Addressing Regulatory Challenges for Ophthalmic Combination Products

By: Jeffrey Tremain and Ania VanDyke, AbbVie Contract Manufacturing


Regulatory authorities now consider ophthalmic formulations designed for administration as eye drops to be drug–device combination products.

The regulatory compliance requirements for such combination products are much more complex than those for drugs alone. Partnering with a full service provider with experience in successfully bringing ophthalmic combination products to market is essential to streamlining development, approval, and commercialization.

Changing View of Dose Delivery for Eyedrops

Dose determination for many drug products is fairly straightforward, with fixed dosage forms, such as tablets, capsules, and pre- filled syringes. For eye drops, however, the dose depends on the size of the drop. His- torically, that concept was not considered an issue.

More recently, however, the U.S. Food and Drug Administration (FDA) and other regula- tory authorities have taken a closer look at the drop size–dose relationship. They have also considered that the dose is delivered from a dropper, whether separate or con- joined with the bottle containing the drug.

Since that dropper/bottle system determines the size of the drop delivered, it also determines the size of the dose. Therefore, eye medications formulated as eye drops are now classified as drug–device combination products.

Reclassification in Response to the Genus DC Circuit Decision

The impetus for the reclassification of eye drop formulations as drug–device com- bination products originated with the DC Circuit’s April 2021 decision in Genus Med. Techs., LLC v. FDA.1 In this case, the court determined that any products that meet the definition of both “drug” and “device” under the Federal Food, Drug, and Cosmetic Act (FDCA) must be classified as devices and not drugs, except combination products, which must meet the relevant requirements for each component.2

The FDCA defines a drug as an “article intended for use in the diagnosis, cure, mit- igation, treatment, or prevention of disease in man or other animals,” while a device is “an instrument, apparatus, implement, machine, contrivance, implant, in vitro re- agent, or other similar or related article, in- cluding any component, part, or accessory, which is … intended for use in the diagno- sis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, … and which does not achieve its primary intend- ed purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabo- lized for the achievement of its primary in- tended purposes.”3

Until the Genus Med. Techs., LLC v. FDA decision, on the basis a 1997 court decision in Bracco Diagnostics, Inc. v. Shalala, the FDA had been regulating some products that met the definitions of both drugs and devic- es according to the FDCA as drugs. In Genus, the court said that the FDA did not have the discretion to do so where a product clearly met the definition of a device.2

In August 2021, the FDA published a Fed- eral Register notice announcing implemen- tation of the DC Circuit’s decision and further soliciting “public comment to inform the Agency’s deliberations about products potentially impacted by the Genus decision and the way in which impacted products should be transitioned from drug to device status.”4 The agency indicated that it would establish a process for the “orderly and ef- ficient determination of which products cur- rently regulated as drugs must be regulated as devices” and specifically mentioned im- aging agents and other product categories “as appropriate.”2

For ophthalmic products, this develop- ment meant that eye drops administered with an eye dropper of some type should be reclassified as drug–device combination products.

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Combination Products Present Greater Regulatory Complexity

Regulatory approval of drug–device combi- nation products is more complex than that for drug products, as requirements must be met under both regulatory frameworks. In addition, there are some notable differenc- es between regulations in the United States and Europe.

The first step is to determine if the drug– device combination product is a single prod- uct with multiple components, separate products packaged together, or products packaged separately but intended for use together. Eye drops filled in a bottle/drop- per –– a prefilled drug delivery system –– fall into the first category.5 The primary mode of action (PMoA) — the mode of action that provides the main therapeutic effect — de- termines which FDA center will have juris- diction for its premarket review. Sponsors submit a Request for Designation to allow the FDA to make product classification and assignment determinations.

Although an investigational application is generally sufficient for a combination prod- uct, all information on the entire combina- tion product must be provided, including the details on the drug and device that typical- ly would be submitted in an Investigational New Drug (IND) and an Investigational De- vice Exemption (IDE) application, respec- tively.6

Medical device development (MDD) in- volves multiple (4–6) phases, beginning with a clinical/market needs assessment and legal/financial review, which is followed by planning the device development, conduct- ing a risk assessment, and establishing a Quality Management System (QMS).6 Next begins the concept and feasibility stage, in which a prototype device is designed and evaluated. Much more detailed design and development, including extensive risk man- agement, comprise the third stage, along with verification and validation to ensure that all quality standards are met. Next comes final validation and launch prepara- tion, including the production of formal de- sign prints, followed by product launch and post-launch assessment.

If a medical device must be evaluated in clinical trials, as is the case for ophthalmic combination products, the sponsor must work with an institutional review board (IRB) to determine whether the device is consid- ered a significant risk or nonsignificant risk before beginning the clinical study.7 The FDA classifies medical devices on the basis of the level of risk posed to the consumer. Eye droppers are Class 2 devices, which are subject to both general and specific con- trols, the latter of which include labelling requirements and specific performance and testing requirements.

Combination Product Implications for Ophthalmic Drug Development

For ophthalmic products formulated as eye drops that were previously considered to be drugs but now are regulated as drug–device combination products, the pharma QMS and current good manufacturing processes (cGMP) must address the regulatory expec- tations, not only for the drug but for the bot- tle/dropper system as well.

In Europe, such an integral combination product with the drug product as the PMoA are submitted to the regulators as a Medici- nal Product, and the device component must comply with applicable General Safety and Performance Requirements from the Medi- cal Device Regulation (MDR).8 In the United States, if the drug substance is a small mol- ecule drug, the combination product can follow a streamlined process outlined in 21 CFR 4.4(b), which requires less information. If the drug substance is a biologic, all appli- cable cGMP requirements for the biologic must be complied with, and thus this approv- al process is more involved.

It is essential to remember, however, that identifying the correct submission route is just one part of the development process for combination products.8 Sponsors must carefully consider the design of the device component, taking into account potential sources of risk, sterility assurance, and pa- tient ease of use, among other factors. Most importantly, the entire design process must be documented in a design history file (DHF) to demonstrate that the device component was developed according to the approved design plan and in compliance with applica- ble regulatory requirements.9

An Outcome to Avoid

The consequences of the transition from classification of a drug to classification as a drug–device combination product for oph- thalmics can be quite serious if drug devel- opers are not proactive about addressing this new reality.

An example of the possible complications was witnessed in October 2021 when Eyeno- via, Inc. found to its surprise that the FDA had reclassified MydCombi™ — the compa- ny’s proprietary, first-in-class combination microdose formulation of tropicamide and phenylephrine for in-office pupil dilation

— as a drug–device combination product in a Complete Response Letter (CRL) for the company’s NDA.10 The FDA had accepted the NDA in March 2021 on the basis of the results of two phase III trials. Eyenovia must provide additional information to the FDA to meet the submission requirements for the device component of the product, which the company said it should be able to do fairly quickly, because it had “taken actions throughout the development of MydCombi to minimize the impact of a potential reclas- sification by the FDA.”

A Successful Example

Submission of new ophthalmic products in compliance with drug–device combination regulations can avoid such unwanted sur- prises. One recent example, also from Oc- tober 2021, is the FDA’s approval of VUITY™ (pilocarpine HCl ophthalmic solution), Abb- Vie’s new once-daily treatment for presby- opia, or age-related blurry near vision, which affects most adults over age 40.11

VUITY is an optimized formulation of pilo- carpine, an established eyecare therapeutic, delivered with proprietary pHast™ technolo- gy, which allows VUITY to rapidly adjust to the physiologic pH of the tear film. By using the eye's own ability to reduce pupil size, VUITY improves near vision without affect- ing distance vision. The FDA’s approval was based on data from two pivotal phase III clin- ical studies.

A CDMO with the Right Regulatory Understanding, History, and Expertise

Going forward, sponsors developing oph- thalmic products formulated for delivery as eye drops must be prepared to pursue development programs that address the regula- tory requirements for drug–device combi- nation products. Partnering with a contract manufacturing organization (CMO) that has experience bringing such products to mar- ket is essential.

AbbVie Contract Manufacturing, as an embedded CMO within AbbVie/Allergan and a leading manufacturing outsourcing partner in eyecare solutions, has the nec- essary regulatory understanding, history, and expertise to support the drug–device combination product development process. The recent approval of VUITY speaks to our ability to successfully enable commercial- ization of ophthalmic drug–device combina- tion products.

We have the knowledge and capabilities to support late-phase development for both the drug and device components, including the establishment of comprehensive design his- tory files. We are aware of the unique chal- lenges associated with device approvals and the additional compliance requirements that must be met for drug–device combina- tion products.

Furthermore, by fully leveraging the ex- perience and assets of AbbVie Inc., AbbVie Contract Manufacturing provides our part- ners with unparalleled support throughout late-phase clinical development, technology transfer, scale-up, manufacturing, packag- ing, supply chain integrity, and more, back- ing this with robust quality processes to ensure compliance with global regulatory requirements.

1.) Genus Med. Techs., LLC v. FDA. United States Court of Appeals for the District of Columbia Circuit Decision. April 16, 2021. No, 20-5026.

2.) Kracov, Daniel A., Mahnu V. Davar, Abeba Habtemariam, and Ira Stup. “FDA Seeks Comments on Transition of Certain Drugs to Device Status Following Genus DC Circuit Decision.” Arnold Porter Advisory. 12 Aug. 2021.

3.) United States Code: Federal Food, Drug, and Cosmetic Act. U.S. Congress. 21 U.S.C. §§ 301-392 Suppl. 5 (1934).

4.) Genus Medical Technologies LLC Versus Food and Drug Administration; Request for Information and Comments. FDA Federal Register Notice. 9 Aug. 2021.

5.) Genus v. FDA D.C. Circuit Court Decision and transition from drugs to devices. U.S. Food and Drug Administration. Guidance and Regulatory Information. 1 Dec. 2021.

6.) “Frequently Asked Questions About Combination Products.” U.S. Food and Drug Administration. 9 Apr. 2020.

7.) Marešová, Petra et al. “Medical Device Development Process and Associated Risks and Legislative Aspects - Systematic Review.” Front. Public Health 30 Jul. 2020.

8.) Court, Laura. “What is 21 CFR 812 - Investigational Device Exemption? Greenlight Gurus Blog. 21 May 2021.

9.) Losantos, Isabel. “Delivery to the eye: overcoming complex regulatory hurdles for combination products.” Cambridge Consultants. 9 Jun. 2021.

10.) Lyons, Jessica. “Design History File (DHF) vs. Device Master Record (DMR) vs. Device History Record (DHR): What's the Difference?” Greenlight Gurus Blog. 29 May 2020.

11.) Eyenovia Announces Reclassification of MydCombi™ as Drug-Device Combination Product by FDA. Eyenovia. 25 Oct. 2021.

12.) U.S. Food and Drug Administration Approves VUITY™ (pilocarpine HCI ophthalmic solution) 1.25%, the First and Only Eye Drop to Treat Presbyopia (Age-Related Blurry Near Vision). AbbVie. 29 Oct. 2021.