As part of the 505(b)(2) drug development and registration process, the applicant of the new drug product can reference the literature and the FDA’s findings of safety and/or effectiveness (e.g., as listed on the Listed Drug product’s label) to fulfill various registration requirements. Since many drug substances have a long history of clinical use, the clinical data can often be used to reduce and/or delay the nonclinical testing requirements in comparison to a new molecular entity registered under the 505(b)(1) pathway. The following example demonstrates how the FDA takes into consideration the available clinical data to determine the extent and timing of nonclinical testing.
Zecuity Iontophoretic Transdermal System
Zecuity is a novel transdermal drug/device combination product for the treatment of migraine headaches that was registered via the 505(b)(2) registration pathway. Zecuity delivers sumatriptan succinate transdermally using a battery-powered iontophoretic skin patch. The transdermal system employs the use of two electrodes with nonwoven pads placed on top of each electrode with one containing the drug formulation (anode) and the other containing a salt formulation (cathode). Application of a low electrical potential across the electrodes facilitates penetration of the ionized drug through the skin and into the systemic circulation.
To support approval as a 505(b)(2) New Drug Application, the Sponsor relied on the FDA’s prior findings of safety and effectiveness for the Listed Drug approvals of sumatriptan oral tablets (Imitrex Tablets; NDA 20,132) and sumatriptan subcutaneous injection (Imitrex Injection; NDA 20,080). Various pharmacokinetic and bioavailability/bioequivalence studies were conducted; however, bioequivalence was not demonstrated between the patch and orally-administered Imitrex. To demonstrate clinical efficacy and safety, a double-blind, placebo controlled, Phase 3 clinical trial (469 patients with 234 patients treated with Zecuity) was conducted to support drug approval. In addition, two open label 12 month long-term safety studies were conducted in a larger number of patients (over 700 patients, with some of them continuing treatment from the Phase 3 efficacy and safety study). For nonclinical, a chronic dermal toxicity study in pigs was conducted.
Clinical Safety Concerns
Zecuity is a serotonin (5HT) 1b/1d receptor agonist indicated for the acute treatment of migraine with or without aura in adults. Zecuity delivers 6.5 mg of sumatriptan over 4 hours. Up to two patches can be applied in a 24 hour period to the upper arm or thigh. The second patch should not be applied any sooner than 2 hours after the first patch and the patch should not be applied to a previous application site until that site remains erythema free for at least 3 days.
In the Phase 3 clinical trial and follow-up safety trials, adverse events (AEs) were predominantly due to application site conditions. Almost half of all subjects in the safety population (376/796, 47%) had an application site AE. Application site reaction, pain, and pruritus were the most common AEs in the Phase 3 efficacy study. The long term safety studies also had AEs due to allergic contact dermatitis (delayed hypersensitivity reaction) from Zecuity application. There was a high rate of severe skin reactions from patch application. Of the 796 subjects in the Phase 3 studies who applied at least 1 patch, 43 (5.4%) sustained a severe AE. There were 3 cases of severe skin burns and 1 case of severe skin discoloration from patch application.
To support the safety of the Zecuity transdermal patch, the Sponsor conducted a 9-month dermal toxicity study in pigmented and non-pigmented pigs. The FDA concluded that the study was not valid due to multiple design flaws such as not using a clinically relevant dosing regimen, not using a sufficient number of doses, not using a sufficiently high dose (e.g., a maximum feasible dose), not using a sufficient number of animals, not including untreated and/or vehicle control groups, and not including detailed toxicokinetics. The Sponsor also conducted a skin sensitization study in guinea pigs, phototoxicity study in pigs, an in vitro agarose overlay cytotoxicity study, and a primary skin irritation study in rabbits.
The FDA concluded that the Sponsor did not provide adequate nonclinical data to support approval of Zecuity based on the lack of an adequate chronic dermal toxicity study and either a dermal carcinogenicity study in one species or sufficient justification for why such a study would not be feasible or informative. The FDA considered the chronic dermal toxicity study important for determining chronic local effects (e.g., preneoplastic) and the need for a dermal carcinogenicity study. The FDA concluded that the Sponsor could reconduct a valid chronic dermal toxicity study and those results could be used to determine if a dermal carcinogenicity study would be needed. Alternatively, the Sponsor could conduct the dermal carcinogenicity study or provide a justification why the dermal carcinogenicity study was not feasible. The Sponsor tried to argue that a dermal carcinogenicity study in rodents was not feasible since the iontophoretic transdermal system was necessary for dermal penetration of sumatriptan and the transdermal patch was too large for rodents; however, FDA concluded that the Sponsor had not provided sufficient evidence that dermal penetration enhancers could not be used to enhance the dermal penetration of sumatriptan in the absence of the iontophoretic transdermal system.
FDA Complete Response
Due to a variety of Chemistry, Manufacturing, and Controls (CMC), device, nonclinical, clinical, and microbiology concerns, the FDA issued a Complete Response Letter to the Sponsor. In particular, the high incidence of AEs at the application site, including severe AEs, in the clinical trials was a major concern for the transdermal system. For nonclinical, the lack of a valid chronic dermal toxicity study and lack of a dermal carcinogenicity study or sufficient justification for why such a study would not be feasible or information were items that needed to be addressed.
In response to the high incidence of application site AEs, the Sponsor redesigned the Zecuity transdermal system by adding a pad detection system that prevented device activation if the patch was misassembled or a medication pad was absent. The Sponsor provided engineering evidence to support that the pad detection system would operate as expected and the FDA agreed that this information was sufficient to address the burn/scarring issue. However, local adverse effects were still a concern such as pain, pruritus, erythema, skin discoloration, vesicle formation, and allergic contact dermatitis. The Sponsor also addressed the other CMC and microbiology issues but did not adequately address the nonclinical issues.
Conditions of NDA Approval
The FDA approved the NDA but required the following post-approval:
- Report all post-marketing cases of burns and scarring as 15-day safety reports.
- Conduct adolescent PK, efficacy, and long-term safety studies.
- Conduct a rodent repeat-dose dermal painting study to determine the feasibility of conducting a rodent dermal carcinogenicity study.
- If determined to be feasible, conduct a rodent dermal carcinogenicity study.
The FDA’s decision to require the nonclinical studies as post-marketing requirements hinged on the clinical benefit in a subset of migraine patients (ie, patients that have prominent nausea or vomiting and who cannot tolerate or are unwilling to use the other marketed formulations of sumatriptan). In addition, the FDA further concluded that requiring the nonclinical studies as post-marketing requirements was acceptable given the vast clinical experience with other formulations of sumatriptan and the absence of a signal for carcinogenicity with the other routes of administration.
Unfortunately, the redesign and incorporation of safety features into the Zecuity transdermal system did not resolve the severe AE reactions once the product was marketed. The Sponsor received post‑marketing reports of application site reactions described as “burn” and/or “scar” in patients treated with Zecuity. Descriptions of these reactions included severe redness, cracked skin, blistering or welts, and burns or scars where the patch was worn. Patients described severe pain, itching, or burning. Although many cases resolved within hours to weeks, there were reports of cases with unresolved skin reactions, typically skin discoloration, after several months. Due to these application site AEs, the Sponsor voluntarily removed Zecuity from the market.
This case study demonstrates that in a 505(b)2 application, the FDA will often use clinical data and the history of drug substance use, even if by alternate routes of administration, in the determination of whether or not nonclinical data are needed and the timing of the nonclinical studies. In this particular case, even though there were local application site clinical safety concerns, the long history of safe clinical use of sumatriptan, the benefit of the drug product in a disabled subset of migraine sufferers, and the lack of a carcinogenicity signal by the oral route of administration, allowed the nonclinical studies to be conducted as post-marketing requirements. As part of the 505(b)2 drug development process, Premier Consulting will evaluate the available clinical and nonclinical data for the drug substance and optimize the nonclinical drug development program, with many programs requiring none to limited nonclinical data to support clinical trials and an eventual 505(b)2 New Drug Application. Contact us to learn more.
William Salminen, PhD, DABT, PMP
Director of Scientific and Regulatory Affairs
 US FDA. Draft Guidance for Industry: Application covered by section 505(b)(2). October 1999.