For many drug products, determining the qualitative (Q1) and quantitative (Q2) formulation for purposes of establishing sameness of formulation to that of the innovator or reference-listed drug (RLD) product can be quite a chore. If you can get it right, then it may be possible to obtain a waiver of in vivo bioequivalence requirements for certain drug products (e.g., ophthalmics, parenterals, and even some topical and solid oral dosage forms). The benefit, of course, may be avoiding costly in vivo studies or bioequivalence studies with clinical endpoints.
The process of establishing Q1 and Q2 is cumbersome and often requires numerous controlled correspondences (CCs) to the Office of Generic Drugs (OGD); even then, often you or the FDA still might get it wrong, resulting in time lost in product development and (more importantly) developing a product based on an erroneous response to a CC from the OGD and finding that out during the review of your application. We have written blogs about this experience several times, most notably our post here titled For Q1 and Q2 Determinations, OGD Nixes “The Price Is Right” Process! This post further explains why the generic industry has had such a hard time with the process (e.g., establishing the ± 5% of inactive ingredients that appear in the innovator formulations in very small amounts, among others).
The FDA has been very protective of how it responds to these CCs as it works to provide information to assist the ANDA applicants but, at the same time, to protect the confidential, trade‑secret information of listed drug holders. However, a bill recently introduced into the House of Representatives may provide some relief to the Agency and, hence, the industry. ”H.R. 7032: The Increasing Transparency in Generic Drug Applications Act requires the FDA to inform ANDA applicants of critical information about the identity of ingredient(s) that cause a proposed generic product not to be Q1/Q2 the same as the RLD and the direction of any identified deviation.” The full draft of the bill can be found here.
The bill features the following changes to the Federal Food, Drug, and Cosmetic Act:
- Upon request (in controlled correspondence or otherwise), the Secretary shall inform the person whether such new drug is qualitatively and quantitatively the same as the listed drug.
- If the proposed formulation(s) in the CC do not conform to the Q1/Q2 nature as that of the listed drug, the Secretary shall identify and disclose to the requestor:
- the ingredient or ingredients that cause the new drug not to be qualitatively or quantitatively the same as the listed drug; and
- the quantity or proportion of any ingredient in the listed drug for which there is an identified quantitative deviation.
In addition, there are provisions that prohibit the FDA from changing or rescinding its determination after the submission of the ANDA unless the listed drug’s formulation has been changed and the original formulation was withdrawn for safety or efficacy reasons. Or if the ”Secretary makes a written determination that the prior determination must be changed because an error has been identified.” This provision appears to give the Agency an out if an error has been made and can still cause trouble for a firm’s development activities or, ultimately, in their ANDA submission. Also, If the bill passes, the Agency is required to issue a draft guidance for comment on this process within one year of passage of the revision to the law.
So, while there is hope on the horizon, it remains to be seen whether this hope will be dashed and the bill will die, or, if it does pass, whether it would be challenged and struck down by the courts! Anyway, the existence of a draft bill is good news for the generic industry as at least some in Congress recognize the ongoing problems ANDA applicants are having establishing Q1/Q2 sameness to the listed drugs. In my opinion, the issue of how this bill would impact the issue of the confidential commercial nature of the information of the listed-drug manufacturer and whether the new law would survive challenge may be the key sticking points.