Convergence: Regulatory considerations in advancing gene and cellular therapies

Regulatory NewsRegulatory News | 13 September 2021 |  By 

Haroon Rashid Hashmi, Ziopharm

When developing a regulatory submission for a gene or cellular therapy, it’s essential to keep the basics in mind, such as how to demonstrate the product’s identity, purity, and potency, Haroon Hashmi, PhD, told attendees at RAPS Convergence 2021.
“Even when we think about these complex technologies -- new emerging technologies -- certain regulatory principles always stay in place,” said Hashmi, senior vice president at Ziopharm Oncology, which has developed the Sleeping Beauty T-cell therapy platform. “When you think about the CMC [it’s] identity, purity, potency,” he added, referring to the common acronym for chemistry, manufacturing and controls.
Advanced therapy sponsors will need to convince regulators that they can identify their therapeutic product based on its unique properties, show where there is the potential for impurities to be introduced during the manufacturing process or the gene transfer, and assess product potency to demonstrate that it is consistent using the manufacturing process, Hashmi explained.
Developers should also keep in mind that the same regulatory pathways that are available to more traditional drug products are also used for advanced therapies. These include orphan drug designation, accelerated or conditional approval, breakthrough designation (BTD), priority medicine (PRIME) and regenerative medicine advance therapy (RMAT), depending on which health authority will be receiving the submission.
Hashmi also emphasized the need for developers to communicate the “story” of their therapy to regulators through module 2 of the US Food and Drug Administration’s investigational new drug (FDA’s IND) application. Many of the questions that developers get from FDA reviewers are because they are not weaving a comprehensive story about the technology within their IND application. “You have to tell the story and you have to connect the dots,” he said.
Hashmi also advised developers to take advantage of the opportunities for early interaction with the FDA through the INTERACT meeting and the additional pre-IND meeting that follows it. And even if the product is initially planned only for clinical trials in the US, Hashmi said it’s advisable to align with European regulators early in the process.
Nonclinical development considerations
As part of nonclinical development, sponsors should consider what experiments need to be conducted and shared with regulators to address the safety concerns that are specific to their investigational therapy. This is especially important in cases where there are no relevant animal models with which to conduct the toxicology assessment.
The key elements to demonstrate include the product’s anti-tumor effect, potential toxicities (both on-target, off-tumor and on-target, on-tumor), and the potential risk of cell transformation.
In the absence of an animal model, sponsors could use in silico sequence homology and in vitro data to show that the therapy is not causing off-tumor toxicities. The FDA will also be looking for data to show that on-tumor effects like cytokine release syndrome or neurotoxicity are not creating a cytokine storm, Hashmi said. (RELATED: Animal models have limitations for safety assessment of gene therapies: FDA adcomm, Regulatory Focus 02 September 2021)
When it comes to the potential risk for cell transformation, sponsors need to provide information on the vector copy number (VCN), which should tie into the manufacturing data. Though FDA has not set a specific VCN in its guidance, a lower number is generally considered safer, Hashmi said, though it will depend on the technology involved.
“The totality of the package has to address all these safety concerns,” Hashmi said.
CMC considerations
Drug substance, drug product, and potency are all important CMC considerations for gene and cellular therapies, Hashmi said.
While some advanced therapy products do not have traditional drug substances, FDA is looking for the same level of information on plasmids and vectors that would typically be submitted for drug substances. That should include information on how the highest quality materials are being used and demonstration of  lot-to-lot consistency. Sponsors should complete all the information required for a traditional drug substance, even if it is to note that the section is not applicable, Hashmi said.
“Cover the details on those plasmids [and] vectors at the same level of detail that you would cover in another traditional drug substance,” he said.
For drug products, key development considerations include:
  • Healthy donor versus patient cells
  • Reagents for cell selection and growth
  • Representative materials for development runs versus good manufacturing practice (GMP) runs
  • Media runs to demonstrate aseptic processing
  • Connecting the VCN to nonclinical data
  • Sterility testing for fresh versus frozen product
To demonstrate potency, sponsors should show process consistency and use multiple assays to demonstrate the mechanism of action and biological activity. “Do not ignore potency,” Hashmi advised.
Clinical strategy
Hashmi advised that the development strategy should be driven by the individual targeted therapy portfolio and the indications of interest. For sponsors with more than one target within a single gene family, a basket framework may be appropriate. In contrast, an umbrella framework may work better if the therapy has multiple targets across more than one gene family in a single cancer type.
Other clinical considerations include identification of targets and HLA alleles (if applicable) early in the process, having a chain of identity throughout the process, setting specific eligibility criteria, having a rationale for the dose selection, establishing clear study pausing and stopping rules, and establishing a protocol for long-term patient follow up.
RAPS Convergence 2021 presentation


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