In a petition response issued on May 23, 2014to Hisamitsu Pharmaceutical Company, the FDA partially approved, but mostly denied the requests of the NDA holder for Salonpas (menthol and methyl salicylate 3%, 10%) Patch in a petition submitted on January 6, 2010. The entire petition response can be found here.
While the response did not come as much of a surprise relative to the NDA holders asks, the fact that the petition was submitted in 2010 and is just now being responded to is somewhat a matter of conjecture. Typically, when a non-505(q) petition is responded to, an ANDA is either approved on the same day or shortly thereafter. Anyway, that is more conjecture than is needed for this blog piece other than to say there is no listing on the paragraph iv (PIV) database for this over-the-counter (OTC) product and, at this time, there are no patents (in fact, no patents have ever been listed for this product) and no unexpired periods of market exclusivity listed in the Orange Book. Suffice it to say that the FDA response is consistent with past responses and action on topical patches where the product is absorbed to a sufficient extent to give the Agency reasonable assurance that the product is bioequivalent from a pharmacokinetic (pK) perspective.
One of the major requests the NDA holder made was for any ANDA for a copy of Salonpas (a product whose ingredients are OTC monograph whose unique dosage form required the submission of an NDA) to require ANDA applicants to conduct a placebo-controlled, non-inferiority, clinical investigation in the indicated patient population. Clearly, FDA’s denial of this request differentiated this product as a topical product for local action, but not a dermatological product to treat a skin disease where one might expect clinical studies to be needed. The petition response cited the Agency’s action on Lidoderm (lidocaine) Topical Patch, also for the treatment of local pain, as a predicate for not requiring clinical studies when pK studies could support bioequivalence. FDA said:
A showing that the active ingredient or therapeutic ingredient in the proposed generic drug reaches the site of drug action as a rate and to the extent not significantly different from that of the listed drug, along with the other information required for approval, permit FDA to conclude that the proposed generic drug can be expected to perform the same way in the body as the listed drug. Bioequivalence testing determines whether differences in formulation (e.g., difference in inactive ingredients) between a proposed generic drug and the RLD have an impact on the rate and extent to which the active ingredient becomes available at the site of action.
The NDA holder also asked that generic applicants for this product perform a standard battery of skin safety studies to support approval. FDA noted that the NDA holder typically needs to perform such studies to establish underlying safety, but a generic applicant relies on the safety determination made by FDA for the innovator product. FDA did note that any ANDA applicant for this product must conduct skin irritation and adhesion studies consistent with requirements for all patch products.
The NDA holder also asked that the generic applicant conduct a pharmacokinetic study using menthol and methyl salicylate topical ointments as the reference for the study. Clearly, we recognize that the goal of an ANDA is to demonstrate equivalence to the Reference Listed Drug (RLD) and not another marketed OTC products that might have required to have been studied in the original NDA. The generic is required to study its product against the Salonpas product.
Lastly, the NDA holder requested that the FDA require that the patch be of the same size and contain the same percentage and total patch amount of active ingredients as the RLD. FDA agreed that the product should be of the same size and contain the same percentage of active ingredient in the adhesive mass (like they did in the Lidoderm generics) but stopped short of requiring the same quantity of active ingredient in the patch where the FDA explained:
Your remaining request – that the generic formulation contain the same total amount of the active ingredient – is denied. Patch drug products such as SPRP [Salonpas pain Relief Patch] operate by maintaining a higher concentration of active ingredient in the patch than beneath the skin. This difference in concentration drives the drug into the skin by diffusion. To continue drug delivery throughout the dosing period, the higher concentration in the patch must be maintained for the entire dosing period. Therefore, when the patch is removed, there are residual amounts of the drug remaining in the patch. A generic formulation could deliver the same amount of active ingredients to the site of action but have more or less residual drug in the patch following the dosing period. In such a case, the different total amounts of active ingredients in the patch would not preclude a finding of bioequivalence between the generic and the RLD. The bioequivalence of the two products is determined not by the total amounts in the patch, but by the rate and extent of the drug’s absorption through the skin to the site of action. Therefore, we [FDA] will not require a generic formulation to have the same total amounts of active ingredients in the patch.
So there we are! Another FDA petition response that further defines the boundaries for certain topical products to be considered ANDAable.