505(b)(2) pathway case studies:

1. An injection product that contains different excipients than the LD — self-evident product

2. Change in formulation of an approved injection product that may have an impact on PK-PD

of the product — on the basis of scientific evidence shown to meet an in vitro test that has

been correlated with in vivo data

3. In vitro-in vivo correlation (IVIVC) was established to bridge the Phase 1 formulation and

Phase 2 formulation of the test product.

Poster

Number

04R1000

PURPOSE

METHODS

RESULTS

• In the 505(b)(2) regulatory setting, an in vivo comparative bioavailability (BA)/

bioequivalence (BE) study between the proposed product and the listed drug (LD) is often

required to establish a scientific bridge to the safety and effectiveness of the LD.

• Unique scientific approaches are available to meet regulatory requirements for BA/BE via

the 505(b)(2) pathway. In some cases a biowaiver can be obtained to avoid conduct of

clinical trials.

• Case studies where strategic regulatory concepts and unique scientific approaches were

used to successfully support biowaiver requests in 505(b)(2) NDA submissions are

presented.

CONCLUSIONS

• Extensive research to understand the key attribute of drug

product which is amenable to be a model to demonstrate

the in vivo performance of the drug product.

• It is imperative to have a thorough understanding of

biopharmaceutics and the opportunities for leveraging

biowaiver strategies in the 505(b)(2) pathway.

• The regulatory drug development process could be

significantly reduced in situations where biowaiver strategy

is feasible.

• Soliciting input from the agency on the strategy and in-vitro

protocol design is critical.

Unique Scientific and Regulatory Approaches:

Biowaivers and 505(b)(2) NDAs

L. Pham, S. Ayres, F. Ajayi, R. Stevens, L. Gold

Camargo Pharmaceutical Services

Corresponding author: Dr. Lynn Gold lgold@camargopharma.com

• Test product B, was an injectable solution with equivalent

active ingredients in the same concentration as the LD, an

injectable solution which contained different inactive

ingredients.

Data input and strategy cascade:

• PD profiles from clinical trials of a range of LD

concentrations is available in the label of the LD

• In vitro method was established to generate PD profiles

of the LD

• Bridging in-vitro protocol was discussed with the Division

• Laboratory tests on pooled human plasma were acceptable

as a bridge to demonstrate sufficient similarity

Case 1: 21 CFR 320.22(b): Self-evident

Case 2: 21 CFR 320.22(d) (3): in vitro - in vivo

• A formulation change was made to the LD. The Test

product is different in the solubility enhancer, stabilizer and

pH adjuster.

• Binding profile - in vitro study was conducted:

o Binding constants of the drug are similar and will

result in similar free drug release profiles

Case 3: 21 CFR 320.22(d)(3) and 21CFR

320.24(b)(1)(ii) IVIVC

What is a Biowaiver? Why BA/BE studies?

Why do you care about biowaivers?

21 CFR 320.22: b) self-

evident products and d)

certain products (in vitro in

lieu of in vivo data)

21CFR 320.24(b)(6): “Any

other approach deemed

adequately by FDA to measure

BA or establish BE”.

CFR. 320: BA and BE Requirements

CFR.320.24: Types of evidence to measure BA or

establish BE (descending order of accuracy, sensitivity, reproducibility)

An in vivo test in humans: drug concentrations

measured in whole blood, plasma, serum)

An in vitro test that has been correlated with and is

predictive of human in vivo bioavailability data

Any other approach deemed adequate by FDA to

measure bioavailability or establish bioequivalence.

(b)(1)

(b)(2) An in vivo test in humans: drug concentrations

measured in urine

An in vivo test in humans: drug efficacy

Well-controlled clinical trials: drug efficacy and safety

(b)(3)

(b)(4)

A currently available in vitro test acceptable to FDA(b)(5)

(b)(6)

• Published literature provided the

justification that substitution of the

solubility enhancer will not alter PK,

efficacy or safety of the drug

therefore the in vivo BA, BE of the

drug product was demonstrated to be

self-evident

Input data for test product IVIVC model:

• Test and Reference Products: MR

• IVIVC model for MR formulation of LD

• Identical dissolution method used for the Test and LD

• In vivo and in vitro data for LD and Phase 1 Test

product (MR)

• PK information of LD, IR

• Worst case and best

case scenarios of

predicted in vivo

systemic exposure for

the Phase 2 Test

product were

generated

• The simulation results together with historical safety

and efficacy data of the product suggested no in vivo

comparative BA study with new formulation was

necessary