US FDA Perspectives on

BE Regulations

Vinod P. Shah, Ph.D. FIP/SIG Chair on Regulatory Sciences

Pharmaceutical Consultant

1st MENA Regulatory Conference on

Bioequivalence, Biowaivers,

Bioanalysis and Dissolution

Amman, Jordan. September 23-24, 2013

Bioavailability and Bioequivalence

• 1977: BA/BE Regulations – 21 CFR 320.

• Bioavailability:

“ … the rate and extent to which the active

ingredient or active moiety is absorbed from a

drug product and becomes available at the site of

action … “

• Bioequivalence:

“ … as the absence of a significant difference in

the rate and extent to which the active ingredient

or active moiety in the pharmaceutical equivalents

or pharmaceutical alternatives becomes available

at the site of drug action when administered at the

same molar dose under similar conditions …”

Drug Regulations

• Pharmaceutical Sciences Provided the scientific basis for the 1984 Drug

Price Competition Act, providing statutory

authority for FDA BE based approval of new

generic drugs, - provided scientific basis for

accepting BE studies as a surrogate for clinical

studies.

• Using the principles of BCS, provided

justification for drug approval based on in vitro

information.

Generic Drug - Standards

To be safe and effective, generic drugs have to meet

the same rigid standards as the innovator drug. To

gain FDA approval, a generic drug must:

• Contain the same active ingredient (s) as the

innovator drug (inactive ingredients may vary)

• Be identical in strength, dosage form, and route

of administration as the innovator drug

• Have the same use indications (labeling)

• Be bioequivalent (PK, PD, Clinical, In vitro)

• Meet the same batch requirements for identity,

strength, purity and quality

• Be manufactured under the same strict standards of

FDA’s good manufacturing practice regulations

required for innovator products.

Study Design and Analysis

Single dose, crossover study design

• T and R Products

• Analysis - Average Bioequivalence (ABE)

Single Dose, replicate study design

• TT and RR Products

• Analysis - Average Bioequivalence (ABE)

Immediate Release Products

• A single dose fasted study comparing the

highest strength of test and reference product

• Food effect study, if required (labeling)

• Must meet BE requirements - criteria

• In vitro drug release

Modified Release Drug Products

• Single dose study is considered more

sensitive in assessing the drug product

quality - release of the drug substance from

the drug product into circulation

• A multiple-dose BE study for MR dosage

forms is not generally recommended

Extended Release Products

ANDA: BE Studies

• A single dose fasted study comparing the

highest strength of test and reference product

• A food-effect study comparing highest

strength of Test and Reference Product

• Must meet BE requirements (criteria)

• In vitro drug release

Guidance for Industry

Bioavailability and

Bioequivalence Studies for Orally

Administered Drug Products

General Considerations

http://www.fda.gov/cder/guidance/index.htm

March 2003

Multiphasic Modified Release

• For MR products designed to have a rapid onset of

drug action followed by sustained response, an

additional metric of partial AUC is required. (e.g., for

Zolpidem Tartrate Extended Release - (Ambien CR)

– The cutoff for partial AUCs may be determined on the

basis of the PK/PD or PK/response characteristics of the

product.

– BE requirement fir a generic product include: Cmax,

AUC0-last or AUC0-∞ and pAUC

Challenges in Meeting BE Requirements

• Certain types of modified release dosage forms

• Highly variable drugs & drug products

• Orally administered non-absorbed drugs

• Topical drug products

• Inhalation drug products

Lower Strengths - Biowaiver

Waiver based on dissolution profile similarity

• Conventional (Immediate) Release

- Formulation proportional

- Dissolution profile comparison with highest

strength under one condition.

• Extended Release

- Formulation proportional

- Same drug releasing mechanism

- Beaded capsules – dissolution profile comparison with

highest strength under one condition

- Tablets - dissolution profile comparison with highest

strength in pH 1.2, 4.5 and 6.8

Thank You for Your Attention