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Back to Basics: 505(b)(2) FAQs Part 4: Regulatory Strategies – Pharmacokinetic Studies

As the 505(b)(2) expert, Premier Consulting is frequently asked questions about how to get a product approved via the 505(b)(2) regulatory pathway and if this pathway is appropriate. Given the growing popularity of the 505(b)(2) pathway for approval of repurposed, reformulated, or unapproved-marketed products, we thought it would be worth providing a refresher. Here is the final installment in our 4 part series of frequently asked questions (FAQs).

Pharmacokinetic Studies

Q1 In the case of a drug product that increases the bioavailability beyond that of the reference product, is it necessary (or usual) to change the dose so that the plasma area-under the curve (AUC) is comparable between products in order to get approval? Would that be a 505(b)(2)?

There are several strategies that can be employed in this situation depending on a combination of the Sponsor’s goals, optimization of the properties of the drug product, and meeting regulatory requirements. In some cases, a Sponsor has developed a product with improved bioavailability compared with the approved product/s. If so, it may be optimal to reduce the lower molar dose to maintain similar systemic exposure to the Listed Drug, and subsequently, bridge to the existing non-clinical and clinical data. In other cases, the Sponsor may be seeking a different indication from the Listed Drug. In this case, the dose will largely be dictated by the appropriate drug levels for efficacy and safety as required for the new indication. However, it may still be possible to utilize some of the existing safety information depending on the comparative bioavailability of the proposed product with the Listed Drug. In other cases again, the increase in bioavailability for the proposed product may be justified by pharmacokinetic approaches appropriate for the product. In all cases, if a Sponsor wishes to use existing data from an approved product or from literature to reduce the size or scope of the studies in the development program, the 505(b)(2) pathway is the appropriate pathway.

Q2 Why are bioequivalence/bioavailability (BA/BE) studies so important for 505(b)(2) approvals?

As we have previously blogged in Part 1 in this series, many 505(b)(2) applications rely on a BA/BE study for approval. This is because the 505(b)(2) pathway allows for the use of existing data for which the Sponsor does not have right of reference. Differences in formulation or dosage form can greatly affect the rate and extent of absorption. In order to use the existing data, it is necessary to demonstrate reasonable similarity to the product being relied upon. Specific regulatory requirements define how similar a product needs to be to the Listed Drug, and in which parameters.

While every product requires characterization of pharmacokinetic properties for approval, a BA/BE bridging study compares the relevant pharmacokinetic parameters between two products. Premier Consulting’s pharmacokineticists have specific experience with 505(b)(2) approvals and can often design one study to accomplish both goals.

Pharmaceutical Quality (CMC)

Q3 How many months of stability data are required for a product submitted for approval via the 505(b)(2) pathway?

Many Sponsors familiar with generics are surprised to learn that 505(b)(2) applications require 12 months of real-time stability data on 3 batches (at least pilot scale) and 6 months of accelerated data (depending on storage conditions) at the time of submission. While generics only require 6 months of accelerated stability data and 6 months of long-term stability data at the time of submission, a 505(b)(2) application is held to the same standard as a 505(b)(1) application (new drug*).

*Both 505(b)(1) and 505(b)(2) applications are New Drug Applications that require full reports of efficacy and safety. Data collected to support approval by the 505(b)(1) pathway typically comes from the Sponsor’s own studies whereas 505(b)(2) applications rely at least in part on existing information.

Q4 If we change the degree of hydration of the active pharmaceutical ingredient (API) in the Listed Drug, is this appropriate for a 505(b)(2) application?

The best way to think about this and other API alterations is to determine first if they qualify as a generic. If not, use the 505(b)(2) pathway.

Regarding hydration of the API, it will depend on the dosage form and on the effect that hydration has on the API. Per the Orange Book preface, anhydrous and hydrated entities are considered to be the same active ingredient. Therefore, changing the degree of hydration would not necessarily qualify a drug for the 505(b)(2) pathway if another approved product with the same active ingredient, dose and dosage form already exists. Such a drug product would need to be filed as a 505(j) application (generic). However, if the change of hydration state affects the absorption, distribution, metabolism, and/or excretion (ADME) of the drug, a case could be made that the resulting drug product would be appropriate for the 505(b)(2) pathway. For example, a difference in ADME could lead to differences in dosage or dosing regimen for a drug product containing a different hydrate of the same active ingredient as a listed drug. The type of dosage form is also important – a solution dosage form in which the drug is fully dissolved would not generally result in an ADME change and would therefore not be appropriate for the 505(b)(2) pathway. By contrast dosage forms such as suspensions, emulsions or solid dosage forms may experience ADME changes due to the change in hydration state.


There are many nuances to the 505(b)(2) regulatory pathway and understanding the pharmacokinetic and quality requirements is no exception. Premier Consulting’s experience with the drug approvals via the 505(b)(2) pathway results in smaller and less expensive drug development programs for Sponsors. Our specialist pharmacokinetic and quality (CMC) teams, along with our regulatory, nonclinical, and clinical experts are available to help with planning an optimized drug development program or getting a stalled program back on track.

For an assessment of whether your product is appropriate for approval via the 505(b)(2) pathway or to learn more about ways that Premier Consulting’s multi-disciplinary team can help you create an optimized development plan to get your product approved, read more here or contact us.

Other installments in “Back to Basics: 505(b)(2) FAQs”:


Angela Drew, PhD
Product Ideation Consultant

Olu Aloba, PhD
Senior Director of Pharmaceutics