BRANDED VS GENERIC PHARMACEUTICALS

Equivalent But Not Exactly the Same

Despite strict FDA oversight, the potential for small differences exists between generic ophthalmic drugs and their branded counterparts.

By Virginia Pickles, Contributing Editor

There’s no doubt generic drugs play an important role in the U.S. healthcare system. From 2004 to 2013, cost savings resulting from their use approached $1.5 trillion, and in 2013 alone, generics saved $239 billion, a 14% increase over 2012 savings.¹ In 2014, 87.5% of all prescription drugs — 79% of prescription ophthalmics — dispensed in the United States were generic.^2,3

The FDA’s abbreviated new drug application process is designed to bring proven drugs to market faster and to give consumers less costly but equally effective alternatives to branded drugs. By and large, the process has been successful, but some inherent differences between topical eye solutions and systemic drugs create some challenges.

FDA’S GOAL: BIOEQUIVALENCE

The FDA requires generic drugs and their branded counterparts to be bioequivalent; i.e., they must have the same active ingredients, strength, dosage form, and route of administration.⁴ Generic drugs for ophthalmic and otic use should also have the same inactive ingredients as the innovator drugs. The FDA may approve a generic with a different preservative, buffer, tonicity adjuster or thickening agent as long as the manufacturer identifies the differences and can confirm that they don’t affect the drug’s safety or efficacy.⁵

According to a 2012 editorial by ophthalmologist Wiley A. Chambers, deputy director of the FDA’s Division of Transplant and Ophthalmology Products and the American Academy of Ophthalmology’s delegate to the U.S. Pharmacopeia, before 1992, manufacturers of ophthalmic drug products were permitted to use inactive ingredients that differed from those in the innovator drugs.⁶ Regulators assumed an ingredient used previously in another ophthalmic drug must be safe. The FDA later revised this policy, recognizing that changing an inactive ingredient can significantly affect the safety and efficacy of an ophthalmic drug. Some of the generic ophthalmic drugs that were approved before the policy change remain on the market today. Although they are labeled similarly, they are not the same as the branded drug.

Another source of confusion, Dr. Chambers noted in the 2012 editorial, is that before 1962, companies independently developed drug products with the same active ingredients and submitted them for approval and marketing. The ophthalmic corticosteroids prednisolone acetate, prednisolone phosphate, dexamethasone and fluorometholone are good examples, according to Dr. Chambers. They were developed and approved independently without consideration of the appropriateness of substituting one for another. “These ophthalmic corticosteroids approved prior to 1962 should not be thought of as true ‘generics,” Dr. Chambers wrote.⁶

Generic drug-makers aren’t required to perform clinical trials for topical ophthalmic solutions — a sticking point for some ophthalmologists — because safety and efficacy were established for the branded drug. Since 1992, however, sponsors of proposed generic versions of post-1962 innovator ophthalmic suspensions, gels, emulsions, and ointments have been required to perform controlled comparative clinical trials and demonstrate equivalent safety and efficacy with the innovator product.⁶

FDA also provides guidance for generic drug-makers to perform in vivo studies, if deemed necessary. For example, the Office of Generic Drugs issued such guidance for both brimonidine and brinzolamide in the past several years, with recommendations, albeit nonbinding, for bioequivalence studies.^7,8

Generic ophthalmic products must match each active and inactive ingredient to within plus or minus 5% of the innovator’s target formulation.⁶ The agency acknowledges there will always be “a slight but not medically important level of natural variability” between a generic drug and its brand-name counterpart, similar to lot-to-lot variations of branded drugs.⁵

THERAPEUTIC EQUIVALENCY

As stringent as FDA’s requirements are, some ophthalmologists question the therapeutic equivalence of generic drugs, and they worry about adverse events owing to even small differences in formulations.

“Generic drugs are similar to the branded drugs they are meant to replace, but they are not exact duplicates,” says Robert D. Fechtner, MD, professor and director of the glaucoma division of Rutgers-New Jersey Medical School in Newark. “There is no requirement for large, randomized, prospective clinical trials on generic ophthalmic solutions, so we will never know how they perform compared with the branded products,” he says.

The lack of data from clinical trials is also troubling to Gregg J. Berdy, MD, particularly because the exact formulations of the branded drugs are proprietary. Generic drug-makers must rely on their own analysis of a branded drug’s ingredients, as well as information from product labels, patents, and FDA to develop a bioequivalent drug.

“No one knows the recipes for the branded drugs,” says Dr. Berdy, who specializes in corneal and external disease in St. Louis and is an assistant professor of clinical ophthalmology at Washington University School of Medicine. “We know the drop that comes out of the bottle of a generic product must have the same concentration of drug as the branded version, but there could be 10 other ingredients that were not so precisely measured,” he says. “It’s like baking a cake and saying you may or may not use flour or baking soda or butter or salt or sugar, or how much of each ingredient you will use. Because of these variables in generic drug formulations, we don’t know how that drop will behave on the eye.

“We have many great studies that validate the efficacy of our branded ophthalmic solutions; whereas, studies are lacking for generics,” Dr. Berdy says. “Are generic drugs equivalent in the bottle, in the concentration of active drug? Yes. Are generic drugs therapeutically equivalent with equivalent bioavailability on the ocular surface as compared with branded drugs? We don’t know, but I don’t think so.”

A fundamental difference between topical and systemic drugs — route of administration — makes validating an ocular drug’s efficacy in patients in the clinic impractical. “The key is drug delivery,” says Keith A. Walter, MD, professor of ophthalmology at Wake Forest University School of Medicine, Winston-Salem, N.C. “With an oral medicine or one that’s delivered intravenously or by infusion, we can measure blood plasma levels to determine if it’s working. We can’t do that with an eye.”

A potential workaround to this shortcoming is under development at Texas A&M University. The Center for Drug Evaluation and Research, part of the FDA, recently awarded a grant to Srinath Palakurthi, PhD, an associate professor of pharmaceutical sciences, to develop a test method to predict the efficacy of generic ophthalmic drugs as compared with their branded counterparts.⁹ (See “Therapeutic Equivalency Test for Generic Drugs” on Page 6)

BOTTLE DESIGN

FDA requires that generic manufacturing, packaging, and testing sites adhere to the same quality standards, known as Current Good Manufacturing Practices, as those of brand-name drugs. However, generic drug-makers aren’t required to use the same bottle materials and designs as the innovator drugs, and when pharmacies change suppliers, which they do regularly, patients may receive their drops in a different style bottle, which can lead to dose inconsistencies and diminished efficacy.

“Patients can potentially get a different type of bottle every month,” Dr. Fechtner says. “In my elderly population of glaucoma patients, this is very confusing, and it also raises questions in my mind. What’s the size of the drop dispensed? Is the bottle difficult to squeeze? I recall a generic timolol that came to market with a sealed bottle that the patient had to puncture using a unique cap. People couldn’t get their timolol out of the bottle. It was only after patients started having problems that I became aware of it. This product is no longer on the market.”

Variations in drop volume as well as other factors appear to occur regularly in ophthalmic drugs. Researchers in Toronto evaluated branded and generic versions of U.S.- and Canadian-made antiglaucoma drops — alpha agonists and gel and aqueous solutions of beta-blockers — and found significant variations in drop volume, viscosity, surface tension, and bottle tip.¹⁰ The researchers recommended that regulators carefully consider drop viscosity and bottle design when evaluating generic ophthalmic products. Research in this area is continuing. (See “Study of Drop Volume Variables Continues” on Page 9)

Generic drugs produced outside the United States, beyond FDA oversight, are also concerning, Dr. Berdy says. “I’m reluctant to trust generic drugs produced in foreign countries, because I can’t be sure what’s in the bottle,” he says. “I’m a big believer in the FDA. Even though the approval process for branded drugs is slow and expensive, we know an approved drug will be safe and efficacious.”

COST CONSIDERATIONS

Although Drs. Berdy, Fechtner and Walter prefer branded drugs over generics, they acknowledge their preferences are often overridden by third-party payers and patients’ finances. “Generics in and of themselves aren’t bad,” Dr. Fechtner says. “They’re just not offering any benefit other than sometimes cost. Many of my patients are using generic medications and they have to be, because that’s what their insurance will support. Sometimes the best choice for them is the least expensive drug. Cost is a discussion we have to have in medicine.” ◆

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