Reforming FDA’s OTC Monograph Process

The US Food and Drug Administration (FDA) is receiving mixed signals in its efforts to improve the current Over-the-Counter Monograph Process for reviewing nonprescription drugs. After holding a public hearing earlier this year and opening the subject to public debate, the FDA is extending its public comment to the end of July. So what has the industry said thus far? DCAT Value Chain Insights takes an inside look.

The US Food and Drug Administration (FDA) has been assessing the OTC Monograph Process and, in particular, has been considering how effectively the monograph system is functioning. The agency has invited public comment to obtain information and comments on the strengths and weaknesses of the current OTC Monograph Process and to discuss ideas for modifications or alternatives to this process. To that end, FDA held a public hearing earlier this year and opened the topic to public comment until May 2014. It has since extended the public comment to July 31, 2014 in an effort to gain further input. The industry is weighing in on the debate as consumer product and consumer healthcare companies, including GlaxoSmithKline (GSK) Consumer Healthcare, Johnson & Johnson (J&J), Bayer Healthcare, and Procter & Gamble (P&G) as well as industry groups such as the Consumer Healthcare Products Association (CHPA), the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas), and the US Pharmacopeial Convention (USP) provided input in the first round of comments submitted to the FDA in May 2014.

Current process
More than 300,000 OTC drug products regulated under the OTC Drug Review process are on the market. Under the current system, Section 21 CFR Part 330 describes the conditions for a drug to be considered generally recognized as safe and generally recognized as effective (GRAS/GRAE) and not misbranded. If a drug meets each of the conditions contained in Part 330, as well as each of the conditions contained in any applicable OTC drug monograph, and other applicable regulations, it is considered GRAS/GRAE and not misbranded, and the OTC drug is not required by FDA to obtain approval of a new drug application (NDA)(1). The regulations require a three-part regulatory rulemaking process, including the publication of an Advanced Notice of Proposed Rulemaking, a Tentative Final Monograph (TFM) or Proposed Rule, and a Final Monograph or Final Rule to establish the conditions under which drugs under the OTC Drug Review are considered GRAS/GRAE and are not misbranded. FDA does not require OTC products conforming to the conditions of a final monograph and other applicable regulations to have approved NDAs prior to marketing. As a corollary, it has also generally been FDA’s enforcement approach since the early days of the OTC Drug Review to not pursue regulatory action against OTC products marketed in conformance with the conditions proposed in a TFM (1).

FDA held the public hearing in late March to listen to ideas for changes to the existing OTC Monograph Process or replacing the process with an entirely new regulatory or statutory framework (1). In opening up the issue to the public, FDA said a solution should encompass several key elements: adopting modern standards for safety and efficacy; implementing an efficient mechanism for finalizing the status of drug products that are currently marketed under pending TFMs; allowing for innovative changes to drug products; providing FDA with the ability to respond promptly to emerging safety or effectiveness concerns; allowing FDA to easily and quickly require additional information or data necessary to develop pediatric labeling where appropriate; and allowing FDA to obtain final formulation information about individual products or readily establish final formulation testing standards (1).

FDA outlined some preliminary ideas on how to achieve those objectives: identifying a streamlined process that would allow prompt resolution of existing TFMs; issuing monographs by administrative order; issuing regulations to require product-specific information and expanding the use of guidances; and expanding the NDA deviation process (see Table I) (1).

 Table I: FDA’s Preliminary Ideas for Modernizing FDA’s Over-the-Counter OTC Drug Review Process
 Idea  Description
 Promptly Resolve Existing Tentative Final
 Monographs (TFMs) Under a Streamlined  Process
FDA is considering ways to more efficiently bring TFMs to closure and is interested in ideas for developing streamlined processes under which it could promptly finalize the existing TFMs.
 Issue Monographs by Administrative Order This idea would involve establishing a process similar to that enacted by the Food and Drug Administration Safety and Innovation Act (FDASIA) for device reclassifications. FDASIA changed the process by which devices are reclassified from notice and comment rulemaking to an administrative order process. Under this model, monographs could be established by administrative order after issuance of a proposed order for comment.
 Issue Regulations To Require Product-Specific
 Information and Expand the Use of Guidances
FDA could issue new regulations that would require that manufacturers submit, prior to marketing, limited information about individual products that will be using active ingredients that have been determined to be GRAS/GRAE. The individual product information requested might be similar to, but less detailed than, what is required under an NDA and could include, for example, labeling, quality, and pharmacokinetic information. FDA could then issue guidances recommending the types of information FDA would be seeking. FDA’s use of guidances under this framework could increase the agency’s flexibility to address specific product issues as they arise.
 Expand the NDA Deviation Process The OTC Drug Review regulations provide a process for approving a drug product that complies with the conditions of a final monograph except for a deviation. In this instance, a sponsor can apply for an NDA deviation by submitting an NDA showing that the product complies with the conditions of the monograph except for the deviation and provide the necessary data to demonstrate the safety and effectiveness of the product with the deviation. For example, an OTC monograph may not cover certain dosage forms of a monograph ingredient. The manufacturer of a proposed different dosage form could submit an NDA that relies on the final monograph to demonstrate the safety and efficacy for the drug except for the differences related to the change in dosage form. The NDA would also need to include the appropriate data to demonstrate the safety and effectiveness of the new dosage form. The approved NDA would be specific only to the NDA sponsor and would not amend the monograph. Industry has not used the NDA deviation process as a pathway to marketing very often. The agency is interested in learning why this is and whether there are changes that could be made to the existing NDA deviation process that would make it a more attractive alternative for industry and that could allow marketing of additional drug products without having to submit a full NDA.
 GRAS/GRAE is generally regarded as safe/generally regarded as effective.
 NDA is new drug application.

 Source: FDA, “Over-the-Counter Monograph System—Past, Present and Future Public Hearing,” Public Hearing Notice, Federal Register, Vol. 79, No. 36, Feb. 24,  2014, pp. 10168-10172.


Industry input
Several companies and associations offered input on the FDA’s suggestions as well as proposed other ideas for improving the OTC Review process. There was general consensus that some level of reform was important to improve the OTC Review process, but there was also concern by some that changes should not be too sweeping.

P&G. In its comments, P&G stated: “Radically changing or aborting the current process will result in unnecessary chaos and delay and will not be in the best interest of consumers. However, we recognize that the OTC review can and should be improved in a manner that respects and sustains what it has already accomplished.” P&G said that it considered the OTC review process to be superior to all viable alternative approaches, for several reasons. First, the company said the process enables the most efficient use of agency resources in contrast to pre-clearance processes for individual products. Second, the company noted that the agency’s reviews are based on sound scientific rigor and involve independent expertise outside of the FDA. It also said that through notice and comment rulemaking, the review process also permits input from and dialogue with multiple industry stakeholders instead of just one entity and that the process provides opportunities to communicate broadly with stakeholders on issues of science and policy.

“While a significant amount of work remains in order for the OTC Review to be completed, a significant change in approach at this stage will likely be highly disruptive and cast significant uncertainty across the entire OTC landscape,” said P&G in its comments. “While we do not fully understand the underlying issues which have contributed to slowing the progress of the OTC Review, we do believe that procedural clarifications and modifications, and perhaps more fundamental changes (as identified and agreed by the key stakeholders in the process) have the potential to streamline the process. We encourage the agency to share specific procedural hurdles and limitations with other stakeholders to enable mutually agreeable solutions.”

One limitation noted by P&G in its comments is that in instances where product innovations may be incremental, the existing NDA Deviation and Section 505(b) (2) pathways are not optimal approaches for manufacturers to request approval of minor changes in an indication or dosage form.  A 505 (b)(2) pathway allow sponsors to obtain approval of NDAs containing investigations of safety and effectiveness that were not conducted by or for the applicant, but for which the FDA has issued an approval. Sponsors must still provide any additional data necessary to ensure that the differences from the reference drug, or other existing information, do not compromise safety and effectiveness.

The company added that “devising a formal pathway in the OTC Monograph, which encourages the inclusion of ingredients approved under an NDA or ANDA [abbreviated new drug application] that now have significant US market history would help achieve uniformity across non-prescription drug products marketed with the same active ingredients or with very similar indications. We believe this would provide significant benefit to the agency, manufacturers, and most importantly, the self-medicating US consumer.” In its comments, the company encouraged the creation of a private-public partnership as a means to help establish these regulatory pathways. “A partnership would facilitate greater communication and collaboration between FDA and its stakeholders, leading to greater transparency and more actionable regulatory processes,” said the company.

P&G also addressed the current process that requires new safety information on the label of a monograph OTC drug product to be subject to the FDA’s complete rule-making. “While a proper and necessary step to establish good public health policy, which can directly affect multiple manufacturers, the pace of rulemaking can be slow compared to the pace of advances in science, medicine, and emerging safety information,” said P&G. “As a result, both manufacturers and FDA currently lack an efficient means to implement and enforce label changes for monograph OTC drug products driven by emerging safety science. The situation is further complicated by the differing regulatory paradigms for implementing safety labeling across various drug-product categories, including prescription and nonprescription NDA and ANDA products, non-prescription monograph products, and combination monograph drug/cosmetic products. This has led to different safety label information being provided on products containing the same ingredient.”

P&G said the FDA should better facilitate updating safety information for OTC Monograph drug products by ensuring the timely implementation of label changes in response to emerging safety and public health issues and ensuring harmonized safety labeling for ingredients or drug classes used across product categories. In its comments, the company said that these goals could be achieved through three possible options: through the enforcement discretion of the FDA; by establishing parameters within its enforcement discretion for manufacturers to voluntarily add safety-related statements to Drug Facts labels concurrent with notification to the FDA, subject to subsequent FDA review, modification, and ultimately adoption into a Final Monograph; and by FDA creating emerging safety issue guidance for application across the entire OTC drug spectrum, addressing its expectations for when label changes are warranted.

P&G also called for greater transparency and more predictable timelines under the TEA process. It also recommend that the FDA and other stakeholders evaluate the possibility of adopting a tiered approach to OTC Monograph Drug regulation, especially for those OTC drug-product categories regulated as both cosmetics and OTC drugs. It said that OTC drugs that could be considered for this low-risk category include topical products that present relatively minimal adverse health risks and that have no dose limits. The company also suggested the use of a reasonable user-fee program for the OTC Review to address as needed, inadequate funding or staffing in progressing the OTC Review process.

GSK Consumer Healthcare In its written comments, GSK Consumer Healthcare offered several suggestions to enhance the existing OTC monograph system. It recommended that the FDA provide an updating mechanism that allows for modified or additional safety information (new or revised warnings, contradictions, side effects, and/or precautions) to be added quickly to existing OTC monographs. It also suggested to accelerate the finalization of existing monographs, possibly through the use of a series of “empowered” Nonprescription Drug Advisory Committee meetings to establish a clear, phased, and time-bound process. GSK also recommended to develop mechanisms in the context of the existing monograph system to allow for changes, such as new dosage forms and additional combinations of active pharmaceutical ingredients (APIs), for products containing inredients known to be safe and effective. The company also suggested that the FDA should issue guidance to provide a framework for manufacturers to collect and maintain the appropriate technical documentation to support the marketing of these product innovations and that the FDA should “clearly articulate” the application of enforcement discretion when sponsors use this framework.

GSK also recommended user fees based for the OTC Review process. It suggested that the fees be based on a sliding scale proportionate to the complexity and reviewing resources required. The company recommended user fees under the Prescription Drug User Fee Act that would be more consistent with the nature and extent of data typically submitted in OTC NDAs. It also suggested that the abbreviated reviews, rather than the full 10-month review cycle, should be considered.

The company also recommended that the FDA establish clear and standardized communication channels to facilitate ongoing and regular dialogue with review to OTC monograph issues. In suggesting on how the FDA could promptly resolve TFMs, GSK suggested that the agency uses the Advisory Committee process. It said that a set schedule should stipulate how long each TFM can remain in each stage gate before moving onto the next to enable FDA to allocate resources accordingly. With respect to requiring product-specific information and expanding the use of guidances, GSK recommended that FDA expand the Direct Final Rule options. GSK said, for example, that FDA can appoint an Advisory Committee to decide when and where the rulemaking and comment process can be expedited, whether a product is ready to proceed to final review, and if not, what else is required. With regard to the suitability of other review processes, such as the one used for medical devices, GSK said it was worth consideration to evaluate. It also said reviewing processes from other regulatory authorities would be useful.

(J&J). In its written comments, J&J emphasized the value of public-private partnerships (PPPs) to address the OTC Drug Review process. The company suggested that an OTC Reviews PPP would operate principally as a series of technical working groups outside the FDA, consisting of representatives from the FDA, drug manufacturers, pharmacists, physicians, consumers, and academia. The PPPs would be staffed with personnel adept at reviewing scientific data and qualified through training and experience to understand the difference between the OTC Monograph GRASE (generally regarded as safe and effective) standard and NDA regulatory standards, would work with the FDA based on prescribed timelines, and maintain communication with ensure that information is provided in a complete and timely fashion. The PPP would focus on three main goals: finalizing the TFM; establishing a process to identify new safety and effectiveness information and recommend labeling changes; assisting the FDA in facilitating innovation by developing a list of minor changes that could be made to monographs through guidance documents, determine the data needed to make those changes, and develop the guidance documents.  From an overall process perspective, the company suggested that recommendations from the PPP would be based on a vote, and the FDA would have the authority to accept or reject the recommendation or return the issue to the PPP for further discussion. The exact mechanism for execution of the PPP would be discussed and aligned upon with the stakeholders in a formal agreement. </p>
<p> J&J also suggested that the FDA should make finalization of the monographs its first priority and that enhanced transparency and increased communication are also necessary. It also offered that additional mechanisms for eligibility for the OTC Drug Review could be broadened to not only include active ingredients of a product approved in the US before 1972 but also the dosage form. It also suggested that the NDA deviation process is not widely used by the industry because it is not well defined and suggested additional guidance from the FDA to clarify data and information requirements to justify different types of deviations would be helpful. And in terms of a specific suggestion by the FDA, J&J said it did not support issuing monographs by administrative orders and the notice and comment rulemaking best serves the public interest.

Bayer Healthcare-Consumer Care. In its comments, Bayer said that it agreed with the position of CHPA that the modernization and streamlining of the OTC Drug Review can be achieved using existing regulatory mechanisms. It also agreed with increasing the transparency of the review process and Bayer suggested that the FDA hold a “State of the OTC Drug Review” meeting, where it can publically present status updates on all open monographs and projected timing for completion. The company also agreed with CHPA’s recommendation that a dedicated team work on monographs. The company further suggested that the agency provide a route-cause analysis to identify the reasons in the delay in reviewing monographs and form a Corrective Action/Prevention Action program to follow up accordingly. The company also suggested that the FDA align its communications for safety information for ingredients subject to the OTC Drug Review with the issuance of rulemaking or guidance with respect to how labeling should be revised.

Industry groups
CHPA. In it comments, the CHPA outlined what it thought were the areas in greatest need of reform. “The aspects of the OTC Review that are most in need of change are accelerating the completion of the final monographs, swiftly addressing urgent safety issues, and identifying an efficient and effective process to amend final monographs, including the addition of new ingredients,” said CHPA in its comments. “In each instance, industry needs more information in order to be helpful. The rulemaking process is not transparent, and industry, therefore, does not have access to precise information concerning the status of the relevant rulemakings. CHPA, therefore, urges the FDA to establish a system under which the status of each rulemaking can be readily determined by all interested persons.”

CHPA also is urging the FDA to streamline the time and extent (TEA) system to make it a more effective tool for including new active ingredients in the OTC review process. It is also calling on the FDA to adopt a comprehensive plan for finalizing the remaining TFMs. It said this could be achieved by appointing a single leader, who should report directly to the Office of the Center Director, not the Office of New Drugs, with accountability for finishing the process. It also said the FDA should prioritize which monographs or submonographs should be completed first. And lastly, CHPA said the FDA should instruct its reviewers to review data in a manner that is consistent with statutory requirements for that drugs are generally recognized as safe and effective and therefore not subject to the NDA requirement. With these priorities, CHPA said that the FDA should establish milestones for completion of the monographs with specific timeframes.

IPEC-Americas. IPEC-Americas asked the FDA to consider the role of atypical active ingredients in the OTC Review process. In commenting on the OTC Review process, IPEC-America put forth its overall position on atypical actives, which seeks to ensure that these substances are not overregulated to the point of being removed by the market by suppliers. In terms of its overall position, the association is seeking clear guidance to define good manufacturing practice (GMP) requirements for the manufacture and handling of atypical actives. It pointed out that increasingly, GMP requirements defined in the International Conference on Harmonization (ICH) Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (API GMP) are expected for these materials, and manufacturers of these atypical actives are often not capable of producing them to ICH Q7 API GMPs due to the types and location of manufacturing processes used. Given the unique nature of these atypical actives (and their inherent demonstrated historical safety), the association is encouraging a risk-based approach and assessment of these materials to define the proper type and level of GMPs for their manufacture, handling, and intended application. IPEC-Americas requested that the FDA carefully consider these issues and its position in developing rules and guidance in the implementation of the FDA Safety and Innovation Act of 2012  and when assessing how best to improve the OTC Monograph system as well as to provide a clear, pragmatic guidance for the manufacture and handling of atypical actives.

USP. In its written comments, USP said that one possible initiative it is considering to help the FDA and the OTC system address the challenge of missing product quality standards is with new group monographs. These new group monographs would allow key essential quality characteristics to be determined by objective compendial quality standards, including, as appropriate, tests and methods and related reference standards. USP suggested that within a group, all products would be covered, from single-component to combination products. The monograph groups could be defined by their applicability to specific assay and impurity (i.e., strength/potency, quality, and purity) and identification procedures. Each group monograph could then include a listing of specific drug products subject to the monograph. These group monographs could then be applied to drug products. “The intent would be to better enable the development of compendial quality standards for finished dosage forms (drug products), thereby supporting the drug substance monographs that already play an important supporting role in the OTC System,” said USP. “Having compendial standards for drug products, not just their ingredients, could also help support some of the future visions of the agency related to improved transparency and information about individual products that will be using active ingredients allowed under the OTC System.”  

1. FDA, “Over-the-Counter Monograph System—Past, Present and Future Public Hearing,” Public Hearing Notice, Federal Register, Vol. 79, No. 36, Feb. 24, 2014, pp. 10168-10172.

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