Topical 505(b)(2) Reformulations at FDA: Pathway Criteria, Systemic Exposure Bridging and Local Efficacy

Topical 505(b)(2) reformulations: when the pathway applies and how FDA bridges local and systemic exposure

A new topical formulation of an approved active ingredient usually goes through section 505(b)(2) when it cannot meet ANDA sameness requirements and needs data beyond bioequivalence to support the change. Recent FDA reviews follow a consistent pattern. Systemic safety is bridged to the listed drug with a maximal-use pharmacokinetic (PK) or relative bioavailability (BA) study. Local efficacy comes from the applicant's own adequate and well-controlled trials, not from a local-exposure bridge. The deciding question for the systemic bridge is whether exposure under maximal-use conditions is no higher than the listed drug's. When it was higher, the bridge failed.

When a topical reformulation is filed as a 505(b)(2)

What an ANDA can and cannot accommodate

An ANDA generally must match the reference listed drug (RLD) in active ingredient, dosage form, route, strength, conditions of use and labeling (subject to permissible differences), and must show bioequivalence. It may contain permissible inactive-ingredient differences only if clinical investigations are not needed to establish safety or effectiveness ²¹⁵²⁵. For topical products specifically:

• Q1/Q2 sameness (same inactive ingredients at the same concentrations) is not required by regulation for topical products. The applicant must still show that inactive ingredients do not affect safety or efficacy, and product-specific guidance may recommend formulation-sameness criteria and particular BE approaches ²¹⁷¹⁵⁷.
• A topical ANDA generally must keep the RLD's dosage form unless an approved suitability petition supports the dosage-form change ²¹¹.
• Ophthalmic and otic products default to Q1/Q2 sameness. The exceptions cover buffers, antioxidants and preservatives, provided the differences are characterized and shown not to affect safety or efficacy ²¹⁷¹⁵⁷. Certain pH-adjuster differences can also be handled through a waiver ²¹⁶.

A change in dosage form, strength or route can go through an ANDA only after FDA approves a suitability petition, and the petition must be approved before the ANDA is submitted ²¹³³¹. A petitioned change qualifies only if its safety and effectiveness can be evaluated without clinical investigations ²¹⁵. Even when approved, a petitioned ANDA is not therapeutically equivalent to the original RLD and does not receive a TE code to it ²²⁴.

Triggers for 505(b)(2)

FDA's guidance Determining Whether to Submit an ANDA or a 505(b)(2) Application points to 505(b)(2) in these cases:

• Formulation changes not permitted in an ANDA, such as an excipient that needs clinical investigations to establish its safety in that drug product ³³.
• Dosage-form changes that rely at least in part on FDA's finding of safety and/or effectiveness for an approved drug, where approval needs studies beyond what section 505(j) allows. Some such changes can instead go through a petitioned ANDA if only BA/BE or limited confirmatory data are needed ²². If the applicant does not pursue or cannot obtain a suitability petition, the 505(b)(2) NDA is the alternative ²¹⁸.
• Changes in rate or extent of delivery. A product whose absorption exceeds or otherwise differs from ANDA BE standards may be filed as a 505(b)(2), and it may need studies showing safety and efficacy at the altered delivery. A 505(b)(2) is generally not appropriate when the only difference is a lower extent of absorption, or an unintentionally lower absorption rate, relative to the listed drug ²⁹.

FDA will generally refuse to file a 505(b)(2) that duplicates a listed drug and is eligible for approval under 505(j) ²⁷. In the recent dermatology approvals discussed below, the common features are new vehicles (lotion, foam, cloth, cream, gel), new strengths, new fixed combinations, and route changes where the listed drug is oral or injectable.

The scientific bridge requirement

Reliance on a listed drug is limited to the characteristics the two products share, such as active ingredient, dosage form, route, strength, indication or conditions of use ²⁵. The applicant must establish a scientific bridge to each listed drug it relies on, for example through comparative BA data. If the product differs from the listed drug, for instance in dosage form or through intentionally greater bioavailability, the application must include data supporting those differences ²⁰. The earlier draft guidance Applications Covered by Section 505(b)(2) states the same principle: a BA/BE comparison with the listed drug, plus studies supporting the change, can provide an adequate basis for reliance without complete safety and effectiveness studies ²¹.

FDA's BA guidance explains why "no higher exposure" supports only half of the bridge. Higher systemic exposure raises safety concerns. Lower exposure can make the product less effective ²²⁹. If comparative BA does not show similarity, the sponsor should show with dose-response or concentration-response data that the differences do not meaningfully affect safety and efficacy. Otherwise the sponsor should consider reformulating or generating additional safety or efficacy data ²²⁹. Exposure-response data generally cannot substitute for clinical data unless the link between measured responses and clinical outcomes is well understood ²³⁷²²⁸. For topical products, where plasma levels do not reflect exposure at the site of action, this is why recent approvals pair a systemic PK bridge with product-specific efficacy trials.

Systemic exposure bridging: the maximal-use PK study

Design elements from FDA guidance

FDA's most detailed maximal-use trial (MUsT) recommendations are in its OTC monograph and sunscreen guidances, but the principles are the ones applied in NDA reviews:

• The study assesses systemic exposure under conditions that maximize dermal absorption and reflect the maximal use in current or anticipated labeling. It uses standard PK measures (Cmax, Tmax, AUC, half-life, clearance, volume of distribution) and collects adverse events ⁴⁵⁴³.
• For a topical NDA, the MUsT uses the specific formulation for which approval is sought ⁴³.
• The population is usually patients with the target disease when disrupted skin is a feature of that disease. Healthy skin is acceptable when it is not, or when the product is preventive ⁴³.
• The amount applied follows the labeled directions and is documented, for example by weighing containers. The treated area reflects the maximum labeled area, such as 30% body-surface area (BSA) if labeling permits use on up to 30%. Dosing follows the highest labeled frequency ⁴².

In NDA practice, FDA reviewers also enforce assay sensitivity. In the TWYNEO program, FDA warned prospectively that an assay not sensitive enough to quantify concentrations for the relative-BA assessment could prevent the clinical bridge from being established ¹⁵⁰.

Two bridging models seen in recent approvals

Topical-to-topical bridge (head-to-head relative BA under maximal use). When the listed drug is itself topical, the proposed product and listed drug are dosed side by side in patients under maximal-use conditions. The bridge holds if the new product's exposure is not greater.

Topical-to-oral bridge (exposure bounding). When the listed drug is oral, the goal is to show that topical systemic exposure stays far below the oral exposure on which FDA's safety findings rest. The comparator can be dosed within the study, taken from another study's data, or replaced by a dose-based calculation.

The same logic applies to other local routes, such as ophthalmic 505(b)(2) products.

Recent FDA approvals: bridging requirements and outcomes

Case notes

Topical-to-topical bridges: ARAZLO, TWYNEO and CABTREO

ARAZLO. The maximal-use study enrolled 48 patients with moderate-to-severe acne. The relative-BA comparison with Tazorac was limited to subjects aged 12 years and older, matching the listed drug's labeled population ¹⁹⁶. On Days 14 to 15, arithmetic-mean ARAZLO/Tazorac ratios were 0.77 (Cmax) and 0.93 (AUC0-t) for tazarotene, and 0.74 for both Cmax and AUC for tazarotenic acid ¹⁹⁹. FDA concluded that exposures were not greater than Tazorac and that the clinical bridge for systemic safety was established ²⁰¹. The reviewer noted that the PK bridge provided no efficacy evidence ¹⁸⁶. Efficacy came from two Phase 3 vehicle-controlled trials ²⁰⁰.

TWYNEO. Study SGT-65-03 was an open-label, randomized, active-controlled maximal-use study. Children aged 9 to under 12 years received TWYNEO only, so there was no pediatric Retin-A comparator ¹⁵¹. FDA asked for application to the cheeks, forehead, nose, chin, shoulders, back and upper chest, with no upper limit on the amount applied ¹⁵⁰. Not every 90% CI comparison met equivalence. Where BE criteria were not met, TWYNEO exposure was lower than Retin-A ¹⁵¹¹⁵⁴. FDA concluded that total tretinoin exposure at steady state was similar in adolescents and adults and that the PK bridge was adequate. FDA waived PK bridging for benzoyl peroxide because its metabolite, benzoic acid, is only about 5% systemically absorbed ¹².

CABTREO. This case shows how rights of reference narrow the bridge. The applicant held rights of reference to clindamycin/BPO products, so FDA required PK bridging only for adapalene, the component taken from Epiduo Forte. BPO bridging was waived because BPO converts to endogenous benzoic acid ¹¹⁶¹⁶⁶. In subjects 12 years and older, adapalene exposure was lower than with Epiduo Forte (Cmax ratio 0.596, AUC0-t ratio 0.653) ¹⁶². The listed drug was not studied in children 9 to under 12, and exposure in the eight younger IDP-126 subjects was higher than in the older cohort ¹⁶⁹. FDA therefore approved the product for patients 12 years and older only and asked for more pediatric PK, safety and efficacy data for the younger group ¹⁶⁹¹⁷².

Topical-to-oral bridges: AMZEEQ, ZILXI, QBREXZA and HYFTOR

AMZEEQ. In Study FX2014-03, 30 adults with acne applied about 4 g of 4% foam to the face, neck, upper chest, upper back, shoulders and upper arms once daily for 21 days. The comparator was a single oral SOLODYN dose of about 1 mg/kg ¹⁵⁸¹⁵⁹. The foam-to-SOLODYN geometric LSM ratios were 0.131% for Cmax and 0.137% for AUC, and FDA's review described systemic exposure as 730 to 794 times lower than with oral dosing ¹⁵⁸. FDA considered the bridge adequate based on the adult maximal-use study ¹⁰⁵.

ZILXI. For the second minocycline foam, FDA said at the pre-IND stage that an in-study SOLODYN comparator was unnecessary. A maximal-use PK trial could be compared across studies with the SOLODYN PK data from FX2014-03 ⁵. This shows that FDA will accept historical comparator data when the exposure margin is expected to be large.

QBREXZA. The maximal-use study dosed the to-be-marketed cloth once daily for 5 days, reaching or nearly reaching steady state. The comparator was oral Cuvposa titrated to its maximum labeled dose ^8777133. Using all data, the adult Cmax ratio was 0.3245 and the AUC0-24h ratio was 0.2447. Pediatric Cmax and AUC0-6h ratios were also below 1, and every 90% CI upper bound was below 1 ⁷⁷. FDA found the bridge established because topical exposure was lower than the listed drug at its highest approved dose ¹²⁹. Because the marketed formulation was used in both the PK study and the Phase 3 trials, no formulation bridge was needed ¹²⁹.

HYFTOR. FDA accepted a bridge without measured exposure ratios. In the single-dose comparative study, nearly all topical sirolimus concentrations were below the 100 pg/mL quantification limit (maximum 116 pg/mL), so no topical PK parameters could be calculated ¹. FDA recommended a maximal-use study, but the applicant used sparse PK sampling in Phase 3 instead ⁷⁴¹. FDA decided a relative-BA study was unnecessary. The maximum topical dose (1.6 mg, or 3.2 mg/day with twice-daily use) was below the estimated bioavailable oral dose of 7.12 mg (40 mg/day at about 17.8% oral bioavailability). Even at 100% absorption, topical exposure could not exceed oral exposure ⁷⁴.

Corticosteroid-containing products: WYNZORA and DUOBRII

Topical corticosteroid reformulations add local and pharmacodynamic endpoints to the systemic bridge.

WYNZORA. The maximal-use study against Taclonex ointment measured calcipotriene, betamethasone dipropionate and their main metabolites, and FDA found the data supported a clinical bridge ⁴. The same study assessed HPA-axis suppression: about 23% of subjects were suppressed at Week 4 and 12% at Week 8. Calcium metabolism was also assessed, with no apparent correlation between the few elevated values and calcipotriene exposure ⁴. A single-point vasoconstriction study against five reference corticosteroids placed the product in the mid-potency class ⁴. The bridge to the second listed drug, Taclonex suspension, came from a Phase 3 trial that showed superiority to vehicle and noninferiority to the suspension ¹⁰.

DUOBRII. This is the clearest recent example of a failed systemic bridge. In the maximal-use study, adults with at least 20% treatable BSA applied a median of about 8 g per day ²⁰²²⁰⁴. Halobetasol and tazarotenic acid Cmax and AUC were both higher with DUOBRII than with Ultravate and Tazorac, respectively, and the 90% CIs for the geometric-mean ratios extended above the 80% to 125% limits ^7206203. FDA concluded the bridge was not established, so the applicant could not rely on the listed drugs' safety findings, including nonclinical data ²⁰⁴². HPA-axis suppression was 15% on Day 29 and 0% on Day 57, versus 5% for Ultravate on Day 15 ²⁰⁴. Vasoconstrictor results were inconclusive, and FDA described potency as upper-mid-strength to high ²⁰⁵⁷⁵. Clinical Pharmacology still found the application acceptable on the totality of evidence (two Phase 3 trials and a long-term safety study) ². The applicant then obtained rights of reference and resubmitted under 505(b)(1), so a clinical bridge was no longer needed ⁷⁵.

Local exposure: what FDA did and did not require

None of the approvals above used an in vitro or pharmacodynamic local bioequivalence method (IVPT, IVRT or a vasoconstrictor BE study) as the 505(b)(2) bridge. The closest thing to a local-effect bridge was WYNZORA's Phase 3 noninferiority comparison with Taclonex suspension ¹⁰. Local efficacy in each program came from new adequate and well-controlled trials. These were usually two Phase 3 vehicle-controlled studies, plus active-comparator or component-contribution studies where needed ^{20016517213310}.

FDA's local-availability methods (vasoconstrictor assay, IVPT, IVRT and clinical endpoint BE studies) are described mainly in the generic-drug context:

• The vasoconstrictor (skin-blanching) assay is a surrogate for the rate and extent of corticosteroid availability at the skin. It uses a pilot dose-duration study to estimate ED50, followed by a pivotal comparison ⁵⁸⁶¹⁵⁷. In the 505(b)(2) programs reviewed here, the assay was used to assign potency class for labeling (WYNZORA, DUOBRII), not to establish BE ⁴²⁰⁵.
• IVPT and IVRT are described as tools for comparing topical products in ANDAs ^63666765.
• Clinical endpoint BE studies are an option when drug concentrations cannot be measured in an accessible fluid, but for corticosteroids they need many subjects and are often insensitive ⁵⁴.

Dermal safety is a separate requirement for new topical formulations. FDA's framework for chronic-use topical products includes cumulative irritation and sensitization patch testing. Phototoxicity and photoallergenicity testing is added when the product absorbs UVA, UVB or visible light ⁹⁰⁹¹⁹³. Some of these studies may be omitted after discussion with FDA, depending on available safety data ⁹⁰. TWYNEO's program, for example, included four Phase 1 studies covering irritation, sensitization, phototoxicity and photoallergy ¹⁵³.

Practical takeaways for topical 505(b)(2) programs

1. Design the maximal-use study to the labeled worst case. Recent programs used patients with the target disease, the to-be-marketed formulation, all plausible treatment areas, and dosing to steady state (about 5 to 28 days) ^{19615116287158}.
2. Match the comparison population to the listed drug's labeled population. ARAZLO and CABTREO restricted the relative-BA comparison to ages 12 and older. Children below the listed drug's labeled age were studied in the test arm only, and in CABTREO this directly limited the approved age range ^196151169.
3. Exposure no higher than the listed drug is the practical pass criterion. Exposure that was lower or similar supported the bridge ^20112162129. Exposure that was higher broke it ²⁰⁴.
4. An oral listed drug can give a large safety margin. FDA accepted cross-study comparators and even dose-bounding calculations when the expected margin was large ⁵⁷⁴.
5. Rights of reference shrink the bridge. Only the components that rely on a third-party listed drug need PK bridging ¹¹⁶. If the bridge fails, obtaining rights of reference and moving to 505(b)(1) is a proven fallback ⁷⁵.
6. Corticosteroid products need HPA-axis data and a potency class. Expect HPA-axis suppression testing under maximal use and a vasoconstrictor study to support potency labeling ^4204205.
7. Budget for efficacy trials. The systemic PK bridge supports reliance for safety. It does not replace product-specific evidence of local efficacy ¹⁸⁶²²⁹.