The question of doubts about a generic version being identical and clinically interchangeable with the original brand has become scientifically and politically prominent with the recent onset of patent expiry of major recombinant biotech medicines that were first launched in the 1980s and were recognised as highly innovative: for example, epoetin alfa (for treatment of anaemia in kidney failure, or after chemotherapy); filgrastim (for treatment of neutropenia in various types of cancer therapy); and interferon beta (for multiple sclerosis).

The traditional approach to generic prescribing and brand substitution after patent expiry is now widely recognised as unrealistic for biologics. In recombinant biotechnology, complex therapeutic protein molecules are not as accurately reproducible as small-molecule drugs obtained by chemical synthesis. Tiny variations in biotech processing may or may not produce changes in clinical performance which may be beneficial, insignificant, or adverse.

In other words, the answer to the first three questions about generics (their safety, quality and interchangeability) cannot be a simple, affirmative ‘Yes’ for biosimilars. It has to be proven. That is why the original description of such medicines as ‘biogenerics’ has been largely replaced by the expressions ‘biosimilars’ or (in the U.S.) ‘follow-on biologics’.

Recognition of ‘bio-similarity’ has created the need to devise new legislation for the pathway to regulatory control of safety, efficacy and quality, before such products can be introduced after patent expiry¹.

In the European Union, an official guideline for regulatory control of biosimilars was issued by the CHMP [Committee for Medicinal Products for Human Use] in 2006. In essence, it requires manufacturers to demonstrate that the active substance of their biosimilar product “is representative of the active substance present in the reference medicinal product” (normally the original brand which must have been authorised for marketing in the EU)².

Unlike the procedures for traditional small-molecule generics which can obtain marketing approval by ‘referring’ to the clinical data originally submitted by the former patent holder, biosimilar applicants in the EU may have to carry out some clinical work of their own in order to demonstrate safety, efficacy and quality comparable with the reference product. The additional costs involved in such regulatory requirements imply that biosimilars have much less scope for deep price cuts below those of the reference brands than is customary for small-molecule generics. This, together with initial hesitation by doctors to prescribe, explains why biosimilars in Europe “are not penetrating the market as quickly as generic firms had hoped”³.

The U.S. is lagging behind Europe in adopting a regulatory pathway for biosimilars, but the Obama administration is intent upon doing so.

The main area of political contention in the U.S. is the length of ‘data protection’. This refers to clinical and other research and development data submitted to the regulatory authorities by the applicant for the original biotech brand. The production of such data involves high levels of expenditure. ‘Data exclusivity’ represents the number of years (usually from the date of market introduction) during which the information remains the exclusive property of the originator and cannot therefore be used by biosimilar applicants as reference material for their own purposes without the consent of the owner.

Although all interested parties in the U.S. now agree that a ‘pathway’ to biosimilar registration should be created and various proposals are being made to Congress, the length of data exclusivity is being hotly disputed:

Congress bill (Waxman et al) 2009⁴                 5 years
White House view⁵                                           7 years
Congress bill (Eshoo et al) 2008 & 2009⁶        12 years
BIO [Biotech industry association]⁷                 14 years

Assuming that a compromise is eventually reached and the pathway is set up, biosimilars will be marketed in the U.S. without first having to go through a complete programme of clinical trials. But by comparison with ‘small molecule’ generics, biosimilars will involve much higher development cost and their capacity for price cutting will be correspondingly lower, at least initially. Health care payers (including YOU – the patient) will nevertheless welcome any reductions in the high cost of biotech medicines as long as their safety, efficacy and quality are guaranteed.

Footnotes

[1] Biosimilars are widely available in countries where the earlier biotech medicines were not protected by basic patents, for example in India, China and South Korea (World Health Organisation, “Informal Consultation on regulatory evaluation of therapeutic biological and medical products”, Geneva 19-20th April 2007).
[2] European Medicines Agency, CHMP, “Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Quality Issues”, London 22nd February 2006
[3] Scrip, “Biosimilars up – but not yet running”, 8th May 2009 (page 22)
[4] D.S.Levine, The Burrill Report, “BIO simmering over Biosimilars”, online 13th March 2009
[5] Pharma Times, “Seven years protection sufficient for brand biologics, says White House”, online 26th June 2009
[6] as Ref.7
[7] as Ref.7

Related article

Generics and You (Part 1): What is a generic drug?
Generics and You (Part 2): The doctor’s choice: brand or generic?
Generics and You (Part 3): In which countries are you most likely to receive a generic prescription?
Generics and You (Part 4): Are generics ‘first class’ medicine?
Generics and You (Part 6): The fourth question about generics
Generics and You (Part 7): You and generics