Abstract

The use of biosimilar drugs is increasing. This article reviews the differences between generics and biosimilars, points out the shortcomings in the
regulatory process for biosimilars, and draws attention to the limitations and potential problems of prescribing biosimilars, while focusing on human
growth hormone.

Introduction

The use of hormones for replacement as well as supplementation has increased dramatically in recent years. Improvements in understanding of
pathophysiology of disease, diagnosis methods, accurate means of monitoring, and manufacturing processes have contributed to the rising use of
recombinant hormones.

Recombinant hormones, such as growth hormone, insulin and erythropoietin, belong to the class of drugs known as biopharmaceuticals.

Biopharmaceuticals are biological medicinal products made by a living organism , or derived from such an organism , by means of recombinant DNA and for
control gene expression methods.¹ Polypeptides, glycoproteins, complex polysaccharides or nucleic acids, have complicated secondary,
tertiary and quaternary structure, with large molecular weights, and often undergo translational modification such as glycosylation or sialylation, and
may not be fully characterized by irritancy analytical tools.^1,2 Biopharmaceuticals are produced by inherently variable biological processes
and depend on the type of host (yeast, E. coli) and growth conditions. They are highly susceptible to environmental conditions like temperature and
humidity. Adverse environment during preparation, storage and transport can lead to denaturation, aggregation or degradation of proteins and affect
therapeutic results. Biopharmaceuticals are potentially immunogenic, and product/process related impurities can lead to unwanted immune response is the
patient. Similar immune reaction can occur even of slight structural deviation drugs manufacture.^{2, 3}

Biopharmaceuticals differ from traditional chemical drugs, which are chemically synthesized. They have small, well defined, easily analyzable, stable,
easily replicable, low molecular weight structure, and do not exhibit immunogenicity.^1,2

In endocrinology, biopharmaceuticals have been available since early 1980s.⁴ The patents on human insulin and human growth hormone have
expired, and copies of these drugs have been developed in both regulated market such as the European Union and semi-regulated countries, like India,
Korea and China.

These copies are known as biosimilar drugs. Other synonyms used are follow- on biologics, biogenerics, or similar biological medicinal
products.⁴ These copies are different from conventional generic medicines.

Requirement For Approval

To be approved by regulatory authority, both generic and biosimilars have to demonstrate that the active substance, form, strength and route of
administration are identical to the reference product. ⁵ Bioequivalence with the reference drug has to be demonstrated for a generic
drug. However, non-clinical studies and clinical trials to establish efficacy, safety and tolerability of a biogeneric are not required. Therapeutic
equivalence is assumed, and does not have to be proven, by generic drug manufacturers. Biosimilars have to go through pharmacodynamic studies, limited
toxicology studies, and comparative quality studies for just a single indication. This is enough to allow approval for all indications for which the
reference biopharmaceutical has achieved approval after going through multiple studies.

While regulatory authorities accept that the biosimilar substance should be similar to the reference product, it is not expected that the biogeneric be
identical. It is also not expected that safety pharmacology, reproduction toxicology, mutagenicity, carcinogenicity, non-clinical pharmacokinetic
studies, and therapeutic efficacy or tolerability studies for every clinical indication be carried out for biosimilar.⁶ Thus biosimilars have a much easier route to approval than the original reference product. This easier road to approval has inherent shortcomings, which may impact clinical efficacy patient safety with biosimilars.

Biosimilar Growth Hormone

Human growth hormone is a single chain, 191 amino acid long, non-glycosylated, 22 KD Peptides, which needs a specific three dimensional
structure to bind specifically to growth hormone receptors.⁴

The efficacy safety and tolerability of originator growth hormone preparations, such as Norditropin, Genotropin, Humatrope, Saizen, Nutropin and
Zomacton, have been studied in various clinical conditions in children and adults, in short term, long term, and post- marketing surveillance studies. ⁴

Biosimilar preparations are now available in Europe, Latin America and Asia. These preparations have not undergone the same long term surveillance.

One biogeneric was prepared from three different sources during the course of its development. This compromised the validity of the results. The drug
was also linked with high levels of anti-GH antibodies and antibodies against E coli proteins during the primary studies. When efficacy data was
analyzed, no last observation carried forward (LOCF) endpoint intention to treat analyses was done.This compromised the quality of data. ⁴ Another biosimilar brand has been approved in Europe, after a year long study in a single clinical indication, without long term
safety data. In India , at least three biosimilar growth hormone preparations are available, which have gone through a fast track approval process,
having had to a demonstrate only bioequivalence, without presenting long term data

No study has been done to prove that substituting a biosimilar for a reference biological product does not impact safety, does not affect therapeutic
efficacy, and does not alter immunogenicity. Thus one can not presume therapeutic equivalence of two different preparations of a biopharmaceutical of a
given patients. One should also not assume therapeutic equivalence of a biosimilar in all indications of the reference biological drugs, if it has not
been studied in those indications. Therefore, one should not encourage or allow automatic substitution, or change of brand names, in biopharmaceuticals
prescription.

Thankfully, no untoward medical incidents have been reported with use of biosimilar growth hormone .Anecdotal reports from Asian endocrinologists,
however, speaks of suboptimal efficacy of these preparations .

Experience with other biopharmaceuticals drugs reveals that even slight changes in formation can be potentially life threatening. A change in
manufacture process and delivery device of epoetin alpha has caused pure red cell aplasia,⁹ while change in storage conditions and
preparations of interferon alpha 2alpha has led to an increase in immunogenicity of up to 10 times.¹⁰

Conclusion:

Biosimilar growth hormone should be used with caution. Use of a biosimilar preparation is justified only in those indications in which the particular
preparation has been studied, over a sufficiently long period of time. Automatic substitution of one preparation for another should not be allowed.
Long term pharmacovigilance studies must be planned to assess the safety, tolerability and efficacy of newer biosimilar preparations.

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About Authors:

Sanjay Kalra, Bharti Kalra, Sandeep Khare, Amit Sharma

Sandeep Khare

Bharti Hospital, Karnal, India