FDA releases 24 new, 14 revised product-specific guidances

Several new and revised product-specific guidance documents published this week by the FDA’s Office of Generic Drugs provide recommendations for the development of various generic drug products, including several complex generics.

• Regulatory Background  

  • Unlike new drug products, generic drugs do not require extensive clinical evidence to demonstrate safety or efficacy. Rather, under the terms of the 1984 Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman Act), a generic drug must only show that it is bioequivalent to the reference listed drug (RLD). Under federal law, companies are required to show that “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.”
  • Demonstrating bioequivalence can still be difficult, though. In order to help generic drug manufacturers navigate this process and increase the likelihood of generating appropriate regulatory data, the FDA publishes product-specific guidance (PSG) documents which detail how a company can demonstrate that its product is generic to the RLD through bioequivalence testing. There are nearly 2,000 PSGs available from the FDA.
  • PSGs typically outline key study considerations for prospective generic drug developments to follow, including the number of studies to be conducted, the types of studies (such as fed or fasting), the design of the study (e.g., crossover design, the number of periods and number of doses), specific measurements to take, the timing of measurements, specific concerns such as interactions with alcohol, and any waivers available for use.

  The FDA has also been focused on advancing complex generic products using various mechanisms including PSGs.  

  • Since the passage of the first Generic Drug User Fee Amendments (GDUFA) in 2012, the FDA has provided extensive research funding in support of the approval of complex generic products through advances in regulatory science.
  • GDUFA II renovated the complex generic drug development and approval process. In 2016, the FDA committed to various programs to enhance the pathway for complex products including guidance and policies for product development meetings, pre submission meetings, and mid-review cycle meetings; complex controlled correspondence; product specific guidances (PSGs) as well as other regulatory science initiatives.

  What’s New

  • This week the FDA posted 24 new and 14 revised PSGs meant to support the new (or continued) development of generic drugs. The agency also updated its planned list of PSGs for complex generic drug products yesterday.
  • Although the newly released and updated PSGs do not contain any of the complex generic products listed by the FDA, some are intended for the development of complex generic products. For example, flunisolide uses a nasal spray meter, naloxone hydrochloride nasal spray and halobetasol propionate topical aerosol foa.
  • Several of these products were approved as recently as 2021. For example, Genentech’s Gavreto (pralsetinib) and Evrysdi (risdiplam) were approved in 2020 while Loreev XR (lorazepam) by Almatica Pharma, Soaanz (torsemide) by Sarfez Pharma, and Kloxxado (naloxone hydrochloride) by Hikma pharmaceuticals were all approved in 2021. These early PSGs are typically helpful to facilitate timely generic competition once the drugs lose patent and exclusivity protections.

  New Draft Guidance  

  Active Ingredient	Brand Name	Sponsor
  Acetaminophen	ACETAMINOPHEN	Upsher-Smith Laboratories
  Arsenic trioxide	TRISENOX	Cephalon Inc
  Asenapine	SECUADO	Hisamitsu Pharmaceutical
  Bupivacaine	POSIMIR	Durect Corporation
  Cedazuridine; Decitabine	INQOVI	Astex Pharmaceuticals
  Chlorhexidine gluconate	PERIOCHIP	Target Research Associates
  Cocaine hydrochloride	NUMBRINO	Cody Laboratories
  Exenatide synthetic	BYDUREON	AstraZeneca
  Exenatide synthetic	BYDUREON BCISE	AstraZeneca
  Flunisolide	NASALIDE	Ivax Research
  Halobetasol propionate	LEXETTE	Mayne Pharma
  Hydrocortisone; Neomycin sulfate; Polymyxin B sulfate	CASPORYN HC	Casper Pharma
  Ibuprofen	INFANT’S ADVIL	GSK
  Lorazepam	LOREEV XR	Almatica Pharma
  Naloxone hydrochloride	KLOXXADOTM	Hikma Pharmaceuticals
  Oliceridine	OLINVYK	Trevena Inc
  Palbociclib	IBRANCE	Pfizer
  Pralsetinib	GAVRETO	Genentech
  Risdiplam	EVRYSDI	Genentech
  Secretin synthetic human	CHIRHOSTIM	Chirhoclin Inc
  Solifenacin succinate	VESICARE LS	Astellas Pharma
  Tegaserod maleate	ZELNORM	Alfasigma
  Torsemide	SOAANZ	Sarfez Pharmaceuticals
  Triheptanoin	DOJOLVI	Ultragenyx Pharmaceutical

  Revised Guidance  

  Active Ingredient	Brand Name	Sponsor
  Acarbose	PRECOSE	Bayer Healthcare
  Doxorubicin hydrochloride	DOXIL (LIPOSOMAL)	Baxter Healthcare
  Linaclotide	LINZESS	Allergan
  Metoprolol succinate	KAPSPARGO SPRINKLE	Sun Pharma
  Midostaurin	RYDAPT	Novartis Pharmaceuticals
  Oseltamivir phosphate	TAMIFLU	Hoffmann La Roche
  Selinexor	XPOVIO	Karyopharm Therapeutics
  Solifenacin succinate	VESICARE	Astellas Pharma
  Testosterone	TESTOPEL	Auxilium Pharmaceuticals
  Theophylline	THEO-DUR (100MG, 200MG, 300MG)	Alembic Pharmaceuticals
  Tiopronin	THIOLA EC	Mission Pharmacal Co
  Torsemide	DEMADEX	Mylan Specialty
  Trametinib dimethyl sulfoxide	MEKINIST	Novartis Pharmaceuticals
  Uridine triacetate	VISTOGARD; XURIDEN	Wellstat Therapeutics

   
   
  Featuring prior research from Lily Rosenfield
  To contact the author of this piece, please email Kedest Tadesse.
  To contact the editor of this piece, please email Alexander Gaffney.

  Key Documents and Dates  

  • Product-Specific Guidances
  • Federal Register Notice
  • Upcoming Product-Specific Guidances for Complex Generic Drug Product Development