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FDA releases 52 new and revised bioequivalence guidelines for generic drugs Posted 06/04/2018

As part of its ongoing efforts to provide product-specific guidance for generics makers the US Food and Drug Administration (FDA) has again released several new and revised bioequivalence documents. The agency announced on 1 February 2018 that it had released 35 new draft guidance documents and 22 revisions to guidance documents on bioequivalence requirements for the development of generics containing 49 different active ingredients.

The new draft bioequivalence guidance documents cover generics of Takeda’s multiple myeloma drug Ninlaro (ixazomib), attention-deficit/hyperactivity disorder (ADHD) treatment Ritalin-SR (methylphenidate HCl) from Novartis, Bayer’s Aleve-D Sinus & Cold (naproxen/pseudoephedrine) and Merck’s cholesterol lowering medication Zocor (simvastatin) among others, see Table 1.

Revised bioequivalence guidance documents include those for generics of Bristol-Myers Squibb’s hepatitis C treatment Daklinza (daclatasvir dihydrochloride), anticonvulsant felbamate, proton pump inhibitors lansoprazole and dexlansoprazole, and opioid pain treatment oxycodone, among others, see Table 2.

FDA bioequivalence requirements demand that the generic drug performs in the same way in the body and has the same active ingredient(s), strength, dosage form and route of administration as the brand-name reference drug.

Table 1: FDA new draft bioequivalence guidance documents

Active ingredient

Route of administration

Dosage form

Link

Alcaftadine

Ophthalmic

Drops/ solution 0.25%

Click here

Amitriptyline hydrochloride/ chlordiazepoxide

Oral

Tablet

Click here

Amphetamine sulfate

Oral

Tablet

Click here

Barium sulfate

Oral

Suspension 98% (334g/ bottle)

Click here

Barium sulfate

Oral

Suspension 2% (9g/ 450 mL)

Click here

Betamethasone dipropionate

Topical

Ointment, augmented

Click here

Bimatoprost

Ophthalmic

Drops/ solution 0.03%

Click here

Bimatoprost

Ophthalmic

Drops/ solution 0.01%

Click here

Bimatoprost

Topical

Drops/ solution 0.03%

Click here

Bupivacaine

Injectable

Liposomal, injection

Click here

Buprenorphine hydrochloride

Buccal

Film

Click here

Cabozantinib S-malate

Oral

Capsule

Click here

Cabozantinib S-malate

Oral

Tablets

Click here

Crisaborole

Topical

Ointment

Click here

Desonide

Topical

Aerosol foam

Click here

Doxycycline hyclate

Oral

Tablet

Click here

Fluocinonide

Topical

Cream

Click here

Hydrocortisone valerate

Topical

Cream

Click here

Ixazomib citrate

Oral

Capsule

Click here

Ketoconazole

Oral

Tablet

Click here

Leuprolide acetate; Norethindrone acetate

Oral/ intermuscular

Tablet/ injectable depot

Click here

Levetiracetam

Oral suspension

Tablet

Click here

Levocetirizine dihydrochloride

Oral

Tablet

Click here

Loteprednol etabonate

Ophthalmic

Suspension/drops; 0.2%

Click here

Mebendazole

Oral

Tablet, chewable

Click here

Naldemedine tosylate

Oral

Tablet

Click here

Naproxen sodium/ pseudoephedrine hydrochloride

Oral

Tablet, ER

Click here

Niraparib tosylate

Oral

Capsule

Click here

Olopatadine hydrochloride

Ophthalmic

Drops/ solution

Click here

Prasterone

Vaginal

Insert

Click here

Rucaparib camsylate

Oral

Tablet

Click here

Safinamide mesylate

Oral

Tablet

Click here

Simvastatin/ sitagliptin phosphate

Oral

Tablet

Click here

Soybean oil

Injectable

Injection

Click here

Soybean oil

Injectable

Injection

Click here

ER: extended release.

Table 2: FDA revised draft bioequivalence guidance documents

Active ingredient

Route of administration

Dosage form

Link

Aspirin/ omeprazole

Oral

Tablet, DR

Click here

Cysteamine bitartrate

Oral

Tablet, DR

Click here

Daclatasvir dihydrochloride

Oral

Tablet

Click here

Dexlansoprazole

Oral

Tablet, DR, OD

Click here

Dexlansoprazole

Oral

Capsule, DR

Click here

Esomeprazole magnesium

Oral

Powder for suspension, DR

Click here

Esomeprazole magnesium

Oral

Capsule, DR

Click here

Felbamate

Oral

Suspension

Click here

Felbamate

Oral

Tablet

Click here

Fluconazole

Oral

Tablet

Click here

Gatifloxacin

Ophthalmic

Solution

Click here

Gentamicin sulfate

Ophthalmic

Drops/ solution

Click here

Ketorolac tromethamine

Nasal

Spray

Click here

Lansoprazole

Oral

Tablet, DR, OD

Click here

Loteprednol etabonate

Ophthalmic

Suspension/drops; 0.5%

Click here

Morphine sulfate

Oral

Capsule, ER

Click here

Naloxegol oxalate

Oral

Tablet

Click here

Oxycodone

Oral

Capsule, ER

Click here

Pantoprazole sodium

Oral

Powder for Suspension, DR

Click here

Potassium citrate

Oral

Tablet, ER

Click here

Sulfamethoxazole; trimethoprim

Oral

Tablet

Click here

Triamcinolone acetonide

Dental

Paste

Click here

DR: delayed release; ER: extended release; OD: orally disintegrating.

The draft guidance documents recommend what in vivo and in vitro studies generics companies should carry out in order to demonstrate bioequivalence. The number of studies, the population to be studied, blood sampling time points and analytes to be measured in blood samples are also detailed in the draft guidance documents. Some of the documents also provide discussion on data formats.

FDA also has an overarching guidance document on bioequivalence recommendations for specific products [1], as well as a dissolution methods database.

FDA Commissioner Scott Gottlieb said that to date the agency has ‘now published about 1,600 of these product-specific guidances laying out the path for developing generics to specific products; including more than 350 guidances for developing generics of complex drugs’.

Comments on the draft guidance documents can be posted to the Division of Dockets Management (DDM) under Docket FDA-2007-D-0369-0015. This can be done via the website www.regulations.gov or written comments can be mailed to DDM (HFA-305), FDA, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

Related article
FDA releases 52 new and revised bioequivalence guidelines for generics

Reference
1. GaBI Online - Generics and Biosimilars Initiative. US guidelines for generics [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Apr 6]. Available from: www.gabionline.net/Guidelines/US-guidelines-for-generics

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Source: US FDA

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