This article summarizes information taken from the following sources:  FDA’s Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application (ANDA) (Dec. 2013) & information set forth in the following link: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm

In order to launch a generic version of an approved reference listed drug (“RLD”), an applicant must file an abbreviated new drug application (“ANDA”) generally demonstrating, among other things, that a proposed generic drug product is bioequivalent (“BE”) to the RLD.[1]

The FD&C Act provides that a generic drug is bioequivalent to the RLD if:

The rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses. . .[2]

 

For most products, the focus of BE studies is on the release of the drug substance from the drug product into the systemic circulation.  During such BE studies, an applicant compares the systemic exposure profile of a test drug product to that of the RLD.

Under FDA regulations, an applicant must use “the most accurate, sensitive, and reproducible approach available among those set forth” in 21 C.F.R. § 320.24(b) to demonstrate BE.[3] As noted in 21 C.F.R. § 320.24, in vivo and/or in vitro methods can be used to establish BE.  In general descending order of preference, these include pharmacokinetic, pharmacodynamic, clinical, and in vitro studies.[4]

The statutory definition of BE, expressed in terms of rate and extent of absorption of the active ingredient or moiety, emphasizes the use of pharmacokinetic endpoints in an accessible biological matrix, such as blood, plasma, and/or serum, to indicate release of the drug substance from the drug product into the systemic circulation.  BE frequently relies on pharmacokinetic endpoints such as Cmax (peak plasma concentration) and AUC (area under the plasma concentration time curve) that are reflective of rate and extent of absorption, respectively.

If serial measurements of the drug or its metabolites in plasma, serum, or blood cannot be accomplished, measurement of urinary excretion can be used to demonstrate BE.

FDA recommends use of a two-period, two-sequence, two-treatment, single-dose, crossover study design, a single-dose parallel study design, or a replicate study design for BE studies.  For most dosage forms that release drug intended to be systemically available, FDA recommends that applicants perform a two-period, two-sequence, two-treatment, single-dose, crossover study using healthy subjects.  In this design, each study subject should receive each treatment (test, and RLD) in random order. The crossover design may not be practical for drugs with long pharmacokinetic half-lives (i.e., longer than 24 hours).  In such cases, investigators can use a single-dose, parallel design where each treatment should be administered to a separate group of subjects with similar demographics.

A replicate crossover study may be an appropriate alternative to the parallel or non-replicate crossover study described above, and can be conducted as either a partial (three-way) or full (four-way) replication of treatment. In this design, one or both treatments should be administered to the same subject on two separate occasions. The replicate design has the advantage of using fewer subjects although each subject should receive more treatments.

According to 21 C.F.R. § 320.24, different types of evidence may be used to establish bioequivalence for pharmaceutically equivalent drug products, including in vivo or in vitro testing, or both. The selection of the method used to demonstrate bioequivalence depends upon the purpose of the study, the analytical methods available, and the nature of the drug product.  Under this regulation, applicants must conduct bioequivalence testing using the most accurate, sensitive, and reproducible approach available among those set forth in 21 C.F.R. § 320.24.

To further facilitate generic drug product availability and to assist the generic pharmaceutical industry with identifying the most appropriate methodology for developing drugs and generating evidence needed to support ANDA approval, FDA publishes product-specific guidances describing  the Agency’s current thinking and expectations on how to develop generic drug products therapeutically equivalent to specific reference-listed drugs.

These guidances are published in an incremental manner and the most recently published new guidances are listed below in alphabetical order according to RLD’s name.

Active Ingredient Route of Administration Dosage Form RLD Application Number
(link to Orange Book)
Azelastine hydrochloride Nasal Spray, metered 022203
Azithromycin Oral Suspension 050693
Barium sulfate Oral Paste 208844
Betamethasone dipropionate Topical Lotion 017781
Budesonide Rectal Aerosol, Foam 205613
Canagliflozin; Metformin Hydrochloride Oral Tablet, Extended Release 205879
Dantrolene sodium Intravenous Suspension 205579
Dapsone Topical Gel 207154
Deflazacort Oral Suspension 208685
Deflazacort Oral Tablet 208684
Docosanol Topical Cream 020941
Empagliflozin; Metformin Hydrochloride Oral Tablet, Extended Release 208658
Epinephrine Intramuscular/Subcutaneous Injectable 020800
Erythromycin Topical Gel 050617
Everolimus Oral Tablet for Suspension 203985
Fluorometholone Ophthalmic Drops, Suspension 016851
Fluticasone propionate inhalation Aerosol, metered 021433
Fluticasone propionate inhalation Powder 020833
Hydrocortisone acetate Rectal Aerosol, Metered 017351
Ivermectin Topical Cream 206255
Levorphanol tartrate Oral Tablet 008720
Lisdexamfetamine dimesylate Oral Tablets, Chewable 208510
Methylphenidate Hydrochloride Oral Tablets, Extended Release 18029
Mometasone furoate Inhalation Powder 021067
Nitisinone Oral Capsule 021232
Olaparib Oral Capsule 206162
Osimertinib mesylate ( Oral Tablets 208065
Permethrin Topical Cream 019855
Pirfenidone Oral Tablet 208780
Salmeterol Xinafoate Inhalation Powder 020692
Telotristat etiprate Oral Tablet 208794
Terbutaline sulfate Oral Tablet 017849
Tiotropium bromide) Inhalation Powder 021395

Seyfarth Shaw will continue to provide updates to the FDA’s Product Specific Guidance as well as other updates on generic drugs provided by the FDA.  If you have any questions or we can provide any assistance, please do not hesitate to contact us.


[1]             See Section 505(j)(2)(A)(iv) of the FD&C Act; 21 C.F.R. § 314.94(a)(7).

[2]             Section 505(j)(8)(B)(i) of the FD&C Act. See also section 505(j)(8)(B)(ii), (C) of the FD&C Act; 21 C.F.R. §§ 320.1(e), and 320.23(b).

[3]             See 21 C.F.R. § 320.24(a).

[4]             See 21 C.F.R. § 320.24(b).