By Kurt R. Karst –
The first iteration of the Generic Drug User Fee Amendments (“GDUFA”) – “GDUFA I” – is now well into Year 4 of the 5-year program, and anticipation is growing as to what the second iteration of the program – “GDUFA II” – might hold for the generic drug industry. According to the various (and not terribly transparent or informative!) minutes from the GDUFA Reauthorization Stakeholder Meetings and the GDUFA Reauthorization Negotiation Sessions, we can expect many small changes and refinements to GDUFA, but probably not a lot of big changes. Many (if not most) of the changes may be captured in what will be the GDUFA II Performance Goals and Procedures letter accompanying the GDUFA II legislation. Most folks probably would not be surprised to learn that we have a GDUFA II wish list: a list of some of the things we hope to see included in the next iteration of the user fee program. Most of the items we’re hoping for are small changes. For example, we would like to see user fee relief for small businesses, prompt posting of all final and tentative ANDA approval letters (along with a return to the “date of submission” listed in the letter – see here) (after all, one of the tenets of GDUFA is transparency) . . . and a deadline for FDA to rule on a citizen petition requesting that the Agency designate a drug as a Reference Listed Drug (“RLD”). That last item may seem a bit out of left field to most folks, but it’s important to ANDA (and to 505(b)(2) NDA) applicants.
FDA stated the Agency’s policy for designating RLDs back in 1992 in the preamble to the Agency’s final regulations implementing certain provisions of the 1984 Hatch-Waxman Amendments. There (57 Fed. Reg. 17,950, 17,958 (Apr. 28, 1992)), FDA stated:
FDA will designate all reference listed drugs. Generally, the reference listed drug will be the NDA drug product for a single source drug product. For multiple source NDA drug products or multiple source drug products without an NDA, the reference listed drug generally will be the market leader as determined by FDA on the basis of commercial data. FDA recognizes that, for multiple source products, a product not designated as the listed drug and not shown bioequivalent to the listed drug may be shielded from direct generic competition. If an applicant believes that there are sound reasons for designating another drug as a reference listed drug, it should consult FDA. Once FDA designates that reference listed drug, that drug will continue to be the reference standard even if the drug is later replaced as the market leader.
FDA’s policy is further described in the recently revised preface to the Orange Book:
By designating a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent, FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart. Such variations could result if generic drugs were compared to different drugs.
However, in some instances when a listed drug is not designated as the reference listed drug and/or not shown to be bioequivalent to the reference listed drug, such listed drug may be shielded from generic competition. An applicant wishing to market a generic version of a listed drug that is not designated as the reference listed drug may petition the Agency through the citizen petition procedure (see 21 CFR 10.25(a) and CFR 10.30). If the citizen petition is approved, the listed drug will be designated as an additional reference listed drug, in which case an ANDA citing the designated reference listed drug may be submitted.
Over the years, FDA has received and responded to scores of citizen petitions requesting that the Agency assign RLD status to various NDA and ANDA approved drug products. FDA only very rarely denies a citizen petition requesting RLD designation (see our previous post here). Given the rarity of denials, and what we think should be a relatively perfunctory process, it’s surprising to us that FDA takes soooo long to issue a decision on an RLD designation citizen petition request. Just take a gander at our FDA Citizen Petition Tracker for all of the pending petitions identified as “”Citizen Petition - RLD Designation” under “Petition Type.” Some have been pending for years with nothing more than the boilerplate interim response required within 180 days after FDA receives a petition.
And worse yet, an applicant is stuck in limbo until FDA grants the petition and designates the identified drug as an RLD. That’s right – an ANDA (and probably a 505(b)(2) NDA as well) would be shot down upon submission unless the drug product identified in the application as the basis of submission is not identified in the Orange Book with a “+” showing RLD status. (See our previous post on the difference between what we’ve termed the “big RLD” and the “little rld.”) In fact, draft FDA guidance (“ANDA Submissions — Content and Format of Abbreviated New Drug Applications”) says as much:
When an applicant wants FDA to designate a second RLD, the request is made through a citizen petition submitted to FDA’s Division of Dockets Management in accordance with §§ 10.20 and 245 10.30. An applicant may submit the application only after the citizen petition has been granted. [(Page 7; emphasis added)]
Moreover, we’ve been told that the Division of Filing Review (“DFR”) in the Office of Generic Drugs would issue a Refuse-to-Receive (“RTR”) letter to an applicant if the incoming ANDA identifies a drug product that is not designated as a RLD as the basis of submission of the application. Although DFR would likely first give the ANDA applicant an opportunity to change the basis of submission to a product that is identified as an RLD before issuing an RTR letter, in most instances that’s not an option for an ANDA applicant.
Other types of citizen petitions are subject to a statutory deadline. There’s the 150-day deadline for so-called “Section 505(q) Citizen Petitions,” a 270-day deadline for FDA to respond to so-called “Section 505(w) Discontinuation Citizen Petitions,” and a 90-day deadline for FDA to respond to an ANDA Suitability Petition. FDA’s been pretty good about meeting the newer statutory deadlines for 505(w) and 505(w) petitions (see our previous posts here and here), but FDA’s 30-plus year history of responding to ANDA Suitability Petitions in a timely manner is pretty dismal (you can read our analysis of that track record here). In any case, if RLD Designation petitions were subject to a statutory deadline, or, better yet, a performance goal under GDUFA II – perhaps 90% of petitions reviewed and acted on within 60 or 90 days of receipt – we would probably see better results. And ANDA applicants would be in a better position to plan and seek approval.