VOLUME 12, ISSUE 16 | MAY 17, 2016

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Panel meetings of the FDA’s ortho-pedic experts are rare and a big

deal. A vote of the group to recommend approval of a PMA (premarket applica-tion) can make or break a technology or a company.

It’s a huge logistical undertaking and the agency only calls the experts from various parts of the country together when review staff wants help in answer-ing some questions about the science of the application.

The giant bluebloods of orthopedics like Stryker Corporation, Medtronic, plc, Zimmer Biomet, DePuy Synthes Companies and Smith & Nephew with thousands of employees and numerous products in various stages of research and development can weather a bad vote from the panel. For instance, Medtronic recently received a negative reaction from the ortho panel for a spine product, but shortly thereafter received FDA approval for another product.

The Agony of Failure

However, if you’re a small company with one product and only few employ-ees, the recommendation of the FDA’s panel experts means life or death for your company and device.

April 20, 2016 was such a make or break day for Cartiva, Inc. and its syn-thetic cartilage implant for the big toe.

Spoiler Alert

Here’s a spoiler alert, at the end of the day, the 12-member panel determined Cartiva’s device was safe, effective and the benefits outweighed the risks to patient.

Eight Years of Preparation

Since 2008, according to Cartiva Presi-dent and CEO Tim Patrick, the com-pany had been developing a clinical study, selecting clinical sites, recruiting patients, analyzing data and submit-ting PMA modules and communicating

with FDA staff. All that work went into preparation for the panel meeting.

The Agony and Ecstasy of Cartiva’s FDA Panel Meeting BY WALTER EISNER

Photo creation by RRY Publications, LLC and logo courtesy of Cartiva

Tim Patrick/Courtesy of Cartiva, Inc.

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Those eight years of effort, product design, material testing and preclinical testing resulted in a 236 patient clinical study, the largest ever for arthritis of the great toe, said Patrick.

“As a small company with 20 employ-ees, you understand that your employ-ees, management team, investors and clinical investigators have poured their heart and soul into this endeavor. The working weekends, long hours, missed birthdays and other sacrifices too numerous to mention by the team all run through your mind as you take your seat at 8AM. By 6PM, there is going to be a decision. A positive or a negative vote on three questions: safety, effec-tiveness and risk/benefit with a binary outcome for a small company.”

Patrick told OTW that the study met its primary clinical endpoint for pain reduction, preservation of function and safety as specified in the statistical anal-ysis plan. “We also met all of the other post-hoc clinical endpoints requested by FDA following review of the data. Patients averaged an 88% reduction in pain and a median functional improve-ment of over 60%.”

To prepare for the meeting, the com-pany set up two mock panel meetings and numerous practice sessions. “We felt confident we were ready to present the clinical information effectively and efficiently. Advisors from the best FDA regulatory firms and great statisticians helped us shape the data on each slide. Nobody in the world knew this data better than we did,” added Patrick.

A Day at the Panel

In a written response to OTW, Patrick wrote about the day of the panel meet-ing.

At 8:15AM, Chairman Raj Rao, M.D., turned the presentation over

to the company. The panel mem-bers want to hear clinical data from clinicians: company VP of Regula-tory and Clinical, Deborah Moore or from the study clinical investi-gators, Baumhauer, Daniels and Glazebrook. The company presen-tation went even better than prac-ticed and I was extremely proud of the great job our presenters did. Following our presentation, the panel asked numerous questions and we felt that we could get the answers they wanted during the lunch break. The FDA then pre-sented and received questions from the panel.

The first surprise came during the question period for the FDA. This became a second opportunity for the panel to ask additional ques-tions to the sponsor rather than to the FDA. While the panel questions were challenging, the real issue now became the sheer number of ques-tions received in what effectively became two question sessions for us. These questions would all need to be answered by our team during a 50-minute lunch break.

Some of the questions required his-tory and context, one of the more difficult issues to deal with in a one-day meeting.

For instance, most clinical deci-sions on study conduct, statistical analysis plans, etc., were made in 2008, before the study began. But the questions were now being asked eight years later, in 2016. So if there had been some changes during that time regarding new FDA practices on study design, inferiority mar-gins or statistical methods from the sponsor (Company) perspec-tive, its frankly irrelevant. The rel-evant issue is where were things in 2008 when the study was being developed and discussed with FDA and clinicians. Taking panel mem-bers back with you to the start of the study rather than where we are today being a very challenging communication issue.

After the patients spoke in the early afternoon session, Deborah Moore was prepared to answer the panel’s morning questions. The answers had been pulled together in a mere 50 minutes during the lunch break. Answering dozens of data driven questions in such a short period of time in our “war room” was the most impressive feat of the day. Every clinical member of our team, our clinical investigators, our regulatory advisors and statisticians were fully engaged in answering specific questions while the clock ticked. Slides were pulled together and ready to go by 1PM. Debbie and the team had prepared 68 slides in 50 minutes. While not all of them were reviewed that afternoon with the panel, the information on those slides was critical in answering the panel’s morning questions.

When the time came to answer the morning questions, the panel began to ask more questions. This was the second big surprise of the day. I fully expected the panel to

Deborah Moore/Courtesy of Cartiva, Inc.

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say “Mrs. Moore, we asked a lot of questions in the morning, now we would like to hear the answers”. I was impressed that Debbie was assertive and continued to focus on the earlier questions and ticked them off the list one after the other.

The day started well and ended well with positive votes from the panel as the day came to a close. The roll-er coaster ride was worth it, I was unbelievably proud of what our small group had accomplished and was happy to have a positive panel meeting in the rear-view mirror.

The Vote

The panel’s vote was pretty overwhelm-ing on the safety, effectiveness, and risk benefit ratio of the implant.

On safety, the panel voted 10 (Yes), 0 (Abstain), 2 (No) that the data shows a reasonable assurance that the implant is safe for use in patients who meet the criteria specified in the proposed indi-cations.

On effectiveness, the panel voted 9 (Yes), 0 (Abstain), 3 (No) that there is a reasonable assurance that the implant is effective for use in patients who meet the criteria specified in the proposed indications.

On the risk benefit ratio, the panel voted 8 (Yes), 2 (Abstain), 2 (No) that the benefits the benefits of the implant out-weigh the risks when used in patients who meet the criteria specified in the proposed indications.

Cartiva Synthetic Cartilage Implant

The Cartiva Synthetic Cartilage Implant, according to FDA documents, “is intend-ed for use in the treatment of patients with degenerative or post-traumatic arthritis in the first metatarsophalangeal joint in the presence of good bone stock along with the following clinical condi-tions: hallux valgus or hallux limitus, hallux rigidus, and an unstable or pain-ful metatarsophalangeal joint.”

To see a video of the surgery, click here: http://cartiva.net/footandankle.html

According to the American Orthopaedic Foot & Ankle Society, arthritis of the first metatarsophalangeal or MTP joint (the big joint of the big toe) can cause pain and swelling. This can lead to difficulty with shoewear and mild activity such as walking. Arthritis develops when the cartilage in the joint wears away and the two bones that make up the big toe joint rub against one another.

Post-Approval Requirements

While the panel was positive about the implant, FDA staff had some questions.

For instance, FDA staff said prospective subjects would likely have the impres-sion that increased mobility will allow for greater function in Cartiva as com-pared to arthrodesis. However, the level of function for Cartiva appears to be the same or worse than arthrodesis from 3 months to 2 years.

The FDA staff asked the panel for advice on how best to objectively cap-

ture patient preferences with regards to either procedure.

Panel members expressed concern that the “allure” of preserving motion was fairly high for patients, and that the expectations for this device needed to be clearly identified so that the device could be labeled appro-priately. The panel recommended that patients be informed that while range of motion may be preserved with the Cartiva device, the functional ability attained with this device may not be substantially differ-ent than the functional ability attained fol-lowing a fusion procedure.

FDA staff also asked the panel to opine regarding the need for PAS (Post Approv-al Study(ies)) and, if required, to suggest questions to be answered by such stud-ies, should the agency determine that the PMA application is approvable.

In general, the panel believed that the existing cohort should be followed for five years total. The panel also recom-mended that if a new cohort is studied, it should also be studied for five years with the implementation of additional exclu-sion criteria including hallux valgus, unstable joints, and possibly Coughlin and Shurnas Classification Grade 2 hal-lux rigidus. The panel also recommend-ed the inclusion of additional functional endpoints as being potentially helpful.

The Ecstasy

At the end of the day, Cartiva, the “Min-now,” the “Mouse that Roared,” “The Lit-tle Engine That Could,” experienced the ecstasy of a big victory. We’re quite the sure the Bluebloods were watching. ♦

Orthopedics This Week is published 40 times a year by RRY Publications LLC, a subsidiary of Robin Young Consulting Group.116 Ivywood Lane, Wayne,PA 19087 1-888-749-2153 www.ryortho.com

Reprinted with permission of RRY Publications LLC© Copyright 2016 RRY Publications LLC