representative of a demonstrated lack of risk in animal reproductive studies but an absence of adequate and well-controlled studies in pregnant women. There is low systemic absorption of azelaic acid from the drug product (~4% of a topically applied dose); additionally, plasma concentration and urinary excretion of azelaic acid are not significantly different from baseline levels following topical treatment with Azelex.

For approval of Azelex, carcinogenicity testing was not required. According to the approved product labeling: “Azelaic acid is a human dietary component of a simple molecular structure that does not suggest carcinogenic potential, and it does not belong to a class of drugs for which there is a concern about carcinogenicity. Therefore, animal studies to evaluate carcinogenic potential with Azelex Cream were not deemed necessary. In a battery of tests (Ames assay, HGPRT test in Chinese hamster ovary cells, human lymphocyte test, dominant lethal assay in mice), azelaic acid was found to be nonmutagenic.”

Azelaic acid was approved as a new dosage form in 2002 – as a 15% topical gel product (Finacea^®; NDA 021470; Bayer Healthcare) – by the Dermatologic and Dental Drug Products Division for the topical treatment of the inflammatory papules and pustules of mild to moderate rosacea. The application referred to much of the information included in the Azelex cream application and would normally have been considered a 505(b)(2) application; however, the sponsor had right of reference to all data with letters of authorization from Allergan, making the application a 505(b)(1) submission. From a pharmacokinetics standpoint, plasma levels of azelaic acid in patients were shown to be the same as those in subjects treated with vehicle alone (see approved product labeling).

Although the active ingredient in Finacea is the same as that of Azelex (azelaic acid) and is included at a lower concentration (15% vs. 20%), and while both products have low systemic absorption of azelaic acid, the approval of Finacea gel was contingent on a postmarketing commitment for a study to determine the photocarcinogenic potential of the product; with a dermal carcinogenicity study subsequently being required. In the Pharmacology Reviews for approval of Finacea gel (15%), the reviewer noted the discrepancy between the approved labeing of Azelex, which required no carcinogenicity testing, and that of Finacea stating that the Azelex labeling “does not incorporate the current state of knowledge” and that “it is not our current policy.” Once the data from the postmarketing studies were available, the approved product labeling for Finacea gel was updated to include the following:

“In a 26-week dermal carcinogenicity study using transgenic (Tg.AC) mice, Finacea gel and the gel vehicle, when applied once or twice daily, did not increase the number of female Tg.AC animals with papillomas at the treatment site. No statistically significant increase in the number of animals with papillomas at the treatment site was observed in male Tg.AC animals after once daily application. After twice daily application, Finacea gel and the gel vehicle induced a statistically significant increase in the number of male animals with papillomas at the treatment site when compared to untreated males. This suggests that the positive effect may be associated with the vehicle application. The clinical relevance of the findings in animals to humans is not clear.”

Another azelaic acid product was approved last month by DDDP, Finacea emulsion aerosol foam (15%; NDA 207071; Bayer Healthcare Pharmaceuticals Inc.), for use in the same indication as Finacea gel (topical treatment of inflammatory papules and pustules of mild to moderate rosacea). However, the approval letter for Finacea foam states that the postmarketing requirement for approval is a 104-week dermal carcinogenicity study in CD-1 mice. Further information on the review of the Finacea foam application is not yet available, although it is likely that Bayer Healthcare Pharms utilized nonclinical data from the Finacea gel application (sponsored by Bayer Healthcare) as the nonclinical information included in the Finacea foam approved product labeling is the same as that of the gel product.

As the reviews for Finacea foam are not available, one can only speculate on the reasoning behind this more stringent requirement for dermal carcinogenicity testing of a product containing an active pharmaceutical ingredient that has been approved for topical use for 20 years; and further considering that the active pharmaceutical ingredient has not been overtly linked to carcinogenicity in the published literature. In fact, a search of the PubMed literature database suggests that azelaic acid has antitumor activity, at least in vitro. It is possible that the results of prior carcinogenicity testing required as a postmarketing commitment for the Finacea gel contributed to the presumptive change in testing requirement; increased papillomas in males (but not females) following twice daily dosing with Finacea gel likely contributed to the DDDP’s requirement for the 104-week dermal carcinogenicity study for this product. The clinical relevance of these findings, however, has not been established and reports of papillomas in humans are not described in the published literature or in the approved product labeling for Finacea or Azelex as adverse events or postmarketing findings. Pharmacokinetics from the approved product labeling of Finacea foam indicate that mean plasma concentration at steady state was similar to the values of subjects treated with Finacea gel and were within the range of the endogenous plasma concentrations of azelaic acid measured prior to treatment initiation; Foam C_max: 51.8 ng/mL; Gel C_max: 42 – 63.1 ng/mL; Endogenous plasma concentrations: < 1 – 105 ng/mL), suggesting that the peak concentrations of azelaic acid were not a cause for the DDDP’s increased safety concern.

The 20-year regulatory history of azelaic acid, a dietary component and endogenously formed substance that is minimally absorbed when included as the active ingredient in topical formulations, is a clear example of how product approval requirements can change over time, either with new information regarding the science of the drug substance or disease state or with shifting attitudes at the regulatory agency regarding the critical requirements for substantive product review. Essentially, the relative “bar” for safety of new approvals for established products, even with apparently adequate safety profiles, has been and is likely to continue to be raised for products under review, as evidenced by azelaic acid.