Primary academic research centers, many in the United States, have conducted the most pivotal cell and gene therapy (CAGT) clinical trials. But the increasing pipeline of second-generation CAGTs and new studies are hurtling toward a bottleneck. Dwindling resources at the leading CAGT institutions—including a post-pandemic exodus of healthcare staff—are starting to limit patient access to experimental therapies and hamper clinical development programs.
Expanding CAGT research to a broader base of investigative sites is imperative to ensure we can test these potentially curative medicines and deliver them to the patients who need them. While some community-based, non-academic hospitals and clinics conduct CAGT trials, many have only completed one or two. Because these trials are known to be complex, time-consuming, and labor-intensive, some sites are not interested in participating.
Yet a growing number of community sites have completed multiple CAGT trials and are willing to ramp up further: several have become trusted partners with the skilled staff, resourcing, and organizational scope to conduct this high-level research. For the field to sustain and increase momentum, sponsors and clinical research organizations (CROs) must nurture those sites.
Identify motivated site and offer a gated path to success
Site interest in CAGT research often revolves around the motivation and engagement of a single principal investigator (PI) or key opinion leader. If that PI is interested in conducting chimeric antigen receptor T-cell (CAR T-cell) or gene therapy trials, then the site is interested. As a result, identifying community-based organizations with a resident PI who wants to conduct CAGT research is to expand the pool of potential sites and reach underserved communities to include more diverse patient populations.
Motivations vary. Many PIs want to offer their patients a chance to receive effective treatment for an intractable illness. Some may also enjoy the recognition and peer-reviewed publications that can accompany successful trials for innovative drugs. But perhaps most importantly, CAGT research can raise a site’s profile and help improve its infrastructure by attracting more patients, trials, and investment.
At Parexel, we identify and precisely profile interested sites, enabling us to match each site to a given protocol by examining the indication, PI, and patient population, among other factors. It comes down to our experience and a robust database of sites’ interests, geographies, and capabilities. We offer sites trials that they can successfully execute. Procedures and assessments must be within their range of abilities, but we train and support them where there are gaps or less experience.
For example, when selecting sites for oral therapy to treat glioblastoma multiforme (GBM) that also involves radiotherapy, we do not turn to a community site with no radiotherapy facilities. Likewise, inexperienced sites should not take on trials of base editing or self-amplifying mRNA therapies. But if a trial or indication demands a diverse patient population, we seek a community site with a large geographic catchment area. If a community site already administers monoclonal antibody (mAb) therapies and has the medical services to monitor and treat immunogenic adverse events, that is a good starting point. It may allow them to ease into administering T-cell therapies properly and prudently. We can expand the network of confident, CAGT-capable institutions one successful trial at a time.
Tightly targeted site selection saves time and money
Feasibility assessments and site selection are standard procedures for CROs. Typically, a CRO will generate a list—using an internal or external database service—of all the sites and PIs that have previously conducted, say, a Phase 2 CAR T-cell therapy cancer trial. This exercise might produce a list of 300 sites. The next step would involve examining the list line by line and prioritizing candidate sites based on existing workload or other details.
This top-down approach is not efficient. Further, it tends to produce a list dominated by the same academic research centers. Instead, at Parexel, we build the list bottom-up by tightly targeting candidates based on the trial protocol and our previous experience with specific sites.
For example, we recently prepared a site list for an emerging biotech company testing an “off-the-shelf” allogeneic T-cell therapy for cancer. Allogeneic products are created from the T cells of healthy donors and do not require the same tracking and handling processes as autologous therapies (which are extracted from a patient’s blood, genetically modified and amplified offsite, shipped back to the site within days, and reinfused into the same patient). The Phase 1 multi-cohort basket trial was designed to enroll relapsed patients with different types of solid tumors and included a combination therapy arm. To identify sites that could execute this protocol, we considered many factors that could impact study execution and patient recruitment, including:
- Genetic testing resources: Can the site perform genetic tests locally to confirm that patients enrolled have the relevant genetic mutation—or else have speedy access to a referral site that can perform the testing and deliver results? The combination therapy arm of the trial required additional genetic testing.
- Trial phase preferences: Since the study has a dose escalation phase followed by a dose expansion phase, will the site participate in both? Some sites are only comfortable with dose escalation trials, so including them could speed up the first part of the study.
- Experience treating a wide range of solid tumors: Does the site diagnose and treat patients with a broad range of solid tumors, such as breast, gastric, colon, lung, and head and neck? Only patients who have failed multiple targeted therapies will be eligible for the trial—so if the site rarely diagnoses and treats such patients, enrollment may be slow.
- CAGT experience: Does the site have any prior experience with CAGT trials? Even though the therapy was a second-generation, allogeneic product that is easier to handle, sites with previous experience may be better prepared and equipped to run the study.
- FACT accreditation: Does the site have accreditation from the Foundation for the Accreditation of Cell Therapy (FACT) or other international certification organizations? (Depending on the protocol, it is not always necessary for a site to have FACT accreditation, but it helps.)
- Biopsy capabilities: Can the site perform fresh tissue biopsies, and would they want to? In our experience, tissue biopsy requirements can reduce PI interest and slow patient recruitment.
After examining the factors relevant to this specific protocol, we identified 31 sites that fit the criteria. We then applied a few additional filters to generate a pre-screened list of 15 top-performing sites, a mix of flagship academic centers and non-academic community-based organizations. However, due to the requirements of the study, the list was heavily weighted toward academic centers. Our site profiling and targeted approach meant we would not need to vet this list further or spend more time on it.
Each sponsor will prefer specific sites for CAGT trials, and many insist on joining the queue and waiting the extra 18 months (or more) to conduct their study at a major academic research institution. Due to the current backlog of industry-sponsored trials at flagship CAGT sites, this is the tradeoff. We can estimate how much faster the trial could start (and finish) if the sponsor includes community sites—some of which can initiate a trial in just three months—into the mix.
Targeted and efficient site selection helps patients
To ensure that patients have continued and expanded access to treatments and trials, Parexel is committed to profiling and pre-screening sites for CAGT research. We know that we can deliver the benefits of these therapies faster to more and increasingly diverse patients if we refine our site selection methodologies to make them more efficient and effective.
Contributing Expert
