Setting Gene-Based Therapies into Motion

Gene Based Therapies, Clinical Trials


Remarkable healthcare advancements have come through gene-based therapies, providing improved outcomes and quality of life for patients with complex and chronic genetically linked conditions.

In the article, “Navigating Through Uncharted Waters,” featured in International Clinical Trials’ November issue, Worldwide Clinical Trials’ experts – Dr. Michael Murphy, Dr. deMauri Mackie, Sophie Humphrey, and Dinah Otieno – shared insight about the challenges associated with setting clinical trials into motion for gene-based therapies and best practices to address them.


By Dr. Michael Murphy, Dr. deMauri Mackie, Sophie Humphrey, and Dinah Otieno

Gene-based Therapy Clinical Trials – Uncharted Waters

The industry witnessed several milestones in the last couple of years regarding gene-based therapies. In 2017 alone, the FDA allowed the first gene-based treatments for an inherited eye disease in the US as well as cleared two other gene-based treatments targeting advanced hematologic malignancies. These developments sparked a push to advance gene-based clinical trials following setbacks from the FDA and EMA, which prompted additional guidance and rigorous review processes.

Current Study Context and Practices – In 2012, the pace of gene-based clinical trials increased, with 100 new studies a year from 2012 to 2017 – and currently about 2,600 worldwide. Most trials are in Phase 1 or Phase 1/2 studies, meaning there is an emphasis on early phase experimental designs structured to understand how the biological properties of gene-based therapeutics can affect long-term outcomes relevant to efficacy, safety, and healthcare utilization. Patient segmentation and the low prevalence of many diseases eligible for gene-based therapeutics also is limiting the number of patients available during clinical development, mandating development strategies that attempt to minimize the total sample of patients who must be evaluated while maximizing the extent of treatment on the investigational agent. Here are some best practices:

Here are some quick takeaways from the framework, addressing multiple perspectives and implications:

  • Minimizing the sample: Minimizing the patient sample for interventional studies occurs through six approaches. Decision nodes influence the choice of design and are based upon reversibility of outcome, rapidity of response, and the amount of time and accessible data on control treatment.
  • Maximizing treatment: Maximizing time and the number of patients receiving active therapy occurs through a variety of design options, most notably adaptive seamless designs for phase 2/3 studies.
  • Applicability to gene therapy: For gene-based therapies, options for clinical trial design are constrained by the long biological activity of the genetic material introduced. Among 12 designs for rare diseases – six being relevant – only a fraction have been utilized. However, a framework exists for exploration of their applicability within regulatory guidance.
  • Long-term Follow-Up: The properties of the vector and the nature of the targeted gene shape requirements for long-term follow-up are balanced against the nature of the viral vector and the targeted gene. These create monitoring conventions that stand apart from those associated with small molecules and biologics, which may vary according to country-specific regulations.

Regulatory Environment in the EU – In Europe, the governing Directive 2001/20/EC created united procedures for trial authorizations; however, national-level procedures and lack of harmonization ATMP definitions across member states can lead to differing assessments and country start-up timelines. In 2019, the Clinical Trials Regulation (EU) 536/2016 will harmonize the clinical trial submission assessment process through a single EU portal – streamlining the review process and timelines across member states.

  • EMA Scientific Advice: The EMA offers developers an opportunity to discuss scientific challenges given the range of products and study methodology employed.
  • Early Access Programs (EAP): EAP in Europe includes the Compassionate Use Program (CUP) and the Named Patient Program (NPP). Therapy may be imported to provide for individual patients upon request of their physician for pre-approval access.

Conclusion: Ensuring Access, Approval, and Outcomes 

The difficulty of integrating design and trial operations with a regulatory and commercial strategy is accentuated in gene-based therapeutics. However, designing clinical trials that balance regulatory requirements, operational challenges and patient safety with therapeutic innovation will set the industry up to change the course of the most complex conditions through gene-base therapies.

To read more about navigating gene-based therapy clinical trials, read the full article here.


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