8 Key Takeaways from the FDA’s Workshop on Advancing Pediatric Cell and Gene Therapy Clinical Trials

The FDA recently held a public webinar organised by the Center for Biologics Evaluation and Research (CBER) on advancing pediatric cell and gene therapy clinical trials. In brief, there seems to be a consensus across industry, academic, clinician, patient advocacy and regulatory stakeholders to defy what is perceived as traditional convention, where it can be ethically and scientifically justified.

Of course, given the types of diseases that are typically cured or mitigated by cell and gene therapies (e.g., small populations, lack of natural history data and diagnostic information), combined with the persistent nature of these Investigational Medicinal Product (IMP) classes, this is far from straightforward.

Here are our eight key takeaways from the productive workshop.

1: There is no “one size fits all” in this space.

In cases where the course of disease is similar in adults, adolescents, and younger children, and where all may perceive benefit, it may be sensible to first gain safety information in older participants, as they will be more neurologically and physically developed.

However, where the patients who are most likely to benefit are younger, and where older patients may already have irreversible damage, this paradigm may be flipped on its head if there’s appropriate nonclinical mechanistic, proof-of-concept and safety data. One phrase noted was use of the “informed clinician test” – would the child’s doctor recommend enrollment knowing the natural history outcome of the disease?

2: Regulation and guidance speak to the concept of direct benefit for pediatric participants.

This point was specifically noted by the FDA during the workshop. However, this is not the same as requiring sentinel adult participants. When seeking to go directly into a pediatric treatment population, sponsors should ensure that there is robust early discussion with the FDA, and where possible, they should leverage patient advocates, caregivers, and other stakeholders who are directly impacted by the disease.

3: The phrase “little kids are not small adults” was spoken early and often.

It was noted that safety signals that are noted in adults may not be reflected in children, and vice versa. Often, adult and pediatric disease manifestations are very nearly separate diseases, and this should be reflected in clinical development.

4: Three main challenges were noted from an industry perspective.

These three challenges were:

1. study staggering of participants receiving IMP administration;
2. knowledge of efficacy endpoints for very young children;
3. and long-term follow-up.

Each of these challenges has the potential to elongate clinical development and obfuscate early results.

5: Panel participants expanded on their interpretation of “prospect” of benefit.

It shouldn’t be assumed to refer to the translational package or prior experience in adults. Rather, it’s a totality of evidence that provides for the high probability side of a treatment effect, whether incremental or broad. It should be inclusive of tangential factors such as disease natural history and available standard of care treatment options. These factors may otherwise dictate no other possible prospect of benefit outside the clinical trial paradigm. Furthermore, in some instances, children with aggressive diseases simply will not have time to wait for treatment or may suffer irreversible damage if too many guardrails are constructed.

On the other hand, regulators noted that a potentially rushed process which results in an ineffective or inappropriate dose may preclude these patients from ever receiving another cell or gene therapy, which must also be accounted for in this calculus.

Still, given the potentially sliding disease progression, age as a linear construct should not be the ultimate arbitrator that governs patient inclusion in a clinical trial.

6: Including patient voice within the drug development pathway was a key theme.

It was noted that this would improve proactivity in understanding symptomology and establishing bespoke endpoints. Where standard of care doesn’t work – or doesn’t exist – the alternative may be the lack of what is perceived as an ordinary life.

A growing body of evidence shows that the decision making of patients’ parents, caregivers and advocates should reshape the discussion on risk tolerance, and that their understanding of daily life with the disease may be informative of prospective benefit. Given the wealth of advocacy groups, advent of social media, and study protocol and results detailed on ClinicalTrials.gov, those surrounding the pediatric patient on a daily basis are better informed than ever.

7: The final discussion on enrollment of pre-symptomatic children into clinical trials was perhaps the most interesting.

The discussion highlighted the abstract concept of whether children at the forefront of these studies are engaging in research or treatment. When little is known about the IMP, and this one-time administration may preclude use of a similar treatment later in life, the lines become blurred. Where possible, this should be informed by robust natural history data, or else it may call into question whether the right population is enrolled, or the right treatment questions are being asked.

Where the disease is well-understood, and particularly with little heterogeneity of clinical manifestation, treatment in a pre-symptomatic population may mitigate against downstream irreversible damage, and should be thought of as ethical even if the child is of very young age. However, if the known natural history dictates that symptomology may not occur until adolescent age for example, it may be best to hold off on treatment until just prior to this point.

The most important point is the robustness and penetrance of understanding of the disease’s natural history. Some uncertainty is ethically tolerable, but pre-symptomatic children represent the highest risk population of all.

8: There appears to be a pan-stakeholder desire to share information.

To be clear, intellectual property concerns will always dictate that some secrecy is necessary. But drug developers may benefit from knowledge sharing, and from FDA sharing (redacted) best practices. It would also inform caregivers who are on the fence of whether to have their children join a clinical trial, or those who are choosing between multiple clinical trials. Above all, it would be of advantage for patients, who are the most important group to potentially benefit.

Conclusion

Especially considering this was the FDA’s first workshop for advancing pediatric cell and gene therapies, it was a great source of knowledge. It also provided an opportunity to hear from a diverse group of stakeholders on cross-cutting topics, each with the principal goal of streamlining development in this important and vulnerable population. We should look forward to additional Agency collaboration in this space, which will hopefully result in expediting the delivery of safe and effective medicines to those who need them most.

You can watch a full stream of the webinar on YouTube.

You can find a list of upcoming public events involving the FDA on their website.

Supporting with clinical project management in the US

Our regulatory affairs professionals have long-standing relationships with the FDA and can provide clients with specialist knowledge and guidance to help support with clinical trial monitoring, site management services, and more. Speak to the team today.