Pediatric Gene Therapy Development Can Benefit From Trial Decentralization

In 2018, a family packed their belongings, boarded an airplane, and moved from Canada to Italy. They left behind family, friends, and pets. Both parents took leave from their jobs; the kids took leave from school. They tapped into their savings, found long-term accommodations, and learned the language and culture of their new home for six months. The difficult decision to uproot and relocate was made out of necessity: One of the children suffers from a progressive and devastating rare disease for which there is currently no cure or adequate treatment. An innovative gene therapy being developed and tested in Italy offered hope to slow or halt the progression of this disease, but the only way to participate in that trial was for the family to drop everything and relocate to Italy for however long was necessary.

This story illustrates how participating in clinical trials of investigational gene therapy products for pediatric patients presents serious financial and opportunity costs. This reality has implications for who can participate in these trials and thus how representative their collected data will be. We suggest that moving toward decentralized clinical trials offers significant advantages for improving these aspects of pediatric gene therapy research.

What Are Decentralized Trials?

Decentralized trials are an agile model for clinical trials, wherein elements such as recruitment and follow-up visits can be conducted without imposing the time and expense of traveling to a centralized trial site on participants and their families/caregivers. Decentralized trials have garnered much attention recently, given their use in COVID-19 vaccine development and their resilient design, which enabled such trials to resume activity during the pandemic faster than their centralized counterparts could resume.

Much like the shift to remote or hybrid work situations, there are varying degrees of decentralization, incorporating tools such as electronic consent, patient monitoring, videoconferencing assessments, and at-home phlebotomy. Indeed, because the development of decentralized trials has spawned numerous working definitions, there is a need to build a standardized infrastructure with elements such as a universal, agreed-upon terminology, metrics for compliance, and regulations for data protection. However, the lack of universal standards should not deter trial sponsors from decentralizing elements of pediatric gene therapy trials, which—when conducted exclusively at a few, non-randomly distributed trial sites—create obstacles for participants and their caregivers.

Requirements For Participating In Pediatric Gene Therapy Clinical Trials

Most gene therapy trials focus on rare diseases. They thus often have small numbers of participants and one or few trial sites, making access to these trials particularly formidable. Like the family we described (that of one of the authors), many families seeking to enroll a child in a gene therapy study travel far, often at their own expense. After arriving at the trial site and establishing temporary accommodations, participants—including those who receive placebo interventions—endure days of extensive testing, lab work, and assessments. For progressive diseases such as Duchenne muscular dystrophy, burden increases as patients experience loss of function, making travel and adherence to clinical trial terms more challenging, especially for those who have lost the ability to walk and must use a wheelchair. This time commitment and its related financial expenses and opportunity costs, especially when compounded by the need for extensive travel, can impact gene therapy trial enrollment and retention.

Trial participation frequently entails out-of-pocket costs––or delayed reimbursement of these expenses by the entity developing the gene therapy product––for those who travel. Families often find and pay for their own accommodations and make provisions for non-participating siblings. Caregivers accommodating the trial participant frequently take leaves of absence or stop working altogether, exacerbating the financial burden of the trial itself. Thus, trial participation increases the pressure on families already dealing with daily challenges of living with complex diseases.

The average annual indirect and non-medical cost per child with a rare disease is $14,326, not counting any trial participation; when the economic burden on a caregiver is factored in, this balloons to $48,400. These accountings merely tally financial costs to children and families, without taking into account the accompanying social and emotional impact. Against this backdrop, it is imperative to limit the extent to which involvement in clinical trials imposes additional practical and financial challenges.

What Does “Decentralization” Look Like For Gene Therapy Trials?

To be clear, safety is the single most important aspect of gene therapy research. Properly assessing potential trial enrollees and monitoring participants will entail visits to the trial site. When only one or few locations are involved in the trial, this necessitates travel. But there are two things that should be considered by trial sponsors to alleviate this burden as much as possible: proactively paying for/rapidly refunding expenses for travel to a clinical trial (a practice that many sponsors are adopting) and using the decentralized model where it is feasible to do so without compromising safety.

For example, many current gene therapy studies use viral vectors to transmit the transgene intended to affect disease expression. Thus, potential trial participants are tested for antibody levels to the virus of interest to ensure that they are receptive to the gene therapy. This testing is crucial to determine suitability for trial participation as study protocols have specified limits on participants’ antibody loads. However, there is no reason this determination must first be made at a trial site. Rather, screening procedures could permit the necessary blood draw to be performed near the patient’s home and the specimen to be sent to a selected laboratory, allowing for remote antibody screening and limiting travel to patients whose antibody levels meet the trial’s specifications. This would prevent ineligible patients and their caregivers from unnecessarily traveling to a trial site; for patients whose antibody status makes them eligible for the trial, this practice would potentially lessen their risk of inadvertent exposure to the virus of interest while traveling for screening.

This is far from the only aspect of pediatric gene therapy trials that could be conducted in a decentralized manner. As another step, trials can send informed consent forms and other educational materials to the potential participant/caregiver ahead of their appointment, allowing them more time to process the information before their screening. After the screening, the potential participant/caregiver can have follow-up conversations with the principal investigator via telemedicine appointment and sign the consent/assent documents using e-consent tools, ensuring more time for families to mull over the trial information and to ask any questions they might have.

Efforts are currently underway to validate remote data collection of clinical outcome measures through home-based video capture with a secure mobile application. Research is also being conducted using wearable devices to measure things such as stride velocity, which is currently approved as a secondary endpoint in Duchenne muscular dystrophy trials by the European Medicines Agency. These efforts could substantially reduce travel burdens and time spent in a clinic, minimizing the resultant emotional and mental impact of isolation from their peers.

Finally, parts of the long-term follow-up safety and efficacy monitoring (typically required with gene therapy) could be done remotely, either avoiding the need to travel altogether or minimizing the time spent at the trial site. Through a combination of these and other strategies, decentralization facilitates less-burdensome, more patient-friendly clinical trials while promoting greater diversity of trial participants—a win-win strategy for all stakeholders involved.

Benefits Of Decentralized Trials For Pediatric Gene Therapy Research

Decentralization would likely bolster trial recruitment, a challenge for many gene therapy product developers, especially when dealing with rare diseases and narrow trial inclusion criteria. Implementing a decentralized model for pediatric gene therapy studies would increase access and inclusion by eliminating a costly barrier to entry and widening the participant pool to better reflect the populations living with the diseases of interest. Gene therapy developers also stand to benefit from innovative trial models, especially given the Food and Drug Administration’s recent industry guidelines requiring long-term follow-up periods of up to 15 years. Adopting tools such as patient monitoring, videoconferencing assessments, and at-home phlebotomy would allow for trial progression and continuity of data collection without in-person visits.

The need for more efficient and patient-centered clinical trials has driven the recent interest in and adoption of a decentralized clinical trial model. It behooves gene therapy developers to be innovative in their use of decentralized models for pediatric gene therapy research if they want more efficient and equitable outcomes (as they should). While the decentralized trial model may have myriad uses, the benefits of this model are particularly salient for pediatric gene therapy research, in which child patients and their families/caregivers face extraordinary logistical, social, and financial barriers to research participation.

Authors’ Note

Cara Hunt and Alison Bateman-House receive salary support from Parent Project Muscular Dystrophy. Alison Bateman-House receives additional salary support from Johnson & Johnson and Pfizer.


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