NDAC Puts Hitch In Oxytrol Switch With Negative Self-Selection Vote

In a 6-5 vote, FDA’s Nonprescription Drugs Advisory Committee said Merck did not show that consumers can appropriately self-select to use Oxytrol for Women in an OTC setting. The company expects to hear from FDA on its Rx-to-OTC switch application by the end of January.

In a close vote, FDA’s OTC drug advisory panel said data for Merck & Co. Inc.’s proposed Rx-to-OTC switch of Oxytrol for Women do not clearly show women can safely self-select the overactive bladder drug in an OTC setting, but left the door open for a possible route to approval.

Despite the 6-5 vote against self-selection by the Nonprescription Drugs Advisory Committee at the Nov. 9 meeting, Merck may have the opportunity to work with FDA on revised labeling to facilitate a switch of the oxybutynin 3.9 mg transdermal system.

The company, which licensed Oxytrol OTC rights from Allergan PLC, expects to hear back from FDA on its new drug application by the end of January, a spokeswoman said. The agency’s options for responding include an approval, rejection or complete response letter requesting more information.

Two NDAC members said their negative votes hinged on relatively minor issues that additional labeling language or package inserts have the potential to address.

Merck's proposed Oxytrol for Women OTC labeling

Image courtesy of FDA

Stuart Howards, a professor of urology and molecular pharmacology at the University of Virginia, said he would have voted in favor of self-selection if Oxytrol were labeled with a maximum age limit, given the potential for anticholinergic drugs such as oxybutynin to have negative cognitive effects in older adults.

Neil Farber, a professor of clinical medicine at the University of California, San Diego, also said he would prefer to see an age limit, along with label language directing consumers to use behavioral modifications, such as exercise, or see a physician about OAB-like symptoms before using Oxytrol.

Merck has proposed a comprehensive urinary health education campaign to accompany OTC Oxytrol, which several members of the advisory panel voiced praised. Some said they would like to see even more information in the product’s box, such as an additional insert or a voucher that women could send in for an instructional DVD on proper exercise techniques.

OAB Self-Diagnosis Challenge

Though the committee was tasked with voting only on the self-selection issue, and not with recommending for or against Oxytrol’s switch, some NDAC members displayed clear reservations about the potential availability of an OTC drug for OAB, which would be first in class.

Chief among the concerns was whether consumers are able to self-diagnose OAB. Walid Gellad of the University of Pittsburgh noted that a urinalysis “should always be done” on consumers with OAB-like symptoms to rule out more serious urinary conditions.

Gellad added that OAB typically is diagnosed only after other conditions are eliminated as possibilities for incontinence.

Merck’s proposed Oxytrol labeling instructs consumers not to use the drug unless they have experienced symptoms for at least three months, to rule out more acute conditions such as urinary tract infections and diabetes.

The firm also directs consumers to consult with a doctor before using if they meet any one of a number of conditions, including a history of diabetes in their immediate family, a history of kidney stones and other potential ineligibilities.

In a report on its three-month actual use study in support of the switch, Merck says 78.5% of 1,069 study participants who elected to purchase Oxytrol had ineligibilities according to the label. The most common ineligibility, reported by 323 subjects, was urinary retention, or the feeling of not being able to completely empty the bladder, which is a contraindication for the drug. In its briefing materials, Merck notes there were 727 subjects were verified to use the drug.

Merck representatives defended the study numbers, noting that the actual use study, unlike a self-selection study, took in a wider swath of the general population and subsequently evaluated their use or discontinued use at specific checkpoints.

FDA officials also said the actual use data were not as troublesome as they first appear. Ryan Raffaelli, a medical reviewer in the agency’s Division of Nonprescription Clinical Evaluation, said the 78.5% figure “seems a bit scary, I agree.” But the division did not find that the prevalence of ineligible users choosing to purchase Oxytrol led to safety signals or delayed diagnoses of more serious conditions.

Still, some NDAC members, including Gellad, admitted to getting hung up on the idea that nearly 80% of consumers would elect to purchase and use a drug when its labeling indicated they should consult with a physician first.

FDA Sees Potential Benefit

FDA’s briefing materials regarding the Oxytrol switch, posted Nov. 7, acknowledge that female consumers experiencing urinary incontinence may have a urinary tract infection, diabetes or bladder cancer, or may be pregnant. The agency was concerned that, as an OTC, Oxytrol could contribute to delayed diagnosis of these conditions.

“However, it is important to note that consumers with these conditions may also have OAB and, therefore, may benefit from use of oxybutynin,” FDA says in the materials.

Merck’s proposed label for OTC Oxytrol instructs women to use the drug only after at least three months of OAB-like symptoms, and to see a doctor if they suspect their urinary incontinence may stem from something more serious than OAB. The firm suggests that this protocol could lead to earlier recognition and diagnosis of such conditions.

FDA notes that “it is important to determine whether there is a potential risk for delayed diagnosis of diabetes with use of the drug,” but acknowledges that Merck plans to address this issue in Oxytrol labeling.

Merck says increasing access to Oxytrol via its proposed OTC switch, along with the company’s planned education program regarding causes of urinary incontinence and behavioral management strategies, offer overall benefits that “outweigh the potential risk of delay in diagnosis of an underlying disease that produces OAB-like symptoms.”

As a transdermal patch, Oxytrol is regarded as better-tolerated than oral delivery forms and has a relatively benign record of adverse event reports. Merck submitted to FDA 604 AERs for the product since its U.S. launch in 2003, with 21% of those categorized as “general and administration site disorders,” 12% psychiatric disorders, 12% nervous system disorders and 8% gastrointestinal disorders.

“The reports do not identify any new safety signals that would prohibit use in the OTC setting,” FDA says.

NDAC Roster Surprises

NDAC Chairman Richard Neill did not attend the Oxytrol meeting (Also see "Merck, NDAC Chair Neill Cross Paths Again For Oxytrol Switch Meeting" - Pink Sheet, 5 Nov, 2012.).

Instead, Marcus Reidenberg, a professor of pharmacology, medicine and public health at Weill Cornell Medical College, acted as chair. Reidenberg, whose research interests include reasons for individual differences in response to medications and barriers to the use of opioids for treating pain, previously served on NDAC from 1992 to 1995 and began his current term in December 2011.

Reidenberg has been a vocal proponent of expanding the availability of affordable OTC asthma products, given the respiratory disease’s prevalence among poor patients (Also see "Asthma Treatment OTC Switches Would Face Tough Barriers" - Pink Sheet, 19 Sep, 2011.).

Reidenberg voted in favor of self-selection for Oxytrol.

In addition to five voting members of the standing committee, NDAC welcomed six temporary voting members with expertise in urology and gynecology, bringing the committee’s headcount to 11.

Up For Discussion

FDA’s draft questions to the committee sought discussion on possible safety concerns relating to delayed diagnosis of conditions with OAB-like symptoms, and the implications of actual use study subjects who used Oxytrol beyond the indicated two-week treatment period when their symptoms either did not improve or worsened (see table).

According to Merck’s data, 14.4% of subjects failed to stop using the drug as directed when their symptoms did not improve, while another 3.4% failed to stop treatment even after their symptoms were mitigated.

Another question from FDA asked whether committee members are concerned about Merck’s label comprehension data, generated over the course of six studies, “given that some of the pre-specified endpoints were not met.”

Among normal-literacy subjects, 85.2% understood the label language indicating that consumers should not use Oxytrol unless they have had OAB symptoms for at least three months. Of low-literate subjects, 67.8% understood this part of the label, for an overall average of 84% comprehension – 1 percentage point short of the success threshold Merck had set.

Pregnant women, whom Oxytrol’s label directs to consult a physician before using, demonstrated some issues with label comprehension and self-selection, especially among the low-literacy cohort. While 92% of general population women indicated they would talk to a doctor before using the drug, only 68% of low-literate women did so.

“While low-literate pregnant women did not score well, the sample may have been atypical of low-literate subjects, since comprehension scores among low-literate women in another study were stronger,” Merck suggested.

The company also updated its proposed Oxytrol front-of-package graphics to present a slimmer female silhouette; an earlier version of the icon may have appeared pregnant to some study subjects and caused them to associate the drug with pregnant women, Merck said.

Merck’s label comprehension studies also evaluated men, who are excluded as target consumers from OTC Oxytrol’s proposal since they can suffer incontinence due to enlarged prostate. In a study of 571 men with urinary symptoms, 90% correctly determined that Oxytrol for Women would be inappropriate for them to use, with those who self-selected incorrectly focusing on the label’s urinary symptoms indication rather than the gender-specific product name.

An earlier study of men that tallied just 72% for correct self-selection helped spur Merck to add “for women” to the Oxytrol name.

In light of its compiled study data, Merck estimates that, overall, “the Oxytrol Drug Facts label is about 80% to 95% effective in communicating key messages regarding self-recognition of OAB and product use.”

Campaign For Urinary Health

Ed Hemwall, Merck’s VP of Rx-to-OTC switch for research & development, said before the meeting that the company believes its proposed labeling for OTC Oxytrol will enable consumers to differentiate between symptoms of OAB and other conditions, while its planned web-based education campaign will help all women – even those who do not purchase Oxytrol – to learn more about urinary health.

Market analysts believe Oxytrol could go from an also-ran in the Rx OAB space to a potentially sizable success story as a first-in-class OTC. But Merck sees the switch as a broader boon for public health, helping to manage a condition that costs the U.S. an estimated $65.9 billion annually from lower worker productivity, job loss and early retirement.

The company points out that since the drug is generally well-tolerated and low-risk, adding OTC Oxytrol to existing self-management regimens would not exacerbate the risks related to other conditions associated with OAB-like symptoms.