FDA OTC Monograph Changes Coming: User Fees, Pre-submission Meetings and Electronic Submissions

FDA User Fees for Reliance on the FDA OTC Monographs?

Although not included in FDARA, there is a reasonable possibility the proposed Over-the-Counter Monograph User Fee Program (OMUFA) will still become law. Assuming passage, Over-the-Counter (OTC) User Fees and electronic submissions will be required and sponsors will have the opportunity to engage in pre-submission meetings with FDA before requesting changes to OTC monographs. The process for effecting such changes will be known as Over-the-Counter Monograph Requests (OMORs).

PDG has significant experience in the strategic product development of nonprescription (OTC) products, including both monograph and NDA pathways. This includes 505(b)(2) submissions for both OTC approval and Rx-to-OTC switches, as well as drafting Citizen Petitions and comments to various dockets. Our proficiency and expertise extends to establishment registration and product listings (NDC codes), Drug Facts Labeling, formulation concerns, quality assurance/GMP challenges, and safety surveillance.

While we live in a Trump era of deregulation, OMUFA stands a realistic chance of becoming law. If not 2017, FDA continues to gear up for eventual passage.[1] According to FDA, additional resources are needed to “modernize the OTC review process to keep up with evolving science and the fast pace of the pharmaceutical and consumer healthcare products industry, and to finalize the pending monographs.”[2] (emphasis added).

The OTC monograph system has been largely unchanged since its beginning as an offshoot of the DESI program in 1972.[3] In the most basic terms, marketing an OTC drug requires a GMP compliant facility (including a system to track adverse events) and formulation/labeling in compliance with a proposed monograph via Advance Notice of Proposed Rulemaking (ANPR), Tentative Final Monograph (TFM) or a Final Monograph (FM). If an OTC drug is in compliance with a FM, it may be legally marketed. OTC drugs in compliance with ANPRs or TFMs, are marketed under FDA enforcement discretion until such time that the monograph is finalized.

Because ANPRs and TFMs have gone decades without being finalized, and include ingredients that are proposed as GRASE (generally recognized as safe and effective), the associated marketing risk to manufacturers has been somewhat manageable. However, only a final FDA determination of GRASE, or an approved NDA, assures a legal marketing status. There are no exclusivities associated with OTC monograph products.

While both the public (through Citizen Petitions or comments to the docket) or FDA may seek a change in a monograph, such changes have been slow, cumbersome and difficult because they require utilization of the rule-making process.[4] In FDA’s view, “innovation under the monograph has been difficult.” While the reliance upon the rule-making process will remain, it is clear that FDA intends to accelerate the OTC Review process and finalize pending monographs as quickly as possible.

The anticipated changes associated with OMUFA are numerous and have been described by FDA in great detail. However, the most significant changes from our perspective include a new regulatory pathway for requesting monograph changes (OMORs), pre-submission and other benchmark meetings with FDA, electronic submissions, and user fees. Following is a brief description of each. For a more detailed discussion, consult the FDA publication entitled Over-the-Counter Monograph User Fee Program Performance Goals and Procedures – Fiscal Years 2018-2022. In addition, FDA plans to conduct a Webinar on August 23, 2017 from 12:30pm-2:00pm eastern time to provide stakeholders with a status update. If you are reading this paper after that date, we will have participated in the webinar and will be happy to answer any questions you may have.

OMOR Submissions

What is an OMOR? Over-the-Counter Monograph Order Requests, or OMORs, are regulatory submissions planned and envisioned by FDA to equip industry to request monograph changes. Types of OMORs will include, at minimum, Innovation OMORs, GRASE Finalization OMORs, and Specified Safety Change OMORs. OMORs will be expected to include “all information, both positive and negative, relevant to the determination of general recognition of safety and effectiveness for the ingredient or other condition(s) of use under consideration”.

OMORs will initially be submitted using content and format recommendations contained in the November 2016 guidance for Industry Nonprescription Sunscreen Drug Products – Content and Format of Data Submissions. FDA notes that the format recommendations contained in this guidance are generally applicable to any monograph submissions.

Innovation OMORs will only be applicable to ingredients with a final GRASE determination. GRASE Finalization OMORs will be filed for ingredients without final GRASE determinations. While FDA expects that Innovation OMORs will be submitted after issuance of a final order regarding the GRASE determination for the ingredient, a requestor will also be permitted to co-submit a single OMOR package that addresses both issues. This will have the effect of allowing FDA a longer review time. For safety-related changes to the Drug Facts labeling, FDA intends a shorter timeline. In order to qualify for the shortened timelines, these types of OMORs will be stand-alone packages, not to include requests for other types of monograph changes. In order to illustrate the concept of the OMOR, we have excerpted from FDA’s description of an Innovation OMOR (Over-the-Counter Monograph User Fee Program Performance Goals and Procedures – Fiscal Years 2018-2022):

Prior to the proposed monograph reforms, innovation under the monograph has been difficult. Under monograph reform, sponsors (hereafter referred to as requestors when referencing submission of OMORs) will be able to submit data packages (Over-the-Counter Monograph Order Requests, or OMORs) to FDA, with requests that FDA issue an administrative order for a change to a monograph. Hereafter, these packages requesting changes to monographs will be referred to as “Innovation OMORs.”

a. Tier One and Tier Two Innovation OMORs
There will be two types of Innovation OMORs, referred to as Tier One Innovation OMORs and Tier Two Innovation OMORs. Most Innovation OMORs will be Tier One OMORs. Examples include, but are not limited to, requests for the following:

 

  • Addition of a new ingredient to a monograph that already has one or more ingredients that have been found to be GRASE
  • Addition of a new indication to a monograph that already has one or more ingredients that have been found to be GRASE, and the new indication applies to one or more of the GRASE ingredients
  • Addition of a new fixed-dose combination of ingredients to a monograph that already has one or more ingredients that have been found to be GRASE
  • Addition of a new test method for a monograph that already has one or more ingredients that have been found to be GRASE, and the new test method applies to one or more of the GRASE ingredients
  • Addition of a new route of administration for a monograph that already has one or more ingredients that have been found to be GRASE, and the new route of administration applies to one or more of the GRASE ingredients
  • Addition of a new dose or concentration for a GRASE ingredient for a particular monograph
  • Addition of a new monograph therapeutic category (each ingredient proposed for the new therapeutic category will be a separate OMOR)
  • All other Innovation OMORs not covered in Tier Two

 

Tier Two Innovation OMORs will be limited to requests for the following:

  • Reordering of existing information in the Drug Facts label (DFL)
  • Standardization of the concentration or dose of a specific finalized ingredient within a particular finalized monograph
  • An ingredient nomenclature change to align with nomenclature of a standards-setting organization
  • Addition of an interchangeable term under 21 CFR 330.1(i)
  • Modification to existing DFL Directions for Use, in order to be consistent with a final order/guidance pair on minor dosage form changes (see Section II.B.2)
  • Addition of information (either required or optional) to be included under the “Other Information” section of Drug Facts labeling, as limited by 21 CFR 201.66(c)(7)
  • Other specific items may be added by FDA later as FDA gains experience with Tier Two OMORs

 

The decision regarding whether a proposed Innovation OMOR meets one of the above criteria for a Tier Two OMOR will be made by the review division after receipt of the OMOR.

Pre-OMOR and Other Benchmark Meetings

Similar to PDUFA meetings, FDA intends to provide requestors with various opportunities to meet with FDA before OMOR submission and during OMOR review. Whereas PDUFA designates such meetings as Type A, B and C, OMUFA will analogously utilize Type X, Y and Z to classify meetings. Type X will be for the discussion of stalled programs, Type Y meetings will facilitate milestone discussions including pre-submission meetings, and Type Z meetings will be for all other OMOR topics.

Type Y pre-submission meetings will allow the requestor to “present a summary of the data supporting the proposed OMOR, and of the proposed format for the OMOR package, to obtain FDA feedback on the adequacy of the proposed package. For an Innovation OMOR, the proposed Tier (One or Two) may also be discussed at the pre-submission meeting. The pre-submission meeting should be held sufficiently in advance of the planned submission of the order request to allow for meaningful response to FDA feedback and should generally occur not less than 3 months prior to the planned submission of the order request.” Such meetings must be preceded by a Meeting Request and a Meeting Background Package. Once an OMOR is filed, FDA will also schedule in-review meetings with requestors (anticipated to be between 8 and 9 months after receipt of the OMOR). In-review meetings may be requested as face-to-face or as teleconferences.

Electronic Submissions

FDA has declared that “all monograph submissions from industry are to be electronic rather than paper” and that “Industry may submit monograph electronic submissions to FDA starting on October 1, 2017.” Below are additional statements relating to submissions:

  • “If the submission is not electronic, each item in the reference list and all in-text references should provide specific location data for the full copy of the referenced material.”
  • “FDA encourages electronic submissions… FDA recommends that the GRASE data submission be organized using the general structure and table of contents (TOC) described in the Common Technical Document (CTD) in effect at the time of the submission.”
  • “Whether the submission is electronic or paper, it should include navigation aids. If the submission is electronic, the TOC should include hyperlinks to each section. An electronic document that references another document in the submission should contain hyperlinks to the cross-referenced document or relevant part of the document. If a submission is not electronic, the submission should also be organized using the eCTD TOC.”

 

FDA plans to issue additional draft guidance addressing electronic submissions by October 1, 2019 and a final guidance for electronic submissions for the monograph by April 1, 2021. In the meantime, the recommendation is to utilize the instructions provided in the previously noted sunscreen guidance.

OTC User Fees

I will never forget the day in January 2007 when my co-author and I attended FDA’s Marketed Unapproved Drugs Workshop. After all the elaborate presentations and description of various regulatory pathways, the floor was opened for questions. The first question went something like this: “Are you guys going to lower user fees?” At that time, NDA User Fees had well over quadrupled from around $125,000 their first year,[5] and are over $2 million today (around $1 million without clinical trials). Original GDUFA Application User Fees (FY 2013) were $51,520 and today (FY 2017) are $70,480.[6]

While the projected fees have not yet been determined, FDA currently has 18 full-time-employees devoted to oversight of the OTC market.[7] The current plan calls for 31 reviewers by FY 2018, 110 by FY 2022 and around 140 by the time they reach what they describe as “steady state required to handle the eventual anticipated full workload of OMUFA activities.” In addition, a technology platform will need to be developed and implemented to support electronic submissions. Current budgeting does not fully address the demand for past document archival and electronic access. Suffice it to say that User Fees are probably lower now ($0) than they ever will be.

Conclusion

Whether you are concerned about the future of your OTC drug products, see opportunity to out-maneuver your competition, or both, feel free to contact PDG to assist with your nonprescription regulatory needs. As noted above, we have extensive experience in the development of both monograph and NDA nonprescription products as well as Rx-to-OTC switches.

About the Authors

Charles Jaap is Vice-President of Operations and Business Development for PDG®, a global pharmaceutical and medical device consultant with extensive experience in the strategic development of drug products and medical devices.

Mikel Alberdi, MPH, RAC is Director of Regulatory Affairs/New Product Development for PDG®. He has over 15 years of regulatory affairs experience, with expertise in facilitating FDA meetings and compiling NDA, 505(b)(2), and ANDA submissions.

The opinions and statements in this paper are solely those of Charles Jaap and Mikel Alberdi and do not necessarily reflect those of PDG®.

Sources:
[1] FDA: Over-the-Counter Monograph User Fee Program Performance Goals and Procedures – Fiscal Years 2018-2022. For the most part, this paper is comprised of information gleaned from that particular document. All quotes without footnotes may be assumed to have come from the document.
[2] Frequently Asked Questions: June 10, 2016 Public Meeting on OTC Monograph User Fees as accessed at www.fda.gov on August 10, 2017
[3] 37 FR 85; 37 FR 7807
[4] Safety related labeling changes may be effected without reliance on the rule-making process.
[5] Paying for Drug Approvals — Who’s Using Whom? Jerry Avorn M.D. New England Journal of Medicine, April 26, 2007.
[6] FDA User Fee Programs as accessed at www.fda.gov on August 10, 2017.
[7] Ibid.@2
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