What Makes an Ophthalmic Generic Bioequivalent?

A researcher discusses how the FDA establishes the bioequivalence of generic ophthalmic drugs

What Makes an Ophthalmic Generic BIOEQUIVALENT?

A researcher discusses how the FDA establishes the bioequivalence of generic ophthalmic drugs

In July 2016, an article called “Clinical, Pharmacokinetic, and In Vitro Studies to Support Bioequivalence of Ophthalmic Drug Products” appeared in The AAPS Journal, a publication of the American Association of Pharmaceutical Scientists. The article illustrates how the Food and Drug Administration (FDA) directs pharmaceutical companies to demonstrate bioequivalence for generic ophthalmic products.1 We discussed the article with lead author Stephanie Choi, PhD, acting associate director for science in the Office of Generic Drugs, Office of Research and Standards.

1. What made you take a specific look at ophthalmic medications for this article?

The FDA publishes product-specific bioequivalence recommendations (PSRs) to assist the generic pharmaceutical industry with identifying the most appropriate methodology for developing generic drugs and generating evidence needed to support Abbreviated New Drug Application approvals. The PSRs support generic drug development by describing the agency’s current thinking and expectations on how to develop generic drug products that are therapeutically equivalent to specific reference-listed drugs.

Since 2008, the FDA has posted 28 PSRs for ophthalmic drug products. These recommendations describe different types of bioequivalence studies (clinical, pharmacokinetic, and in vitro) that can be conducted for specific ophthalmic drug products. We felt that an article outlining these different types of bioequivalence studies for ophthalmic products would be helpful for pharmaceutical scientists and the ophthalmology community.

2. What criteria does the FDA apply to its evaluation of new generic medications?

Generic drug manufacturers have to prove the active ingredient is the same as the brand name drug that is being copied. They also must show that the right amount of the active ingredient goes to the place in the body where it has an effect, and that any inactive ingredients used are safe. Companies also must show that the drug will not deteriorate through time, that the manufacturer can produce the same drug every time, and that the labeling is the same as the brand name drug.

At the FDA, healthcare professionals and scientists with a wide range of expertise work together to make sure that FDA-approved generic drugs are safe, effective, high quality, and substitutable for the brand name drug. We also conduct a thorough examination of the data submitted by the generic drug company, as well as an evaluation of information obtained by our investigators while inspecting the related testing and manufacturing facilities. With these reviews, patients can be confident in the generic drug they are taking. One reason for the recent increase in PSRs is that we were able to hire more staff to develop them. These PSRs provide a clear pathway for generic developers to enter the ophthalmic market.

3. Can the FDA’s current approach to determining bioequivalence offer reassurance to ophthalmologists who have transitioned reluctantly to generic medications?

When the FDA becomes aware of new information that could impact successful generic substitution, the scientific requirements considered necessary for approval must evolve. The FDA’s current approach in determining bioequivalence of generic ophthalmic drug products show the agency’s enduring commitment to ensuring that generic drugs perform as expected and are held to high standards.

As a result of new information and findings, the FDA has published and/or revised these recommendations for industry with new scientific information. The FDA has established tight statistical limits for comparison of clinical and pharmacokinetic endpoints, and requests a battery of characterization tests on physicochemical properties of both generic and brand products. The FDA also requests information about the drug product relating to its formulation, manufacturing, and product characteristics.

As part of the implementation of the Generic Drug User Fee Amendments of 2012, the FDA has also funded regulatory science research to develop new tools to evaluate drug equivalence and support generic drug development in all product categories, including ophthalmic drug products. Results from regulatory science research have contributed to the FDA’s understanding of ophthalmic formulations and the development of improved methods necessary to demonstrate bioequivalence. Physicians can read more about this research on our Ophthalmic Products web page.

New FDA Guidance for Generic Facilities

In September, the FDA finalized new guidance for “human generic drug facilities, sites, and organizations” to self-identify through an online tool. According to the FDA, “The information provided through self-identification enables quick, accurate, and reliable surveillance of generic drugs and facilitates inspections and compliance.” It also helps the FDA identify which facilities must pay user fees.

Self-identification is a requirement under the law called Generic Drug User Fee Amendments of 2012, which was passed to speed generic drugs to market. Reporting requirements are detailed in the full document, “Self-Identification of Generic Drug Facilities, Sites, and Organizations Guidance for Industry,” which can be found at ■

The Orange Book App

The FDA publishes Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book, which details every drug the agency approves, including “therapeutic equivalence evaluations.” In the book’s app (available for iPhone and Android), users can search the database by active ingredient, proprietary name, applicant, application number, dosage form, route of administration, or patent number. ■

4. What do you think eyecare practitioners should know about the analysis in your paper?

The FDA’s rigorous standards for equivalence in ophthalmic products are described in the 28 PSRs and supported by advances in our ability to measure the physicochemical characteristics of ophthalmic drug products. The FDA developed stringent guidelines for the approval of generic ophthalmic products, which ensure that the generic product will produce the same therapeutic effect as the brand name product. The standards are product specific, and are developed with consideration of the drug product characteristics.

After the FDA approves a generic drug application, both patients and prescribers can have confidence that it can be substituted for the brand product, because it has met rigorous standards for safety, quality, and bioequivalence. ■


1. Choi SH, Lionberger RA. Clinical, harmacokinetic, and in vitro studies to support bioequivalence of ophthalmic drug products. AAPS J. 2016;18(4): 1032-1038.