The Journey To Droxidopa
Overcoming Challenges In Clinical Trial Recruitment
An Unmet Need
The simple act of standing up was making several of Dr. Steve Greer’s patients feel dizzy. Within minutes or even seconds, they would often collapse or faint.
Their condition — neurogenic orthostatic hypotension, or nOH — results when the neurotransmitter norepinephrine reacts erratically, causing blood pressure to drop so rapidly upon standing that they feel they’re about to blackout.
Dr. Greer, as head of the Baptist Health Heart Institute Syncope Clinic in Little Rock, Arkansas, was one of few specialists in a 250-mile radius with an interest in treating these patients.
The episodes aren’t just frightening. They can cause serious injuries such as bruises, sprains, or broken bones. Simple pleasures such as hobbies or exercise, or even necessities like housework and cooking meals, become arduous or nearly impossible.
In severe cases, nOH robs people of their careers, confines them to their homes, or forces them to use wheelchairs or to spend most of their time in bed.
Dr. Greer’s patients weren’t just up against an extremely debilitating disease: they had little in the way of effective treatment. nOH is relatively rare — it affects about 80,000 people in the United States or 0.002 percent of the U.S. population. As is the case with most of these orphan diseases, few pharmaceutical companies had invested in drug development for nOH.
“Orphan products are orphan for a reason. Often that reason is the development costs are not offset by market potential,” says John Boland, vice president of product development at Atlantic Research Group (ARG), a Charlottesville, Virginia-based clinical research organization (CRO). ARG specializes in helping biopharmaceutical companies shepherd orphan disease drugs through clinical trials and on to FDA approval.
With nOH low on drugmakers’ priority lists, patients were left with only one FDA-approved medication — midodrine. But it didn’t always deliver the symptom relief that patients needed.
Although originally FDA approved to treat neurally mediated syncope, midodrine was never clinically proven to alleviate nOH symptoms. The basis for its approval was clinical trial data showing that it increased blood pressure when standing, a surrogate for symptom relief rather than symptom relief itself.
What’s more, midodrine’s label carried a black box warning to caution physicians and patients that the drug raised blood pressure when lying down. Patients suffering from nOH may experience elevations to blood pressure in a lying position, so midodrine had the potential to worsen an already risky situation.
“I had patients that were in need of an alternative therapy,” Dr. Greer says.
The Droxidopa Era: Old Drug, New Indication
In the mid-2000s, Dr. Greer agreed to participate in clinical trials testing another potential treatment for nOH: droxidopa. Once ingested, the medication is metabolized into an active agent that boosts norepinephrine levels in the peripheral nervous system. This increases dangerously low blood pressure and helps prevent dizziness and fainting upon standing.
This wasn’t a new, experimental drug fresh from the laboratory. Regulators in Japan had approved it in 1989 for people with neurological conditions, such as Parkinson’s disease, who were prone to feeling dizzy or faint when they stood up.
Seven years later, Chelsea Therapeutics of Charlotte, North Carolina, licensed the drug in the United States with plans to launch clinical trials that specialists like Dr. Greer and thousands of patients hoped would lead to FDA approval with an indication for nOH.
At the time, Boland was senior clinical operations manager at Chelsea. “We had a development program that consisted of six studies,” he recalls. One of the pivotal studies was NOH 301. The FDA gave its blessing to the study protocol and designated droxidopa for fast-track approval in 2008.
The CRO that Chelsea contracted with to manage NOH 301 enrolled the first patient in September 2008. Recruiting patients for orphan disease drug trials can be complicated. They’re few in number to begin with. For NOH 301, 95 clinical sites in nine countries eventually enrolled 168 patients — a relatively small number — over a two year period. Some non-rare disease trials covering such extensive ground enroll thousands of patients.
So if you’re a CRO scouring the world to find a few hundred patients who fit the trial’s inclusion criteria, how do you find t he proverbial needle in a haystack?
“There is no one silver bullet formula for finding rare disease patients,” Boland says.
CROs that don’t recognize those challenges at the outset of trials for orphan diseases may find themselves at a loss as a trial moves forward. That’s what happened with the first CRO that Boland and Chelsea Therapeutics contracted with to launch NOH 301. The company worked primarily in trials with sizeable numbers of participants who didn’t have orphan diseases. So, for them, this was unfamiliar territory. Consequently, recruitment went slowly; the company struggled to locate patients who were appropriate for the trial.
“I just don’t think they had the experience in rare disease to know what to do next,” Boland says. “They looked at it very much like any other large patient population study, which is you cast your net and you wait.”
A Fresh Perspective
As NOH 301 recruitment lagged, the FDA asked for additional data to ensure that droxidopa didn’t have a similar adverse effect as midodrine. That meant starting a new supportive trial — NOH 305 — and hiring a new CRO to launch it. ARG was selected to lead this new safety study.
“We knew ARG was nimble and flexible,” Boland says. Its president and CEO were former colleagues of Boland’s, and the company previously worked with Chelsea Therapeutics on a drug for intradialytic hypotension.
Instead of waiting for patients to come to the trial, Boland adds, “ARG went on the hunt.”
The first patient was enrolled in the more recent NOH 305 trial within six weeks. “That’s a stretch goal, if not leaping over a tall building in a single bound,” Boland says.
“Speeding up enrollment was something that we really worked hard on,” says Emily Cooke, now a project manager at ARG who worked on NOH 305 as a clinical research associate (CRA). “Other CROs would probably look at that and think we’re attempting the impossible. But we took it to heart and made it happen.”
Within five months, ARG enrolled the 20 patients needed for NOH 305. In comparison, Boland says, the original CRO took significantly more time to enroll 12 to 15 patients in the NOH 301 trial. However, the patients that ARG enrolled played dual roles: Because NOH 305 was a sub-study of NOH 301, the patients that ARG enrolled played dual roles by participating in both trials. So ARG not only completed enrollment for NOH 305, but also simultaneously boosted enrollment in the stalled NOH 301 trial.
“It’s pretty compelling to see how tough it was to recruit, but then ARG gets involved and there’s a spike in enrollment,” Boland notes.
A Rare Understanding
“You really need to target clinical sites — find the right sites with the right patients,” Cooke says. “A CRO that has done rare disease work will understand that.”
In the case of nOH and droxidopa, that meant looking beyond the obvious. It makes sense that people with a degenerative neurological condition like Parkinson’s disease who develop nOH could be found in neurology centers. But what about the patients who were shuffled from doctor to doctor in search of the correct diagnosis?
Patient advocacy groups can make connections with patients. “They really help get the word out,” Boland says. Call centers and a website also directed patients to clinical sites for the droxidopa trials.
“You’ve got to put your detective hat on and think about where else you might find these patients,” Boland says.
Cardiology clinics emerged as a somewhat surprising venue. “Someone with fluctuating blood pressure sees a primary care physician who says, ‘Go see the cardiologist.’” That line of thinking led to finding Dr. Greer for the droxidopa studies. An electrophysiologist, his clinical work involves using devices to treat heart rhythm disorders but he also has a special interest in syncope. Dr. Greer has participated in clinical trials for more than 30 years, and he credits ARG with maintaining a low profile that kept the trial running smoothly without disrupting care for his patients.
“The good [CROs] are the ones that can blend into the background,” Dr. Greer says. “They’re there when you need them to help if there’s a problem, but otherwise they’re making sure that nothing goes wrong for patient safety while still meeting trial goals.”
Good CROs also know that monitoring a trial is more than checking off boxes on training forms and completing electronic signatures.
“You have to show that you care to learn things from the site’s perspective, not just from the study protocol or a book,” Cooke says. As a CRA, she understood the importance of listening to study coordinators and working with them on their scheduling and follow-up issues. “You learn how to engage the people at your sites, and then they become more engaged, too,” she adds.
Sometimes that means addressing problems that aren’t directly related to the trial, Cooke says. For example, when database problems arise — entering data is tricky or the system throws out puzzling queries. “It’s important to sit down with them, walk through their concerns, and go through everything line by line,” she notes. “Again, it’s caring enough to learn what they’re experiencing.”
Results Through Strong Relationships
During NOH 305, Boland traveled to each of the clinical sites to meet with the investigator and site staff along with the ARG monitors. Cooke, he says, built strong relationships with the site staff and the principal investigators. “That helps,” he says. “You want to do more for the people you like and get along with.”
Strong relationships also help break down barriers that can slow progress at a trial site.
Take, for example, a situation that arose at an NOH 305 site outside Seattle, Washington. The study coordinator didn’t have a stethoscope sensitive enough to register a pulse from a patient with extreme hypotension. So ARG’s monitor at the site stepped up and purchased stethoscopes with the proper sensitivity for all the site staff. It made the difference between knowing and not knowing whether certain patients met the inclusion criteria for the trial.
At another site, in Tulsa, Oklahoma, ARG helped a principal investigator, who was new to clinical research, learn the ropes. The site covered a wide catchment area — all of Oklahoma, half of Texas, and several other states — and so attracted a high number of patients.
“ARG was part of the process to train them on what clinical research is and what they would need to do to maintain and manage the resource burden that came with doing this study,” Boland explains.
In the end, ARG’s experience and knowledge in rare disease paid off: In 2014, the FDA approved Droxidopa, now known by the brand name NORTHERA®, for the indication of nOH. Emily Cooke had left ARG for a brief time, but her former colleagues shared the good news.
“When I got the email, I very much still felt like I was part of the team,” she recalls. “I was so proud to hear about it. That’s an ultimate feeling of accomplishment, to know that the drug was approved.”