The Digitek Recall Shows Us Once Again That the FDA Can’t Protect Us
A Brief History of Digitek
In 1779, the English doctor William Withering discovered that the Foxglove plant could be used to treat congestive heart failure, and in 1785 he published An Account of the Foxglove and some of its Medical Uses. Foxglove is the common name for the roughly twenty plants in the Digitalis family.
In 1930, a scientist named Sydney Smith at the Wellcome Chemical Works in Dartford, England was working with the plant Digitalis Lanata and extracted a substance he dubbed Digoxin. Digoxin is the active ingredient in several heart medications, including Digitek. Wellcome (now GlaxoSmithKline) brought the first Digoxin product to market in the United States in 1934.
While there was an FDA in 1934, it was nothing like the FDA we have today. The Federal Food, Drug, and Cosmetic Act that granted the FDA many of its powers wasn’t passed until 1938. And it wasn’t until 1962 that amendments were passed that allowed the FDA to make pharmaceuticals prove drugs were safe and effective before they could be sold to the general public.
After the 1962 amendments were passed, the FDA began the difficult task of ensuring that existing drugs – many of which had been sold for decades – were also safe and effective. By the late 1960’s, the FDA was convinced that the drug Digoxin was safe and effective if manufactured properly. Drug manufacturers in the 1960’s had a very hard time ensuring the Digoxin pills they produced were of appropriate strength. In April of 1970, the FDA began working with pharmaceuticals to test individual lots of Digoxin tablets. Between April and November of 1970, there were 79 recalls of Digoxin tablets. Deja vu, anyone?
In 1974, the FDA enacted a series of regulations designed to ensure the safety of Digoxin tablets. Even with those regulations in place, there were still safety problems with Digoxin; the problems continued into the 1990’s. By that time, the FDA believed the only solution to the Digoxin safety problem was to treat Digoxin as a new drug, and require pharmaceuticals to submit new applications to the FDA. Treating Digoxin tablets as a new drug would force pharmaceuticals to run tests and studies that didn’t even exist when Digoxin first came to market in 1934.
The FDA went to GSK (who merged with Wellcome, the original inventor of Digoxin) and asked them to submit a New Drug Application for a Digoxin product. in 1993, GSK submitted an application for a Digoxin drug it called Lanoxin. The drug was approved in 1997. Lanoxin was approved as a new, brand-name drug, which means that other pharmaceuticals could choose to make a generic form of Lanoxin.
One such manufacturer was Amide Pharmaceuticals, who asked the FDA to approve a generic drug it called Digitek. (Actavis bought Amide Pharmaceuticals in May of 2005.) The FDA approved Digitek on December 23rd of 1999 and Amide began manufacturing Digitek in Little Falls, New Jersey. Here’s an overhead shot of the factory, courtesy of Google Maps:
In February of 2001, Amide and Bertek (a distributor of Digitek and the source of the “B” stamped on Digitek tablets) wrote to the FDA urging it to eliminate the 1974 Digitek regulations. Amide wanted the FDA to require all Digoxin manufacturers to submit the same applications to the FDA that it did to bring Digitek on the market. In this excerpt of the letter, Amide specifically acknowledges the difficulty in manufacturing Digoxin tablets:
Just seven years later, Actavis would recall every drug made in the Little Falls plant - including Digitek - because it couldn’t maintain consistency between product batches.
The FDA finds Serious Problems at the Little Falls Plant in 2006
The FDA inspected the Little Falls plant in January & February of 2006 and issued a warning letter to Actavis on August 15th of 2006. (Yes, the warning letter was issued six months after the inspection.) The FDA found several problems which they determined were “serious:”
Pharmaceuticals must tell the FDA about any patients who experience an adverse event while taking any drugs the pharmaceutical manufactures. Actavis (and Amide before it) failed to report at least six adverse events related to several drugs, including Digitek.
Actavis didn’t have a proper system to monitor adverse events, and it wasn’t properly following up on the adverse events it learned about.
Actavis never filed the “periodic safety report” it was legally obligated to file with the FDA
Actavis was also manufacturing drugs that had not been approved by the FDA. Amide had a similar violation some years earlier.
The FDA warned Actavis that, “The specific violations noted in this letter are serious and may be symptomatic of underlying problems.” (Emphasis added.)
The online archive of FDA warning letters only goes back to 11/1996, so a search for Amide leaves out the 13 years it operated prior to 1996. That said, a search of the archive only turns up one warning letter for Amide: In 2002, they were manufacturing an unapproved extended-release version of an expectorant. In other words, the Little Falls plant hadn’t failed any inspections since at least 1996. So what happened between May of 2005 when Actavis bought the plant and the January 2006 inspection? Did too many people quit or get fired for Actavis to run the plant safely?
Considering the first failed inspection took place just months after Actavis bought Amide, it’s possible that the FDA missed problems in prior inspections and that Actavis merely inherited existing problems. But even if that’s the case, Actavis knew that there were serious problems at the Little Falls plant but didn’t correct them.
The Problems Had Worsened By July of 2006
The FDA inspected the Little Falls plant again in July and August of 2006, and things had gotten decidedly worse. Now, Actavis wasn’t just failing to report adverse events, it was failing to follow “Good Manufacturing Practice” regulations. Here’s what Actavis has to say about Good Manufacturing Practices: “Good Manufacturing Practice (GMP) is a regulatory guideline imposed on all manufacturers of pharmaceuticals to ensure that finished products have the identity, strength, quality and purity they are required to have.”
Here are some of the most disturbing parts of the warning letter the FDA sent Actavis in February of 2007:
“Significant deficiencies were found in the operations of your firm's quality control unit, and as a result there is no assurance that many drug products manufactured and released into interstate commerce by your firm have the identity, strength, quality and purity that they purport to possess.”
“Our investigators observed numerous instances where your firm's quality control unit either ignored or failed to recognize that some tablets that did not meet in-process specifications.”
“[W]e are concerned about the quality of drug products that have been released from your facility under the serious lack of cGMP controls found during the inspection. Your response provides no assurance that the records and conditions of manufacture and testing of each such lot of drug products released and marketed by your firm will be evaluated to assure that the released drug products have their appropriate identity, strength, quality, and purity. “
Remember, Amide had previously told the FDA that it’s very difficult to maintain consistency in the manufacture of Digoxin tablets. Yet the FDA found “significant deficiencies” in the quality control unit and the manufacturing unit. These violations are never excusable at any facility, but they’re even worse when the facility makes a highly toxic drug like Digitek that is so easy to manufacture incorrectly.
Why Did It Take So Long To Recall Digitek?
On April 25th of 2008, over a year after receiving the February letter, Actavis issued a recall notice for all of its Digitek tablets. A remarkably tight-lipped recall notice; the notice doesn’t indicate how many tablets are being recalled or a time range for the recalled tablets. You can read the actual recall notice here.
I dug a little deeper, and found a copy of the recall notice that was sent to pharmacies at the North Carolina Board of Pharmacy. According to that notice, the recall applies to Digitek that was distributed between March of 2006 and April of 2008. Even still, that notice doesn’t give us any idea of how many tablets were distributed. Normally, a pharmaceutical company tells the FDA the quantity being recalled. But in the latest Enforcement Report, the FDA only states that there are 166 Lots being recalled.
An even more important question than how many tablets are being recalled is why did Actavis wait so long to recall them? In August of 2006, the FDA told Actavis that it had serious problems at the plant. Just six months later, the FDA told Actavis what it likely already knew: Serious deficiencies in its manufacturing and quality control process were putting lives at risk. Actavis should have been recalling drugs by April of 2007, not April of 2008.
What’s even worse is that despite being thoroughly warned by the FDA in February of 2007, Actavis continued manufacturing defective drugs for another year before initiating the recall. After receiving that letter, shouldn’t Actavis have stopped manufacturing potentially deadly drugs and fixed the problems?
One has to wonder just how bad the “significant deficiencies” that the FDA found in Actavis’ quality control unit when one considers what the defect was: Some Digitek tablets were twice as thick as they should be. What kind of quality control program can’t spot pills coming out twice as thick as they should? The FDA found that the quality control department was ignoring some defects. Surely they couldn’t have been so incompetent as to ignore a double-thick tablet, could they?
Actavis Recalls “All” Drugs Made at Little Falls
On August 2nd of 2008, Actavis issued a recall of “all drug products manufactured at its Little Falls, New Jersey facility.” There are two interesting facts about this recall. First, it was triggered after an FDA inspection that presumably didn’t go well. Second, the recall notice states that it applies to “all” drugs made at the Little Falls factory, and enumerates them. One drug is missing from that list: Digitek. Did Actavis cease manufacturing Digitek? Did it move production to a safer factory? Or is Digitek still being produced and distributed at Little Falls?
Four days after the recall, Actavis’ CEO stepped down for purportedly unrelated reasons.
How Could This Have Been Prevented?
It’s too early to put attribute a death toll to the defective Digitek, but I’m aware of several individuals who were taking Digitek pills subject to the recall and died from Digitalis Toxicity. Countless others have likely been hospitalized and suffered other injuries because of Actavis’ incompetence and a weak FDA.
The warning letters the FDA sounded harsh but amounted to not much more than a dog with a big bark and a little bite. Where are the multimillion dollar fines? Where are the criminal prosecutions? How many strikes does a pharmaceutical get before they’re out?
Thankfully, preemption won’t prevent injured individuals from suing Actavis because their injuries were caused by manufacturing defects, and not design defects. But the Digitek recall shows us that the FDA either cannot or will not keep us safe from pharmaceuticals who place profits above all else.