The goal was to define through PK modeling/simulation whether a twice-a-day (q12), test formulation was bioequivalent (BE) to an immediate-release, 3 times-a-day (q4), RLD formulation at steady-state, including the assessment of the C min,ss parameter. The FDA has clearly emphasized the importance of integrating PK/PD information in drug development and its potential impact on decision-making.(Miller, 2005) The strategic use of PK modeling and steady-state simulation in 505(b)(2) drug development programs could prove valuable.īased on this approach, the Sponsor elected to use data obtained in the single-dose BA study to model/simulate steady-state conditions for both the test product and RLD (as the FDA requested a PK steady-state BE assessment as part of the 505(b)(2) submission). Integration of PK/PD in early development helps with formulation selection and guides creation of an efficient clinical development strategy. If an unfavorable outcome is predicted from the modeling, the Sponsor may elect to re-formulate the product prior to conducting any further PK studies. The ability to predict the ER test formulation’s ability to meet the 505(b)(2) bridging BE requirements under steady-state conditions, using data obtained from initial single-dose study(s) may enhance the efficiency of drug development as well as provide a real cost saving benefit. A steady-state study on the highest strengthĥ05(b)(2) applications for proposed drug products where the rate and/or extent of absorption exceed, or are otherwise different from the approved drug may require additional clinical studies to document safety and efficacy at the different rate and extent of delivery.A single-dose, food-effect study on the highest strength.A single-dose, fasting study on all strengths of the products.The Guidance for Industry: BA and BE Studies for Orally Administered Drug Products - General Considerations recommends that the following BA studies be conducted for an ER drug product submitted as an NDA:
WINNONLIN FOR PK FULL
One of the BA/BE requirements for an NDA (e.g., 505(b)(2)) of an extended-release (ER) drug product must ensure that the drug product’s steady-state performance is equivalent to the currently marketed noncontrolled release drug product which is subject to an approved full NDA.
As such, a 505(b)(2) application should include a bioavailability (BA)/bioequivalence (BE) study(s) comparing the proposed product to the listed product to establish a “bridge” to provide an adequate basis for reliance upon FDA’s finding of safety and effectiveness of the reference listed drug (RLD).
The following posting was prepared by our lead researcher, Stacey Ayres, PhD and Sunny Tse, a PhD-candidate intern, under the direction of Camargo’s CSO, Ruth Stevens PhD, MBA.įor changes to a previously approved drug product, Section 314.54 permits a 505(b)(2) applicant to rely on the Agency’s finding of safety and effectiveness of the previously approved drug product, coupled with information needed to support the change from the approved product. Modeling avoids the cost of making multiple formulations and performing several multi-arm pharmacokinetic studies. Modeling can be used as a cost effective way to estimate the effect of changing an oral product from immediate release to extended release. Sponsors and their investors continue to seek cost efficient ways to meet their financial milestones.