At first glance, an Israeli biopharma focusing on cancer treatments and a Pennsylvania-based biotech developing respiratory therapies for newborns seem to have little in common. But VBL Therapeutics and Windtree Therapeutics have both overcome challenges in selecting sites for mid- and late-stage clinical trials, and they have tips for other companies involved in the process.
For VBL, country requirements and working with a contract research organization, as well as operating under Special Protocol Assessments, made finding sites for its gene therapy a complicated task. Meanwhile, Windtree faced the challenge of working with very young children, as well as developing a drug that doesn't have a clear development pathway.
Working with CROs
VBL knew it needed a first-class contract research organization (CRO) to run its GLOBE Phase 3 study evaluating the efficacy of its lead candidate ofranergene obadenovec (VB-111) in treating patients with recurrent glioblastoma. (Interim analysis is expected in mid-2017, and top-line data from the final analysis should come in the first quarter of 2018.)
VBL CEO and founder Dror Harats was familiar with CROs from his work as chairman of an institutional review board (IRB) handling about 600 new trials each year and supervising about 3,000 ongoing studies.
Yet, despite his broad experience, Harats found challenges related to his own company’s investigational work and site selection. "Everyone will tell you CROs are very helpful,"he said, "but they can be at times quite difficult." For VBL, that difficulty initially came in the form of meeting patient recruitment goals; the CRO needed to be pushed. While having a quality CRO is important, Harats added, it requires a strong in-house team as well to support that work.
The next challenge came when choosing sites for the VB-111 study. The Israeli biopharma had to find countries where the control drug, Avastin (bevacizumab), was cost-effective. While this was a key reason for selecting the U.S. to host the trial, requirements from the Food and Drug Administration further solidified this choice. The FDA has required VBL to have 70% of its patients from the U.S. since only one trial is being conducted. Beyond the U.S., VBL also chose its home-base of Israel, as well as Canada as the other host countries. These decisions were driven by underlying patient demand and simplified distribution.
"We decided not to do it in Europe because of the costs for the control drug. It might be $10,000 per patient or more, and with 256 patients, it can be quite expensive,"Harats said.
Key opinion leaders, mostly found in sophisticated medical centers, are needed to help design trials, "but many times the KOLs are not the best recruiter for patients,"Harats noted. He said the right mix must be created, involving centers and physicians who are adept at patient recruitment.
"We were in a good position because we ran Phase 2 with oncologists in the U.S., got some on the advisory board to run the trial with us, and they gave us a big list of candidate centers,"Harats said.
In addition, the international principal investigator (PI), the U.S. PI and a steering committee helped VBL select centers on the list able to help with patient recruitment. VBL ended up with 57 centers, with 45 in the U.S.
"It’s not always this way,” he said. "The company is not always experienced, but I believe it’s better to have a good understanding with the medical community…and you need to know how many patients each center can recruit and how much time it will take to recruit…You can always add more centers."
One question always on the questionnaire for potential sites is how many competing trials the center has at the same time, Harats said. Beyond site capacity, VBL needed to make sure that all of the sites selected has the knowledge and skill to handle a gene therapy like VB-111. An institutional review board was required to assess each site for this reason.
While all of VB-111’s Phase 2 centers (three in the U.S. and one in Israel) were included in the Phase 3 trial, only 20 to 30 patients came from Phase 2 sites, and when mass recruitment began in early 2016. The trial is being performed under a under a Special Protocol Assessment granted by the FDA and VBL was able to finish patient recruitment five-and-a-half months ahead of schedule.
Finding ways to enroll preemies
Windtree, on the other hand, faced different challenges when enrolling patients who would be treated with its synthetic KL4 peptide-containing surfactant. The drug is meant to treat preterm babies with respiratory distress syndrome who are in neonatal intensive care units (NICUs). So, unlike trials that can use outpatients, the company had to find hospitals with a significant amount of NICU capability, said Steve Simonson, Windtree's chief development officer.
The biotech is in the midst of a Phase 2b program for its most advanced therapy — a drug/device combination to administer the surfactant to premature babies. The study, which began in 2016 and should finish by mid-year 2017, has no clear development pathway to follow, "so we’re blazing a trail here," he said, adding that patient recruitment is a major issue to address.
In fact, he said, "It’s always difficult to recruit,"even if site personnel are "otherwise enthusiastic…and that’s why we need to go to so many trial sites" to ensure trial results are delivered "as fast and efficiently as possible."
"In our case, for our most advanced trial, we’ll employ approximately 50 sites and are looking to enroll up to 240 patients," he said. Windtree completed its site selection and is now involved in training to conduct the trial and handle data entry.
The biotech sought sites capable of treating babies with a potentially life-threatening complication right at birth — with protocols allowing physicians to discuss therapy with parents beforehand so therapy wouldn’t be delayed in a highly stressful situation. Moreover, "you need to find sites with excitement for the therapy you’re bringing forward so they’re intrinsically motivated," Simonson said.
Windtree needed hospitals with a Level 3 NICU, including non-academic medical centers. Sites also needed a principle investigator with research experience in premature births, a research pharmacy and an engaged research coordinator. Windtree has a steering committee of neonatologists to determine whether centers have good quality and patient recruitment efforts.
The company evaluated the number of premature births at given sites to ensure "potential numbers to justify our investment in the site," Simonson said. Additionally, the biotech wanted to ensure potential sites followed clinical guidelines and had acceptable outcomes data over the past three years — information from a North American NICU database.
Yet, while some sites did well when Windtree audited its previous surfactant program (using breathing machines), the company didn’t use all sites again for various reasons, including departures of principle investigators and research coordinators. "You have to evaluate sites in real time to ensure their performance in your program going forward," he warned.
The biotech also is looking for diversity among sites. "When we complete our program, we want our results to be generalizable," he said. "At first, you’re looking for safety…but in late Phase 2 and Phase 3 programs, we do want outcomes to be generalizable geographically, across patient types and care practices." He noted that the trial is going to sites in Europe, Latin America and Canada for appropriate diversification.
If potential sites pass a paper screening and initial talks seems positive, Windtree sends a physician onsite to look at the NICU, determine things like whether the research pharmacy has capabilities for appropriate storage and rapid delivery of the drug.
"You’ve got to walk through every scenarios with the hospital," Simonson said. "You’re really interested in the trial, but can you do it?"