About a year ago, people taking a certain generic form of Wellbutrin XL 300mg, called budeprion, started reporting what sounded like symptoms of depression. The FDA went on to announce the in-equivalence of this generic, which was taken off the market. This past Thursday, the FDA released an update:
Based on data submitted by Watson, FDA has determined that that company’s generic bupropion HCl ER 300 mg tablet product is not therapeutically equivalent to Wellbutrin XL 300 mg. Watson has agreed to voluntarily withdraw this product from the distribution chain. Also, FDA has changed the Therapeutic Equivalence Code for the Watson product from AB (therapeutically equivalent) to BX (data are insufficient to determine therapeutic equivalence) in the Orange Book. FDA does not anticipate a drug shortage.
We recommend that patients taking the Watson product continue taking their medication and contact their health care professional or pharmacist to address any concerns.
So how does a generic drug come to be?
First, let's have some definitions and review.
According to the World Health Organization, "A generic drug is a pharmaceutical product, usually intended to be interchangeable with an innovator product, that is manufactured without a license from the innovator company and marketed after the expiry date of the patent or other exclusive rights."
What makes a generic drug "interchangeable with an innovator product" is the fact that it contains the same Active Pharmaceutical Ingredient (API), and demonstrates Bioequivalence:
Generics are not required to replicate the extensive clinical trials that have already been used in the development of the original, brand-name drug. These tests usually involve a few hundred to a few thousand patients. Since the safety and efficacy of the brand-name product has already been well established in clinical testing and frequently many years of patient use, it is scientifically unnecessary, and would be unethical, to require that such extensive testing be repeated in human subjects for each generic drug that a firm wishes to market. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner) to the pioneer drug.
One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream and its concentration in the bloodstream in 24 to 36 healthy, normal volunteers. This gives them the rate and extent of absorption-or bioavailability-of the generic drug, which they then compare to that of the pioneer drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the pioneer drug.
Using bioequivalence as the basis for approving generic copies of drug products was established by the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act. Brand-name drugs are subject to the same bioequivalency tests as generics when their manufacturers reformulate them.
You may recall this graph:
It's blood concentration vs. time for an oral drug. Sequential blood samples are taken after ingestion of the drug, to generate the curve. Peak concentration, Cmax occurs at time, Tmax.
Rate of Absorption = Cmax/Tmax.
and Total Extent of Absorption = Area Under the Curve (AUC)
(which is simply the integral of the function that describes the curve).
A generic drug is considered equivalent to the brand drug if its Rate of Absorption and Extent of Absorption do not significantly differ from those of the brand drug. In other words, the curves look the same, or almost the same.
How much is almost?
"Most regulators worldwide have decided that a 20% variation is generally not clinically significant.
Two versions of a drug are generally said to be bioequivalent if the 90% confidence intervals for the ratios of the geometric means (brand vs. generic) of the AUC and Cmax fall within 80% and 125%. The tmax (brand vs. generic) must also be comparable — and there should not be any significant differences between different patients." (same source as graph).
Once they've established bioequivalence, generic drugs are given Therapeutic Equivalence Codes. There are different codes for different types of meds, e.g. tablets vs. injectables. The highest rating seems to be AA-drugs that "contain active ingredients and dosage forms that are not regarded as presenting either actual or potential bioequivalence problems or drug quality or standards issues. However, all oral dosage forms must, nonetheless, meet an appropriate in vitro test(s) for approval." I'm not clear on what would constitute a "bioequivalence problem". An example of an AA drug is Acetaminophen/codeine, and this is what the heading looks like in the Orange Book (see below):
AB seems to be a more typical rating for generics. There are some subcategories in which a drug is rated compared to a specific version of the drug, for example, levothyroxine:
For those who are interested in the whole shpiel, this is a link to Approved Drug Products with Therapeutic Equivalence Evaluations , aka The Orange Book. It's called The Orange Book because the original edition was published in October, and with Halloween coming up, they decided on an orange cover.
And here's another link to FDA slides on bioequivalence:
And here's another link to FDA slides on bioequivalence: