Current INN policy on biological products

The WHO INN Programme was established to assign nonproprietary names to medicinal substances so that each substance would be recognized globally by a unique name. Such names are needed because chemical descriptions are usually very complex for even relatively small molecules. Unlike trademark names, INNs do not give proprietary rights and can be used freely since they are in the public domain. The INNs provide standardized terminology for the international exchange of scientific information and form an essential part of the regulatory process in many countries where a nonproprietary name is a requirement for licensing.

INNs have been assigned to biological medicines since the early days of the INN Programme and include biotechnology-derived products such as monoclonal antibodies and recombinant DNA-derived plasma derivatives and hormones. INNs have not been assigned to natural human blood products nor to vaccines. Instead, the WHO Expert Committee on Biological Standardization formally assigns scientific names to these biologicals when developing the appropriate WHO recommendations and these become international names.

With novel scientific and biotechnical developments taking place at an increasingly fast pace, biotechnology is expanding and many new biological products are currently being introduced for the prevention, diagnosis or treatment of human disease, with many more anticipated in the future. Indeed, biotechnology-derived medicine is one of the fastest growing sectors of the pharmaceutical market.

The complexity of the biologicals area is well recognized and in January 2002 WHO convened a meeting to review policies used by the INN Expert Group when naming biological products. The objective of the meeting was to seek specialist advice on nomenclature issues, in particular from the Expert Committee on Biological Standardization (1). The meeting led the way to further cooperation and collaboration between INN and biologicals experts and recognized a future need for assigning INNs to gene therapy products.

Monitoring Group on Gene Transfer Medicinal Products

In parallel to these activities, a WHO Monitoring Group on Gene Transfer Medicinal Products has been established and two meetings have taken place (2-3) to review the situation concerning gene therapy. After reviewing the current situation on product development, the Group recommended global harmonization of regulations for gene transfer medicinal products as a priority activity, and identified a need for WHO guidelines and a nomenclature system.

In this latter regard, the Group discussed a nomenclature system for nonproprietary names for gene therapy products proposed by the United States Approved Names (USAN) Council. It was agreed that the system had interesting potential, but more work would be needed to achieve a flexible, all encompassing and appropriate INN nomenclature system suitable for use with gene transfer medicinal products. In particular, the INN system would need to be sufficiently robust to capture latest developments in biotechnology while covering a varying range of products. It would also need to be adaptable to definitions of gene therapy products used within different jurisdictions.

The need for nomenclature of gene therapy products

On 27 January 2005, an informal consultation was held at WHO to discuss the elements of an INN policy on nomenclature for gene therapy products. Participants reviewed the current range of gene transfer products which could be included in a future INN nomenclature policy. This policy would need to be sufficiently flexible to encompass all desired product types. Three broad types of gene transfer products were identified:

• gene therapy:
• DNA/nucleic acid vaccines (4); and
• live viral vector based vaccines (5).

Although commercial entities and clinical grade materials are available for nucleic acid vaccines, most of the work is at the proof of concept stage in humans. For gene therapy products, however, many clinical trials have been undertaken - the majority being in the cancer field - including for treatment of monogenic diseases, multiple sclerosis and rheumatoid arthritis, or in bone regeneration and angiogenesis. A range of different vectors (adenovirus, adeno-associated virus, herpes virus, pox virus, retroviruses, naked DNA) and genes for antigens, tumour suppressor cytokines, and hormones have all been studied, sometimes using systems involving the transfer of ex-vivo genetically manipulated cells. The field is thus highly complex, with a wide range of potential products, including the same genes in different vectors and different genes in the same vectors.

Even then, it would be expected that each gene and vector combination would have its own specific characteristics. Only a small percentage of clinical trials (2-3%) are presently at the Phase III stage of development but there is no doubt that clinical success is possible in some areas. Recent reports (6, 7) describe the successful correction by gene therapy of immunodeficiency in children with the X-linked form of severe combined immunodeficiency disease (SCID-X1), which is characterized by a block in the differentiation of T and natural-killer cells as a consequence of defective expression or function of gamma c-cytokine receptor-subunit, or both. Thus, the field of gene transfer has become a clinical reality and serious consideration has to be given to the development of an INN nomenclature policy for these products.

Regulatory policy and nomenclature: country reports

In Japan, no consideration has yet been given to developing a policy on systematic names for gene transfer products. The emphasis has been on providing detailed guidance on quality and safety issues, including those issues related to the route of administration. If ex-vivo methods (systems involving the transfer of ex-vivo genetically manipulated cells) are to be used, consideration will be given to the target cells, to donor selection criteria, ex-vivo cell culture, and acceptance criteria and methods of administration of transduced cells. When in vivo administration of the vector/gene is used, target cells are again an issue, as are administration methods and the possible transfer of genes to non-target cells.

Japan had less experience of clinical trials of gene transfer products than the USA and Europe but nevertheless a number of trials have been approved. The range of vectors and disease targets is similar to other countries. Safety is of paramount concern and there is a need to explain clearly the potential risk of severe serious adverse events in the informed consent form. Consideration is also being given to viral shedding and monitoring, and an important goal will be development of vectors with better targeted delivery.

In the USA, a nomenclature system which would satisfy statutory requirements is under development. Gene therapy products are regulated as biologics by the Food and Drug Administration (FDA) and no medicinal product can be licensed unless a proper systematic nonproprietary name is in place and displayed on the label. The FDA cannot therefore grant a license to market a biological product that does not meet labelling requirements. A nonproprietary name is thus essential for gene therapy products. The need for an INN is considered to be linked to product safety. If there is a problem in the field, possibly in another country, then it is vital that both vector and gene construct be rapidly identified through a common name.

The FDA considers that the nomenclature system for gene therapy products needs to identify the product as a vector carrying a gene to be transferred, but that the indication should not be part of the name, nor should the name incorporate the finer details of the construct. The simpler the name the better, while avoiding the danger of over simplification. The Center for Biologics Evaluation and Research (CBER) has been discussing potential nomenclature systems with USAN since 2001.

A nomenclature scheme should include four elements in order to distinguish a gene therapy product and convey safety information to the user. These would be:

• Indication of the mechanism of action (pharmacologic class).
• Complete identification of the gene being transfected.
• Vector type.
• Indication of the vector’s ability to replicate in vivo.

Specific nomenclature elements would include:

A prefix: a distinct compatible syllable or element to provide a unique identification of the molecular entity.

An infix: to identify the gene product’s mechanism of action. In many cases existing INN infixes for biological products could be incorporated, such as “ermin” for growth factor or “lim“ for immuno-modulator.

A stem: “gen”(e) to serve as a suffix for all gene therapy products.

A qualifier could be added to indicate vector type (plasmid, adenovirus, retrovirus, etc.) and the term “replicating” to indicate a capacity to replicate in vivo.

However, problems are foreseen with such a system if multiple genes are incorporated at the same time into one vector. Such products are already at the developmental stage. It is unclear also how vector-modified cells will be named and more thought is needed on this aspect. The FDA sees several benefits of developing a systematic nomenclature system for gene therapy products: it will satisfy regulatory requirements for labelling, standardize the assignment of nonproprietary names, and expand the pool of possible names for related, but unique, molecular entities.

Like the USA, European Union legislation foresees reference to the INN, where one exists, in medical product literature. There are advantages to a global harmonized common name, and the INN process is a well respected and recognized system which can serve this purpose. The definition of a gene therapy product in the EU is quite broad and flexible. It considers gene transfer to involve an expression system contained in a delivery system known as a vector, which can be of viral as well as non-viral origin. The vector can also be included in a human or animal cell.

Difficulties to be overcome in developing an INN nomenclature system for gene therapy products would include the best way to impart information on the gene of interest and especially on similar or related genes, the problem of multigenes, the use of different types of vectors and the issue of small but possibly important differences within one type of vector. However, a systematic name should be easy to use and to understand.

Building on the experience gained for other complex biological substances such as fusion protein conjugates, which have a two component system, a two word system could be possible. A two word system would give more flexibility and allow similar genes and vectors to be more easily recognized. The proposal for an INN policy for gene therapy products based on two words involves Word 1 as the name for the gene component and Word 2 as the name for the vector component.

The specific nomenclature elements for each word would include a prefix, infix and suffix in a way similar to that already proposed by the FDA and USAN.

Word 1 (gene component)

Prefix: contributes to the distinctive name: e.g., al- bel- val-

Infix: identifies the gene using, when available, existing infixes for biological products as proposed by the FDA or use similar infix as for the protein for which the gene codes.

Suffix: gen or gene

Word 2 (vector component)

Prefix: contributes to the distinctive name

Infix: lenti (lentivirus), retro (other retroviruses), adeno (adenovirus), herpa (herpes virus), or naked DNA, etc. The infix “mul” could be used in the case of multigenes.

Suffix: to indicate viral vector “vec”.

More details of the structure/composition could be given in INN publications in an analogous fashion to other biological products such as recombinant proteins.

A distinction can be made between gene therapy medicinal products where the primary mode of action is the delivery and expression of a gene, and somatic cell therapy medicinal products where the primary mode of action is the delivery of cells with different physiological or other characteristics. It is recognized that gene therapy medicinal products can be administered to a patient’s cells ex-vivo; in this scenario, ex-vivo could be considered as the route of administration (i.e the cells are not included in the INN scheme).

Discussion of this issue concluded that the suffix “vec” would be more appropriate. “Vac” could easily be misinterpreted as indicating “vaccine”, but “vec” would clearly be seen as indicating “vector“. It was agreed that the suffix for word 2 be “vec”. It was also agreed that the suffix for the first word (gene component) should be “gene” not “gen”.

Participants reviewed four gene therapy INN requests to evaluate how products and proposals would fit into a two-word INN system. Two of these applications were from USA and one each from Germany and Japan. The exercise proved useful and highlighted the need for some thought to be given to infixes for plasmid vectors.

Conclusions

Several important recommendations emanated from the consultation.

1. It was recommended that a systematic nomenclature system for gene therapy products be developed by WHO within the INN framework.

2. It was recommended that the INN for gene therapy products should be based on a two word system. The first word should describe the expression gene, and the second word the vector component.

3. It was agreed that in the case of gene therapy medicinal products administered by transfecting a patient’s cells ex vivo, the cells themselves should be seen simply as the route of administration and should not be included in the INN system.

4. It was agreed that, for the present, gene transfer products covered within the INN policy should not include DNA/nucleic acid vaccines nor live viral vector vaccines to be used for prophylaxis. However, discussion should take place on this point including whether therapeutic or cancer vaccines should be included in the INN system.

It was agreed that further work and broader consultation was needed to refine the proposed INN policy on nomenclature of gene therapy products.

References

1. World Health Organization. Consultation on International Nonproprietary Names (INN) and Biological Products, Geneva, January 2002. INN Working Document 00.118 (unpublished).

2. World Health Organization. Informal Consultation of the WHO Monitoring Group on Gene Therapy, Geneva, May 2002. (QSB unpublished document).

3. World Health Organization. Report of the WHO Monitoring Group on Gene Transfer Medicinal Products, Geneva, June 2003. (QSB unpublished document).

4. World Health Organization. Guidelines for assuring quality of DNA vaccines. Annex 3. WHO Technical Report Series, No. 878 (1998).

5. World Health Organization. Informal Consultation on Characterization and quality aspects of vaccines based on live viral vectors, Geneva, December 2003. http://www.who.int/vaccine_research/documents/en

6. Cavazzana-Calvo, M., Fischer, A. Efficacy of gene therapy for SCID is confirmed. Lancet, 364: 2155-2156 (2004).

7. Gaspa, H.B., et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet, 364: 2181-2187 (2004).