New Preparations Comprising Recombinant Human Growth Hormone: Deliberations on the Issue of Biosimilars

Abstract

Manufactured recombinant human GH (rhGH) has been available for more than 25 years. In the meantime, the GH produced by various manufacturers has been approved for application in replacement therapy in children and adults with GH deficiency or a number of disorders involving small stature in children. Until recently approval for each individual diagnosis was only granted after extensive studies on the long-term efficacy (e.g. adult height reached) and safety of the various products. Meanwhile, the European approving agency, the European Medicines Evaluation Agency (EMEA), has relinquished this restrictive stance. Thus, new rhGH preparations can count on gaining approval for existing indications even without conducting standard clinical studies of their efficacy and safety for each of these indications. The EMEA’s reconsideration is apparently based on the rationale that recombinant GH can, in effect, be considered equivalent to the tried and tested preparations in wide use, provided certain specifications are met. The term ‘biosimilars’ was coined to denote the similarities between the products rather than their parity, as is the case with generics for instance. The higher complexity of biopharmaceuticals relates not only to the substances themselves but also to the manufacturing process. It is generally believed that modifications to a manufacturing process – which are a prerequisite for a patent – may cause modifications of the active substance which then may lead to different long-term effects. Thus, the term ‘biosimilar’ does not indicate that complex biopharmaceuticals deriving from the same substance are entirely identical, nor does the approval of a ‘biosimilar’ ensure this. The factual information provided here is offered towards clarification of some uncertainties and as a contribution towards resolving open questions relating to the topic of biosimilars. The final choice of product to be prescribed must be made by the informed, independent physician.

Biosimilars: what clinicians should know

“…Concerns have been expressed that the safety database of biosimilars could be insufficient at the time of approval, with immunogenicity being a particular concern. [12][13][14][15][16][17][18][19] For a biosimilar, an extensive comparability exercise with the reference product is required, including human efficacy and safety data. Based on similarity being demonstrated with the reference product, the biosimilar can also refer to the safety experience gained with the reference product.…”

“…Concerns have been expressed about using biosimilars in indications or in patient populations that are approved for the reference product but have not been formally investigated during the clinical development of the biosimilar and, therefore, have been licensed on the basis of extrapolation of efficacy and safety data. 6,12,17,19,[25][26][27][28] In this respect, particular concerns have been raised regarding the use of biosimilar G-CSF for the mobilization of stem cells in healthy donors and the use of biosimilar epoetins in patients with cancer. 25,29,30 In addition, there is growing concern in the rheumatology, gastroenterology, and dermatology communities regarding the future use of biosimilar anti-inflammatory monoclononal antibodies based on extrapolation of data.…”

Biosimilars: the science of extrapolation

“…This appears to be especially true for therapeutic indications, for which no specific clinical trials with the biosimilar have been performed and that have been licensed based on extrapolation of efficacy and safety data from other indications. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Several learned societies have issued statements discouraging the use of biosimilars in such "extrapolated" indications. [13][14][15][16][17][18][19][20] The reasons for this distrust may be manyfold.…”

A Primer on Biosimilars: FDA-Approved and those in the Pipeline

“…The first biosimilar molecule approved in the EU in April 2006, was Omnitrope, a version of somatropin. The protein structure of Omnitrope is well characterized: it is not glycosylated, the mechanism of action is known, and its safety and efficacy profile is well-documented [29]. As of 2016, the EU has approved 22 applications, and is continually updating its guidelines, both general and product-specific [30].…”