In this installment of OPDI, we describe the basics of the ophthalmic monograph and its implications for product development. While this monograph has been in place for many years, our research and consulting group often receives questions from new entrepreneurs (and even experienced developers) regarding what the monograph is/isn’t and how it applies in specific situations. Here, we’ll provide some background and attempt to correct a few common misconceptions.
What is the Monograph?
In 1983, the U.S. Food and Drug Administration issued a proposed rulemaking in the form of a tentative monograph to establish conditions by which over-the-counter ophthalmic products are recognized as safe and effective and not misbranded. The FDA then issued this as a final monograph in 1988 (21 CFR 349).
21 CFR 349.1 starts by stating: “An over-the-counter ophthalmic drug product in a form suitable for topical administration is generally recognized as safe and effective and is not misbranded if it meets each of the conditions in this part and each of the general conditions established in 330.1.” In other words, if one follows the specifications of the regulation, a New Drug Application isn’t required for FDA review of products which contain the monograph-specified active ingredients, the indication for use, and labeling.
There are six defined categories of active ingredients listed in the monograph: demulcents; astringents; emollients; hypertonicity; vasoconstrictors; and eyewashes. Within each category there are specified active ingredients and concentration ranges that are acceptable for use. For each category of active ingredient, the monograph specifies the acceptable language that can be listed as the indication on the label. For example, hypromellose in the range of 0.2 to 2.5% can be labeled “For use as a lubricant to prevent further irritation or to relieve dryness of the eye.” For each category there is a specified wording that’s deemed acceptable as a statement of identity, indication, warnings and directions. There’s also an allowance in 21 CFR 349.30 for specified combinations of two—or in some cases more—listed ingredients.
Implications for OTC Products
Referring to drug products, there are two pathways for development and marketing of OTC products in the United States, 1) monograph; and 2) following the NDA (or 505b2) pathway.
Products that follow the monograph aren’t reviewed by FDA prior to marketing. There are standard requirements for labeling, such as those for expiration dating based on stability data, labeling requirements per 21 CFR 201.66 and the requirement that the products are made according to Good Manufacturing Practices. But there’s no formal review by the FDA like there is a for a new drug product with an NDA. Manufacturers are responsible for ensuring quality and a compliant product. Keep in mind that while there isn’t a formal FDA review or requirement for it, distributors may have a separate need for a certain amount of stability to support desired shelf life and inventory, and therefore it’s the manufacturing that’s generally the rate-limiting step when launching a new OTC monograph product. Note that adhering to 21 CFR 349.1 assumes the drug maker is also following CFR 330.1, which, among other labeling mandates, requires that the facility at which the product is manufactured be registered, and the product listed in compliance with part 207 of the chapter. (Part 207 covers requirements for manufacturing establishment registration and listing of the drugs to obtain a National Drug Code.) The monograph also mandates that the product only contain suitable inactive ingredients that are safe and don’t interfere with the product’s effectiveness.
While this article isn’t intended to be an extensive review of formulations, a brief note on inactive ingredients: For a monograph product, inactive ingredients can be chosen from the current FDA database. This lists substances generally known to be safe in certain concentrations/amounts and for certain methods of dosing. Ingredients are added to the list after being formally reviewed as part of past NDAs for other products.
Existing OTC products generally fall under the monograph, meaning there was no formal review by the FDA in advance. One example of a non-monograph product that was a direct-to-OTC NDA product, however, is Lumify (brimonidine 0.025%, Bausch + Lomb). B+L used the extensive history of safety of Lumify’s active ingredient at higher concentrations to obtain approval based on a clinical program for redness relief. The antihistamine ketotifen is another example of a current OTC, but non-monograph, ingredient. For example, Alaway (ketotifen 0.025%, B+L) was a reformulation of an already approved and marketed product (containing the antihistamine ketotifen), using the same concentration of the active ingredient. This was approved based on a single bioequivalence trial using the standard conjunctival allergen challenge clinical model for allergy.
One question we frequently receive is: If a product changes some ingredients, but they’re still contained in the monograph, do clinical studies need to be performed, or can one make those changes and just launch a product? We’ve heard this asked both for OTC and Rx products. The short answer is that such changes can’t simply be made without filing to the FDA with supportive clinical data. The FDA views any changes in OTC or Rx formulations, including changing into/out of an inactive ingredient, or modification of concentration (including simply removing a preservative) as a change that may impact the pharmacokinetics of the active ingredient, and thus efficacy and safety. A change in preservative may impact penetration of the drug; changing a demulcent could impact viscosity and dwell time of the drug, impacting PK; and even simple changes in a buffer can impact comfort. Therefore new formulations (even altering an ingredient from the monograph list that’s in the product as an inactive ingredient) require submission of clinical data. Such a change would go through the NDA (or 505b2) process. In some cases, all that might be needed is a single clinical trial as a pathway for FDA review. In our May 2018 column, we discussed the 505b2 pathway, which allows applicants to reference other data in their submission, including already published data or data from a prior review by the FDA. Such a discussion is beyond the scope of this article, however.
Another question is: For a given non-monograph product (Rx or OTC), if one adds a monograph ingredient, can the monograph label indication be included in the labeling of the product? Again, the short answer is no. If a product was approved by FDA as non-monograph (whether due to an ingredient or indication that’s non-monograph), and a formulation change is being pursued, then it needs to follow requirements for an NDA pathway (or 505b2 as applicable). Note that the monograph is different from developing and gaining approval of a generic under 505(j) as an Abbreviated New Drug Application (ANDA); that’s used for generic products with non-monograph active ingredients.
From a development perspective, the monograph provides flexibility for marketing products that consist of well-known ingredients, and streamlines the labeling. Of course, one has to thread the needle between time, cost and differentiation, and develop the reason-to-believe and positioning for new monograph formulations, to ensure you get the maximum value. This has been achieved, for example, with tear substitutes, all of which currently fall under the monograph, yet many have differentiated clinical performance characteristics. If you have questions about the nature of specific ingredients, labeling or pursuing monograph deviation, we, as always, encourage early interaction with the FDA.
Mr. Chapin is senior vice president of corporate development at Ora, which offers device and drug consulting, as well as clinical research and development. The author welcomes your comments or questions regarding product development. Please send correspondence to firstname.lastname@example.org or visit oraclinical.com.