Santa Rosa medical device maker TriVascular quickens FDA heartbeat

While devices invented at TriVascular Technologies of Santa Rosa save lives of heart-disease patients, no one benefits until the U.S. Food and Drug Administration nods approval. That crucial regulatory approval might - or might not - come after years of painstaking and expensive efforts to leap over FDA hurdles.

TriVascular reported financial results on May 5 that its 2015 first-quarter total revenue reached $8 million, with about $5.5 million of that from the U.S. market. Revenue is up 14.1 percent over the 2014 first quarter,

Unlike many biotech and med-tech companies that struggle with the arduous process of managing clinical trials under the FDA’s watchful eye, TriVascular adopted an unusual approach: make an ally of the regulators.

The chief architect of that amicable approach is Shari O’Quinn, vice president of clinical, regulatory and quality at TriVascular. She works at headquarters part of each month.

TriVascular’s main product is its Ovation Prime endograft system used by surgeons to treat an abdominal aortic aneurysm - a weak and bulging spot in the aorta, the main blood vessel that moves blood from the heart into the body. If such an aneurysm ruptures from pressure, it kills the patient 80 percent of the time, often within minutes, due to internal bleeding. Abdominal aortic aneurysms in the United States have tripled in number in the past three decades, are the 10th most common cause of death for men 65 to 75 years of age, and kill nearly 15,000 a year.

The Ovation Prime is a minimally invasive implant system that places reinforcing structures inside the blood vessels, creating a customized polymer-based seal that adapts to each patient’s internal anatomy. The polymer starts as a liquid inside the artery and cures in about 14 minutes to a semisolid seal “almost like a rubber eraser on a pencil,” she said.

O’Quinn has worked at TriVascular for nearly six years. “It has been a wonderful experience working with a startup company,” she said. “The co-founders of TriVascular are passionate about what they do.”

The company had its initial first-human-use clinical implants in 2009 at the Catholic University in Santiago, Chile. O’Quinn engineered the entire clinical trial process, initially with Francisco Valdes. “He trained in the U.S. at Cleveland Clinic,” she said. “They have incredible imaging equipment.”

Most patients in Chile are covered by government-sponsored insurance that won’t cover the cost of such implants. “Many patients who have abdominal aortic aneurysms don’t receive treatment,” she said, or they have to have high-risk open surgery instead of a minimally invasive procedure such as endovascular aneurysm repair.

The Ovation Prime implantation costs about $15,000.

“He has a large patient population who have a need for this device,” O’Quinn said, “so we partnered with him to do the study there” in 20 patients, mostly smokers, with average age of 78, over about a year. Smoking poses the greatest risk factor - 80 percent of patients are smokers - followed by genetics. Men suffer such aneurysms four times as often as women.

“The success rate with his patients was 100 percent,” she said, “really incredible. Those results were so encouraging.”

The study follows patients for five years post-implant. The first patient, treated in his mid-80s, came back for a test after five years. The “aneurysm is basically non-existent,” O’Quinn said. The treatment worked and has been durable over several years.

At the bottom of the heart, the large aortic artery, roughly the diameter of a garden hose, splits into two smaller arteries. That’s where aneurysms are likely to occur, and where the TriVascular stent system can be used to head off ruptures. “This area of the body is at greatest risk,” O’Quinn said.

Parallel studies

To speed up the process, O’Quinn started a parallel clinical study in Europe while the Chilean study was underway. “It’s a smoother regulatory pathway if you have patients that you pulled from that continent,” she said. This study in 2010 treated 30 patients in Germany, the largest market in Europe. “That’s why we selected Germany,” she said.

Each country in the EU has its own regulatory agency - the equivalent of the FDA. Once one country in the union approves a device with a CE mark (French for Conformité Européene, or European Conformity), most other countries accept that. The symbol must be placed on the product label. TriVascular obtained its CE mark from Germany in about a year, by August 2010.

Even before the German study wrapped up, O’Quinn enrolled the first of 111 patients in a U.S. study with broad geographic representation. That brought the total sample size to 161.

“We needed a total of approximately 150” to finish the trial in order to apply for premarket approval by the FDA, a process that takes about six months, she said. The FDA classifies devices as low-, medium and high-risk. Most cardiovascular-implant devices are considered high-risk - Class III.

“We were the first company in the endovascular aneurysm–repair space to use outside-U.S. data” in addition to domestic data, O’Quinn said. “The FDA felt very comfortable with our outcomes and the quality of the research,” and accepted data from the studies in Chile and Germany. “It saved a lot of time,” she said.

She considers the FDA’s requirements the strictest in the world. Europe has traditionally been more lax, with more products reaching market but some having to be recalled due to safety concerns. “Europe is trying to raise the bar,” O’Quinn said.

She chose clinical trial patients from a variety of medical centers, including private practice and academic facilities, and physician specialties, including vascular surgeons, interventional cardiologists and interventional radiologists, who treat heart disease through catheter-based procedures. The device was successfully placed in all 161 patients.

Abdominal aortic aneurysms are more common in the southeast regions of the United States, where smoking has a higher incidence, she said, along with lower exercise rates and more prevalence of saturated fat in the diet.

Most clinical trials for endovascular aneurysm–repair devices include only 7 percent to 10 percent women, O’Quinn said, because they are susceptible to complications and don’t qualify for trials. Her trial had 13 percent women, more than usual.

Women get a third ?of the devices

“One of the initiatives that TriVascular is starting this year is to do a study where we specifically look at outcomes in women,” O’Quinn said. “We’re launching a new clinical study that will be focused on the advantages of our product in women.” The O-ring seal of the Ovation Prime system - polymer-filled - doesn’t require a long neck of healthy tissue above the aneurysm, she said, making it work well for women.

Women typically have smaller femoral arteries than men, and the TriVascular device has an unusually small profile of 14 French (less than 4.7 millimeters in diameter).

Not only does the femoral artery in women tend to be smaller, “but more tortuous,” O’Quinn said. The narrow delivery system is more flexible than that of competitors, she said, helping it to navigate turns in the artery.

A third of the patients in which the Ovation Prime system is implanted are now women, she said.

The company has numerous refinements of the system in its product pipeline that will help adapt it for use in a variety of patients.

Roughly half an hour elapses from the moment the femoral artery is punctured to insert the device until the time the device is deployed inside the aneurysm. Fluoroscopy - using radiation to visualize progress of the system through the artery - helps the physician accurately place the device, which has a main body and two legs.

The device is designed to be opaque, highly visible, for the first 30 days. During placement, opacity helps with accurate positioning. “It’s designed to dissipate over time,” she said, allowing visibility of the graft using a CT scan (computed tomography). “You want to be able to see what’s around it.”

In follow-up studies for the first year after placement, TriVascular looked for “endo-leaks” in patients who participated in the clinical trials. The device requires a robust seal inside the artery in order for it to work properly and reduce pressure inside the aneurysm. A neutral third party analyzes the CT scans in follow-up research.

To smooth the clinical trial journey toward FDA approval, O’Quinn “communicated very closely with the FDA to make sure we understood what their expectations were for a trial design,” she said.

The FDA uses an international standards organization that sets forth many of its expectations; she examined those in advance of designing the TriVascular studies. In a sense, she reverse-engineered a successful FDA approval process, tailoring clinical trials to maximize prospective approval.

Blend of art and science

“It’s a blend of art and science,” O’Quinn said. “You want to make sure you are capturing all the data that’s needed, but you also have to make sure that you craft an entire program that you know is going to meet the expectations of the FDA at the end.” She set the company’s research standards higher than those of the FDA so that the results easily cleared government standards. “We want it to be clear that we exceeded it,” she said. “That’s the culture we have had from the very beginning.”

TriVascular conducted more tests than the FDA required. Each product or new technology can introduce fresh safety issues or challenges.

The process can take three or more years. A negative result can devastate a company financially. “You’ve invested a lot of time and money in this program just to be told that you didn’t hit the mark,” she said. “You have to start over. It’s critical that you know their expectations, that you design a program around that,” ensuring the integrity of the data produced. Having a product that consistently achieves good results is also crucial.

The clinical trials around many great products failed because they did not get good data, she said. She monitors the process to make sure each research center inputs clean, accurate data into the database, verified back to patient medical records. “Some companies stumble because they don’t have programs that are designed well even if they have a good product,” she said.

“You can design a perfect clinical program, but if the device doesn’t work, you can’t meet your study hypothesis because of complications that occur during the study,” she said.

The entire process must be orchestrated with constant communication between the company and research centers, and with patients. TriVascular needed 128 of its 161 clinical trial patients to reach the one-year point for followup testing. Without that number, the company would have failed its endpoint goals of safety and effectiveness. “We wouldn’t have had enough power to drive our hypothesis testing,” O’Quinn said. She controls all the variables and maintains oversight of the study.

A former premed student doing Alzheimer’s research in Virginia, O’Quinn became fascinated with cardiovascular disease research. TriVascular is the third company where she has worked on clinical trials with endovascular aneurysm repair. The catheter on its device is far smaller and more flexible than others on the market, she said, a feature that made her want to participate in the research.

To date, nearly 6,000 patients have received the TriVascular implant. FDA approval occurred in October 2012. “It was surprisingly smooth sailing,” O’Quinn said of the ride to approval. “We had a great technology that performed as we designed it, and we made sure that we really understood what the FDA’s expectations were so we could design a program to deliver that.”

She took only nine months to obtain the necessary trial enrollment in the United States. The next-closest competitor needed 12 months. Most others in the field required 18 months - twice as long - for similar devices.

Revenue about $37 million

The marketplace has proven the value of the research. “Our commercial data is validating that clinical data,” she said.

The company’s revenue growth on a constant currency basis was 19.3 percent in the first quarter of 2015, with underlying implant growth exceeding 25 percent in the United States and internationally. In all of 2014, the company lost about $57 million, with total accumulated deficit of nearly $300 million.

“We continued to gain share and our revenue growth was strong relative to the overall market in the first quarter of 2015,” said Christopher Chavez, TriVascular’s president and CEO. TriVascular expects total revenue of $36 million to $39 million for full-year 2015.

“I love the research process,” O’Quinn said. “It was exciting to see these new technologies become available to patients. These guys are so innovative. That’s what made me want to be part of this.”

Her team includes about 30 people out of a total staff of more than 250. Running a clinical trial program with full-time employees rather than contractors helped ensure a speedy, positive result. “We built a team of internal employees that took a lot of ownership,” she said. “It cost more up front but it paid off in terms of efficiency of program. Speed to market is key.”

She uses a statistician to calculate the number of patients needed in the study, which usually includes a margin of 15 percent. Some patients die from other causes and don’t make it through the study, or they move and cannot finish the program. “These are all elderly patients,” she said. “They may go to a nursing home where they don’t have the ability to come in for followup visits.”

She carefully selected research centers that had good experience doing research. The data had a lot of integrity. High-profile centers such as UCSF have instant recognition at the FDA, and help instill credibility in a clinical trial. Smaller centers that do high volume of this type of procedure can also build trial credibility.

Plainly, the TriVascular system saves lives. “It’s so rewarding,” O’Quinn said. “That’s what drew me to this profession - the fact that we’re creating products that are saving people’s lives.”

The company keeps count of lives saved with its devices. “It keeps everybody focused,” she said. “ Make sure you always think about the patient. It’s not just a component to a product. This is something that’s going to go into someone’s mother, their sister, their family member. Take the same pride in your work as if this were going to go into your mother.”