Article Date: 11/1/2011

Pathway to Approval
Branded vs. Generics

Pathway to Approval

FDA officials explain how their process results in generic and brand drugs that are therapeutically equivalent.

Since 1938, the U.S. Food and Drug Administration (FDA) has approved medications that are similar to previously approved medications. To do so, it has used several different mechanisms, including various forms of New Drug Applications (NDAs). In 1984, Congress passed the Drug Price Competition and Patent Term Restoration Act, also known as the Hatch-Waxman Act, which is the basis for the current FDA process for approving generic drugs.

The purpose of the 1984 legislation was to facilitate market entry for less costly generics, by way of Abbreviated New Drug Applications (ANDAs), while extending patent protection for brand-name drugs as a way to help ensure continued innovation. Under the Act, makers of generic drugs are incentivized to challenge innovator patents. First applicants who prove a patent is invalid or not infringed by their proposed generic drug may be entitled to 180 days of their own market exclusivity. Hatch-Waxman contains many other provisions, including allowing manufacturers of brandname drugs to reclaim up to 5 years of patent protection to make up for time lost while products were going through the FDA approval process. (Although the term of a patent is generally 20 years, the Congressional Budget Office reports the average period of marketing under patent protection for drugs approved between 1992 and 1995 was 11.5 years.1)

The Hatch-Waxman Act greatly expanded the number of generic drugs eligible for approval via an ANDA, requiring them to 1) contain the same active ingredient, be the same strength and dosage form, and have the same route of administration as the previously approved drug referenced in the application, i.e., the innovator drug, and 2) be “bioequivalent” to the innovator drug. The FDA defines bioequivalence as the lack of a significant difference in the bioavailability of the innovator and proposed generic drug, i.e., the rate and extent to which the active ingredient is absorbed and becomes available at the intended site of action. The idea is that the bioequivalence standard allows FDA to approve generic drugs that are therapeutically equivalent to innovator drugs, without requiring generic companies to repeat drug discovery, preclinical animal studies and human clinical trials to prove the efficacy and safety of the active ingredient.

How Bioavailability is Compared

Given the Hatch-Waxman framework for ANDAs and approval of generic medications, as implemented by the FDA, most orally administered generic drugs gain approval based on results of one or more in vivo bioequivalence studies, usually conducted in healthy subjects. The number of subjects required depends on the innovator drug's pharmacokinetic variability, and studies on patients may be required if there are safety issues. The primary means of comparison is the drugs' availability in blood serum. FDA scientists have retrospectively evaluated how generic drugs compared with their corresponding innovator drugs on key measures in bioequivalence studies such as Cmax (rate of absorption) and area under the plasma concentration time curve (AUC, extent of absorption).2,3 In one such analysis of 2,070 single-dose clinical bioequivalence studies of oral generic drugs, the average difference in Cmax and AUC between generic and innovator products was 4.35% and 3.56%, respectively.3 Also, in nearly 98% of those bioequivalence studies, the generic product's AUC differed from that of the innovator product by less than 10%. FDA says the results of such analyses show that its objective of approving generic drugs that are therapeutically equivalent to innovator drugs is being met.

Despite such assurances, and the lack of widespread serious issues with generic products, the ability of the system to ensure that all generic drugs perform the same in the body as the innovator drugs has been questioned. For example, neurologists have long questioned and debated if generic anti-seizure medications are interchangeable with innovator medications.

What About the Eye?

In ophthalmology, concerns about therapeutic equivalence have been frequently expressed. Critics of the ANDA approval process say drug levels in the blood, which are used to compare oral medications, aren't relevant to the efficacy of ophthalmic medications. They also point out that proposed ophthalmic generics typically are not required to undergo any clinical testing at all, and their inactive ingredients are permitted to differ from what is contained in the innovator drug. They further contend that how a drug behaves in the eye is highly dependent on its inactive ingredients and the concentrations in which they are present. How then, they ask, in the absence of clinical testing, can doctors be sure a generic drug will not differ from a brand-name drug on key parameters such as penetration into ocular tissue?

According to the Code of Federal Regulations Title 21 Part 314 Section 94 (21CFR314.94), the submitter of an ANDA can seek approval of a generic ophthalmic drug that contains different inactive ingredients than the innovator drug. However, in doing so, it must identify and characterize the differences and provide information that demonstrates to the satisfaction of FDA that the differences do not affect the safety or efficacy of the proposed product. Also, as outlined in 21CFR320.22, FDA may waive requirements for in vivo bioavailability testing for some proposed generic drug products (including solid oral dosage forms in some circumstances). The regulations state that in vivo testing for ophthalmic solutions may be waived because their bioavailability may be considered self-evident — if they contain the same active and inactive ingredients in the same concentrations as the drug they are meant to duplicate.

According to Wiley Chambers, MD, Deputy Director of FDA s Division of Transplant and Ophthalmology Products, the regulations take into account that inactive ingredients can affect the absorption and distribution of an ophthalmic product. “The vast majority of ophthalmic generics have the same active and inactive ingredients in the same concentrations as the innovator drugs,” he said. “When that is the case, the generic drug would be expected to act the same way, which is the goal.”

Generic drugs are, by necessity, reverse engineered. Generic drug manufacturers know what ingredients are included in the brand drug they want to copy because they're listed on the label. They do not, however, know the concentrations of the inactive ingredients because that information is proprietary. FDA isn't permitted to share those numbers. “Generic manufacturers defragment the brand-name drug to determine the exact quantity of each ingredient present in the drug product,” says Anurag Sharadendu, PhD, Review Chemist, Division of Chemistry I, Office of Generic Drugs. “That's how they make the Xerox copies.” As explained by Robert L. West, MS, RPh, Deputy Director of FDA's Office of Generic Drugs, “Sometimes they don't get it right. If the quantities are off, we do not accept their application.” For some drug characteristics that are a function of ingredients, such as pH level, a value within a certain range may be acceptable. “Differences from generic to innovator are commonly not greater than differences between two lots of innovator products,” says Rita R. Hassall, Associate Director for Operations and Communications in the Office of Generic Drugs.


“In reality, our review process is stricter than the regulations require for generic ophthalmics,” West said. “For at least 10 years now, we generally require the formulation for an ophthalmic generic solution to be ‘Q and Q’, which means the ingredients have to be qualitatively and quantitatively the same as the innovator drug. If those criteria are met, a waiver of bioequivalence testing is granted. Applicants still need to provide analytical studies to show stability and to guarantee other safety parameters. While clinical studies are not required under a waiver, volumes of data must be submitted by the applicant.”

West explained another aspect of why it's acceptable to FDA to waive in vivo testing requirements for generic solutions, whether they're ophthalmic, oral or for injection. “In vivo bioavailability testing for some medications is necessary to ensure the active ingredient gets out of the vehicle once it is in the body. For example, in an oral tablet, the ingredients are tightly packed. Compare that to a solution, where the active ingredient is already free; it is not embedded in the dosage form.”

The agency's approach to waivers for ophthalmic solutions was reflected in its 2008 Draft Guidance for companies planning to seek approval of a generic latanoprost product, based on the brand-name drug Xalatan. It stated, in part, “Changes in any of the inactive ingredients can change the safety and efficacy of an ophthalmic drug product. Therefore, an in vivo clinical endpoint bioequivalence study is requested for any latanoprost ophthalmic solution that has a different inactive ingredient or a difference of more than 5% in the amount of any inactive ingredient compared to that of the RLD (reference listed drug). Please submit a protocol to the Clinical Review Team in the Office of Generic Drugs for review and concurrence prior to conducting the in vivo clinical endpoint BE study for such a product.”

Formulations Other Than a Solution

Xalatan, and therefore the recently approved generic latanoprost products, are solutions, as are most of the medications used in ophthalmology. Other types of formulations raise different issues for the generic approval process. “With suspensions, ointments and gels — anything that's not a solution — there are manufacturing issues that have to be addressed,”

Dr. Chambers says. “For example, depending on how drug particles are milled, they can differ in size, which can affect how they are distributed throughout the formulation. That could lead to an unacceptable difference between a brand and generic product, which is why FDA generally asks for clinical studies in order to approve formulations that are not solutions.” It is also why, according to West, FDA doesn't approve many ophthalmic suspensions. “It is more difficult to show to FDA's satisfaction that a suspension would be equivalent.”

As noted in the accompanying article “Generics in Practice,” some doctors have concluded that some of the prednisolone acetate suspensions used in ophthalmology aren't as effective as the branded product Pred Forte. FDA officials said not all prednisolone acetate products are representative of today's approval process for generic drugs. “Many are older drugs,” Dr. Chambers says. “Some were approved under different mechanisms, submitting their own NDAs. They did not try to match the ingredients or effectiveness of a previously approved drug because they were not required to.”

Equivalence “Has Not Been Disproven”

FDA's Hassall said the agency is aware that skepticism about generic drugs exists. She said FDA receives many anecdotal reports along those lines and has encouraged outside entities to submit systematic studies related to their concerns, but none have materialized.

“It is convenient to attribute clinical changes — such as an increase in intraocular pressure — to a generic medication, but many things go on in a patient's life that can cause such a change,” West says. “Also, generic drugs are so much more inexpensive than brand-name drugs, and in our culture, a common belief is you get what you pay for. We certainly do not see it that way. The fact that generic drugs are the same as brand drugs has not been disproven over all of these years.” ■

Nonclinical Considerations

Issues surrounding ingredient quality and manufacturing standards have also been part of the discussion about generic medications. According to FDA, generic drug manufacturers must:

■ fully document the generic drug's chemistry, manufacturing steps and quality control measures
■ assure FDA that the raw materials and finished product meet specifications of the U.S. Pharmacopoeia, the organization that sets standards for drug purity in the United States
■ show that a generic drug will remain potent and unchanged until the expiration date on the label
■ comply with federal regulations for good manufacturing practices and provide the FDA a full description of facilities used to manufacture, process, test, package and label the drug; FDA inspects manufacturing facilities to ensure compliance.

Added Rita R. Hassall, Associate Director for Operations and Communications in the Office of Generic Drugs: “Generic drug manufacturers are held to the same standards as the manufacturers of innovator drugs. All of the chemistry reviewers at FDA are within the Office of Pharmaceutical Science structure, and the same staff members inspect all of the plants.”


1. The Congress of the United States Congressional Budget Office. How increased competition from generic drugs has affected prices and returns in the pharmaceutical industry, July 1998. Available at:; accessed August 9, 2011.
2. Henney JE. Review of generic bioequivalence studies. JAMA 1999;282(21):1995
3. Davit BM, Nwakama PE, Buehler GJ, et al. Bioequivalence: comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother 2009;43(10):1583-1597.

Optometric Management, Issue: November 2011