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Clinical Study Program for 505(b)2 NDA Application – The Fast Path to Approval

PRESENTED AT: CSPS Annual Conference, Toronto, Canada (June 2009)
PRESENTED BY: Juan He*, Masood Bhatti, and Lorelei Lutter, BioPharma Services Inc. Toronto, ONT, Canada


The 505(b)(2) application is one type of NDA, and it potentially saves pharmaceutical companies time and money. This route can be utilized for a wide range of products with limited change from an approved drug. One change suited for 505 (b)(2) application is the application of modified release technology to achieve improved therapeutic and safety profiles with the existing approved products. There have been several approvals exemplifying this, such as Stavzor ® (soft gel of valproic acid) and Zolpimist® (oral spray of zolpidem).

Clinical pharmacokinetic studies comparing the bioavailability of active pharmaceutical moiety from the modified release products to that of the innovator are the important part of the 505 (b)(2) submissions, serving as the bridge of PK response and therapeutic efficacy. The program usually starts with the initial trial comparing overall bioavailability of the compound of interest from modified-release and innovator formulations under the fasted condition. If the desirable bioavailability is obtained, the food effect of the modified-release formulation should be tested; the consistent food effect which was seen in innovator is preferable. The steady-state comparative pharmacokinetics assessment should be carried out to investigate the accumulation of both modified-release and innovator formulations.

Drug interaction studies will provide useful information especially when the compound is metabolized via CYP 2D6 or 3A4. Chronopharmacokinetics should be assessed if the compound is known to produce different systemic and peak exposures at morning or evening dosing. The dose-strength equivalence and dose-proportionality studies are essential, if the new products will have more than one strength. The special population (renal and hepatic) PK studies are added value to 505 (b)(2) programs.

The gender and age effect should be explored in the aforementioned studies. The active metabolite(s) should be assessed for understanding of the biotransformation, and the chiral assay should be employed when the products involve the active enantiomers.

The clinical studies described above have a similar design to those within an ANDA program. The trials are 2-way crossover with 2-sequences; except for dose-proportionality and special population studies. The trials are easily handled from clinical practice and data analysis perspectives. Such programs can provide efficient FDA approval. There are about 30 505 (b)(2) applications approved during 2008. An example of 505 (b)(2) clinical program will be discussed.


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Clinical Study Program for 505 (b) (2) NDA Application

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About Author’s affiliation: BioPharma Services, Inc.: BioPharma is an FDA inspected CRO focused on Phase I/IIa clinical trials, and BE studies, with a 158-bed clinical facility in Toronto, Canada. Through our sister company, ADA Medical Ltd., BioPharma can recruit patients through our network of over 115 physicians in Canada and US.
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