Improving NDA Approval Odds for New Dosage Forms of Approved Products
There are numerous reasons why a Sponsor may wish to market a new dosage form of an approved product. Aside from the obvious financial benefits to the sponsor, providing a more convenient and/or faster-acting dosage form of a well-chosen drug provides significant benefits for patients.
Examples of new dosage forms include oral solutions and suspensions of drugs that were previously only approved as solid oral dosages forms. Liquids are more appropriate for some pediatric and geriatric populations and for patients with difficulty swallowing. Other products designed to enhance ease of swallowing include chewable or effervescent tablets, oral films, and orally disintegrating granules. Sponsors may wish to market both capsule and tablet forms of their product for patient convenience. Faster-acting oral dosage forms such as buccal lozenges or films are beneficial for indications requiring a rapid onset of action.
Why is Approval Necessary for Alternate Dosage Forms?
Approval of a new dosage form of a drug requires a new NDA. If the route of administration and indication are the same, comparative bioavailability studies are often needed to demonstrate equivalence to the approved product. If the dosage forms are not bioequivalent, additional data and/or justification will be required to demonstrate that the product is as efficacious and safe as the approved product.
If there are differences in the route of administration or indication, additional studies are usually required to demonstrate the safety and efficacy of the product specific to the new route of administration or indication. This may involve local and/or systemic exposure studies depending on the indication and route of administration. Additional nonclinical and clinical studies efficacy and safety studies may also be required.
Sometimes, the regulatory standards for approval change after the approval of the Listed Drug. In such cases, approval of a new dosage form may require additional studies to meet the current standards. More information and examples can be found in our blogs on the Pediatric Research Equity Act (PREA) (here and here) and nonclinical studies (here and here).
Which Approval Pathways are Appropriate for New Dosage Forms?
The 505(b)(2) regulatory pathway is typically utilized for approval of products that represent new dosage forms of approved drugs. This is because these products do not qualify as generics (505(j) pathway), and at the same time do not require a 505(b)(1) application containing complete evidence of efficacy and safety. The 505(b)(2) pathway allows reliance on data from a listed drug or from publicly available literature.
The use of publically available data in lieu of Sponsor-conducted studies requires the establishment of a scientific bridge from the Sponsor’s product to the data. Design of a bridging study to establish this bridge can be very nuanced. Seeking advice from a 505(b)(2) expert can prevent the need for additional bridging studies, and can minimize the need for additional efficacy and safety studies.
Classification of a New Dosage Form
Upon filing an NDA, the FDA typically assigns an NDA classification code to the application. At the time of approval, a reassessment of the classification, relative to other approved products, is made. According to the Center for Drug Evaluation and Research’s Manual of Policies and Procedures 5018.2, a Type 3 NDA is for a New Dosage Form of an active ingredient that has been approved or marketed in the United States by the same or another applicant but in a different dosage form. The indication for the drug product does not need to be the same as that of the already marketed drug product. Once a new dosage form has been approved for an active ingredient, subsequent applications for the same dosage form and active ingredient will be classified as Type 5 (New Formulation or Other Differences).
505(b)(2) Approval Statistics for New Dosage Forms
A review of Camargo’s 505(b)(2) database finds that 183 NDAs were approved as New Dosage Forms between 2003 and 2016. Of these NDAs, tablets were the most frequent dosage form, followed by oral solutions and suspensions, capsules, and injectables.
‘Oral solution’ category includes oral suspensions.
‘Topical’ category includes creams, cloths, lotions, ointments, shampoos, swabs, gels, and aerosol foams.
‘Spray’ category includes oral, nasal, topical, sublingual, and /inhalation products.
‘Otic/ophthalmic’ category includes solutions/drops and suspension/drops.
‘Other’ category includes aerosols (inhalation, nasal, sublingual, inhalation), films (buccal and oral), powders (inhalation and intrapleural), patches, and an intravitreal implant.
Of the oral tablet, capsule, and solutions approved as new dosage forms, 38 are extended or delayed release. Twenty-four products have features to allow rapid absorption, such as sublingual or buccal delivery, or orally-disintegrating tablets. Aside from these rapid-absorption products, a further 30 oral products offer alternatives to swallowing a tablet or capsule such as solutions, suspensions, and effervescent or chewable tablets.
Many of the new dosage form NDAs represent combination products. Twenty-nine are fixed-dose drug combinations and 15 are drug-device combinations.
What Studies are Needed to Get a New Dosage Form Approved?
In many cases, few if any clinical studies are required for approval of a new dosage form. For 16 of 166 (9.6%) products approved as new dosage forms, no clinical studies were required. These products were frequently injectables, and several oral solutions. When approved via the 505(b)(2) pathway, development programs for these products may receive a biowaiver of the requirement to perform in vivo studies, and rely on literature and approved products to demonstrate safety and efficacy.
For 33.1% of products, only Phase 1 (pharmacokinetic) studies were required for approval. Over-represented in this group are oral solutions and orally disintegrating tablets. In the remaining products (57%), at least one Phase 2 or 3 study, or a human factors study was required for approval. These products were frequently oral extended- or delayed-release products, topical products, and drug-device combination products.
Nonclinical studies were required in 64.1% of applications. In the remaining 103 (35.9%) nonclinical studies were not required for approval but 2 studies had nonclinical post-marketing commitments.
In 7.2% of applications, no clinical or nonclinical studies were required for approval (see our blog on literature-only or ‘paper’ 505(b)(2) NDAs).
The mean time between submission and tentative/full approval was 18 months with a median time of 13 months, and a range of 3 to 83 months. Interestingly, there was no correlation between dosage forms and review time or between applications with or without studies and review time. Typically, the quality and completeness of an application determines the review time.
In 12 cases, a significant review delay was noted, frequently the result of deficiencies in Chemistry, Manufacturing, and Controls (CMC) documents and data. Lengthy review times were often the result of flaws in Phase 1 study design or interpretation, labeling issues, inadequate bridging to the Listed Drug, and missing studies.
Many of these costly review delays can be avoided by engaging a 505(b)(2) expert in designing the development strategy. Camargo has helped numerous Sponsors avoid review delays and refuse-to-file actions by performing due diligence on the development program and/or reviewing the NDA before submission to the FDA.
To learn more about getting a new dosage form approved via the 505(b)(2) pathway, or to get assistance with avoiding deficiencies in the development program or CMC data, contact us.
Angela Drew, PhD, Product Ideation Consultant, Camargo Pharmaceutical Services
Olu Aloba, Ph.D., Senior Director of Pharmaceutics, Camargo Pharmaceutical Services