BRUSSELS, Belgium - Recent European thinking on developing gene therapy products has been drawn together into a new guideline from the European Medicines Evaluation Agency (EMEA), in London - the body that provides the scientific input for European Union authorization decisions on new biotechnology products.

The EMEA's draft guideline on gene therapy product quality aspects in the production of vectors and genetically modified somatic cells, covering the safety studies to support clinical trials and marketing authorizations for gene therapy products, has been put out for consultation in Europe.

The EMEA said the gene therapy product should be sufficiently characterized to provide reassurance that the preclinical studies have been conducted with material that is representative of what is going to be administered to humans in the clinical studies. Any modifications to the manufacturing process need to be checked, and changes to genetic sequences that alter the gene product or use alternative promoter and enhancer sequences may require additional safety evaluation in animal studies.

Companies developing new products in this area should investigate and discuss the extent of integration of the new gene into the host genome, the EMEA said. Depending on the extent of integration of DNA into the host genome and the clinical indication, studies may be required to investigate the potential for tumor formation or disruption of normal gene expression.

For genetically modified somatic cells, in vitro studies should examine any effects on cellular morphology, function and behavior, such as proliferation, immortalization or the induction of a malignantly transformed phenotype.

For autologous modified cells, the histocompatibility and immunological characteristics of the genetically modified cells also may be altered and this should be investigated.

Reintroduced cells should be free from extracellular gene therapy products (nucleic acids), which could be distributed and result in exposure of distant tissues and organs to the nucleic acids.

The EMEA said repeat dose toxicity studies will be required where multiple dosing of human subjects is intended. The route, mode, frequency and duration of administration in the animal studies should mimic the clinical dosing regimen.

Where patients' treatment is long-term, toxicity studies should generally be of six months' duration. The duration of the recovery phase investigations should be based on the persistence and expression of the gene therapy product.

The EMEA guideline also offers advice on assessing reproductive performance and developmental toxicity. An important issue to address is the possibility of distribution to, and localization of, the gene therapy product in germ-line cells.

Providing there is no persistent expression of the gene therapy product in germ-line cells, studies to investigate fertility and general reproductive function may not be necessary for the gene therapy, particularly in the clinical trial stage.

Embryo-fetal and perinatal toxicity studies may be required on a case-by-case basis - depending on the disease and clinical population to be treated - if women of child-bearing potential are to be exposed to gene therapy products.

The EMEA guideline's range is wide. It covers nucleic acids in their naked state; complexed with salts, proteins or polymers; encapsulated in liposomes; and coated on gold particles. It also extends to replication-deficient viral vectors such as retroviruses and adenoviruses, and to genetically modified fibroblasts and myoblasts.

The EMEA is seeking comments on this draft of the guideline before July. *