X4 Pharma is a company focused on delivering innovative treatments for patients with rare diseases of the immune system. With the COVID pandemic afflicting patients around the world, those with a compromised immune system were at even greater risk. The company is currently conducting a global Phase 3 trial that was underway when the pandemic hit. The trial is for patients with WHIM Syndrome, who are born immunocompromised. The study is particularly demanding as it is being run in 17 different countries.
X4 Pharma’s Phase 3 trial is a randomized, placebo controlled, double blinded study. That is a rigorous study design that requires a significant commitment from patients. Participants in the trial had to be seen at the beginning of the study and then once every three months for a year. The treatment is a once daily orally administered drug. The visits required a blood draw to monitor white blood cell counts as well as a photographic image of changes in a patient’s lesions.
COVID Brings Clinical Challenges
The team at X4 Pharmaceuticals was part of an investigator meeting outside the U.S. in early March 2020. That is when Paula Ragan, president and CEO of X4 Pharma, first heard talk about COVID and the impact it could have on trials. In April, the company began proactively reaching out to sites and clinicians and also conducting a survey of patients to get their opinions.
“For us, April was the month when we conducted a lot of information gathering,” says Ragan. “We did not want to rush decisions without first hearing input from our site partners and patients. We assessed the input we received and in May we began to adjust our trials based on that feedback. While some sponsor companies opted to suspend their trials, we chose to forge ahead.”
One of the ways X4 Pharma opted to deal with the crisis was to allow as many study metrics as possible to be done in patient homes or settings outside a hospital. The approach was better endorsed in some countries than others, and Ragan notes privacy issues in a few countries proved to be a limitation to out of hospital care.
Home Visits Keep Trial On Track
When the pandemic hit, the company did not have mechanisms in place that allowed for broad remote assessments and monitoring. Ragan notes the company had some early experience and was aware of the broader applications for remote monitoring, but past feedback received from sites indicated they preferred to see patients face-to-face. Still, that knowledge was valuable. As the pandemic unfolded and in person visits became more difficult, the company was prepared to make the necessary accommodations.
“We use patient diaries, which allow patients to record how they feel, and which would alert physicians if there was a potential issue,” says Ragan. “That would then lead to a patient/physician interaction. We had implemented those solutions prior to the pandemic, so we were ahead of the game in that respect. For us, the challenge was really finding the people who could go to patient’s homes and perform the required checkups and blood draws.”
If patients are not coming into the clinic, arrangements also must be made for getting them their medicines. Ragan has worked in manufacturing and supply chain and notes there are always challenges that exist.
“I believe supply chain is the unsung hero of our industry,” she says. “COVID has had an impact on the regulatory agencies and certainly on the ability of companies to transport drugs. That forces companies to put more intensity and focus on their supplies and timelines. There were situations that arose, and we had to address them, but thankfully it did not impact our patients.”
Timely Response From Regulators
When the pandemic hit in March, the FDA was quick to issue industry guidance on modifying protocols and keeping patients safe. Ragan felt both the FDA and EMA did a good job of keeping ahead of the virus and working with pharma companies to protect patients from the virus. That helped X4 Pharma make the necessary adjustments to its trials.
“What companies needed most at that time was the flexibility to care for patients who might not be willing or able to attend scheduled appointments in hospitals,” states Ragan. “That flexibility was something the industry needed. Both agencies were proactive in encouraging and allowing remote visits. Normally, if remote visits are not written in your protocol, you cannot perform them. The regulators allowed sponsor companies to make those adjustments and document their actions to demonstrate adherence to regulatory guidance.”
Those adjustments are not easy, and Ragan notes you cannot modify a protocol overnight. For many companies it likely took weeks or even months to incorporate the needed changes, depending on the nature of the modifications. Still, the FDA and EMA guidance allowed for short-term solutions that enabled companies to manage trials during the pandemic. Sponsor companies, along with their IRBs, will now have to determine what the long-term solutions will be.
Not only did X4 Pharma keep its trials going throughout 2020, but it also continued to enroll patients. Ragan notes recruitment is always a challenge, even without a pandemic. However, the company’s focus remained on its patients. She notes X4’s internal team was prepared and ready to enroll study participants when those patients felt they were ready to join the trial.
CRO’s Help Determine Options
X4 Pharma does work with CROs, and in fact is working with a different CRO for each of its three clinical trials. Although managing multiple CROs can be a chore, Ragan believes each trial presents a different scenario in which CROs can assist the company.
“When conducting a Phase 3 trial in multiple countries, you want a CRO that has the breadth and capabilities in certain countries,” says Ragan. “That helps ensure everything will happen smoothly and efficiently. That global trial we are conducting is obviously very different from our severe congenital neutropenia Phase 1B trial, which is being conducted entirely in the U.S. at a small number of sites. Different trials have different workloads and require different expertise. We take that into account in our selection process and select partners to match the local or global needs we require.”
When trials become as complicated as they did in 2020, CROs can help in navigating the hurdles. Ragan has a huge amount of respect for her CROs and even refers to those partners as heroes in the clinical trial process. Still, she is quick to note that in any trial the sponsor company must be the study leader, using information gleaned from partners. They have to own the strategy and the ultimate execution of the trial.
“A good leader will seek input from key partners, and we do that,” says Ragan. “I think our CROs have been very good at sharing their learnings. We then use that information in our decision making. I would say what we have is a symbiotic relationship. CROs have the knowledge to help you understand your options and company leaders use that information to make the right decisions.”
The Future Of Clinical Trials
If pharma has learned anything from trial conduct in 2020, it is that companies can take trials to the patient. Ragan believes the future will bring more of those opportunities.
This year businesses learned employees can be successful working from home. In fact, that model has likely proven to be more effective than many people would have predicted prior to the pandemic. Likewise, the success of virtual trials has shown pharma can feel confident when taking trials to patients.
Despite that success, Ragan believes the industry should proceed with caution.
“Clinical trial operations are incredibly difficult,” she states. “High quality data is paramount to our industry's success. Right now, it is too early to know if the data being collected in these remote settings is of equal quality to that collected in clinics. We just don't know yet. I believe every company is doing the best they can, but we will need to see wins across the industry before committing to a fundamental shift in how we approach it.”
Some visits to the clinic will always be necessary. But as home visits become more common, the value of in-person appointments will increase and make both physicians and patients more efficient. That may be one bright side of the COVID pandemic.
“With the COVID pandemic continuing to wreak havoc on healthcare systems and clinical trials, our focus really needs to be on our patients,” adds Ragan. “I believe one of the positive long-term outcomes of COVID is that the safety of patients will be even more in the forefront as companies plan and execute trials.”