How Often Are Drugs Withdrawn For Safety or Effectiveness Reasons (and How Many)? Not Too Often in Recent Years, But There is a Tranche of Withdrawals Historically

By Kurt R. Karst –

Sometimes curiosity gets the better of us . . . .  We take some bait and go down a rabbit hole.  That’s what happened last week after FDA published a notice in the Federal Register announcing the Agency’s determination that Ondansetron (ondansetron HCl) Injection, in PL 2408 Plastic Container, 32 mg/50 mL, single IV dose, approved under NDA 021915, was withdrawn from sale for reasons of safety or effectiveness and that FDA will not accept or approve ANDAs for generic versions of the drug.  FDA issued a separate notice formally withdrawing approval of NDA 021915, as well as approval of four ANDAs for Ondansetron HCl and Dextrose in 32 mg single IV doses, all of which are indicated for prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy in adult patients.  According to FDA, the 32 mg, single IV dose of Ondansetron HCl should be avoided because of the risk of a QT interval prolongation, which can lead to potentially fatal Torsades de Pointes.

On to the bait. . . . 

When we saw the FDA notices for Ondansetron HCl Injection, our thought was: “There’s something you don’t see every day; FDA withdrawing approval of marketing applications over safety or effectiveness concerns.”  That thought was reinforced by a headline on the Lachman Consultants Blog in a post by Bob Pollock.  So this blogger got to thinking: “How many times has FDA, in fact, issued a notice in in the Federal Register announcing the Agency’s determination that a drug was withdrawn from sale for reasons of safety or effectiveness?”  It turns out that the answer to that question is a little more complicated to come by that we initially thought. 

Down the rabbit hole . . . .

Often – but not always – FDA makes a determination that a drug was discontinued for safety or effectiveness reasons in response to a so-called “discontinuation petition” submitted to the Agency pursuant to 21 C.F.R. § 314.161(b).  FDA may also make such a determination on its own initiative.  FDA is supposed to respond to a discontinuation petition within 270 days of receiving it.  (See our previous post here for an analysis of FDA’s track record on responding to discontinuation petitions.)  If a drug was discontinued for safety or effectiveness reasons, then it is removed from the Orange Book and it cannot serve as a basis for another applicant’s ANDA (or 505(b)(2) application) submission.  If FDA determines that a drug was not discontinued for safety or effectiveness reasons, then it remains in the Orange Book and can continue to serve as a basis for another applicant’s submission.  FDA updates the Orange Book each month a lists titled “FR Notice Determination of Safety or Effectiveness List.” 

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 with a title along the lines of: “Determination That [Drug] Was [Not] Withdrawn From Sale for Reasons of Safety or Effectiveness.”  Given this styling, we searched the Federal Register database on the Government Publishing Office website, which database goes back to 1994. 

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.  Below is a table with a year-by year breakdown, followed by a bullet point list of the 11 safety/effectiveness withdrawal decisions.

• 80 Fed. Reg. 32,962 (June 10, 2015): Determination That Ondansetron (Ondansetron Hydrochloride) Injection, USP in PL 2408 Plastic Container, 32 Milligrams in 50 Milliliters, Was Withdrawn From Sale for Reasons of Safety or Effectiveness.
• 78 Fed. Reg. 23,273 (Apr. 18, 2013): Determination That the OXYCONTIN (Oxycodone Hydrochloride) Drug Products Covered by New Drug Application 20–553 Were Withdrawn From Sale for Reasons of Safety or Effectiveness.
• 77 Fed. Reg. 41,412 (July 13, 2012): Determination That CHLOROMYCETIN (Chloramphenicol) Capsules, 250 Milligrams, Were Withdrawn From Sale for Reasons of Safety or Effectiveness.
• 76 Fed. Reg. 51,037 (Aug. 17, 2011):  Determination That Halflytely and Bisacodyl Tablets Bowel Prep Kit (Containing Two Bisacodyl Delayed Release Tablets, 5 Milligrams) Was Withdrawn From Sale for Reasons of Safety or Effectiveness.
• 76 Fed. Reg. 3143 (Jan. 19, 2011): Determination That ALBAMYCIN (Novobiocin Sodium) Capsule, 250 Milligrams, Was Withdrawn From Sale for Reasons of Safety or Effectiveness.
• 75 Fed. Reg. 24,710 (May 5, 2010): Determination That BREVIBLOC (Esmolol Hydrochloride) Injection, 250 Milligrams/Milliliter, 10-Milliliter Ampule, Was Withdrawn From Sale for Reasons of Safety or Effectiveness.
• 75 Fed. Reg. 13,292 (Mar. 19, 2010): Determination That HalfLytely and Bisacodyl Tablets Bowel Prep Kit (Containing 4 Bisacodyl Delayed Release Tablets, 5 Milligrams) Was Withdrawn From Sale for Reasons of Safety or Effectiveness
• 75 Fed. Reg. 12,760 (Mar. 17, 2010): Determination That CERNEVIT-12 (Multivitamins for Infusion) Was Withdrawn From Sale for Reasons of Safety or Effectiveness.
• 73 Fed. Reg. 52,357 (Sept. 9, 2008): Determination That TEQUIN (Gatifloxacin) Was Withdrawn From Sale for Reasons of Safety or Effectiveness.
• 70 Fed. Reg. 53,019 (Sept. 6, 2005): Determination That Penthrane (Methoxyflurane) Inhalation Liquid, 99.9 Percent, Was Withdrawn From Sale for Reasons of Safety or Effectiveness.
• 64 Fed. Reg. 45,973 (Aug. 23, 1999): Determination That Astemizole 10-Milligram Tablets Were Withdrawn From Sale for Safety Reasons.

As we perused the list of 11 determinations, we immediately noticed that something was missing.  Where were the FDA determinations on Terfenadine (SELDANE and SELDANE-D), Trimethobenzamide HCl (TIGAN), and other old drug products, including drugs evaluated under the Drug Efficacy Study Implementation program?  They’re contained in other Federal Register notices where FDA announces the “Withdrawal of Approval” of a marketing application.  There are about 250 of those notices since 1994 for both human and animal drugs.  The notices typically announce the withdrawal of approval of a marketing application for general reasons – perhaps because a sponsor has failed to do something, or because the sponsor requested or consented to withdrawal of approval.  Some of those decisions are available here, here, here, here, here, here, here, here, and here.

Considering this other tranche of FDA notices and determinations, what’s the total number of human drugs approved under NDAs and ANDAs that FDA has withdrawn for safety or effectiveness reasons?  We don’t have an exact figure, but based on a list of such withdrawals we obtained from FDA a few years ago, and considering some recent withdrawals, we think the total number is somewhere around 600 applications.