On April 10, U.S. Senators Maggie Hassan (D-NH), Rand Paul (R-KY), John Hickenlooper (D-CO), and Mike Lee (R-UT) reintroduced bipartisan legislation S. 1302 that would prevent the FDA and industry from participating in a protracted guessing game regarding the amount of an inactive ingredient for a subset of generic drugs that are either required by regulation or found from a scientific perspective to be acceptable for the use of this approach to result in a formulation that is both qualitatively (Q1) and quantitatively (Q2) the same as the reference listed drug that it proposes to copy.
This has been a historical problem since the early days of Hatch-Waxman and became a major sticking point in the review of ophthalmic, otic, and parenteral drug products as well as drug products in solution. If your product was Q1 and Q2 the same, you may be able to use physicochemical characterization and other in-vitro testing to obtain a waiver of in-vivo bioequivalence study requirements; this could potentially save firms hundreds of thousands of dollars by not having to conduct expensive in-vivo tests. It has become even more important today as science has moved forward; now this approach can be used for a number of solid oral dosage forms, suspensions, creams, and ointments, etc. It was often quite a guessing game and the parameters of how you could guess changed over time. Sometimes acknowledgement of success was through a wink and a nod!
As the FDA website for Product-Specific Guidances (PSGs) for Generic Drug Development (here) notes:
“According to 21 CFR 320.24, different types of evidence may be used to establish bioequivalence (BE) for pharmaceutically equivalent drug products, including in vivo or in vitro testing, or both. The selection of the method used to demonstrate BE depends upon the purpose of the study, the analytical methods available, and the nature of the drug product. Under this regulation, applicants must conduct BE testing using the most accurate, sensitive, and reproducible approach available among those set forth in 21 CFR 320.24.”
As you scroll through the PSGs, you’ll find quite a few recommendations that provide an option to perform either in-vivo studies or in-vitro testing to establish bioequivalence. For instance, a newly published draft guidance for the acne treatment gel “Adapalene; Benzoyl Peroxide; Clindamycin Phosphate” (here) outlines the following two options for meeting bioequivalence:
“(1) one in vitro bioequivalence study and other characterization tests or (2) one comparative clinical endpoint bioequivalence study.”
The catch for the in-vitro option is as follows:
“The test product should contain no difference in inactive ingredients or in other aspects of the formulation relative to the reference standard (RS) in the same packaging configuration (tube or pump) that may significantly affect the local or systemic availability of the active ingredients. For example, if the test product and RS are qualitatively (Q1) and quantitatively (Q2) the same, as defined in the most recent version of the FDA guidance for industry on ANDA Submissions – Refuse-to-Receive Standards and the criteria below are also satisfied, the bioequivalence of the test product may be established using a characterization-based bioequivalence approach.”
Because reference listed drugs do not usually report Q1 Q2 formulation data, generic applicants must go through a process of submitting controlled correspondence (CC) to the OGD to ask whether their proposed formulation meets the Q1 Q2 requirements. An applicant can send up to three proposed formulations in a CC. The OGD must review each submitted formulation and can only respond that the proposed formulation either meets or does not match the formulation of the reference listed drug. This utilizes valuable resources from both the applicant and the FDA. And what’s worse is that multiple CCs may be required to hit the “Price is Right” Q1 Q2 jackpot. You can see how frustrating the process is for applicants as well as how much time the OGD must spend evaluating these requests.
The proposed legislation would eliminate the guessing game and endow the FDA with authority to provide accurate Q1 Q2 data to ANDA applicants upon request, saving both the FDA and industry the scarcest of all resources, time. Also, it will enable certain generic drug products to be brought to market sooner, which will save money for the American consumer. While a text copy of the reintroduced bill is not yet available, here is the text of the previous bill for your review.
