No FDA review

FDA's OTC drug registration process relies on voluntary manufacturer compliance with all applicable laws.

The integrity of OTC drug manufacturing is threatened by outdated laws which limit the FDA's ability to monitor safety of OTC products.

Understanding the FDA’s OTC drug listing system

FDA provides a rulebook.

FDA has a set of rules for companies that want to make or sell OTC eye drops. This rulebook (called an “OTC Monograph”) includes a specific list of allowed active ingredients and a “mix & match” collection of indications, warnings and other required consumer information.

There are also rules about preservatives and safe packaging, as well as allowed inactive ingredients. Those live outside the Monograph because they apply to all eye drops, not just OTC.

FDA is not tasked with evaluating whether companies comply with the rules.

FDA provides software.

FDA maintains a software system for companies to upload and manage their product listings in the FDA’s database. A product listing includes ingredients, essential label information (“Drug Facts”), and a flattened-out version of what the product’s outer box looks like.

Each company is responsible for maintaining all of its own product listings.

FDA does not review OTC product information uploaded by companies.

FDA provides a drug lookup tool.

FDA’s database connects to the National Library of Medicine’s drug search tool, called DailyMed. Doctors, consumers and the general public can use DailyMed to look up every OTC drug that has been listed with FDA.

Search results display active and inactive ingredients, other label details, and a flattened-out version of the product’s outer box.

FDA states that it “has not evaluated” whether a product complies with applicable regulations and policies.

Case 1: Lack of competence

The EzriCare Tragedy

EzriCare Artificial Tears is an FDA-registered OTC ophthalmic drug.

The CDC blames this product for an 18-state outbreak of treatment-resistant Pseudomonas aeruginosa infections which, so far, have led to 4 deaths, 14 cases of vision loss and 4 enucleations (surgical removal of an eyeball).

About the companies involved

  • The manufacturer is Global Pharma, a facility operating in Mumbai, India.

  • The importer is Aru Pharma in Mount Vernon, New York.

  • The marketer is EzriCare LLC, an OTC drug wholesaler in Lakewood, New Jersey.

About the product

EzriCare Artificial Tears is a cheap (~$5.99 per bottle), generic artificial tear like dozens of others listing carboxymethylcellulose sodium (CMC) as their active ingredient.

It was well-reviewed and popular on Amazon.

EzriCare claims to be similar to Refresh Plus, a preservative-free 0.5% CMC product packaged in single-use vials. But EzriCare has twice as much CMC (1.0%) and is packaged in a conventional multi-dose bottle, which makes it more similar to Refresh Liquigel - except that, unlike Refresh Liquigel, EzriCare does not contain a preservative.

Why does this matter? A 1.0% CMC drop will be much thicker, and therefore potentially last longer, than 0.5% CMC drops - a feature discussed in Amazon reviews - but Refresh Plus has better brand recognition than Refresh Liquigel., so it’s a more attractive comparison to make.

EzriCare’s FDA status

EzriCare Artificial Tears has been listed with the FDA as an OTC drug since 2020. A nationwide recall was issued in February 2023.

The bacterial contamination tragedy

CDC has linked EzriCare Artificial Tears to an 18-state outbreak of extensively drug-resistant Pseudomonas aeruginosa infections which, as of the 5/15/23 update, have infected 81 people. Four people have died, 14 have experienced vision loss, and an additional 4 patients have experienced enucleation (surgical removal of the eyeball).

Exactly how the eye drops became contaminated is not yet understood. The investigation is ongoing.

Potential factor: Packaging safety rule violation

The earliest reports from CDC and FDA both highlighted the fact that EzriCare Artificial Tears lacked a preservative despite being packaged in a multi-dose bottle. This is a violation of Federal regulations for packaging of liquid ophthalmic preparations. See “Unsafe Bottles” for more information about why it is a safety issue.

Three companies involved with EzriCare Artificial Tears - the manufacturer, the importer and the distributor - either did not know or did not care about this safety violation.

When a company uploads drug information into FDA's listing software, an automated validation process occurs which checks the data for certain required information such as an allowed active ingredient, and the identity and location of the manufacturing facility. This software does not check the drug information for simple, obvious violations such as absence of a preservative when one is necessary. There is no human review that might identify violations that the software is not designed to identify.

Unfortunately, EzriCare is not the only artificial tear listed with the FDA that violates packaging safety rules. There are others still being marketed for sale. See Product Alerts.

Potential factor: Violations of Current Good Manufacturing Practices (cGMP)

FDA has identified manufacturing irregularities that have sterility implications. FDA’s first inspection of Global Pharma, however, did not take place until after the infection outbreak was announced in February 2023. The manufacturing facility was first inspected by the FDA in 2023, after EzriCare Artificial Tears had been on the market for years.

Case 2: Lack of integrity

The Regener-Eyes Scam

Regener-Eyes Lite and Regener-Eyes PRO are unapproved prescription drugs that, somehow, are also FDA-registered OTC ophthalmic drugs.

Regener-Eyes successfully manipulated the FDA’s OTC listing system to bolster its reputation with eye doctors even while under direct attack from the FDA’s own biologics division.

About the companies involved

  • Regenerative Processing Plant LLC, a manufacturing facility in Palm Harbor, Florida.

  • Regener-Eyes LLC, a part-owned subsidiary of the manufacturer and also based in Palm Harbor, Florida. It appears to be financed in part by Texas-based Eyemart Express.

About the products

Regener-Eyes has two versions of its eye drops, Regener-Eyes Lite and Regener-Eyes Pro. They retail for $75 to $200 for a 3mL bottle, which is about 1/5 the size of most over-the-counter eye drop bottles.

What are the ingredients?

  • The manufacturer refuses to identify the ingredients in its products.

  • The FDA’s biologics division says Regener-Eyes eye drops are made of amniotic fluid.

  • The drug listings that the manufacturer had uploaded to FDA’s OTC database says Regener-Eyes is made of glycerin, water and “Tonicity Solution™”. “Tonicity Solution™” does not match any substance in the FDA’s ingredient database and appears only in the public-facing part of the drug listing, not in the complete downloadable listing.

Regener-Eyes’ FDA status

It depends who you ask.

According to FDA’s Center for Biologics Evaluation and Research (CBER) Regener-Eyes products are unapproved biological drugs. They require clinical trials and prescription drug approval prior to being marketed for sale.

According to DailyMed, the search tool for prescription and OTC drugs, Regener-Eyes products are now OTC drugs - even though CBER says they are unapproved prescription drugs and one of the listed ingredients does not exist. Clearly, the FDA’s system can be manipulated.

Safety problem #1: Potential for bacterial contamination

Like EzriCare Artificial Tears, Regener-Eyes’ products are preservative-free but packaged in simple multi-dose bottles. Read more about unsafe bottles.

Safety problem #2: Creating the illusion of legitimacy by manipulating FDA’s own software.

Regener-Eyes’ products have been endorsed and promoted by many prominent eye care professionals. The company has aggressively and successfully marketed to eye doctors, including persuading doctors that they are not violating FDA regulations.

After Dry Eye Foundation’s Regener-Eyes exposé in summer of 2022, Regener-Eyes pivoted to a new marketing plan using FDA OTC drug listings as pseudo-evidence that they are FDA compliant. Many doctors continue to accept Regener-Eyes as FDA-compliant products, even after the FDA issued a Public Safety Notification about these products in April 2023.