Building on the premise that biologicals are growing ahead of the overall pharmaceutical market, he forecast: "In 2010, nearly 50% of all new approved pharmaceuticals will be of biotechnological origin."
Biopharmaceuticals’ share of global prescription sales
Source: IMS Health, BioGeneriX
With a clutch of first-generation biologicals approaching patent expiry, the potential for biogenerics appears great. But in reality biogenerics face an uncertain future. Much of this uncertainty is down to their unusual regulatory position. "As biopharmaceuticals are defined by their production process, any change can impact safety and efficacy and therefore demands new approval," said Pollano. In effect, it is impossible to replicate the biological process exactly, which makes it difficult to prove essential similarity, or equivalence.
Most importantly of all, according to Pollano, no clear regulatory framework yet exists for the market authorisation of biogenerics. "Proof of bioequivalence in an abbreviated process is not accepted by the EMEA or the FDA," he noted. "The European comparability guideline indicates that a complete new filing and clinical trials on a case-by-case basis are required."
Blockbuster biotechnology products with patent expiry before 2007
| Product |
Innovator company |
Active substance |
Patent expiration |
Global sales, 2002 |
| Humulin |
Lilly |
human insulin |
2001 |
$1.0bn |
| Intron A |
Schering-Plough |
alpha-interferon |
2002 |
$2.5bn |
| Procrit |
Amgen/J&J |
erythropoietin |
2004 |
$4.3bn |
| Epogen |
Amgen |
erythropoietin |
2004 |
$2.3bn |
| Neupogen |
Amgen |
filgrastim (GCSF) |
2006 |
$1.4bn |
What that means in practice is that an already difficult patent position for biopharmaceuticals is complicated by the fact that, in Pollano’s view, "biogenerics don’t really exist". He prefers the term ‘biosimilars’ because, as the regulations stand, therapeutically similar products must be different to the original. As such, they cannot rely on the original data and must therefore submit full market authorisations via the EMEA’s centralised procedure (the obligatory or preferred route to market for most biopharmaceutical products). biogenerics don’t really exist". He prefers the term ‘biosimilars’ because, as the regulations stand, therapeutically similar products must be different to the original. As such, they cannot rely on the original data and must therefore submit full market authorisations via the EMEA’s centralised procedure (the obligatory or preferred route to market for most biopharmaceutical products).
Pollano noted that the development time for biogenerics is at least twice as long as conventional generics, and the costs 8-100 times higher. As a result, biosimilars will need to be branded and marketed very differently to existing generics and may take on more of the characteristics of ‘me-too’ products in the originals market. "It’s not really a generic question," concluded Pollano – not least because biosimilars will not be substitutable for originals.
Omnitrop case highlights EU uncertainties...
The EMEA has taken a relatively cautious approach to biogenerics. The first such product, Sandoz’s (Novartis) human growth hormone (hGH) Omnitrop, has suffered a series of knockbacks since first receiving a positive opinion from the EMEA’s Committee for Proprietary Medicinal Products in June 2003. In an unusual step, the European Commission rejected the CPMP’s recommendation, citing filing irregularities. While the precise situation remains unclear – negotiations are not in the public domain – there appears to be some confusion between the CPMP and the EC over the appropriate regulatory pathway for Omnitrop. Sandoz believes it used an appropriate pathway to file the drug and is working to resolve the dispute. The company has also filed suit against the EC.
Unlike the US, the EU has published guidance on appropriate pathways for the clinical approval of biogenerics. Issued in December 2003, however, the Omnitrop case demonstrates that the development of the regulatory framework is an ongoing project. Even so, Europe still has an edge over the US. Commenting on registration procedures, Gordon Johnston, Vice President of Regulatory Affairs for the US Generic Pharmaceutical Association, said: "The EU is clearly ahead of the US. Even though growth hormones and human insulins, for example, are relatively simple proteins, we won’t see interchangeable biogenerics for some years to come." Johnston conceded, however, that "even the FDA is beginning to think about an abbreviated approval system for biogenerics".
...FDA guidelines up for negotiation
The FDA believes interchangeable generic biologics are inevitable, provided, in the words of the FDA Commissioner, "we can find a safe path to generic or follow-on biologics". The precise timelines for exploring changes to current laws are unclear, although general FDA guidance is expected in summer 2004. This is expected to outline:
-
an abbreviated process for limited types of biologics
-
types of tests to demonstrate structural similarity and comparability
-
immunogenicity testing requirements.
"Expect a two-tiered approach," predicted Johnston. "Tier one will outline the requirements for an abbreviated data package for approval. And tier two will be a more rigorous characterisation of approval requirements for interchangeability." Specific guidance may follow tier one for products such as hGH and insulin: Sandoz has filed Omnitrop for FDA approval under 505(b)(2), but it is unclear whether the agency will actually be able to use this statute for biogenerics.
Interchangeability for biologics represents a fundamentally more complex issue – an approach to which Johnston thinks "does not appear likely in the near term". The FDA has particular concerns over the need for large comparative crossover studies for interchangeability rating and the acceptance of biogenerics by the medical community.
With FDA workshops and meetings with constituents scheduled for after the initial guidance is issued, and Congressional hearings likely to begin later in the year, it all points to a fierce public debate. Biotech giant Genentech has already filed a petition with the FDA, asking it to refrain from approving generic versions of any of its products, as the company believes this would be impossible without infringing on its trade secrets.
The branded industry is already active with lawmakers and the generics industry is engaging with the FDA, as battle lines are drawn in what is a complex scientific argument – one that will be easy to confuse both lawmakers and the public. If the many real concerns about the development of the biogenerics business can be overcome, however, the market potential for biogenerics is great.
Neil Turner is Editor at PPR Communications, a division of IMS Health: for further information about PPR, please visit pprconciseguides.com. The PPR Concise Guide to Generics can be bought directat IMS' Online Store.