BRUSSELS, Belgium - The European Medicines Evaluation Agency is seeking to bolster the risk-assessment requirements for medicinal products that use tumorigenic cells of human origin.

The agency produced a draft position statement warning that these cells are likely to contain sequences not present in the non-tumorigenic state, such as a mutated p53 gene or a translocation event which generates a novel gene such as bcr-abl or myc. The statement points out that the principal risk associated specifically with continuous cell line-derived products is residual cellular DNA - not DNA per se, but the actual sequence encoded by the residual DNA.

A tumorigenic cell line may also contain a biologically active viral oncogene or a virus genome that may present a greater concern than a mutated cellular oncogene, because when expressed, the multi-functional properties of the encoded protein mean that it has the potential to cause greater biological effect than a cellular oncogene whose product generally has a single biological property, says the EMEA draft. The sequences of concern with human tumorigenic cells are those encoding a growth-promoting factor or those controlling expression (such as promoters) and which have the potential to be expressed once integrated into a recipient's cell.

The EMEA's biotechnology working party contends that their use raises issues not covered adequately by current regulatory guidelines - including characterization of the cell substrate, genomic and phenotypic stability, residual cell substrate DNA, and biologically active growth factors with transforming potential. The EMEA draft, now out for consultation until November, says that while human tumorigenic cells have not been widely used for the production of biologicals for human use, "they are increasingly being considered" and that there is a need to "address the issues presented by their use."

The position statement covers purified products derived from human continuous cell lines obtained either from solid or fluid tumors of leukemic or myeloid origin, or from human cells that have been transformed in vitro by biological, chemical or genetic engineering techniques. It does not cover biological products derived from tumorigenic cells of human origin that receive no or minimal purification or consisting of replicative systems, such as live vaccines.

"There is at present no incontrovertible evidence to show that DNA extracted from human tumors is capable of inducing tumors in vivo," the draft concedes. However, it goes on, there is published literature showing that DNA from highly tumorigenic cells of human origin is capable of transforming certain mouse cell lines in vitro, and it has been reported that nucleic acids extracted from oncogenic viruses such as polyoma can induce tumors in animals.

A risk assessment should be properly carried out, and risk factors should be defined, as far as possible, in a quantitative manner, the draft advises, even though it acknowledges that for novel cell substrates, risks may be difficult to define qualitatively or quantitatively because the endpoints are either theoretical or cannot be measured.

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