By Desmond Cabrera, Project Director, Cell and Gene Therapy
With today’s cutting-edge technology, we are on the cusp of developing truly magnificent therapies using cell and gene science. However, as with any new therapy, we must always consider the patient first.
Guidelines to Ensure Patient Safety
As far back as 2001, as new cell and gene therapies (CGTs) came online for clinical trials, regulatory agencies have been reviewing patient safety for these trials. While there has always been a follow-up guideline for a clinical trial, the parameters have changed for CGT. We are using new technologies and bringing advanced methods of safety monitoring into this evolving field.
Regulatory agencies agree that long-term follow-up (LTFU) for patients in clinical trials for human CGT products is necessary, and both U.S. and EU regulatory bodies have issued guidelines. These guidelines, which aim to ensure patient safety and avoid potential risks of delayed adverse events (AEs) following product exposure, are excellent for establishing follow-up time frames and protocols. But there are additional considerations beyond regulatory requirements that anticipate patient needs in LTFU studies and encourage retention over the length of the study. The guidelines recommend 5 to 15 years of follow-up, post-treatment, but how do you operationalize a trial of such a prolonged duration?
Protocol Development for LTFU Studies
When we discuss protocol development for CGTs with our clients, we want to ensure that they are leaning into the expectations and requirements of the regulatory agencies for follow-up. LTFU studies are required to collect data on delayed adverse events related to gene therapy products but are not intended to provide evaluation or treatment data for the underlying disease. However, the assessment of long-term clinical efficacy and durability is supported by regulatory authorities as long as it will not add burden or risk to study subjects. In the protocol, medical and regulatory experts will often recommend an increase of data points to maintain continuing interest and engagement of patients for safety measures.
A second recommendation for protocol development is to start early with the schedule of assessment of requirements by including patient-centric approaches such as telehealth, ePRO, home healthcare, e-consent, e-source, and so on. With the plan in place at the outset, we will have established achievable goals for study compliance and success in collaboration with investigators and patients.
A Plan for Remote and On-Site Monitoring
Setting up a monitoring plan for the safety review of data both remotely and on-site can go a long way toward lessening the burden on sites. Remote considerations include electronic site files, access to EMR, central monitoring of safety data points, and triggers to on-site visits based on ongoing quality. All of these will reduce the efforts of traditional monitoring to enhance site engagement and foster relationships with sites and CROs for future studies.
Central monitoring will give us a structured data review, looking at known risks at regular intervals and including quality tolerance limits (study risks). By using this model, we can review data holistically through these analytics, gaining insight into safety risks and allowing the sites to work without the constant pressure of site visits.
Site Engagement
Flexible clinical research solutions are necessary to successfully navigate the complexities of managing multinational programs across early and late-stage development, including clinical trial operations for LTFU studies. Site identification and selection are vastly different for a gene therapy trial versus an observational late-phase trial. Typically, for a First-in-Human (FIH) gene therapy trial, a site is a large academic center with a cell lab and multiple departments that can conduct advanced treatments and processes, as well as follow-up. It is vital to ensure that personnel at these sites understand the requirements post-treatment for follow-up and that the burden of site activities is manageable for these studies.
For example, sites need to be productive and punctual with data entry, but we want to avoid unnecessary data collection. One recommendation is to include specific questions to the site’s Standard of Care (SOC) for follow-up at the feasibility stage. If we include the trial requirements while the site is conducting its SOC, we are more likely to have one-visit site engagement rather than an unnecessary second or third visit out of sync with the protocol. During these early stages of design, it is essential to work with data management to ensure that the eCRF is built to accommodate the SOC to the greatest extent possible because this will lessen additional data entry for a site coordinator.
As we progress from design to implementation, the Informed Consent becomes the first place to educate the patient on the follow-up requirements. In traditional early-phase studies, a follow-up period to detect any type of event might be 30 days, a year, or longer – a period often described as active follow-up. But after these windows, it is important to describe to the patient the expectations for the next several years. Setting expectations at the start will help ensure the patient’s compliance, because, for many CGTs, treatment can be one-and-done without additional follow-up – a unique aspect of these trials. Further, keep in mind that patients will relocate and staff will turn over; it will be vital to ensure that sites have access to patients’ primary care physicians, and in the case of oncology, their primary oncologists.
Patient Retention and Compliance
When considering an LTFU, keep in mind the ecosystem of the program and the overall patient pathway, which will help ensure compliance throughout the duration of follow-up. One of the best ways to ensure long-term success is to use a patient-centric approach. As we learned during the COVID pandemic, remote assessments became essential to trial continuity in all phases. When we think about how to lessen the patient burden for compliance, let’s look at various options:
- Develop a schedule with a mix of in-clinic and remote visits (telehealth)
- Engage the subject through technology:
- ePRO: Patient-reported outcomes
- eClinRo: Clinical report (site)
- ObsRO: Observational (parent/caregiver)
- eConsent
By incorporating these technologies in a long-term plan, we can improve data quality and management for the site and add trial flexibility and resiliency through long follow-up periods.
Financial Considerations
Finally, sponsors should be aware of financial considerations and weigh the benefits of decentralized clinical trials (DCTs) with patient outcomes and project budgets. Technology should be introduced not as a cost-saving measure but as a way to improve trial conduct; in fact, technology can increase costs. But patients in a clinical trial are the key to its ultimate success, and reducing their burden must be a top priority. Using DCT elements, along with emphasizing patient compliance and the overall quality and thoroughness of data collection, will continue to advance our goal of finding cures via cell and gene therapies.
Allucent believes strongly that patients must come first in clinical trial operations. Our team utilizes years of experience and knowledge in designing, executing, and supporting DCTs from the beginning through long-term follow-up. Contact a member of our team to discuss how we can help bring your therapy to light.