Innovation in Chemistry, Manufacturing, and Controls—A Regulatory Perspective From Industry

Abstract

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.

Major Causes Associated with Clinical Trials Failure and Selective Strategies to Reduce these Consequences: A Review

“…There are different critical steps in the drug development process, including many phases and stages within each of them (Figure 1). These various phases and stages develop an in-depth understanding of the entire process [4,5].…”

Recent Progress of Potentiating Immune Checkpoint Blockade with External Stimuli—an Industry Perspective

“…While it is often appropriate for researchers to be unconstrained in their design by potential issues in the CMC space, the lack of a line of sight or a perceived high CMC complexity can also be a barrier to more widespread adoption or exploration of a novel delivery system. [ 109 ] This is especially true when considering factors in the previous sections, that make it difficult to understand or quantify the potential benefits fully. Platforms requiring complex and multistep synthesis can be very challenging to manufacture on a large scale.…”

The Confluence of Innovation in Therapeutics and Regulation: Recent CMC Considerations

“…Clinical success of this technology has led to the approvals of Novartis' Kymriah®, Gilead's Yescarta®, and more recently Gilead's Tecartus®. 20,21 Current innovation in this field seeks to improve the functionality of CAR T cells in light of issues such as the oftenimmunosuppressive TME, an obstacle in the treatment of solid tumors because of the many mechanisms that cancer cells can utilize to prevent the CAR T cells from functioning appropriately. 22,23 New engineering designs that incorporate additional immunomodulatory payloads into the engineered cell product are entering clinical trials, such as a Phase I CAR design in which the extracellular portion consists of the IL-4 alpha subunit combined with an intracellular IL-2/IL-15 beta subunit, thereby utilizing IL-4 in the TME to activate T cells.…”

“…In the US, expedited regulatory pathways are granted for a broad range of therapeutic modalities that address critical patient needs (breakthrough designation, fast track, accelerated approval, or priority review). 20 In general, the Center for Biologics Evaluation and Research (CBER) is responsible for overseeing biologics, with the Office of Tissue and Advanced Therapies (OTAT) responsible for cell and gene therapies. Cellular therapies include cellular immunotherapies, cancer vaccines, or other types of autologous and allogeneic cells for therapeutic indications including hematopoietic and embryonic stem cells, while gene therapy is used to modify or manipulate the expression of a gene to alter the biological properties of living tissues for therapeutic use.…”