The World Health Organization (WHO) has issued a white paper for consultation that proposes a risk-based framework for regulating cell and gene therapy products (CGTPs) to promote global convergence among health authorities.
It proposes that autologous human cell and tissue (HCT) products for medical use be accorded a lower level of regulatory control than advanced therapy medical products (ATMPs), such as cell and gene therapies or tissue engineering products.
The paper’s goal is to “outline the fundamental principles that are important for providing adequate regulatory oversight for different types of CGTPs and should be reviewed in that context. In the future, WHO plans to develop more comprehensive written guidance, as needed, on specific topics relevant to regulation of CGTPs.”
The proposal for the white paper came out of a September 2018 meeting of the International Conference of Drug Regulatory Authorities (ICDRA) in Dublin, Ireland.
ICDRA’s press release from the meeting said that “WHO is to develop with Member States a ‘current state of the art’ document capturing areas where agreement among experienced regulatory authorities exists, noting where harmonization has yet to be achieved, and documenting existing areas of uncertainty; areas covered could include definitions, quality attributes, standards, and clinical development pathways.”
WHO aims to promote convergence
WHO said “the varied nature of CGTPs” has prompted different regulatory frameworks to emerge in Europe, Asia, Australia, North and South America and Africa.
WHO said that the goal of the paper is to work toward global convergence on regulatory expectations for CGTPs, which potentially can lead to regulatory harmonization.
The paper said that “as high-income countries work towards further regulatory convergence for these products, it is important to ensure that regulators in low- and middle-income countries (LMICs) are familiar with the scientific principles and regulatory issues for CGTPs also. Important factors include understanding of the scope (breadth and the nature of HCTs and ATMPs), risks and the key regulatory concepts relevant to ensuring that the more complex products are shown to be safe and effective prior to their widespread deployment.”
Different framework for human cells and ATMPs
In the document, WHO proposes a different regulatory classification for HCTs that are minimally manipulated or intended for homologous use, as opposed to ATMPs which are derived from human or animal cells and involve more extensive manipulation.
The paper states that “simple, minimally manipulated cells and tissues are often used for same essential function in the recipient as in the donor (transplantation, transfusion) and are regulated mainly to prevent possible disease transmission.”
It adds that “in contrast to HCTs that are minimally manipulated and undergo homologous use, ATMPs are more complex because they require controlled steps for manufacturing and significant manipulation of the cellular or genetic starting material for the intended effect … Therefore, ATMPs require more comprehensive regulation and demonstration of safety and efficacy, for which good quality, biological activity and manufacturing consistency are proven for the products prior to marketing authorization.”
In addition to the precautions required for screening and controlling HCTs, WHO writes that ATMPs require more stringent manufacturing and quality controls, nonclinical studies to generate pharmacodynamic and pharmacokinetic (PD/PK) biodistribution and safety data, and clinical studies “with proper design and control to collect robust and reliable safety and efficacy data … and long-term follow-up of the patients.”
The paper offers some examples of CGTPs, demonstrating their broad range of complexity and risks.
Autologous bone marrow cells, which involve the collection of bone marrow cells and are indicated for hematopoietic reconstitution pose a minor risk compared to allogenic CD19 targeted CAR T-cells used to treat hematopoietic malignancies. These products are made by removing the HLA-gene from the T cells, and involve gene editing and expansion, posing genotoxic and immunotoxic risks.
WHO acknowledged that “minimal manipulation and homologous use are regulatory concepts that have been embraced by multiple regulatory authorities for making the distinction between HCTs that present lower risk and ATMPs that present higher risk and which must be regulated more stringently.”
**Countries with “rudimentary” systems can regulate HCTs **
WHO states that “use of HCTs that do not require premarket authorization can potentially be implemented in settings with more rudimentary regulatory systems as long as the appropriate regulatory framework is in place to ensure that transmission of infectious diseases is minimized, and that products can be traced and recalled if necessary. Under those circumstances, countries can potentially deploy HCTs even in situations where they are relatively resource constrained.”
Yet “for jurisdictions with more extensive experience with the approval of simple ATMPs that have established safety surveillance systems, it may be reasonable not only to review and approve marketing applications for those ATMPs, but also to allow the investigational use of these products locally under appropriate regulatory framework and ethics committee oversight.”
WHO calls for increased collaborations between regulators “to increase access to quality-assured, safe and effective ATMPs” and to “leverage resources more efficiently.”
The organization promoted the African Vaccine Regulatory Forum (AVAREF) as an initiative that brings together regulators from the region to conduct joint reviews of clinical trial applications. Another initiative is the WHO collaborative procedure (CRP), which facilitates the marketing authorization of WHO-prequalified medical products approved by a stringent regulatory authority.
The deadline for commenting on the paper is 24 January.
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**WHO Whitepaper **