The Launch of the Biosimilar Product

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By Alex D. Kanarek, PhD

Earlier this year, the progress on the introduction of generic (off-patent) biological products to the European and North American markets took a major step forward. In January, the European Committee on Medical Products for Human Use (CHMP) issued a positive opinion on Sandoz’s (Holzkirchen, Germany) application to market its recombinant human growth hormone (rHGH) Omnitrope®. This was followed in February by the CHMP issuing a favorable opinion on another rHGH, Valtropin™ from BioPartners (Baar, Switzerland). These favorable opinions, as usual, were followed by market authorizations in April.

The way had been opened for the approval of certain “biosimilar products,” as they are termed in the European Union (EU) by the publication of the CHMP’s CHMP/437/04 Guidelines on Similar Biological Medicinal Products on October 30, 2005. Specific annex guidelines on similar medicinal products containing somatropin, recombinant human insulin (rHI) and recombinant granulocyte-colony stimulating factor were issued in February 2006, and took effect on June 1. New guidelines on quality issues and the non-clinical or clinical testing of biosimilar products have the same timeline. The annex on biosimilar erythropoetin was adopted in March, and will come into effect in July. A further concept paper on recombinant alpha-interferon was released for consultation on April 26, with comments requested by August 1.

These products were singled out for early approval since they are relatively simple molecules, whose structure is well-known and whose purity and efficacy can be well defined by analytical methods. This means that less emphasis has to be placed upon the actual manufacturing process to define the finished product. The maintenance that “the process is the product” has been the main reason cited by the U.S. Food and Drug Administration (FDA) and brand-name manufacturers for delaying the issue of guidance documents for those wishing to market biosimilar products in the U.S. The main thrust of the new EU documents is that, provided adequate in vitro and pre-clinical characterization of the product can be performed, the requirements for clinical testing could be greatly reduced (although they would not be eliminated).

Taking recombinant insulin as an example, the EU guidance on rHI states that short comparative studies against an approved product, both pre-clinical and clinical, should be sufficient to ensure that the new biosimilar product was approvable. Toxicology studies can be restricted to one repeat-dose study of at least four weeks, in only one relevant species (the rat, for example).

Pharmacodynamic data should be derived from one double-blind cross-over hyperinsulemic euglycemic clamp study. With this technique, a constant rate of insulin is infused via IV into laboratory animals to increase the uptake of circulating glucose into insulin-sensitive tissues and to inhibit endogenous glucose production by the liver. The decline in plasma glucose is prevented by a concomitant variable rate of glucose infusion. The amount of exogenous glucose required to maintain plasma glucose at its initial level is a measure of insulin’s ability to increase glucose uptake and suppress glucose production in a given subject.

Given satisfactory in vivo results, a single cross-over clinical study in man that would take a few months should be sufficient to determine the time-concentration profile of the new drug and its behavior in typical diabetics. The EU guidance considers that equivalence can be demonstrated from these studies and that a full-scale trial of clinical efficacy in humans would not be needed.

So far, despite intense discussion and meetings, the FDA has not yet issued any comparable documents to guide manufacturers in the licensing of “follow-on biologics,” to use the U.S. term. Pressure, however, is building. More biologicals of major economic importance are due to come off patent in the coming two years. The chief legislative proponents of generic pharmaceuticals in the U.S. are Representative Henry Waxman (D–Calif.) and Senator Orrin Hatch (R–Utah). Waxman plans to introduce a bipartisan bill later this year that would “establish a regulatory pathway for generic biologics.” Waxman and Hatch recently sent a letter to then-acting FDA commissioner Andrew von Eschenbach asking him to allow the approval of generic versions of rHI and rHGH. The commissioner’s response is not known.

Sandoz brought the fight to the U.S. this January, by requesting a federal court provide a summary judgment to force the FDA to make a decision on Sandoz’s NDA for Omnitrope, which was filed in June 2003. The company sued the FDA last September after the agency refused to approve or deny the application, and refused to explain why it had not handed down a decision or provided a timetable for such a decision. Those actions are still sub judice.

The position that a biologic is only defined by its manufacturing process is now more difficult to maintain, in view of the fact that at least five different companies produce rHGH. Each of these companies uses a different process, but all have been approved for use. In addition, Eli Lilly and Co. (Indianapolis, IN) and Novo Nordisk (Bagsverd, Denmark) use different methods for the production of their licensed rHI. There are also at least three companies in India now making biosimilar insulins by other processes, which have been approved for use in that country. It was significant that, following the introduction of the first generic insulin in India, Novo Nordisk cut the price of certain of its insulin products in that country by about 40 per cent. One of the Indian manufacturers, Biocon Ltd. (Bangalore, India), has indicated its intention to market rHI in Germany, having already launched the product in parts of the Middle East and Africa.
Health Canada has not yet issued any specific guidelines on the approval of biosimilar products. Subsection C.08.002.1 (1) of the Food and Drug Regulations states that an Abbreviated New Drug Submission (ANDS) can be filed, where, in comparison with a Canadian reference product (already approved for marketing in Canada by the innovator),

“a) the new drug is the pharmaceutical equivalent of the Canadian reference product;
b) the new drug is bioequivalent with the Canadian reference product, based on the pharmaceutical and, where the minister considers it necessary, bioavailability characteristics;
c) the route of administration of the new drug is the same as that of the Canadian reference product; and
d) the conditions of use for the new drug fall within the conditions of use for the Canadian reference product.” (author’s emphasis)
In the absence of any more specific guidelines, it should therefore be possible for a Canadian manufacturer to submit an ANDS for a generic biological on the basis of studies similar to those proposed by the EU. It is not known if this theory has been tested in practice.

Copies of other blockbuster drugs such as erythropoetein are already on the market in several parts of the world, especially China. Manufacturers in North America will lose out on an extremely lucrative market unless the regulators face up to the challenge and, in the near future, issue clear guidelines for the manufacture, testing and approval of biosimilar, follow-on biological products.

Alex D. Kanarek, PhD, president of Bio-Development Consulting Services (Uxbridge, ON), received a BS in microbiology from Imperial College, University of London (London, U.K.), a PhD on virus research from the University of Cambridge (Cambridge, U.K.) and Membership in international pharmaceutical business development from the Royal Chartered Institute of Marketing (Berkshire, U.K.). He has more than 30 years of experience in the biopharmaceutical industry with the Wellcome Foundation (now GlaxoSmithKline, Middlesex, U.K.) and Connaught Laboratories (now Sanofi Pasteur, Lyon, France) in North America. Bio-Development Consulting was founded in 1993, and specializes in regulatory compliance in drug-development laboratories and manufacturing plants, technology transfer and biopharmaceutical product development.

Kanarek can be reached by e-mail at
biodevelopment@sympatico.cal