The "Scandal" of "Untested" Generics

I am in the process of writing up a review of this rather terrible Forbes piece on the FDA recall of one manufacturer's version of generic 300 mg bupropion XL. However, that's going to take a while, so I thought I'd quickly cover just one of the points brought up there, since it seems to be causing a lot of confusion.

Forbes is shocked, SHOCKED to learn that things
 are happening the same way they always have:
call Congress at once!

The FDA’s review of the recall notes that when the generic was approved, only the 150 mg version was tested for bioequivalence in humans. The 300 mg version was approved based upon the 150 mg data as well as detailed information about the manufacturing and composition of both versions.

A number of people expressed surprise about this – they seemed to genuinely not be aware that a drug approval could happen in this way. The Forbes article stated that this was entirely inappropriate and worthy of Congressional investigation.

In fact, many strengths of generic drugs do not undergo in vivo bioequivalence and bioavailability testing as part of their review and approval. This is true in both the US and Europe. Here is a brief rundown of when and why such testing is waived, and why such waivers are neither new, nor shocking, nor unethical.

Title 21, Part 320 of the US Code of Federal Regulations is the regulatory foundation regarding bioequivalence testing in drugs.  Section 22 deals specifically with conditions where human testing should be waived. It is important to note that these regulations aren't new, and the laws that they're based on aren't new either (in fact, the federal law is 20 years old, and was last updated 10 years ago).

By far the most common waiver is for lower dosage strengths. When a drug exists in many approved dosages, generally the highest dose is subject to human bioequivalence testing and the lower doses are approved based on the high-dose results supplemented by in vitro testing.

However, when higher doses carry risks of toxicity, the situation can be reversed, out of ethical concerns for the welfare of test subjects. So, for example, current FDA guidance for amiodarone – a powerful antiarrhythmic drug with lots of side effects – is that the maximum “safe” dose of 200 mg should be tested in humans, and that 100 mg, 300 mg, and 400 mg dosage formulations will be approved if the manufacturer also establishes “acceptable in-vitro dissolution testing of all strengths, and … proportional similarity of the formulations across all strengths”.

That last part is critically important: the generic manufacturer must submit additional evidence about how the doses work in vitro, as well as keep the proportions of inactive ingredients constant. It is this combination of in vivo bioequivalence, in vitro testing, and manufacturing controls that supports a sound scientific decision to approve the generic at various doses.

In fact, certain drugs are so toxic – most chemotherapies, for example – that performing a bioequivalence test in healthy humans in patently unethical. In many of those cases, generic approval is granted on the basis of formulation chemistry alone. For example, generic paclitaxel is waived from human testing (here is a waiver from 2001 – again demonstrating that there’s nothing terribly shocking or new about this process).

In the case of bupropion, FDA had significant concerns about the risk of seizures at the 300 mg dose level. Similar to the amiodarone example above, they issued guidance providing for a waiver of the higher dosage, but only based upon the combination of in vivo data from the 150 mg dose, in vitro testing, and manufacturing controls.

You may not agree with the current system, and there may be room for improvement, but you cannot claim that it is new, unusual, or requiring congressional inquiry. It’s based on federal law, with significant scientific and ethical underpinnings.

Further reading: FDA Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations