The sumatriptan iontophoretic transdermal system (Zecuity®) was a combination drug patch, manufactured by Teva Pharmaceuticals, designed to treat migraine attacks. The US Food and Drug Administration (FDA) approved the patch in January 2013 for the acute treatment of migraine in adults. However, after less than a year on the market, the FDA issued safety warnings about the use of the patch, indicating possible side effects of serious burns and skin irritation. This prompted Teva to issue a pharmacy recall and, in June 2016, it voluntarily stopped selling the transdermal device.
What went wrong?
In an article recently published in Headache, lead author Elizabeth Loder, MD, MPH, Division of Headache, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, and colleagues analyzed the development and approval process for Zecuity. The authors examined publicly available information about it in an effort to determine what went wrong and how to prevent similar issues from arising in the future.
This single-use migraine treatment combined the FDA-approved drug sumatriptan with a battery-powered iontophoretic transdermal patch device. Although sumatriptan had long been on the market in oral, injectable, and spray formulations, the original developer NuPathe Pharmaceuticals (which was later acquired by Teva Pharmaceuticals) justified the need for the transdermal delivery system by highlighting the demand for non-oral migraine treatments, especially among those who suffer from nausea and vomiting during migraine attacks.
The new drug application (NDA) for the migraine patch was based on a single phase 3, multicenter, randomized clinical trial: PREDICT (Phase III Research into the Efficacy of TransDermal Sumatriptan in Acute Migraine). PREDICT compared participants who applied the sumatriptan-loaded patch with those in the placebo group who applied a saline-filled patch. However, the participants in the placebo group also activated the patch electrodes, generating an electrical current; therefore, only the drug portion of the product was compared with placebo.
According to NuPathe, results of the phase 3 trial showed that 18% of patients in the treatment group had headache relief within 2 hours compared with 9% in the placebo group. The incidence of triptan-associated adverse events, known as “atypical sensations” and “pain and other pressure sensations,” was 2% each in treated patients. The most common side effects (greater than 5%) were application site pain, tingling, itching, warmth and discomfort.
In addition to PREDICT, two other non-randomized, open-label safety trials were conducted. Although reports for all three clinical trials were eventually published on clinicaltrials.gov, the authors noted that changes were made to the original participant outcomes in all the studies. Furthermore, in one of the safety studies, only 65 out of nearly 200 participants completed the 1-year trial. For the other safety study, more than one-third of participants experienced a negative side effect.
During the FDA approval process, the original NDA was rejected. “The FDA knew about problems with burns and scarring prior to approval of the product, and turned down the initial new drug application for this reason and because of other quality problems with the patch,” Dr. Loder and coauthors wrote.
In addition, the FDA did not agree with the company’s argument that the patch fulfilled an unmet need because non-oral alternatives already existed for patients with migraine.
After rejection, NuPathe Pharmaceuticals submitted a reapplication after redesigning the patches and testing the new design in healthy participants. Against the recommendation of several reviewers, the FDA approved the Zecuity patch with the stipulation that the company report any case of burns to the FDA within 2 weeks. However, NuPathe did not place warnings about potential burns in the product’s package insert; the company merely issued warnings about placing the patch on already burned skin.
The price for a single-use patch was roughly $300.
Within the first 6 months that the device was on the market, 7,234 prescriptions were written, but there were also 389 reports of adverse events—117 of which cited burns at the patch application site.
Efficacy and safety?
Overall, the analysis by Dr. Loder and her colleagues identified several issues that arose during the development and approval process of the patch:
- The reason for the product’s development was inadequate, considering that better non-oral alternatives were already on the market.
- Outcomes for the three original clinical trials were changed well after registration, which raised the possibility of selective reporting.
- The efficacy trial determined that 40 out of 226 participants who used the sumatriptan patch had migraine relief after 2 hours. This is in comparison to 21 out of 228 participants who used the saline-filled patch, which indicated that the Zecuity patch was not highly efficacious.
Finally, the authors sought to address why the FDA chose to approve the patch following the first rejection and against recommendations of FDA reviewers. The authors note that possible reasons included that Zecuity was approved before a Prescription Drug User Fee ACT (PDUFA) deadline, as well as pressure from consumer advocates.
As of June 2018, the FDA Adverse Events Reporting System public dashboard had received 2,889 safety reports from patients and health professionals regarding the Zecuity patch. Of these, 904 were classified as serious.