The latest issue of ISMP’s QuarterWatch™ (see box below) provides a review of new drug safety issues reflected in adverse drug events reported to the US Food and Drug Administration (FDA) during the first quarter of 2016. This report examines two signals for problems with devices that administer drugs to patients rather than the underlying risks associated with the drugs themselves:
- ZECUITY (SUMAtriptan iontophoretic transdermal system), which uses small electrical currents to deliver SUMAtriptan through the skin to treat migraine headaches, was withdrawn after just 9 months on the market because of burns, scarring, and other skin injury.
- Patients with type 2 diabetes are struggling to use the recently approved, once-weekly self-injection TANZEUM (albiglutide) pen.
Overall QuarterWatch™ report totals
In the first quarter (Q1) of 2016, FDA received 320,102 new case reports about adverse drug events involving 1,411 different primary suspect drugs, an increase of 19.2% over the previous quarter and 33.8% over the same quarter in 2015. However, the number of reports indicating fatal, disabling, or serious outcomes declined. In this key subset, a total of 74,834 new cases in Q1 was 4% lower than the previous quarter and 20.8% below the same quarter in the previous year. Overall, 96% of the reports received by FDA were prepared by drug manufacturers, who are required to report all adverse events about which they learn. The remainder were voluntarily submitted directly to FDA by health professionals and consumers.
Zecuity patch withdrawal: A case study of the perils of innovation
Zecuity paired a drug for migraines that has been available for more than 20 years with a novel iontophoretic patch delivery system that included two lithium batteries, a microprocessor, and two electrode pads—one saturated with the drug and the other with a salt formulation. A patient experiencing a migraine headache had to assemble the system, wrap it around their upper arm or affix it to their thigh, and activate it for 4 hours by pressing a button. The iontophoretic technology had been used for at least one other product, the IONSYS (fentaNYL iontophoretic transdermal system) patch used by hospitalized patients, which was first marketed in 2015. However, the drug, patch design, and treatment setting differ for the two patches.
Adverse event reports. The Zecuity patch came to our attention when adverse drug event reports submitted to FDA indicated that the patch was causing skin injury, including application site burns (n = 117), severe pain (n = 125), and smaller numbers of skin exfoliation, vesicles, scars, bruises, and chemical injuries. Reports were also submitted for battery issues (n = 63) and device leakage (n = 59). Within the first 6 months on the market, 389 adverse drug event reports were submitted to FDA. This number of reports might be considered modest if the drug was being used by hundreds of thousands or even millions of people. But only 7,235 prescriptions for Zecuity were dispensed during this time period, according to data from IMS Health. Additional patients could have been exposed if provided with free samples of the device.
The FDA’s Office of Surveillance and Epidemiology had issued a Drug Safety Communication in June 2016, saying it was investigating the issue. A week later, the patch was withdrawn by the manufacturer, Teva Pharmaceuticals. When further research showed that burns and other skin injuries had been an FDA concern both before and at the time of drug approval, we conducted a case study to examine the problem.
Zecuity approval history. The advantages, if any, of the new patch design were not immediately clear during clinical trials when compared to the tablet, nasal spray, and injection. In phase III efficacy trials, applying the patch resulted in an additional 8.5% of patients becoming pain free after 2 hours compared to placebo. This appeared to be an inferior result to both the SUMAtriptan injection (50% pain free at 2 hours compared to placebo), and to the nasal spray (13%-33% pain free compared to placebo). While FDA approval requires substantial evidence of a benefit, it does not require evidence that a new drug treatment is more effective than existing drugs.
Nevertheless, FDA approval of the product was initially rejected due to extensive deficiencies, including 71 problems in chemistry and manufacturing. One of the critical clinical problems involved serious concerns about the potential to cause severe burns and permanent skin lesions. One year later, a redesigned patch was submitted for review and approved. The usability trials demonstrating no burns were small (26 and 32 healthy subjects), but the company told FDA that the previous burns were caused when patients did not assemble the complex patch properly, which was said to be remedied by the new patch redesign. FDA documents show, however, that the review team was uncertain whether problems with the patch had, in fact, been remedied, citing a lack of “clinical evidence” (as opposed to “engineering evidence”).
Conclusion. In an era where pressures mount to speed up the approval of new drugs, this is the cusp of the regulatory dilemma that occurs when FDA has to balance rapid approval of innovative drug treatments against the amount of testing necessary to assess the risk of injury to patients. Since the patch had been extensively redesigned, FDA could have required a new long-term clinical trial. Instead, the agency required enhanced postmarketing surveillance and immediate reporting of any device problems. Patients unwittingly became test subjects to determine if the redesigned device would cause scars, burns, device leaks, erythema, and pruritus. The result was that thousands of patients were unnecessarily exposed to a defective device, and hundreds of patients reported injuries.
Problems using the Tanzeum self-injection pen
TANZEUM (albiglutide), a second-line treatment for type 2 diabetes from GlaxoSmithKline that lowers blood sugar through its effect on glucagon-like peptide-1 (GLP-1) receptors, was approved in April 2014. It’s one of four currently available GLP-1 receptor agonists.
Adverse event reports. All of the GLP-1 receptor agonists carry an FDA warning for pancreatitis and thyroid cancer. There may also be an increased risk of pancreatic cancer. In 12 months of data ending with 2016 Q1 for all of the GLP-1 receptor agonists combined, we continued to see evidence of these adverse effects, including 555 reported cases of acute and chronic pancreatitis, 399 cases of pancreatic cancer, and 111 cases of thyroid cancer. What sets Tanzeum apart from the other GLP-1 agonists is more than 1,500 reports of patients having problems using the pen correctly.
By comparison, for TRULICITY (dulaglutide), also a GLP-1 agonist approved for weekly injection, FDA received 673 adverse event reports for the same 12-month period, but no reports of device issues, maladministration, or medication errors.
Patient directions for use. Examination of the 10-11 page Tanzeum patient instruction leaflet in the full prescribing information (www.ismp.org/sc?id=2815) reveals that the process to prepare the pen for use is lengthy and complicated. The process takes more than 30 minutes and requires more than a dozen separate steps, including gently rocking (but not shaking) and twisting the pen assembly in three separate steps to dissolve and prepare the drug for injection. If patients observe undissolved particles, they should not use the pen. After attaching the needle, patients must tap the cartridge to bring large air bubbles to the top, although “small” air bubbles can remain throughout the cartridge. Deciding between large and small bubbles seems problematic, as is identifying enough undissolved particles to render the pen unusable. We communicated with GlaxoSmithKline (Tanzeum manufacturer), but the company was unable to offer additional information about potential medication errors patients should be aware of when using the pen.
By comparison, again, the use of Trulicity involves just four steps: 1) Uncap the pen; 2) Place the clear base against the skin; 3) Unlock by turning the lock ring; and 4) Press and hold the injection button.
Conclusion. Evidence shows that patients are struggling with use of the complex Tanzeum pen. Problems were first identified in adverse drug event reports, and the device compared unfavorably to the ease of use with the Trulicity pen. We recommend that GlaxoSmithKline substantially improve its efforts to educate patients about use of the pen. Physicians should consider the ease of use when prescribing a GLP-1 agonist pen if a drug in this class is needed, and ensure that patients know how to use the device if prescribing the Tanzeum pen. However, with all of these GLP-1 agonists, we continue to see concerns with the risk of pancreatitis, pancreatic cancer, and thyroid cancer.
The full report with references can be found at: www.ismp.org/sc?id=1702.
What is QuarterWatch™?
QuarterWatch™ is an independent ISMP surveillance program that monitors adverse drug events reported to FDA by manufacturers, health professionals, and the public. The agency releases excerpts of all reports it receives into the FDA adverse event reporting system (FAERS) for research and data analysis. The goal is to identify signals that may represent important drug safety issues which require further investigation to determine their frequency and establish a causal relationship to the suspect drug.