Not all drugs approved by the US Food and Drug Administration (FDA) stand the test of time. In some cases, the drugs are eventually removed from the market, either because they are unsafe, ineffective or just because their sponsor no longer feels like making them. But how often do these withdrawals take place, and to what extent do they reflect concerns about the safety or efficacy of a drug?

Background

The question is the subject of a new analysis by Hyman, Phelps & McNamara's (HPM) Kurt Karst who, in a posting on the firm's FDA Law Blog website, admits his initial interest in the topic led him "down a rabbit hole."

The question is of particular consequence for manufacturers of generic drugs. When FDA responds to a "Discontinuation Petition" (21 CFR 314.161(b)) and announces the withdrawal of a drug, it is for either of two reasons:

• FDA has determined the drug was withdrawn from sale for reasons of safety or effectiveness
• FDA has determined the drug was not withdrawn from sale for reasons of safety or effectiveness

If a drug was not withdrawn for reasons of safety or effectiveness, that means that generic drug manufacturers can continue to reference the drug's approval status in their own applications, thereby allowing them to bypass the traditional drug approval process (using the New Drug Application) in favor of the abbreviated generic drug approval process (using the Abbreviated New Drug Application).

This is intended to ensure that companies don't simply introduce new versions of a marketed drug subject to patent protections and withdraw older drugs from the market to stymie generic drug competition. It is also meant to ensure if a company withdraws a marketing application because it found a drug insufficiently profitable or otherwise undesirable, another company can later manufacture the drug again without requiring extensive use of FDA's regulatory review resources.

However, if a drug has been withdrawn for reasons related to its safety or efficacy—for example, a company finds a drug has an unexpected and severe side effect and immediately withdraws the drug from the market—FDA's declaration (in the form of the withdrawal notice) ensures that future generic drug products may not reference the withdrawn application.

In practice, some companies have also successfully used this pathway to remove their original, non-abuse-deterrent drugs from the market after new, abuse-deterrent iterations obtain approval.

A Rare Decision

But as Karst's analysis shows, use of the withdrawal process is relatively uncommon, and especially so for reasons of safety or efficacy.

"When FDA makes a determination on whether or not a drug was discontinued for safety or effectiveness reasons, the Agency typically publishes a notice in the Federal Register," Karst explained. "Of the 215 notices we were able to find, only 11 of them – or 5.1% – included a determination that a drug was withdrawn from sale for safety or effectiveness reasons."

There has, however, been something of a recent uptick in withdrawals using this method (FDA has some other methods of withdrawing drugs as well). Between 1996 and 2005, there were 66 withdrawal notices, of which just two were for reasons of safety or effectiveness. In comparison, between 2006 and 2015 there were 149 withdrawals, of which nine were for reasons of safety or effectiveness.

Karst estimates FDA has only withdrawn "around 600" applications for safety or effectiveness reasons in its entire history.

FDA Law Blog