FDA Assesses Its Role In Limiting Physician Access To Auxilium's Xiaflex

Deciding whether to mandate a Risk Evaluation and Mitigation Strategy when the safety of a product may be a function of the health care provider's skill is the question FDA is debating as it reviews Auxilium's Xiaflex for advanced Dupuytren's disease.

"The company has already provided quite a restricttive plan" to ensure the appropriate practitioners are dispensing the injectable enzyme, Bob Rappaport, Director of the Division of Anesthesia, Analgesia and Rheumatology Products, told the Arthritis Advisory Committee Sept. 16.

Perhaps FDA should wait to see if it works, he said.

The committee recommended approval of Xiaflex (collagenase clostridium histolyticum) in a 12-0 vote. But members shared FDA concerns about how to ensure that those dispensing the biologic have the knowledge to deliver it accurately and avoid the rare but serious side effect of tendon rupture (¹ (Also see "Auxilium Xiaflex's Advisory Committee To Focus On Physician Expertise, Training" - Pink Sheet, 14 Sep, 2009.)).

One option to control the risk is for FDA to issue a REMS program that mandates who could administer Xiaflex and the training they must undergo.

If that approach were taken, FDA would be "imposing a huge burden ... we have to consider how much of a burden we're placing on the health care system," Rappaport explained. "There's a huge burden and huge price to be paid for every restriction put on any kind of medication."

FDA has to consider the issue of "how far you want to go in having the federal government actually being the restricting agent," he said.

Should the firm's plan prove inadequate, "if we see increasing problems with tendon rupture over time ... or other new problems, we still have the authority to step in and provide additional restrictions."

"It doesn't matter whether you call it a REMS or a risk management program, it's important from our perspective to appropriately train physicians to use this product well," Auxilium CEO Armando Anido said in an interview. "We've provided a pretty comprehensive program for that."

Complications Few But Severe

Eleven serious adverse events in treated extremities (Xiaflex is injected directly into the hands), including three cases of tendon rupture, occurred during the clinical trials. Trial investigators were primarily hand and orthopedic surgeons, with a small number of rheumatologists.

Auxilium's risk management plan calls for Xiaflex to be distributed only to health care professionals experienced in the treatment of Dupuytren's, including hand, plastic and orthopedic surgeons, general surgeons (with a hand focus), and rheumatologists.

Practitioners would be required to attest to completing the training program, which includes a video and manual.

"Our concern clearly has to do with the variability of the skills and of the physicians out there to be able to perform" the procedure safely and whether the educational program is sufficient to achieve that goal, Michael Weisman, Cedars-Sinai Medical Center, said.

"There's a low rate of complications, but when it occurs, it's quite severe," he pointed out.

Dupuytren's disease results from collagen deposits accumulating in the palm of the hand and forming nodules or cords that retract the fingers toward the palm. Xiaflex acts by enzymatically disrupting the cord and must be delivered there to avoid disruption of other collagen-containing components of the hand.

Panel members were mixed in their reviews of the proposed training program. Kenneth Saag, University of Alabama at Birmingham, expressed "serious reservations about the average rheumatologist administering this product" without more extensive training than that proposed by the sponsor.

"The average rheumatologist does not have enough knowledge of the anatomy of the hand and the experience of performing manipulation tests after injections, or differentiating post-injection inflammation versus infection," he noted.

But other panelists were not as worried. The training "is more than adequate," Saul Kaplan, Mid-Atlantic Permanente Medical Group, said. The injection procedure seems relatively simple, Mustafa Haque, Georgetown University, agreed.

More Outcomes Data By Specialty

"The numbers are too small ... to really inform us one way or another whether any part of [the risk] is mediated by skill level," Timothy McAlindon, Tufts University, pointed out.

Kathleen Mazor, University of Massachusetts, suggested that more data are needed on whether there are different outcomes for rheumotologists and surgeons.

There's no way to study whether the training is adequate or that practitioners should be from certain groups "without another 10 years of expensive clinical trials that I'm not sure can even be done. And in the meantime, we've got patients who really benefit from this," FDA's Rappaport pointed out.

Auxilium VP-Clinical Affairs James Tursi reported that all three of the tendon ruptures occurred in patients treated by hand surgeons. Two of these patients were among those receiving the first 734 injections in the trial program.

This prompted a revision in the injection technique and more investigator training, he said. Afterwards, a single tendon rupture occurred among patients receiving another 1,896 injections, he said.

"Our injection training and the entire risk management program is designed with this experience in mind," Tursi added.

A key to the training is making practitioners aware of the potential for rupture, according to F. Thomas D. Kaplan of Indiana University and an investigator in a Xiaflex trial. "It's not just where you give the injection, but what we're treating is the cord and if you can't feel the cord, if you can't access it safely, don't give the shot."

Mandatory Registry Or Postmarketing Trial?

The conversation returned to the possibility of a REMS with a suggestion from Weisman that the relationship of practitioners' skills to outcomes could be measured by enrolling all patients receiving Xiaflex in a mandatory registry. They could then be monitored to see "whether or not the risks of this had exceeded ... our expectations."

The resultant data also could answer the question of who is administering the drug, whether they are doing so in a safe manner and whether their training has been sufficient to protect patients, he added.

While partial registries have been included in post-marketing studies, mandatory registration of all patients is one of the more restrictive REMS that can be put in place, Office of Drug Evaluation II Director Curtis Rosebraugh pointed out. "It's very extreme for us to do that" and it's undertaken only if the safety issue is such that monitoring is needed to protect patients and allow a drug to be approved, the FDA official noted.

Mandatory registries are not used just to collect data, he said, explaining that that is the function of post-marketing trials.

"Randomized trials give us better information, cleaner information, about just about anything," Rappaport pointed out. "Trying to tease out the type of information that we'd like to get here about safety and [who] is using [the drug] from a registry is going to be in my mind far more difficult than from a controlled trial."

Saag argued that an observational approach would be the only way to get the information. "A registry is going to be necessary or some type of an observational design, to understand the safety signal," the panelist contended.

Practitioner Self-Assessment Questioned

In discussing the access management program, the company noted that enrolling physicians would indicate their specialty, including a category of "other." This raised the concern of patient representative William Brackney, who suggested that enrollment be selective at the outset until more information is available on outcomes related to the type of doctor administering the medication."

Haque questioned the adequacy of leaving practitioners on the honor system to complete the training. He suggested instead that physicians be required to pass an online exam.

Xiaflex has orphan status for advanced Dupuytren's and Peyronie's disease in the U.S. The Xiaflex BLA was filed Feb. 27, 2009, and received priority review status. Its user fee date of Aug. 28 was missed because of FDA's desire to have hand specialists involved in the advisory committee review, Anido said.

- Cathy Dombrowski ( ² [email protected] )