Some of the biggest-selling biological drugs developed during the first phase of the biotechnology revolution in the 1980s - including human growth hormone, interferon alpha and insulin - have already lost or will lose patent protection in the next few years, opening up a $23bn market that is growing at 10 per cent a year.
But regulators and the generics industry have found it difficult to agree ways to ensure that copies of the original drugs are safe and effective, short of carrying out a full - and expensive - clinical development programme.
Undeterred, Pliva and Mayne say they will collaborate on the development of the Croatian's firm's most advanced 'biogeneric' projects, the white blood cell stimulator G-CSF and red blood cell equivalent erythropoietin (EPO), over the next three years. Pliva stands to receive €21m from Mayne over that period, during which the two companies aim to complete clinical development of the two products.
Based on figures produced by IMS Health, worldwide sales of EPO and G-CSF reached a combined market value of more than $14bn in 2004, up 17 per cent over 2003.
The collaboration "combines Pliva's expertise in the development and manufacturing of high quality and technically complex products with Mayne's position as the leading generic hospital player in the EU," said Pliva CEO Zeljko Covic in a statement.
The high cost of biologics (often tens of thousands of euros per patient a year) lends some urgency to the approval of biogenerics for healthcare budgeters, and the generics companies are trying to respond.
For example, Switzerland-based BioPartners and Sandoz have filed applications to market so-called 'biomilar' versions of hGH in the EU, but while the former dossier is still active, Sandoz offering was turned down on procedural grounds. BioPartners has also filed for approval of a generic version of interferon alpha for hepatitis C, but while biosimilar drugs have been launched in Asia and other territories around the world, to date none has been approved for marketing in Europe and the US.
Pliva has already developed and submitted a generic EPO for registration in Croatia, and plans to launch it this year, said Covic. "To the best of our knowledge, this launch will position us as one of the first companies to successfully, develop, produce, and sell a generic EPO on the commercial global market, and the first on the European continent," he added.
In Europe and the US, regulators have found it hard to develop an approval route for biogenerics because production of biologic drugs can be more of an art than a science. In contrast to chemically synthesised drugs, it is hard to develop quality standards for biologics: so the tools needed to show 'bioequivalence' - the standard measure by which a generic is shown to behave in the same way as an originator drug - are lacking.
Their decision is made the harder by suggestions that small changes in a biologic production process can have dramatic consequences on a product's safety and efficacy. One often cited example is the case of Johnson & Johnson's Eprex (epoetin), which was associated with 250 cases of a serious red blood cell disorder in the late 19990s, eventually blamed on changes in the handling and administration of the drug.
Because of these difficulties, biologics tend to be approved on the basis of purity, potency and identity, rather than safety and efficacy as is the case with conventional drugs. In the eyes of the biotechnology industry, this distinction is crucial, as it means that a biologic must always be produced using an identical manufacturing process. This is very difficult for biogenerics companies to achieve, and until recently meant that a full development programme was the only option.
Recognising these difficulties, Stuart James, Mayne's managing director, said: " "Biological products are technically complex, requiring specialised expertise in development and manufacturing that would be expensive and risky for Mayne to develop internally. Pliva's advanced progress in the development of EPO and G-CSF ideally complements Mayne's international sales and marketing and regulatory strengths."
Last year, Europe adopted new legislation that for the first time set out a potential marketing application process for biosimilar drugs. Meanwhile, the US Food and Drug Administration has just acknowledged in a public forum that it should be possible to seek approval for copies of biologic drugs without a full marketing application.