Biosimilars: controversies as illustrated by rhGH

Abstract

Background and scope:

Similar biological medicinal products, also called ‘biosimilars’, are copies of biopharmaceutical products whose patent has expired. Whether biosimilars are truly comparable and interchangeable with their reference biopharmaceutical products in terms of quality, efficacy and tolerability, is still a matter of debate. This review discusses the controversies related to the criteria for regulatory approval of biosimilars. These concerns are illustrated using recombinant human growth hormone (rhGH) biosimilars as an example.

Methods:

Publications on the regulatory approval of biosimilars in general and rhGH biosimilars in particular were searched in MEDLINE by exploding and combining the medical subject heading terms ‘human growth hormone’, ‘efficacy’ or ‘safety’ and the free-text words ‘biosimilar’, ‘biopharmaceutical’, ‘similar biological medicinal product’, ‘follow-up biologic’ or ‘biogeneric’. Searches were limited to full-text English-language articles. The websites from the European Medicines Agency (EMA) and from the American Food and Drug Administration were also consulted.

Regulatory status:

To obtain regulatory approval of a biosimilar product by EMA, demonstration of comparability with an approved reference biopharmaceutical product in terms of quality, efficacy and tolerability is needed. Thus, comparative quality studies, non-clinical and clinical efficacy and tolerability studies are required. However, in contrast to the reference product, comparative non-clinical pharmacokinetics, safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies are not mandatory to obtain approval of a biosimilar. In addition, comparable efficacy and tolerability only needs to be established by one study in a single population during a limited time interval (12 months) and often allows extrapolation to all other approved indications of the reference product. Consequently, for the currently approved rhGH biosimilars, long-term efficacy and tolerability in all indications has not been proven to the same degree as for the reference products.

Conclusions:

The validity of the current criteria for comparability and interchangeability of biosimilars and their reference products remains controversial. The authors conclude that long-term clinical investigations and systematic monitoring of the efficacy and tolerability of rhGH biosimilars in all indications are needed. In addition, the medico-economical environment should allow physicians to take a free and informed decision about the type of rhGH to be prescribed.

Key words::

• Biopharmaceutical
• Biosimilar
• Follow-on biologic
• Healthcare economics
• Human growth hormone
• Similar biological medicinal product

Transparency

Declaration of funding

This study was funded by an unrestricted grant from Pfizer Emerging Markets Europe.

Declaration of financial/other relationships

M.G. has disclosed that he has received speaker fees from Merck Serono and Novartis and is supported by an OTKA grant No. 68660. C.N. has disclosed that he has received honoraria for consultancy/advisory board attendance from Ipsen Pharma and Pfizer. M.B.R. has disclosed that he has received honoraria for advisory board attendance from Pfizer, Germany. J.Z. has disclosed that she has received grants/research funding from Eli Lilly, Novo Nordisk and Pfizer; honoraria for consultancy/advisory board attendance from Eli Lilly, Novo Nordisk and Pfizer; and speaker fees from Eli Lilly and Pfizer. F.D., P.J.D., S.K., I.M., V.P. and N.V. have not declared any conflicts of interest regarding rhGH products.

Some peer reviewers receive honoraria from CMRO for their review work. The peer reviewers of this paper have disclosed that they have no relevant financial relationships.

Acknowledgements

The authors acknowledge medical writing assistance from Ismar Healthcare NV for which they received an unrestricted grant from Pfizer Emerging Markets Europe.

Although Pfizer Emerging Markets Europe was given the opportunity to review the manuscript, the authors felt no obligation to address any comments; the views expressed are solely those of the authors and not those of the involved company.

Notes

* Genotropin is a registered trade name of Pfizer Inc., New York, USA.

† Norditropin is a registered trade name of Novo Nordisk Inc., Bagsvaerd, Denmark.

‡ Humatrope is a registered trade name of Eli Lilly and Company, Indianapolis, USA.

§ Saizen is a registered trade name of Merck Serono SA, Geneva, Switzerland.

** Zomacton is a registered trade name of Ferring Pharmaceuticals, Copenhagen, Denmark.

†† Nutropin is a registered trade name of Ipsen Pharma, Boulogne-Billancourt, France.

‡‡ Omnitrope is a registered trade name of API Sandoz GmbH, Kundl, Austria.

§§ Valtropin is a registered trade name of BioPartners GmbH, Reutlingen, Germany.