Debunking a Common Pharmacy Myth: The 80-125% Bioequivalence Rule

JUNE 07, 2016
One of the most common myths I hear from fellow pharmacists is that a generic product must contain between 80% and 125% of the brand-name product in order to be considered bioequivalent. In reality, that isn’t how the FDA determines bioequivalence.
This article walks through the myth of the 80-125% rule, the reality of the FDA’s bioequivalence requirements, the reasons behind the misunderstanding, and the practical implications for pharmacists.
The Myth
When a brand-name product’s patent expires and loses its exclusivity protection, generic versions are permitted to be launched in the market. The FDA requires that the generic product must be determined to be pharmacokinetically bioequivalent to its branded counterpart in order to ensure the generic’s safety and efficacy.
The FDA defines bioequivalence as the absence of a significant difference in the rate and extent to which the active ingredient becomes available when administered at the same molar dose under similar conditions in an appropriately designed study.

Many in health care mistakenly believe that the FDA requirement for bioequivalence permits a generic product to contain anywhere from a minimum of 80% to a maximum of 125% compared with the reference, or brand-name, product. Under this belief, the generic drug concentration could have up to a 45% total variance to the brand-name product.

I’ve personally heard this myth from a number of pharmacy students, technicians, and pharmacists when explaining the difference between generic and brand-name products. Additionally, this myth is frequently perpetuated in message boards, news outlets, and even some pharmacy schools.
The Reality
The truth behind the FDA’s requirements for bioequivalence is actually much more complicated.

In order to determine bioequivalence, a randomized, crossover trial is conducted with both the generic drug being assessed and the brand-name drug as the control. In these studies, a number of pharmacokinetic (PK) parameters are assessed, including maximum serum concentration of a drug (Cmax) and drug exposure over time (AUC).1

These parameters help assess how the rate and extent of the availability of the generic drug compares to the control. As the FDA requires, there must be no significant difference in the rate and extent to be deemed bioequivalent.

It’s true that the PK values are required to fall between 80% and 125% of the reference value in these randomized, crossover trials. More importantly, however, the entire 90% confidence interval (CI) of the observed PK value must also fall between 80% and 125%.

As a general reminder, CIs are ranges of values we can be confident the true result falls, which in this case is 90% of the time.

To explain bioequivalence with an example, imagine that a brand-name product was shown to have an AUC of 100 units in a crossover study. In the same study, let’s say the generic product was shown to have an observed mean AUC of 93 with a calculated 90% CI of 84-110. Because the FDA requires the mean AUC of the generic product as well as its entire 90% CI must fall between 80 and 125 units, this would meet the bioequivalence requirement.

Of course, this is a very simplified explanation. In reality, multiple PK values are being assessed based on ratios of the generic and reference drug, and CIs are being calculated around the observed means. The key takeaway is that because the entire 90% CI has to fall within the 80-125% range, the actual PK values of the generic drug must be very close to the mean PK value of the reference product.

Using the statistical criteria required by the FDA, it would be difficult for any generic product to differ more than 10% from the reference to meet the CI requirements, and it would be nearly impossible to meet the CI requirements if the difference approached 20%.
According to 1 FDA study, the mean difference for AUC values between test and reference products was found to be 3.5% in the 2-year period following the Waxman-Hatch Act, and 80% of the absolute differences between generic products approved since 1984 and the corresponding innovator products were within a 5% range.2
Where did the specific limits of 80% and 125% originate from? According to the FDA this is based on a clinical judgment that a test product with bioavailability that falls outside this range should be denied market access. A 90% CI is used, since a 5% statistical error is allowed at both the upper and the lower limits. Therefore, the total error is 10%, generating the 90% CI. 

Timothy O'Shea, MS, PharmD
Timothy O'Shea, MS, PharmD
Timothy O'Shea, MS, PharmD, is a Clinical Pharmacist working at a regional health insurance plan on the east coast. Additionally he works per diem at a nationwide retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. He completed his M.S. in Health Services Administration, with a focus on Health Economics and Outcomes, in 2018. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.