Clinical Research: Phase 1 - Phase 4

Tackling Common Issues in Gene Therapy Trial Operationalization

Between navigating relatively uncharted territory and the practical limitations of most gene therapy delivery systems, ensuring successful clinical trials of these products is a serious challenge for even the most experienced researchers. Compounding this is the long-term nature of most gene therapy trials — it’s not unusual to have follow-up periods of a decade or more.

The best way to overcome these obstacles? Take into consideration and address these common issues throughout each stage of your gene therapy trial. Don’t let what can be a simple fix early on snowball!

  1. Planning

Perhaps even more so than other clinical trial types, gene therapy trials require intense, careful planning at the early stages of operationalization. All parties involved must examine and address each of these initial considerations.

Finding the Right Vendors

Especially for sponsors new to gene therapy trials, the selection of appropriate experienced vendors, CRO, and/or regulatory consultants makes a major difference. This includes working with a reliable shipping vendor who can properly manage the supply chain, ensuring the stable, secure, and timely shipments of your product.

Why is shipping so key? Simple: Timing is especially critical with gene therapy products because bio-hazardous samples need to be delivered quickly and securely to manufacturing sites, and study patients may have only a narrow window where these treatments will be effective. Carefully spaced conditioning phases may also be necessary. Patients and their families understand this and are already in a heightened emotional state; don’t let something as simple as a shipment delay result in treatment failure or patient drop-out.

Starting With a Timeline

Gene therapy often requires more oversight than more conventional treatments. As such, your trial will need to undergo Institutional Biosafety Committee (IBC) and/or Recombinant DNA Advisory Committee (RAC) review, which can be a very slow process. RAC, in particular, meets quarterly, and all materials must be submitted eight weeks ahead of time. This means one mistake during the early stages of a gene therapy trial can easily lead to delays of six months or more — a prospect that is unacceptable for both patients and your budget.

Selecting Sites

Intense site selection effort is key. Plan ahead and consider specific countries willing to participate in gene therapy trials. Make sure that local laws and regulations are consistent with the trial’s needs and that the location has the necessary infrastructure.

It may be necessary to bring entire families to specialized centers. In these cases, sponsors may decide to get help from a vendor for coordinating travel and obtaining any required medical visas. Personnel may need to act as cultural mediators for families coming to a country where they don’t know the language or may be unable to support themselves (e.g., because they may be legally unable to work in the host country). Day-to-day activities, such as education, must not be overlooked when considering the burden of the clinical trial. Do everything you can to support and ease this stressful process, whether it’s a long-term stay or frequent trips across the border.

Remembering Key Considerations

Many aspects of a gene therapy trial will need to be determined based on features unique to:

  • Patient population — Is the target indication a rare disease? Will you be working with juvenile patients?
  • Method of administrating gene therapy — Who is able to administer the therapy and is specialized training needed?
  • Availability of study support team members — Does your trial need robust, real-time issue resolution? Do you have the personnel to implement it?
  • Proactive development of patient/family materials — Do your study materials explain all aspects of the study in an age-appropriate manner? Are you providing support and educational materials to patients’ siblings? Are you treating cases of multigenerational disease with compassion?
  • Strategy for obtaining informed consent — Can you obtain informed assent for pediatric patients? Have you considered using video assent when working with young children? Is the language used appropriate for the age?
  • Monitor workload resource allocation — Are you working with site staff to navigate periods of high complexity?
  1. Site Setup

Always be aware that site-specific regulatory or ethics committees or approvals have the potential to significantly impact timelines. Likewise, things don’t always go as expected, so remember to have back-up/mitigation plans for all components of the trial. Be sure to provide extremely detailed support materials for all study team members.

Common site-specific procedures regarding the gene therapy product to consider are:

  • Pharmacy policies and staffing
  • Investigational product receiving, storage, transport, waste disposal, exposure control plans, and infectious waste plans
  • Multimillion-dollar infrastructure may be needed, such as:
    • A clean room and other expensive equipment
    • Specialized staff
    • A very large study team, including geneticists, surgeons, MRI guidance, etc.
  1. Recruitment

Once a site has been set up, there is no guarantee that successful recruitment will follow. A hands-on, patient-centric approach is key. Starting with identifying patients and families to participate, gene therapy researchers will often be working with rare diseases where incidence and prevalence may not be clear. Because of the high cost of genetic testing in such cases, providing support to families and access to genetic testing can be a useful recruitment and screening tool. Likewise, researchers often partner with advocacy and patient support programs to find eligible enrollees.

When a target indication is a rare disease, geography is a major barrier. As such, many researchers work with vendors to provide patients with “concierge” service, along with a robust cross-border enrollment plan that’s worked through well in advance.

  1. Retention

For gene therapy trials, retention rates are a critical barrier that needs to be overcome. The duration of follow up is often years (5–15) and patient/family movement is frequent. Likewise, site staff turnover can further complicate things.

So how can researchers make sure patients come back? By proactively taking steps to reduce burdens on patients. For example, implement remote data capture whenever possible for follow-ups with patients who would otherwise need to travel. This strategy reduces the number of in-person visits and, consequently, travel time. Likewise, digital devices can also be used to stay in touch between visits and promote patient — and family — engagement. Gene therapy trials should have a plan to continue education and dialog throughout.

Another factor affecting retention rates is the typical patient population. Because early pediatric intervention is key for many gene therapies, it is not unusual for study patients to age through different assent levels or reach majority in their country. It can be much more difficult to convince a teenager or young adult to follow up compared with a concerned parent of a small child.

Patients and/or their families may lose their interest in lengthy follow-up periods. For many gene therapies, whether or not the treatment “works” for a given patient is recognized much earlier than the required follow-up period. In these cases, patients must be educated about the importance of staying in the trial: to generate robust, thorough data for themselves and for future patients like them.

Making It All Happen

The truth is gene therapy trials pose an enormous challenge, even for experienced sponsors and CROs. But it’s still a challenge that can be overcome with the right tools! For more information, check out our white paper on Operationalizing Gene Therapy Trials.