White Paper
Clinical Trials
1. Introduction
This White Paper provides an integrated compilation of the regulatory, nonclinical and clinical (safety and efficacy information generated with the new SALONPAS® PAIN RELIEF PATCH (SPRP) which was approved by the United States Food and Drug Administration (FDA) on February 20, 2008. SPRP is specifically approved for the temporary relief of mild to moderate aches and pains of muscles and joints associated with arthritis, sprains, strains, bruises and simple backache. The alternative trade name, SALONPAS® ARTHRITIS PAIN, is also approved for use in the United States. The SPRP New Drug Application (NDA) approval represents the first successful U.S. regulatory program for a nonprescription topically applied external analgesic product and is a marketing milestone for this category of nonprescription products. In order to appreciate the unique advantages of SPRP, relevant data and information pertaining to the currently marketed, non-approved competitor products are also provided. In this way, all marketing-related product comparisons may be fully considered in the development of SPRP launch materials.
2. Market Background
The nonprescription pain relief marketplace exceeds $2 billion per year for oral and topical dosage forms including tablets, capsule, ointments, gels, creams and patches. Among the widely recognized topical patch products are BenGay® (Johnson & Johnson), Icy Hot® (Chattem), WellPatch® (Mentholatum) and Salonpas® (Hisamitsu). These patch products along with other minor brands and store brands are found at most U.S. chain drug stores, grocery stores, pharmacies, mass merchant retailers and membership warehouses throughout the U.S.
SALONPAS® is the trade name for the currently marketed nonprescription pain relief products (ointments, gels, sprays, patches) marketed worldwide by Hisamitsu Pharmaceutical Company, Inc. of Japan. The Salonpas line is currently marketed in over 50 countries and is manufactured in multiple countries. These products have been marketed in the U.S for over 50 years. Over 17 billion Salonpas patches have been sold worldwide over the last 10 years. Approximately 1 billion patches were sold in the United States between 2000 and 2005.
3. Regulatory Overview
Unlike SPRP, the currently marketed topical external analgesics are sold without FDA approved NDAs. This situation arises because the pharmaceutical active ingredients employed with these products are included with the Tentative Final Monograph (TFM) for External Analgesic products, published in 1983, by FDA, as part of its OTC Drug Review. Section III of this White Paper provides extensive details relating to this regulatory issue. It is important to note that this TFM has never been finalized, and in 2003, was amended by FDA to specifically exclude occlusive formulations of these active ingredients (including patches) because of safety concerns and potential health risks. If, as expected, the current TFM is finalized, patches and other occlusive formulations will no longer be legally marketed without approved NDAs.
In the mid 1990’s, Hisamitsu became aware of FDA’s escalating concerns with topical analgesic patch products. Hisamitsu requested a series of meetings with FDA to discuss their concerns and to determine the regulatory program (including nonclinical and clinical studies) required to confirm the safety and efficacy of these formulations. FDA informed Hisamitsu that a complete NDA would be required including full nonclinical (animal) studies, clinical safety and efficacy trials and complete manufacturing-related submissions. Hisamitsu completed all necessary trials and those data are fully described in the next section.
4. The Salonpas PAIN RELIEF PATCH (SPRP) NDA
Hisamitsu conducted the necessary studies over a ten year period and was able to secure the first FDA approval (NDA #22-029) for this category of drug products in February, 2008. In all, over 80 studies were conducted and submitted to FDA. To date, Hisamitsu is the only manufacturer to submit and secure FDA approval for an NDA providing a nonprescription topical patch delivery system containing external analgesic products. As will be fully described later, the FDA approved SPRP market packages are permitted to specifically note two very unique advantages. These stated advantages are that this product is FDA approved and that its efficacy was confirmed in clinical trials. The FDA-approved Drug Facts accompanying the market package provides significantly more safety information than the unapproved products (marketed only pursuant to the TFM). Clearly, patients and prescribers are much better served with the proven safe and effective SPRP for topical pain relief with external analgesics.
5. Overview of the SPRP NDA Studies
In brief, the SALONPAS® PAIN RELIEF PATCH (7cm x 10cm) consists of an adhesive mass contained between a layer of light brown backing cloth and a removable plastic film. The adhesive mass contains the two active ingredients. The patch is applied to the skin by removing the plastic film and placing the adhesive mass in contact with the site, leaving the cloth backing as a protective outer layer. The drug content of each patch is 105 mg methyl salicylate and 31.5 mg l-menthol (10% methyl salicylate; 3% l-menthol). The safety and efficacy of this patch composition was confirmed following extensive nonclinical, pharmacokinetic, pharmacodynamic, clinical and manufacturing studies conducted by Hisamitsu and approved by FDA.
1) Nonclinical Studies
Hisamitsu conducted an extensive battery (more than 60) of nonclinical trials to confirm the safety of SPRP, its active ingredients, methyl salicylate and menthol, the employed inactive excipients and the patch components (backing cloth, dyes, films, etc). These studies included topical and systemic studies designed to assess safety, irritation, mutagenicity, reproduction and phototoxicity in a variety of species. Based on their review of these extensive data, FDA has concluded that Hisamitsu has proven the safety of the active ingredients, inactive ingredients and the patch system for its labeled indications. Tabular summaries of these studies are included in the following section.
2) Clinical Trials
FDA informed Hisamitsu in 2001 that the Agency was concerned that the patch formulations of topical analgesics may be associated with increased safety concerns when compared with ointment (or other non-occlusive) preparations. Specifically, FDA noted concerns relating to increased skin irritation and sensitization and enhanced systemic absorption of the active ingredients with the patch products. FDA informed Hisamitsu that multiple pharmacokinetic and skin safety studies would be needed to address these issues. FDA later (2002) requested that a Phase III clinical safety and efficacy trial be completed to compare SPRP with matching placebo patches in patients presenting with mild to moderate aches and pains of muscles and joints.
Hisamitsu designed and conducted all clinical studies considered necessary by FDA including Clinical Pharmacology trials (7 pharmacokinetic trials), Controlled Clinical Studies (1 pilot and 1 Phase III) and Skin Safety Trials (3 Irritation and 2 Sensitization Trials). In total, Hisamitsu evaluated over 800 U.S. patients in their premarketing trials. These studies have confirmed the safety and efficacy of SPRP for its approved label indications.
The pharmacokinetic data generated by Hisamitsu confirmed the active ingredients in SPRP are not well absorbed into the systemic circulation. These data also indicated that SPRP is less bioavailable than topical ointments formulated to contain the monograph limits of methyl salicylate and menthol. Pharmacokinetic interaction evaluations confirmed that the concomitant administration of methyl salicylate and menthol did not interfere with the disposition of either active ingredient given alone. There were no serious adverse medical events reported in these pharmacokinetic studies. In general, skin irritation was not significant when SPRP was used according to the labeling instructions in these studies.
Five skin safety trials were conducted with the SPRP product. These studies address FDA’s concern that patch formulations of counterirritant ingredients may be associated with unacceptable skin toxicities. These studies were conducted using standard study designs. Increased frequencies of irritation and sensitization endpoints were not found when SPRP is compared with its matching placebo and administered according to the labeled instructions. Tabular summaries are also provided in the next section.
Hisamitsu conducted both pilot and pivotal Phase III trials to confirm that significantly more pain relief is associated with SPRP when compared with placebo patches in patients for whom the patch is indicated. The pilot study was conducted to confirm the appropriateness of the selected primary efficacy endpoint (summed pain intensity differences over eight hours with movement) and to assess the required patient population for the Phase III trial. Based on successful pilot data, the pivotal trial was conducted and significantly greater pain relief was observed both with the primary and secondary pain relief endpoints. The observed treatment differences dissipated when the patches were removed following eight hours of application. The consistency of the treatment compared across the efficacy endpoints provided robust affirmation that the SPRP product is a highly effective analgesic drug product for the pain associated with muscle strains.
The clinical safety of the SPRP was also confirmed in the clinical studies. There were no serious adverse medical events. Overall, the adverse event profile was similar between the active and placebo treatment groups. In addition, no clinically relevant changes in physical examination findings or vital signs were observed during the study.
The FDA approved SPRP market packages and Drug Facts labeling are provided with this White Paper. These are quite unique because Hisamitsu was actually permitted to employ statements noting its “FDA Approved” status and that its “Effectiveness was confirmed in clinical trials.” This White Paper also illustrates the marked differences between the SPRP materials and the labeling employed with the unapproved products. As such, prescribers, patients, healthcare providers, commercial venue formulary managers, risk assessors and others involved in the distribution of these product lines need to appreciate the marked differences among these products. Only SPRP has been clinically studied and confirmed by FDA to be safe and effective for its labeled indications.
As described in this report, FDA and federal drug reimbursement agencies have recently effected several regulatory actions limiting and/or discontinuing certain unapproved prescription and nonprescription drug products including those with inadequate labeling. It is, therefore, likely that the differences between the marketed but non-FDA approved topical external analgesic patches and the new SPRP will be closely scrutinized by regulatory authorities.
Click here for more information of "Drug Approval Package".
