The significance of FDA industry guidance on cell and gene therapies 

On 4 November 2022, the FDA’s Center for Biologics Evaluation and Research released guidance for the industry on studying multiple versions of a cellular or gene therapy (CGT) product in an early-phase clinical trial in a single disease1. This guidance finalises the draft guidance of the same title dated September 2021. DDW’s Megan Thomas outlines the key takeaways from the document and speaks with industry experts about why this is a significant regulatory milestone. 


At the Alliance for Regenerative Medicine’s Annual Board Meeting in 2018, Scott Gottlieb, who at the time was the Commissioner of the FDA, said: “We’re at a key point when it comes to cell and gene therapy. These therapies have the potential to address hundreds, if not thousands, of different rare and common diseases. For a long time, they were largely theoretical constructs. Now they’re a therapeutic reality. And it’s my expectation that they will soon become the mainstay of how we treat a wide range of illness.”2 In 2018, the FDA had more than 500 active investigational new drug applications involving gene therapy products and it could be said that the regulatory organisation’s faith in the sector is evidenced by this new guidance.  

Researchers and scientists who are studying multiple versions of a CGT product in parallel and are responsible for manufacturing all versions of the CGT product have long-expressed the desire to be able to gather preliminary evidence of safety and activity in just one clinical trial – also known as an umbrella trial. While it is possible for multiple versions of a product to be studied together in this way, each version of the product is distinct and therefore is usually iterative and requires submission to the FDA to be done in a separate investigational new drug application (IND).1

The guidance explains: “The objective of these early-phase clinical studies is to guide which version(s) of the product to pursue for further development in later-phase studies. Thus, these studies are not intended to provide primary evidence of effectiveness to support a marketing application and generally are not adequately powered to demonstrate a statistically significant difference in efficacy between the study arms. In this guidance, we, FDA, provide recommendations for studies that evaluate multiple versions of a cellular or gene therapy product, including how to organise and structure the INDs, submit new information, and report adverse events.”1

Key takeaways 

The guide reiterates that its purpose is to recommend a more efficient and flexible model to evaluate multiple versions of an investigational product that would otherwise be evaluated in separate clinical studies1. The guidance covers:  

  • How to add arms to a study, providing recommendations on how to proceed depending on if the additional arm includes a new version of the investigational CGT product 
  • How to submit other types of changes or new information such as revisions to the umbrella trial clinical protocol that do not add a new arm, or for other types of new clinical information, as well as what to do if the new information is specific to one product or multiple products  
  • Guidance on clinical holds and responses to holds, for example how to respond in the event that FDA issues an order placing the entire study on clinical hold 
  • Guidance on reporting, such as with annual reports 
  • How to proceed with regards to the completion of a study or arm(s) 
  • The next steps for alternative approaches to structuring and organising INDs. 

Real-world impact 

So, what impact will this regulatory landmark have for those working in the field? Ryan Leahy is a science communication expert in cell and gene therapy from Phacilitate, hosts of events which focus on the science and commercialisation of advanced therapies in the medical field. He told DDW: “This is a particularly exciting development for the FDA and will potentially be transformative for cell and gene therapy. We’ll look forward to seeing how this plays out for organisations who can test multiple versions of a therapy in a Phase I study with umbrella trials. If this leads to increased efficiency of clinical trials, quicker validation of effective therapies and brings medicines to market sooner, this will have a massive impact for patients that previously had no options. 

“The guidance is comprehensive and clear in its output, from IND application, the process of adding completing various study arms, the implications of clinical holds and submitting safety documentation. It ostensibly cuts down submission time with shared information and cross referencing for multiple INDs covering variations of the same product. It will be interesting to see how this plays out and how much it benefits submitted CGT products.” 

Nicole Paulk is an AAV Gene Therapy Prof at University of California San Francisco (UCSF). Dr Paulk’s lab, unlike others in the field, are species/disease/organ/tissue/cell type/pathway/gene agnostic. Her team works at the platform level to forge new paths engineering novel ways to make all AAV gene therapies cheaper, easier and faster for rare diseases and cancer, with a focus on developing enabling technologies to bring these transformative therapies to patients. She spoke to DDW about the impact this regulatory milestone will have on her work. 

“This regulatory breakthrough opens the doors for whole new trial designs in numerous areas of gene therapy. Scientists and clinicians in AAV gene transfer gene therapy can now compare several AAV components of interest simultaneously in one trial to see which works best in patients (e.g. capsids, promoters, regulatory elements, codon optimisations, ITR configurations, payload designs, synthetic circuits, and beyond). This will allow engineers and investigators like myself to be more creative during construct design. I’m a big believer in streamlined componentry when feasible and I think we are going to see more “universal gene therapies” in the near future.” 

Commenting on how this approval will affect other researchers in the field, she said: “In the short term, running a multi-arm Phase I clinical trial will still be prohibitively expensive for all but big pharma, but I see this as a reason for smaller startups to partner with big pharma sooner, to gain access to the capital and know-how to run a comparative multi-arm Phase I so that the startup doesn’t just have ‘one shot on goal’ with their lead programme. Also, when paired with the new federal mandates to share clinical trial data, this will enable others to benefit from these trials so they can implement the same improvements into their construct designs so that all boats rise together.” 



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