Stakeholder Suggestions to Improve Gene Therapy Draft Guidance

The American Society of Gene & Cell Therapy (ASOCT) says an FDA draft guidance on leveraging prior knowledge in developing human gene therapy products incorporating genome editing would have greater value if it applied more broadly across cell and gene therapy modalities and provided greater clarity about how knowledge accumulated throughout a product’s lifecycle may be leveraged, including knowledge generated in the post-approval setting. The ASOCT comment letter says the guidance would also benefit from greater flexibility in the regulatory mechanisms through which prior knowledge, including shared or third-party information, may be referenced, particularly at the licensure stage. The letter provides line-by-line recommendations.

In its comment, the Biotechnology Innovation Organization says it and its members strongly support agency efforts to establish a science-based framework that enables sponsors to appropriately leverage prior knowledge and experience across product development programs. The association makes these recommendations:

• broaden the scope of the guidance beyond genome editing products;
• establish a risk-based framework for similarity assessments;
• clarify expectations for bridging and confirmatory evidence;
• clarify application of prior knowledge across the product lifecycle;
• improve regulatory predictability through additional examples and decision-making factors;
• clarify terminology and relationship to existing regulatory frameworks; and
• expand clinical development examples.

Pharmaceutical Research and Manufacturers of America (PhRMA) says the draft guidance “represents an important step toward recognizing that public knowledge and platform experience may, in appropriate circumstances, support more efficient product development and regulatory review. PhRMA recommends that FDA:

• expand the scope and title of the final guidance to reflect the applicability of leveraging prior knowledge across the broader spectrum of cell and gene therapy products and clarify which recommendations apply outside the genome editing context;
• articulate a structured, risk-based framework for determining when prior knowledge may support full reliance, reliance with bridging information, or de novo data generation and identify the factors the agency will consider in making those determinations;
• clarify the scope of “public knowledge”;
• explain the relationship between the draft’s concept of “platform knowledge” and the statutory Platform Technology Designation Program, including when sponsors should use one framework or the other or both;
• provide additional examples illustrating how FDA evaluates similarity, bridging, and scientific justification across chemistry, manufacturing, and controls (CMC), nonclinical, and clinical contexts;
• clarify the role of master files in supporting platform knowledge across CMC, nonclinical, and clinical disciplines and reconsider policies that unnecessarily limit efficient reliance on referenced information in BLAs;
• revise the draft guidance to clarify that leveraging prior knowledge must be accomplished consistent with existing protections for sponsor-owned data, trade secrets, and confidential commercial information;
• explain when and how published literature may appropriately be relied on in support of a BLA;
• revise passages of the draft that may be interpreted as categorical prohibitions on leveraging and recognize that scientifically justified leveraging may be appropriate when supported by bridging data, platform experience, or other evidence;
• provide a clearer framework for leveraging prior knowledge throughout the product lifecycle;
• establish a clearer process for adjusting long-term follow-up and other post-approval requirements based on cumulative safety experience and product-specific risk;
• make clear that sponsors may discuss leveraging strategies with the agency at any stage of development or post-approval and that FDA will provide actionable feedback about proposed leveraging approaches; and
• encourage using platform-based predictive methodologies, off-target assessment frameworks, and bioinformatics tools and clarify how sponsors should manage updates in previously leveraged analytical approaches.

The Friends of Cancer Research recommends that FDA:

• establish a structured framework for leveraging prior knowledge;
• link additional evidence to residual uncertainty;
• clarify how prior knowledge can streamline clinical development; and
• clarify use across programs and submissions.