The pharmaceutical industry is complex and expensive. Companies and investors deserve certainty. Imagine asking an agency what to do, the agency tells you to do X, you invest time/effort/resources into doing X, and when you file the drug application on X, the agency says “oops, it’s not-X”. The applicant is ambushed and doesn’t know why or how to resolve the issue. Much money and time is spent. This situation can arise in the ANDA context when determining “sameness” to the Reference Listed Drug.
The requirement for sameness in certain generic drug applications is rooted in regulatory mandates rather than statutory law. The FDA enforces these requirements under 21 C.F.R. §314.94(a)(9), with varying degrees of strictness depending on the type of drug product.
For solid oral dosage forms, the FDA allows some deviations from strict sameness. Conversely, the requirements for parenteral drugs are more strict for sameness. Per 21 C.F.R. §314.94(a)(9)(iii), generic injectables must closely mimic the reference listed drug (RLD), although certain exceptions apply for non-active components such as preservatives, buffers, or antioxidants. Similarly, ophthalmic and otic products fall under 21 C.F.R. §314.94(a)(9)(iv), where limited non-sameness is permitted.
In essence, the FDA’s Q1/Q2 sameness standard requires generic formulations to be qualitatively (Q1) and quantitatively (Q2) the same as the brand-name product. Q1 sameness refers to the use of identical inactive ingredients, while Q2 sameness ensures these ingredients are present in essentially the same concentrations. When a proposed generic drug fails to meet these requirements, the FDA can issue a Refuse to Receive (RTR) letter, complete response letter (CRL) denying the application outright, or significantly delay the approval process. This can compel the generic manufacturer to abandon the application or reformulate the product, both of which increase costs and prolong market entry.
To address trade secret-related formulation uncertainties, generic drug applicants must navigate the FDA’s Controlled Correspondence process, as outlined in FDA guidance for industry, including the Dec. 2020 document titled “Controlled Correspondence Related to Generic Drug Development.” This process allows manufacturers to submit up to three proposed formulations for preliminary review. If none meet Q1/Q2 requirements, manufacturers receive no substantive guidance other than confirmation of non-compliance. According to the FDA’s guidance on Q1/Q2 sameness, the agency “does not intend to provide clarification on why a formulation is not Q1/Q2 the same as the RLD.” In other words, the FDA will reject the proposed formulations but not tell the ANDA applicant why or which ingredient is problematic.
Given the vast number of potential formulation permutations, generic manufacturers often endure multiple rounds of correspondence before identifying an acceptable composition. This iterative process drains time and resources from both the FDA and the industry, further delaying the availability of cost-saving generic medications.
Now assume the ANDA applicant participated fully in the Q1/Q2 controlled correspondence process and the FDA agreed that proposed formulation #2 was compliant. The ANDA sponsor completes the development, pays the GDFUA fee, and then gets ambushed by a Refuse to Receive (RTR) the ANDA. What options exist now?
1. Check the clock – you get one shot at division-level “Request for Reconsideration” (RfR)
| Rule | What it does | Deadline |
|---|---|---|
| MAPP 5200.12 / GDUFA III § II.E | Ask the Division of Filing Review (DFR) to reverse an RTR without opening a new ANDA | 7 calendar days from the RTR letter |
| Guidance “Requests for Reconsideration at the Division Level Under GDUFA” (Oct. 2024) | Lists the four required elements (cover sheet, point-by-point rebuttal, clean copy of the module, certification that no new data are added) | same 7-day or 30-day window |
Practical tips
- Attach the FDA-authored minutes (or the actual response) to your earlier controlled correspondence that named Formulation #2 as Q1/Q2-compliant.
- Quote back the Q1/Q2 regulation 21 C.F.R. §314.94(a)(9)(iii)-(iv) and show that the RTR relies on §314.101(d)(3), the same provision FDA already applied and blessed.
- Keep it surgical; you cannot tack on new information in an RfR (see 21 C.F.R. §10.75(d)).
2. If the division digs in, climb the formal dispute ladder:
- After divisional reconsideration, administrative/procedural appeals can be made to the Ombudsman (21 C.F.R. §314.103(b)) or for scientific/medical issues to the Director level (§314.103(c)).
- More information can be found in the Guidance: Formal Dispute Resolution Sponsor Appeals Above Division Level (Nov. 2017, Rev. 1 (May 2019).
- Commissioner level appeal are under 21 C.F.R. §10.75.
3. “Receive over protest” is not available for ANDAs
§314.101(a)(3) (the “file-over-protest” option) only covers NDAs. For ANDAs the RfR/FDRR path is the surrogate.
4. Resubmit or amend the ANDA and keep your user-fee credit alive:
- FDA treats a complete resubmission that fixes every deficiency in the RTR letter as a new receipt date, but you may carry forward the original GDUFA fee (no second payment).
- Resubmitting within 12 months preserves your place in the review queue; after that, it is a brand-new application. See §314.101(b)(3)(iii); also, Guidance: ANDA Submissions: Refuse-to-Receive Standards, pg. 17 (Dec. 2016, Rev. 2).
If you are convinced the FDA is simply wrong, you can resubmit the ANDA unchanged and continue the dispute in parallel; note this counts as a new cycle for GDUFA metrics.
5. Citizen petition or petition for stay of action
When the RTR looks like an unstated policy shift (e.g., a new excipient limit), a 21 C.F.R. §10.30 petition forces FDA to put its rationale on the public docket. Doing this does not toll your RfR deadlines, so file both concurrently. The Petition should include all arguments as to why the RTR is wrong, including if the sponsor is challenging the decision as being unlawful. Unlawful FDA actions include slavishly following non-binding guidances, policies, or manuals; to violating a stated regulation (arguing the FDA is not following the regulation as stated or the regulation is ultra vires of any implementing statute); and to violating any governing statute.
6. Judicial review under the Administrative Procedure Act
Once FDA finally denies the ANDA (e.g., after the dispute-resolution chain or a second RTR), you can sue under 5 U.S.C. §706(2)(A). Courts have vacated agency actions that contradicted earlier advice without reasoned explanation, see, Apotex Inc. v. FDA, 414 F. Supp. 2d 61 (D.D.C. 2006), aff’d, 226 F. App’x 4 (D.C. Cir. 2007). Sponsors must assure themselves that FDA is following statutes first, then regulations, and not following non-binding manuals or guidances first over clear statutes or regulations.
7. Secondary levers
- CDER Ombudsman: handy for process snarls when you just need someone inside FDA to shepherd the file.
- Congressional inquiry: politically sensitive but occasionally useful where public-health impact or drug shortages loom. The “policy” side of the FDA is sensitive to when politicians send letters to the agency asking why the agency did X versus Y. Such actions also help build an administrative record for later judicial review.
- Suitability petition (§355(j)(2)(C)): only if you decide to embrace the formulation differences rather than fight the Q1/Q2 point.
8. Lessons for next time
- When you receive controlled-correspondence advice, send an informal “request for clarification” within 20 days if the FDA minutes are ambiguous because that helps locks in the record.
- Archive the Agency email header that shows the responsible discipline; most RTR fights hinge on whether the same discipline is now taking a new position.
- For complex products, consider a pre-ANDA meeting instead of relying solely on controlled correspondence; those meeting minutes have stronger evidentiary weight.
- Often times the ANDA sponsor will request the controlled correspondence and gain FDA buy-in but then file the ANDA itself many months or even years later. The ANDA sponsor is surprised that the agency issued the RTR, but maybe circumstances drastically changed. Accordingly, if the sponsor expects that the ANDA filing itself will be long after the FDA agreement, the sponsor should docket some touch points with the agency to continuously inform and seek clarification if any criteria have changed.
Bottom line
An RTR is not the end of the road. Start with a fast but thorough Request for Reconsideration, preserve every piece of documentary reliance, and be ready to escalate through FDA’s appeal ladder. If the Agency still refuses to square its new stance with the written advice it already gave you, the courts have shown they will step in.
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