The 505(b)(2) pathway, between brand and generic

On Jan. 28, 2025, FDA approved an oral suspension of hydrochlorothiazide, a diuretic long sold as tablets and capsules. The application was not a generic one, and it did not have to rest entirely on the applicant's own studies either. It used a third route in federal law, section 505(b)(2), which lets an applicant lean partly on what FDA already knows about a drug the applicant did not develop.

That route is busier than most people realize. Of the 111 original new drug applications FDA's drug center approved or tentatively approved in calendar 2025, 47 were 505(b)(2) applications, according to CDER's year-end approvals report¹. In 2024 the pathway accounted for more than half, 53 of 96, by the 2024 report².

The 505(b)(2) pathway explains a lot of what sits between brand drugs and generics, such as oral liquids of drugs once sold only as tablets, injections in new concentrations or ready-to-use forms, and combinations of older ingredients. These products arrive with their own applications, their own patents and sometimes their own exclusivity, and they are not generics, even when the active ingredient has been generic for years.

Three ways to get a drug approved

The federal drug law, 21 U.S.C. 355⁴, describes three kinds of applications. A full new drug application under 505(b)(1) contains the sponsor's own studies of safety and effectiveness. An abbreviated application under 505(j), the generic route described in our guide to how a generic gets approved, shows that a product is the same as an approved drug and bioequivalent to it. A 505(b)(2) application sits between them. FDA's regulations define it as an application for which "at least some of the investigations" relied on for approval "were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use."

Both shortcuts date to the Hatch-Waxman Act of 1984, which added them to the law in the same package that created patent term restoration for brands.

Fees in the table come from FDA's fiscal 2026 prescription drug user fee notice⁹ and generic drug user fee notice¹⁰, both published July 30, 2025. Because a 505(b)(2) application is a new drug application, it generally pays the brand-side fee.

What a 505(b)(2) application has to show

FDA's rule for these applications, 21 CFR 314.54⁶, starts from a limit on generics. The law does not permit approval of an ANDA for a new indication, or for other changes to a listed drug, if investigations other than bioavailability or bioequivalence studies are essential to approving the change. A company seeking that kind of modification may file a 505(b)(2) application, and the application "need contain only that information needed to support the modification(s) of the listed drug." The rest comes from FDA's earlier finding about the original product.

FDA has also drawn lines around the pathway. Its May 2019 guidance⁵ on choosing between the two abbreviated routes says FDA "generally will refuse to file a 505(b)(2) application for a drug that is a duplicate of a listed drug and eligible for approval" as a generic. The same guidance describes an alternative for some changes. An applicant can ask FDA, through a suitability petition, for permission to file a generic application for a product that differs from the reference drug in route, dosage form or strength, or in one ingredient of a combination, if FDA agrees no new safety and effectiveness studies are needed.

Patents work much as they do for generics. A 505(b)(2) applicant must certify to each patent listed for the drug it relies on, and a Paragraph IV challenge can draw a lawsuit and a 30-month stay. The reward side is different. Under 21 CFR 314.108⁷, an application for a previously approved active moiety that contains new clinical investigations essential to approval earns 3 years during which FDA will not approve competing applications for the same conditions of approval. FDA issued draft question-and-answer guidance¹³ on that 3-year exclusivity in March 2026. The five-year protection for a new molecule works differently, as explained in New chemical entity exclusivity.

What FDA approved through the pathway, 2023 to 2025

CDER's calendar-year approvals reports for 2023³, 2024 and 2025 list every original NDA approval, and the handful of tentative approvals, with a column marking 505(b)(2) applications. GxRadar counted those flags and compared them with original generic approvals in openFDA data, the same counts shown on our approvals page.

Seventeen of the 158 505(b)(2) entries carry FDA's footnote for a tentative approval or an approval under the President's Emergency Plan for AIDS Relief (PEPFAR), which our piece on tentative approvals explains. We then matched all 158 to Drugs@FDA data files¹² dated Oct. 30, 2026, which record each application's chemical type. Sixty-two were classed as a new formulation or new manufacturer, 55 as a new dosage form and 18 as a new combination. Ten involved a new active ingredient, such as a different salt of an approved molecule, and eight were classed as new molecular entities, a reminder that the pathway is not limited to reformulations. By route, 66 were taken by mouth and 60 were injected.

A sample of 2025 approvals shows the pattern, along with one from 2023:

• Atorvastatin oral suspension, approved Feb. 1, 2023, a liquid form of the statin sold generically as atorvastatin tablets.
• Hydrochlorothiazide for oral suspension, Jan. 28, 2025.
• Metoprolol tartrate oral solution, April 10, 2025, a liquid counterpart to metoprolol tartrate tablets.
• Bumetanide nasal spray, Sept. 12, 2025.
• Furosemide solution for injection under the skin, Oct. 7, 2025, a different route for a drug best known as furosemide tablets.
• Clonidine oral solution, Oct. 23, 2025, alongside generic clonidine tablets.

In the Orange Book product file dated October 2026, each of those six is listed as a reference listed drug with no therapeutic equivalence code.

Why these products are not generics

A therapeutic equivalence rating is what allows a pharmacist, under most state substitution laws, to fill a prescription with a different company's product. FDA's Orange Book preface¹¹ says products are therapeutic equivalents only if they are pharmaceutical equivalents, which means "identical dosage forms and route(s) of administration" with identical amounts of the same active ingredient, and bioequivalence has been shown. An oral solution and a tablet of the same drug are different dosage forms, so neither can be rated equivalent to the other. Our explainer on therapeutic equivalence codes covers the ratings in detail.

A 505(b)(2) product is therefore its own market. It can carry a brand name and a brand price while tablets of the same molecule cost almost nothing; in October 2026, pharmacies paid an average of about 1.1 cents per hydrochlorothiazide 25 mg tablet, according to GxRadar's analysis of CMS NADAC data⁸. It can also become the reference drug that later generic applicants copy once its patents and exclusivity run out. Whether a reformulated version is worth its price for a given patient is a question for a pharmacist or prescriber.

CDER's approvals report for calendar 2026 will run through Dec. 31 and will show whether the 505(b)(2) share keeps sliding from its 2024 level of 55 percent. The March 2026 draft guidance on 3-year exclusivity, which many of these products seek, remains a draft until FDA finalizes it.