Clinical trials for cell and gene therapies present a unique set of challenges, beginning with patient identification and recruitment and continuing on through implementation and long-term follow-up. Optimized solutions require CROs with extensive experience in managing complex trials — more specifically, in supporting cell and gene therapy, rare diseases, and the design and deployment of decentralized trials (DCTs).

Facilitating Recruitment in Distinct Patient Populations

Currently, most cell and gene therapies target rare diseases. Consequently, recruitment for these trials can be challenging, considering that the targeted patient population can be sparse and widely distributed across the globe. Decentralized trial models can enable this type of research by eliminating the need for patients to travel long distances to participate. Gene and gene-modified cell therapies can also present challenges relating to the concerns patients may have regarding new therapies. As a result, it is critical to develop a patient recruitment engine that leverages patient advocacy groups and key opinion leaders to build awareness of these new modalities and drive recruitment, as well as to build multiple modes of communication into studies.

A key component of this engine is education about the gene therapies themselves and the long-term implications comparable to hematopoietic stem cell transplantation. The decision to participate is a significant one, because once a patient has received a gene therapy treatment, they can no longer participate in any other clinical trials or receive any other gene therapy products. As a result, the decision to participate is often one that is made by the patient and their entire family or network of loved ones. There is a heavy responsibility on study teams and clinicians to ensure that the educational package is appropriately detailed and offered not just to the patient, but to others invested in their care.

Gene and gene-modified cell therapies are overwhelmingly based on viral delivery, so there is also a need to determine if the patient already has antibodies against the virus capsid used to deliver the therapy. The most efficient way to perform this type of screening is in a completely decentralized manner that brings the study to the patients, but it must be done carefully given the implications of the results. After analyzing these samples, patients who are shown to have antibodies to the vector under study may not be eligible to receive the particular treatment involved in the given study. However, immune responses against vectors and transgene products remain a hurdle to uniform efficacy. A better understanding of these immune responses will lead to improved vector designs and more targeted immune modulations. This holds potential to expand gene therapy to a wider set of human conditions. For instance, steroid drugs are currently widely employed in systemic, hepatic, and ocular AAV gene therapy to counter inflammation and antiviral T cell responses. Lessons from CAR-T cell therapy, where physicians learned to prevent cytokine release syndrome by inclusion of monoclonal antibodies in the immune modulation regimen to counter IL-6 signaling, may be helpful in that management of immunotoxicities in viral vector gene therapy.

Whether other members of the patient’s household have the same disease is another factor affecting eligibility for trial participation for therapies based on viral vectors. There is a potential for viral shedding after the patient’s gene therapy treatment. If this occurs, then people in the household with the disease who have not been treated could potentially develop antibodies against the viral vector, in turn, rendering them ineligible for treatment in the future. Here again, only blood draws are needed to screen for viral shedding, so the test can be performed in a remote setting outside of the investigator site. 

Expanding Research to Common Diseases

Concurrently with digital advances in the industry, we are seeing an increasing number of candidates intended to treat more common diseases in today’s clinics. These patients generally have greater access to various existing therapies and may thus be resistant to treatments that cause modification of their DNA. Once again, education to create awareness and ensure that patients are equipped with necessary insights to make decisions around participation in cell and gene therapy clinical trials is paramount.

It will be equally important to manage patient expectation in terms of the potential impacts of these treatments over the longer term. One-time administration of a therapy that may be corrective for a particular abnormality or defect could mean less time in the hospital, reduced need for conventional treatments, and a better quality of life.

Collecting Consent Electronically

Participation in gene and cell therapy clinical trials is a big decision that can be life-changing but also carries real risk. Consent must therefore take place in the presence of the patient’s physician and in some cases a geneticist to ensure that the patient — who in many cases is a child — and the parents and/or caregivers can really understand what involvement in the clinical trial entails and to ensure that everyone has the opportunity to ask questions. 

There is a heavy ethical requirement for completing this process, because it is such a significant step. However, the COVID-19 pandemic has presented challenges to traditional methods — including meeting in person for these types of conversations and transactions. As a result, telemedicine has become a much more widely accepted option, as has remote electronic consent (eConsent). PPD Digital has developed tailored eConsent solutions designed to provide the necessary environment for this process, including access to the people and resources needed to help patients fully understand the myriad ramifications of the decision to participate in a clinical trial.  

Bringing the Study to the Patient

One of the greatest patient burdens associated with clinical trials is having to travel to the investigator site more often than would be required for their normal standard of care. One of the ways to reduce that burden is to align the protocol to the standard of care as much as possible. The other is to bring the study to the participant using a flexible protocol that incorporates decentralized (DCT) strategies, such as eConsent, home-health nurses, televisits, and electronic patient-reported outcomes (ePROs) within decentralized trial designs.

An extension of PPD’s DCT strategies is the dedicated patient concierge service, which facilitates travel where the need arises for patients to travel to different countries in order to receive a particular gene therapy. Our patient concierge option is the ultimate white glove service for reducing the burden of patients traveling to foreign countries.

Addressing Unique Logistics Needs: Immediate and Long-Term

Advanced therapies are complex, particularly autologous, personalized approaches. Very specific cells are being modified with very precise viral vehicles to get genes or constructs into cells. For personalized therapies, there is also a higher degree of CMC and manufacturing management, logistics, and communication requirements, and thus the integrity of the trial’s ecosystem and interaction of stakeholders is crucial.

These therapies take a multidisciplined approach to address needs for tissue/cell procurement and collection, including sample delivery at low temperature in limited timeframes, manipulation within a manufacturing process (which can take 4–12 weeks), preparation of the patient before treatment with the drug product, and ultimately monitoring of the clinical effect during post-reinfusion/recovery and over the long term. 

Within those steps, we need to consider whether the patient will be in a clinic, doctor’s office, or hospital or at home. Many different laboratories are also involved — to onboard the patient, analyze the therapeutic material, and monitor the safety and health of the patient during treatment and follow-up — each with its own regulatory compliance requirements. 

The chain of custody for the samples going to labs is also vital to the trial’s final data and endpoint analysis. The different samples, demographic information, and results must all be tracked and tied back to the correct patient — not just during the treatment period, but for up to 15 years afterward. During this time, some patient information may change, regulations will likely evolve, different testing requirements could be introduced, different laboratories might be used, and the sponsor or the product may be acquired by another firm with a totally different strategy. 

The very high level of communication and coordination required to achieve successful cell and gene therapy trials over the long term can only be achieved today because of technological innovations that have occurred in recent years. PPD can monitor every step of the process and ensure the necessary level of oversight. Technological innovation is particularly helpful as sponsors expand to broader patient populations and larger clinical trials. Having access to advanced digital databases and technologies provides answers and options that enable more efficiency in the process. 

Simplifying Long-Term Follow-up Requirements for Patients

Clinical trial participation for cell and gene therapies, as mentioned above, does not simply end following the treatment. There is generally a follow-up period as part of the treatment protocol that involves frequent visits and more intense assessments to assess the safety and efficacy of the therapy. Patients then move into the long-term follow-up period, which can last 5–10 or more years, depending on the therapy and duration of follow-up in the treatment protocol. Many cell and gene therapies can also have post-authorization safety study (PASS) requirements that are similar to the long-term follow-up included in the clinical development process, but not all patients who receive these therapies post-commercialization must participate.

These long-term studies are conducted to assess safety and long-term durability of gene and gene-modified cell therapies. Gene therapy products are intended to achieve a prolonged or permanent therapeutic effect, but they may also result in undesirable or unpredictable adverse outcomes. Genetic modification of cells therefore carries risk, and it is essential to understand those risks in terms of well-defined outputs, such as secondary malignancies, impairment of gene function, autoimmune-like reactions, and latent and persistent infections. It is critical to ensure that the necessary vigilance systems are in place to continue collecting the required safety data. 

It is particularly important during the long-term follow-up period to keep the patient experience in mind and identify solutions that optimize efficiency and effectiveness of data collection. Study teams must carefully consider the necessary level of connection with the patient, the site, and the physician and how burden can be minimized for everyone involved. Patient safety is always our top priority.

Application of digital technologies, approaches, and experiences for data collection are other notable elements to consider. For instance, detailed case histories, including records of exposures and the emergence of new medical conditions of interest, that need to be established during the initial three- to five-year follow-up period can largely be collected using new electronic and remote modes of communication. 

The subsequent long-term follow-up can be set up as a fully decentralized process, which would include consistent, ongoing contact via telephone or questionnaires on a recurring basis to maintain the patient connection. Home health nurse visits and telemedicine can be employed, along with eConsent, ePROs, and other digital options to meet the needs of timely endpoint collection. Ultimately, the key is to leverage modern decentralized technologies to better retain connectivity with the patient while minimizing burden. This will also define how optimized AAV gene therapy dosing strategies are determined.

Additionally, many gene therapies are intended to treat rare diseases that occur in children. This means, if a five-year-old receives the treatment, at the end of the 15-year treatment and follow-up period, he or she would be a grown adult at 20 years old. As children grow and mature, priorities shift in terms of what is important to them and the best ways to engage with them. At the outset of the trial, they are highly dependent on their parents, whereas by the end of the period, they may be living on their own. Parent and caregiver needs evolve as well. It is also possible that the same parent or caregiver will not be involved over the entire course of the follow-up. For children, especially, it is therefore important to consider their journey as trial participants and instill a sense of continuity and consistency. One way to do this is by designing a protocol that allows for flexibility in technology, devices, geographies, and modes of communication throughout the years of research.

Comprehensive Solution Backed by Years of Experience 

PPD’s leading pediatric, rare disease, and cell and gene therapy centers of excellence are a direct example of how our teams have been invested the field of cell and gene therapies for over a decade. Our innovative spirit demonstrates we are not entrenched in a certain way of doing things, but instead constantly explore new ways to improve efficiency and effectiveness — decentralized solutions have always been a part of that. Working closely with PPD Digital, PPD’s decentralized clinical trials business unit, our teams offer an unrivaled solution to support remote cell and gene therapy trials. Active engagement with the scientific and medical communities allows us to stay abreast of technology and compliance.

With our integrated approach, PPD has the necessary functions working collectively across the organization to ensure the end-to-end clinical paradigm is covered. Within this enterprise spectrum of capabilities, PPD provides the essential agility and personalization of solutions needed to succeed. As a result, we are able to develop bespoke solutions for each client and trial that allow optimal connectivity with the patient and continuous data collection both within and outside of standard care. Whether a virtual startup or widely recognized global biopharmaceutical and biotech organization, we contribute value across the board — ultimately helping our customer’s cell and gene pipeline excel in today’s environment. 

As we move into a new era of clinical research, PPD recognizes the growing complexities that organizations face around long-term follow-up in the cell and gene therapy ecosystem and how modern technologies are taking form to fit the needs of those patients. We are committed to staying at the cutting edge through our partnerships with companies and sponsors developing these highly innovative, novel therapies that ultimately change the lives of patients.