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The New World of Biosimilars: What Diabetologists Need to know about Biosimilar Insulins
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Authors and Disclosures
Irene Krämer,1 and Thomas Sauer2
1Pharmacy Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany
2Industrial Affairs, Chemistry and Biotechnology, sanofi-aventis Germany, Frankfurt, Germany
From The British Journal of Diabetes and Vascular Disease
The New World of Biosimilars: What Diabetologists Need to know about Biosimilar Insulins
Irene Krämer; Thomas Sauer
Posted: 09/01/2010; British Journal of Diabetes and Vascular Disease © 2010 Sage Publications, Inc.
Abstract and Introduction
Abstract
Biosimilar pharmaceuticals are emerging as patent protection on the original biopharmaceutical products expires. However, biopharmaceuticals are particularly complex molecules, and biosimilar insulins present special challenges. In part this reflects their structure and chemical modification after synthesis to attain a biologically active form. Their therapeutic window is narrow and the accuracy of their dosing is highly dependent on the formulation and quality of the administration device. For these reasons, the European Medicines Agency has issued stringent guidelines that must be fulfilled in order to receive approval as a biosimilar soluble insulin. Prescribers should therefore consider issues of manufacture, protein quality, formulation, reliability of supply, and other factors that might affect efficacy, safety and tolerability when making choices regarding the selection of biosimilar products.
Introduction
Biopharmaceuticals are biological medicinal products derived from recombinant DNA and expressed by genetically engineered organisms to produce the target therapeutic proteins in large quantities. The first biopharmaceutical introduced into clinical use was recombinant human insulin (Humulin, Eli Lilly) in 1982. Since then, hundreds of biopharmaceuticals, including cytokines, enzymes, antihaemophilic factors and monoclonal antibodies have received marketing authorisation in various jurisdictions.
As patents for the early biopharmaceuticals have already expired, requests for marketing authorisation of 'similar' biological medicinal products (so-called biosimilars) have been submitted in the EU, and various biosimilars such as epoetin alfa, somatotropin and GCSF are already available. The EMA was the first regulatory authority to implement a regulatory framework for the marketing authorisation of biosimilars. This requires the submission and approval of a dossier that, while comprehensive, is less detailed than that of the innovator product. Comparable procedures are in place in other jurisdictions including Malaysia, Taiwan and Australia. In the USA, the Food and Drug Administration is also preparing a regulatory framework; products assessed by this new licensing procedure will be referred to as follow-on biologics (FOBs).
In Europe, several human insulins are available, each with an independent marketing authorisation based on a full dossier. The different brands are authorised for use with specific administration devices (generally a single-use or reusable pen). In some countries where patent regulations are less rigorous human insulin and insulin analogues are available that are (by definition) neither innovator products nor biosimilars and are therefore called 'other insulins'. In 2007, an application to the EMA for marketing authorisation of three biosimilar insulins was withdrawn after the CHMP issued a provisional opinion that the products could not be approved for human use.[1]
Biosimilars are not interchangeable with originator molecules or with each other as are traditional small-molecule generic drugs.[2] In fact, the EMA has stressed that because biosimilars and their reference molecules are not identical, the interchange of a reference medicine for a biosimilar medicine should be based on the opinion of a healthcare professional.[3] Hence, it is essential for prescribers to appreciate these issues in order to make informed choices about the biosimilars they will encounter. This article discusses key aspects to consider when evaluating a biosimilar, with a special focus on biosimilar insulin.
Complexities in the Manufacture of Insulin Biopharmaceuticals
Protein molecules have molecular weights which may be orders of magnitude higher than those of traditional small molecule drugs. Their structures are also far more complex, requiring consistency of their primary structure (amino acid sequences), secondary and tertiary structures (three-dimensional folding patterns), and quaternary structure (stable association of two or more identical or different subunits).
In the case of recombinant human insulin, the precursor protein is synthesised by genetically modified organisms and must be proteolytically cleaved to produce active insulin (figure 1). The insulin preparation must also be formulated to control the formation of discrete hexamers (complexes of six insulin monomers), to confer the required absorption characteristics (figure 2). The more recent insulin analogues contain additional or substituted amino acid residues or other functional groups introduced by genetic engineering or by biochemical modification. These changes alter the speed of bioavailability and thereby modify the PK and PD profiles of the molecule.
Figure 1. The biosynthesis of insulin
The insulin precursor preproinsulin contains a signal sequence that is proteolytically cleaved to yield proinsulin, whose C chain links the future A and B chains of mature insulin. Cleavage of the C chain converts proinsulin to insulin.
Adapted from Joshi SR et al. J Assoc Physicians India 2007;55(suppl):19–25[14]
Figure 2. Association of insulin monomers in the presence and absence of zinc and phenolic excipients
Insulin readily associates into dimers, aggregates and (in the presence of divalent cations such as zinc), into hexameric forms. The presence of phenolic excipients causes these hexamers to undergo conformational changes that increase their stability.
Key: R6 = hexamer with insulin molecules whose B1–B8 residues are in an a-helical (R) conformation; T6 = hexamer with insulin molecules whose B1–B8 residues are in an extended (T) conformation.
Adapted from Beals et al. Informa Healthcare: New York, 2008;265–80[22]
Given their structural complexities biopharmaceuticals are far more difficult to manufacture than small-molecule drugs. The use of living organisms introduces an inherent variability in the manufacturing process. To guarantee the quality and compliance of each production batch, absolute consistency of the manufacturing process is required. Even apparently slight changes in any of the manufacturing or formulation steps can have major clinical consequences.[4–8] Manufacturers of biosimilar products must develop proprietary expression systems and processing steps independently. Thus biopharmaceuticals can never be identical copies of originator molecules, even when they have demonstrated comparable physicochemical and biological properties to a reference product using currently available tests. The most they can achieve is 'biosimilarity'.[5,9,10] For non-glycosylated products such as human insulin, PK and PD differences are most probably caused by differences in formulation, while for glycosylated products (e.g. epoetin), the glycosylation pattern is probably the major source of PK/PD variations. The essential steps in the manufacture of a biopharmaceutical and the loci of potential variability in their manufacturing processes are shown in figure 3.[11]
Figure 3. Manufacture of a biopharmaceutical: opportunities for variation between manufacturers[11]
Adapted from Mellstedt H et al Ann Oncol 2008;19:411–9[11]
The first commercial insulins, extracted from beef and pork pancreata, became available shortly after the discovery of insulin in 1921, and the first long-acting insulins, PZI and NPH, had been developed by the 1940s. However, patients using animal insulin products that were not highly purified often had local injection site reactions or more rarely, systemic reactions such as IgE-mediated anaphylaxis.[12] Highly purified products and recombinant insulins are associated with decreased levels of anti-insulin antibodies. Nonetheless, there is little evidence that antibody formation affects glucose control or causes other complications of insulin therapy.[13] The more recent recombinant insulin analogues contain additional or substituted amino acid residues. The first short-acting analogues, insulin lispro and insulin aspart, were introduced in the late 1990s, and the first long-acting analogue insulin glargine in 2000. Each of these innovations was made with a view to improved onset and duration of action,[14–16] to reduce hypoglycaemia and hyperglycaemia and to improve tolerability. The history of developments in insulin is summarised in figure 4 and a summary of available insulins is given in figure 5.
Figure 4. The development of therapeutic insulin: a timeline[14–16]
Since the discovery of native insulin in 1921, successive discoveries have improved the production of therapeutic insulins as well as their pharmacokinetic and pharmacodynamic properties. Work on therapeutic insulins has garnered three Nobel Prizes.
Key: NPH = neutral protamine Hagedorn; PZI = protamine zinc insulin.
Figure 5. Insulin medicinal products currently available: a summary
In the manufacture of recombinant human insulin, the recombinant organism that actually expresses the precursor protein is generally Escherichia coli or a yeast such as Saccharomyces cerevisiae. The engineered gene encoding for the precursor protein must be inserted into a suitable stable expression vector. The choice and the characteristics of this construct will affect key aspects, such as the degradation characteristics of soluble proteins and the yield of the process. The recombinant cells are screened, and a well characterised master cell bank is established from a single clone. This master cell bank is used to create uniform working cell banks that are used to cultivate the cells and produce the desired product. During product synthesis the culture and fermentation conditions are tightly controlled in order to optimise yields and avoid formation of unwanted by-products.[17] Generally, impurities come from either the growth medium (especially for products isolated from cell culture supernatant) or the host cells. These impurities can be host-related (e.g. endotoxins, HCPs, DNA, viruses), product-related (e.g. denatured protein, aggregates, protein fragments, deamidated species, conformational isomers), or process-related (e.g. growth medium components, metals, column material). When the product is recovered, modified and purified the formation of inclusion bodies (for example in high-yield E. coli processes), requires the disruption of the cells to release preproinsulin. This is then isolated, purified and folded, and then enzymatically cleaved to produce the mature insulin molecule.[18–20] In the case of insulin, impurities such as desamido forms may arise as by-products of conversion from proinsulin to insulin by removal of the C-peptide and regeneration of the three-dimensional form of the molecule.[21]
After numerous purification steps, the insulin is crystallised or lyophilised and formulated. The insulin molecule is negatively charged at neutral pH, and readily associates into dimeric complexes or into zinc-containing hexamers (figure 2). Thus, zinc may be added to trigger aggregation into soluble discrete hexameric structures containing two zinc ions per hexamer.[14] Phenolic excipients, added as antimicrobial agents, also bind to specific sites on hexameric insulin, changing its conformation to a more stable form (so-called T–R transition). Other agents added at the formulation stage may include physiological buffers (to maintain pH) and agents that maintain isotonicity (to minimise injection pain and tissue damage).[22]
Any variations in the entire process of insulin synthesis and formulation may result in a product which may be physicochemically very similar to an appropriate reference product, but which differs subtly in its clinical PK or PD characteristics.[9,14] The steps in the manufacture of insulin are summarised in figure 6.
Figure 6. A highly complex process: steps in the manufacture of insulin
Reproduced with kind permission from sanofi-aventis group.
Insulin Devices: An Added Complexity
For biosimilar insulins, the additional dimension of the administration device should also be considered. Stringent regulatory requirements for insulin administration devices specify use of durable labels and distinguishing marks, visibility of the dose and accuracy with which it is dispensed after storage and handling under a variety of environmental conditions, including having been physically dropped. For example, cartridges, syringe/needle systems, disposable and reusable pens and pumps must be tested with each insulin formulation and concentrations that will be used. Since the combinations of insulin and device may differ widely in their dosing characteristics, it cannot be assumed that an insulin biosimilar will be compatible with an existing administration device. For this reason the EMA requires that compatibility is demonstrated.[23,24] Insulin pen injectors and cartridges (3.0 ml cartridge in the U-100 strength is the current market standard) provide more accurate and reproducible dosing than syringes and vials. They are also more convenient, easier to transport and may improve safety and adherence,[25–27] suggesting that the availability of pen injectors should be a requirement for insulin biosimilars.
Regulatory Requirements for Insulin Biosimilars
In recent years the EMA has produced an overarching guideline on biosimilars[28,29] as well as guidance documents addressing quality issues, 30 non-clinical and clinical issues, 31 and guidelines for specific biosimilars, including soluble recombinant human insulin.[21]
As mentioned earlier[9] the EMA requires that biopharmaceuticals undergo comprehensive comparability studies of both the drug substance and product to provide evidence that the biosimilar is indeed similar in quality, safety and efficacy to a single appropriately chosen reference product that has the same pharmaceutical form, strength and route of administration that is already approved in the EU. In general, required preclinical data include primary pharmacology and repeat-dose toxicology data. The EMA requires toxicological studies that focus on potential immunogenicity, as well as in-vitro affinity bioassays, assays for insulin and IGF-1 receptor binding, and tests for intrinsic activity.[28–31]
One of the main concerns when switching or substituting insulin products is hypoglycaemia caused by differences in activity of different brands. Therefore, it is obligatory to ensure that the effects of any insulin product in clinical use are highly consistent and predictable. The EMA requires at least one PK single-dose crossover study that compares the biosimilar insulin with the reference product, using subcutaneous administration, preferably in patients with type 1 diabetes. Clinical activity must be determined in a comparative PD study, designed as a double-blind, crossover, hyperinsulinaemic, euglycaemic clamp study, to demonstrate the product's hypoglycaemic response profile. Current EMA guidelines for soluble insulin biosimilars do not require a clinical efficacy trial, but do require a clinical safety study. The product's immunogenicity must be investigated through clinical studies of at least 12 months, including a comparative phase lasting at least 6 months. Finally, the manufacturer must also design a pharmacovigilance programme that will rapidly detect any clinically significant immunogenicity that may emerge over extended time periods.[21,28–30] The application for marketing authorisation of three biosimilar insulin formulations in March 2007 suggested deficiencies in long-term efficacy and inadequate immunogenicity testing.[32–34] The details of these applications were recently reviewed by Kuhlmann and Marre in this journal.[35]
What Clinicians Should Know Before Selecting a Biosimilar Insulin
When contemplating biosimilar insulins, it is important to consider the manufacturer, protein quality and formulation, batch consistency and reliability of supply (table 1).[36,37] Reassurance can be gained from full disclosure of information to the healthcare community about the manufacturing process and about safety testing.
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Table 1. A checklist of issues to consider when selecting a biosimilar insulin product[36]
Manufacturer
v R eputation, reliability, experience with biopharmaceuticals
v Location of manufacture of the medicinal product
v Location of the manufacture of the active drug substance (are third parties involved?)
v Dissemination of safety updates and changes in manufacturing process
Protein quality and formulation
v Bioassays: appropriateness, comparisons with reference product
v Levels of foreign proteins, DNA, pyrogens, endotoxins, aggregates
v Formulation: choice of excipients, stabilisers and preservatives
v Administration device or technique; teaching materials for use of a different administration system
v Shelf life, susceptibility to degradation
v Consistency between batches; appropriate quality controls
Reliability of supply
v Stock position
Clinical efficacy
v Clinical trials carried out with different batches of the biosimilar product itself: adequacy of design, results, consistency and generalisability of results
Clinical safety and tolerability
v Comparison of safety and tolerability profile with reference product
v Precautions or contraindications for use of the biosimilar
v Serious adverse events
v Immunogenicity (especially as compared to reference product); selection of antibody tests
v Post-marketing risk management programmes: required laboratory tests, antibody testing, pharmacovigilance programmes to detect infrequent adverse events
With regard to quality suppliers should be asked for a written statement that covers aspects such as the purity of the biosimilar protein, the upper limits for impurities such as aggregates or endotoxins, differences in isomer pattern, and clinical consequences of any potential differences. In the case of insulin impurities such as desamido forms may arise as by-products of conversion from proinsulin to insulin by removal of the C-peptide and regeneration of the three-dimensional form of the molecule.[31] Moreover, with regard to formulation any differences between the biosimilar and the originator molecule plus choice of excipients, stabilisers and preservatives should be provided, Additionally administration (either device or technique) should be explicit. If the biosimilar is administered by a different method from the originator product, e.g. with a new device, teaching materials should be available to train patients and caregivers to use the different system. It is also important to know the product's shelf life and its susceptibility to degradation if it is stored improperly (for example, if accidentally stored at room temperature instead of being refrigerated).
Quality control to ensure batch-to-batch consistency is paramount with insulin preparations. There should be a guaranteed stock position which will maintain supplies if a newly produced batch fails to meet all the required standards of quality. A sustainable supply chain with reliable transportation conditions should also be established.
Particular attention should be given to any differences in clinical activity, biological activity per unit, relative biological potency and dosage of a biosimilar compared with the originator molecule. The known safety and tolerability profile of the biosimilar, as well as precautions or contraindications for its use, should be comparable with the originator molecule. Because clinical trials which enrol relatively small numbers of patients cannot identify rare side-effects, it is obligatory to monitor safety during the post-approval phase. The use of more than one biosimilar product (for example, a biosimilar insulin and a biosimilar epoetin for the diabetic patient with renal failure) may present an additional layer of complexity regarding safety issues.
Similarly, substituting one insulin for another may require dose adjustment. While the development of antibodies to insulin rarely has major clinical consequences, it may have an impact on efficacy (because higher insulin doses may be necessary) and tolerability (mainly in the form of local injection site reactions). Hence, a biosimilar product should receive thorough antibody tests extending into the post-marketing period.
Summary and Conclusions
Biosimilar products such as epoetin alfa biosimilars are already marketed in the EU, and biosimilar insulins are expected shortly. Patients with diabetes are often candidates to receive both types of products. Therefore, it is imperative for prescribers to be aware of issues presented by biosimilar products, and particularly the special challenges presented by biosimilar insulin. Biosimilars are not interchangeable with the corresponding originator biopharmaceuticals in the same way that non-peptide, small-molecule generic molecules are interchangeable with the original products. Any apparently minor modification in the manufacturing or formulation of a product such as insulin, or in the administration device, has the potential to cause untoward clinical consequences, even if the product appears to be physicochemically equivalent to an accepted reference standard. The consequences are particularly relevant for insulin as the therapeutic window is narrow. For this reason, the EMA has developed robust regulatory requirements before marketing authorisation can be granted for a biosimilar insulin. Prescribers should consider critical issues regarding the manufacture, protein quality and formulation, supply, clinical efficacy, safety and tolerability of biosimilar insulins before substitutin
Sidebar
Key Messages
•Unlike non-peptide small molecule generics, biosimilars are not identical to the originator
•Biosimilar insulins are challenging because insulin has a complex structure and a narrow therapeutic window
•The dosing accuracy of biosimilar insulins depends on the quality of the administration device
•Regarding biosimilars, consider the manufacturer, protein quality, formulation, reliability of supply, clinical efficacy, safety and tolerability
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References
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18.Panda AK. Bioprocessing of therapeutic proteins from the inclusion bodies of Escherichia coli. Adv Biochem Eng Biotechnol 2003;85: 43–93.
19.Winter J, Lilie H, Rudolph R. Renaturation of human proinsulin: a study on refolding and conversion to insulin. Anal Biochem 2002; 310:148–55.
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21.Committee for Medicinal Products for Human Use. Annex guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing recombinant human insulin. London: EMA, 2006. http://www.emea.europa.eu/pdfs/human/biosimilar/3277505en.pdf (accessed 13 April 2009).
22.Beals JM, DeFilippis MR, Kovach PM. Insulin. In: Crommelin DJA, Sindelar RD, Meibohm B (eds.). Pharmaceutical Biotechnology: Fundamentals and Applications, 3rd edition. Informa Healthcare: New York, 2008;265–80.
23.European Medicines Agency. Guideline on the suitability of the graduation of delivery devices for liquid dosage forms. Doc Ref EMEA/CHMP/QWP/178621/2004. London: EMA, 2004. http://www.emea.europa.eu/pdfs/human/qwp/17862104en.pdf (accessed 10 May 2009).
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27.Korytkowski M, Bell D, Jacobsen C, Suwannasari R. FlexPen Study Team. A multicenter, randomized, open-label, comparative, two-period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or 2 diabetes mellitus. Clin Ther 2003; 25:2836–48.
28.Wiecek A, Mikhail A. European regulatory guidelines for biosimilars. Nephrol Dial Transplant 2006;21(suppl 5):v17–20.
29.Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. London: EMA, 2005. http://www.emea.europa.eu/pdfs/human/biosimilar/043704en.pdf (accessed 13 April 2009)
30.Committee for Medicinal Products for Human Use. Guidelines on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues. London: EMA, 2006 http://www.emea.europa.eu/pdfs/human/biosimilar/4934805en.pdf (accessed 13 April 2009)
31.Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London: EMA, 2006 http://www.emea.europa.eu/pdfs/human/biosimilar/4283205en.pdf (accessed 13 April 2009)
32.European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment Report for Insulin Human Rapid Marvel. 21 February 2008. Document reference EMEA/CHMP/317778/2007. London: EMA, 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/insulinhumanrapidmarvel/31777807en.pdf (accessed 1 May 2009)
33.European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment Report for Insulin Human Long Marvel. 21 February 2008. Document reference EMEA/CHMP/70349/2008. London: EMA: 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/insulinhumanrapidmarvel/7034908en.pdf (accessed 1 May 2009)
34.European Medicines Agency. Pre-authorisation Evaluation of Medicines for Human Use. Withdrawal Assessment Report for Insulin Human 30/70 Mixed Marvel. 21 February 2008. Document reference EMEA/CHMP/70179/2008. London: EMA: 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/insulinhumanrapidmarvel/701790en.pdf (accessed 1 May 2009)
35.Kuhlmann M, Marre M. Lessons learned from biosimilar epoetins and insulins. Br J Diabetes Vasc Dis 2010;10;90–7.
36.Krämer I, Tredree R, Vulto AG. Points to consider in the evaluation of biopharmaceuticals. EJHP Practice 2008;14:73–6.
37.Crommelin D, Bermejo T, Bissig M et al. Pharmaceutical evaluation of biosimilars : important differences from generic low-molecular-weight pharmaceuticals. Eur J Hosp Pharm Sci 2005;11:11–7.
Abbreviations and acronyms
CHMP, Committee for Medicinal Products for Human Use; CMC, chemistry, manufacturing, controls; EMA, European Medicines Agency; EU, European Union; GCSF, granulocyte colony-stimulating factor; HCP, host-cell protein; IGF, insulin-like growth factor; NPH, neutral protamine Hagedorn; PD, pharmacodynamic; PK, pharmacokinetic; PZI, protamine zinc insulin
Acknowledgment
Editorial support for this article was provided by the medical writing agency PHOCUS and by sanofi-aventis groupe. The opinions expressed in the current article are those of the authors. The authors received no honoraria or other form of financial support related to the development of this manuscript.
Declaration of conflict of interest
IK has been a consultant, speaker and member of advisory boards of various (bio)pharmaceutical companies, which had no influence on the content of this article. TS is an employee of Sanofi-aventis Deutschland GmbH.)
British Journal of Diabetes and Vascular Disease © 2010 Sage Publications, Inc.
www.medscape.com
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Authors and Disclosures
Irene Krämer,1 and Thomas Sauer2
1Pharmacy Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany
2Industrial Affairs, Chemistry and Biotechnology, sanofi-aventis Germany, Frankfurt, Germany
From The British Journal of Diabetes and Vascular Disease
The New World of Biosimilars: What Diabetologists Need to know about Biosimilar Insulins
Irene Krämer; Thomas Sauer
Posted: 09/01/2010; British Journal of Diabetes and Vascular Disease © 2010 Sage Publications, Inc.
Abstract and Introduction
Abstract
Biosimilar pharmaceuticals are emerging as patent protection on the original biopharmaceutical products expires. However, biopharmaceuticals are particularly complex molecules, and biosimilar insulins present special challenges. In part this reflects their structure and chemical modification after synthesis to attain a biologically active form. Their therapeutic window is narrow and the accuracy of their dosing is highly dependent on the formulation and quality of the administration device. For these reasons, the European Medicines Agency has issued stringent guidelines that must be fulfilled in order to receive approval as a biosimilar soluble insulin. Prescribers should therefore consider issues of manufacture, protein quality, formulation, reliability of supply, and other factors that might affect efficacy, safety and tolerability when making choices regarding the selection of biosimilar products.
Introduction
Biopharmaceuticals are biological medicinal products derived from recombinant DNA and expressed by genetically engineered organisms to produce the target therapeutic proteins in large quantities. The first biopharmaceutical introduced into clinical use was recombinant human insulin (Humulin, Eli Lilly) in 1982. Since then, hundreds of biopharmaceuticals, including cytokines, enzymes, antihaemophilic factors and monoclonal antibodies have received marketing authorisation in various jurisdictions.
As patents for the early biopharmaceuticals have already expired, requests for marketing authorisation of 'similar' biological medicinal products (so-called biosimilars) have been submitted in the EU, and various biosimilars such as epoetin alfa, somatotropin and GCSF are already available. The EMA was the first regulatory authority to implement a regulatory framework for the marketing authorisation of biosimilars. This requires the submission and approval of a dossier that, while comprehensive, is less detailed than that of the innovator product. Comparable procedures are in place in other jurisdictions including Malaysia, Taiwan and Australia. In the USA, the Food and Drug Administration is also preparing a regulatory framework; products assessed by this new licensing procedure will be referred to as follow-on biologics (FOBs).
In Europe, several human insulins are available, each with an independent marketing authorisation based on a full dossier. The different brands are authorised for use with specific administration devices (generally a single-use or reusable pen). In some countries where patent regulations are less rigorous human insulin and insulin analogues are available that are (by definition) neither innovator products nor biosimilars and are therefore called 'other insulins'. In 2007, an application to the EMA for marketing authorisation of three biosimilar insulins was withdrawn after the CHMP issued a provisional opinion that the products could not be approved for human use.[1]
Biosimilars are not interchangeable with originator molecules or with each other as are traditional small-molecule generic drugs.[2] In fact, the EMA has stressed that because biosimilars and their reference molecules are not identical, the interchange of a reference medicine for a biosimilar medicine should be based on the opinion of a healthcare professional.[3] Hence, it is essential for prescribers to appreciate these issues in order to make informed choices about the biosimilars they will encounter. This article discusses key aspects to consider when evaluating a biosimilar, with a special focus on biosimilar insulin.
Complexities in the Manufacture of Insulin Biopharmaceuticals
Protein molecules have molecular weights which may be orders of magnitude higher than those of traditional small molecule drugs. Their structures are also far more complex, requiring consistency of their primary structure (amino acid sequences), secondary and tertiary structures (three-dimensional folding patterns), and quaternary structure (stable association of two or more identical or different subunits).
In the case of recombinant human insulin, the precursor protein is synthesised by genetically modified organisms and must be proteolytically cleaved to produce active insulin (figure 1). The insulin preparation must also be formulated to control the formation of discrete hexamers (complexes of six insulin monomers), to confer the required absorption characteristics (figure 2). The more recent insulin analogues contain additional or substituted amino acid residues or other functional groups introduced by genetic engineering or by biochemical modification. These changes alter the speed of bioavailability and thereby modify the PK and PD profiles of the molecule.
Figure 1. The biosynthesis of insulin
The insulin precursor preproinsulin contains a signal sequence that is proteolytically cleaved to yield proinsulin, whose C chain links the future A and B chains of mature insulin. Cleavage of the C chain converts proinsulin to insulin.
Adapted from Joshi SR et al. J Assoc Physicians India 2007;55(suppl):19–25[14]
Figure 2. Association of insulin monomers in the presence and absence of zinc and phenolic excipients
Insulin readily associates into dimers, aggregates and (in the presence of divalent cations such as zinc), into hexameric forms. The presence of phenolic excipients causes these hexamers to undergo conformational changes that increase their stability.
Key: R6 = hexamer with insulin molecules whose B1–B8 residues are in an a-helical (R) conformation; T6 = hexamer with insulin molecules whose B1–B8 residues are in an extended (T) conformation.
Adapted from Beals et al. Informa Healthcare: New York, 2008;265–80[22]
Given their structural complexities biopharmaceuticals are far more difficult to manufacture than small-molecule drugs. The use of living organisms introduces an inherent variability in the manufacturing process. To guarantee the quality and compliance of each production batch, absolute consistency of the manufacturing process is required. Even apparently slight changes in any of the manufacturing or formulation steps can have major clinical consequences.[4–8] Manufacturers of biosimilar products must develop proprietary expression systems and processing steps independently. Thus biopharmaceuticals can never be identical copies of originator molecules, even when they have demonstrated comparable physicochemical and biological properties to a reference product using currently available tests. The most they can achieve is 'biosimilarity'.[5,9,10] For non-glycosylated products such as human insulin, PK and PD differences are most probably caused by differences in formulation, while for glycosylated products (e.g. epoetin), the glycosylation pattern is probably the major source of PK/PD variations. The essential steps in the manufacture of a biopharmaceutical and the loci of potential variability in their manufacturing processes are shown in figure 3.[11]
Figure 3. Manufacture of a biopharmaceutical: opportunities for variation between manufacturers[11]
Adapted from Mellstedt H et al Ann Oncol 2008;19:411–9[11]
The first commercial insulins, extracted from beef and pork pancreata, became available shortly after the discovery of insulin in 1921, and the first long-acting insulins, PZI and NPH, had been developed by the 1940s. However, patients using animal insulin products that were not highly purified often had local injection site reactions or more rarely, systemic reactions such as IgE-mediated anaphylaxis.[12] Highly purified products and recombinant insulins are associated with decreased levels of anti-insulin antibodies. Nonetheless, there is little evidence that antibody formation affects glucose control or causes other complications of insulin therapy.[13] The more recent recombinant insulin analogues contain additional or substituted amino acid residues. The first short-acting analogues, insulin lispro and insulin aspart, were introduced in the late 1990s, and the first long-acting analogue insulin glargine in 2000. Each of these innovations was made with a view to improved onset and duration of action,[14–16] to reduce hypoglycaemia and hyperglycaemia and to improve tolerability. The history of developments in insulin is summarised in figure 4 and a summary of available insulins is given in figure 5.
Figure 4. The development of therapeutic insulin: a timeline[14–16]
Since the discovery of native insulin in 1921, successive discoveries have improved the production of therapeutic insulins as well as their pharmacokinetic and pharmacodynamic properties. Work on therapeutic insulins has garnered three Nobel Prizes.
Key: NPH = neutral protamine Hagedorn; PZI = protamine zinc insulin.
Figure 5. Insulin medicinal products currently available: a summary
In the manufacture of recombinant human insulin, the recombinant organism that actually expresses the precursor protein is generally Escherichia coli or a yeast such as Saccharomyces cerevisiae. The engineered gene encoding for the precursor protein must be inserted into a suitable stable expression vector. The choice and the characteristics of this construct will affect key aspects, such as the degradation characteristics of soluble proteins and the yield of the process. The recombinant cells are screened, and a well characterised master cell bank is established from a single clone. This master cell bank is used to create uniform working cell banks that are used to cultivate the cells and produce the desired product. During product synthesis the culture and fermentation conditions are tightly controlled in order to optimise yields and avoid formation of unwanted by-products.[17] Generally, impurities come from either the growth medium (especially for products isolated from cell culture supernatant) or the host cells. These impurities can be host-related (e.g. endotoxins, HCPs, DNA, viruses), product-related (e.g. denatured protein, aggregates, protein fragments, deamidated species, conformational isomers), or process-related (e.g. growth medium components, metals, column material). When the product is recovered, modified and purified the formation of inclusion bodies (for example in high-yield E. coli processes), requires the disruption of the cells to release preproinsulin. This is then isolated, purified and folded, and then enzymatically cleaved to produce the mature insulin molecule.[18–20] In the case of insulin, impurities such as desamido forms may arise as by-products of conversion from proinsulin to insulin by removal of the C-peptide and regeneration of the three-dimensional form of the molecule.[21]
After numerous purification steps, the insulin is crystallised or lyophilised and formulated. The insulin molecule is negatively charged at neutral pH, and readily associates into dimeric complexes or into zinc-containing hexamers (figure 2). Thus, zinc may be added to trigger aggregation into soluble discrete hexameric structures containing two zinc ions per hexamer.[14] Phenolic excipients, added as antimicrobial agents, also bind to specific sites on hexameric insulin, changing its conformation to a more stable form (so-called T–R transition). Other agents added at the formulation stage may include physiological buffers (to maintain pH) and agents that maintain isotonicity (to minimise injection pain and tissue damage).[22]
Any variations in the entire process of insulin synthesis and formulation may result in a product which may be physicochemically very similar to an appropriate reference product, but which differs subtly in its clinical PK or PD characteristics.[9,14] The steps in the manufacture of insulin are summarised in figure 6.
Figure 6. A highly complex process: steps in the manufacture of insulin
Reproduced with kind permission from sanofi-aventis group.
Insulin Devices: An Added Complexity
For biosimilar insulins, the additional dimension of the administration device should also be considered. Stringent regulatory requirements for insulin administration devices specify use of durable labels and distinguishing marks, visibility of the dose and accuracy with which it is dispensed after storage and handling under a variety of environmental conditions, including having been physically dropped. For example, cartridges, syringe/needle systems, disposable and reusable pens and pumps must be tested with each insulin formulation and concentrations that will be used. Since the combinations of insulin and device may differ widely in their dosing characteristics, it cannot be assumed that an insulin biosimilar will be compatible with an existing administration device. For this reason the EMA requires that compatibility is demonstrated.[23,24] Insulin pen injectors and cartridges (3.0 ml cartridge in the U-100 strength is the current market standard) provide more accurate and reproducible dosing than syringes and vials. They are also more convenient, easier to transport and may improve safety and adherence,[25–27] suggesting that the availability of pen injectors should be a requirement for insulin biosimilars.
Regulatory Requirements for Insulin Biosimilars
In recent years the EMA has produced an overarching guideline on biosimilars[28,29] as well as guidance documents addressing quality issues, 30 non-clinical and clinical issues, 31 and guidelines for specific biosimilars, including soluble recombinant human insulin.[21]
As mentioned earlier[9] the EMA requires that biopharmaceuticals undergo comprehensive comparability studies of both the drug substance and product to provide evidence that the biosimilar is indeed similar in quality, safety and efficacy to a single appropriately chosen reference product that has the same pharmaceutical form, strength and route of administration that is already approved in the EU. In general, required preclinical data include primary pharmacology and repeat-dose toxicology data. The EMA requires toxicological studies that focus on potential immunogenicity, as well as in-vitro affinity bioassays, assays for insulin and IGF-1 receptor binding, and tests for intrinsic activity.[28–31]
One of the main concerns when switching or substituting insulin products is hypoglycaemia caused by differences in activity of different brands. Therefore, it is obligatory to ensure that the effects of any insulin product in clinical use are highly consistent and predictable. The EMA requires at least one PK single-dose crossover study that compares the biosimilar insulin with the reference product, using subcutaneous administration, preferably in patients with type 1 diabetes. Clinical activity must be determined in a comparative PD study, designed as a double-blind, crossover, hyperinsulinaemic, euglycaemic clamp study, to demonstrate the product's hypoglycaemic response profile. Current EMA guidelines for soluble insulin biosimilars do not require a clinical efficacy trial, but do require a clinical safety study. The product's immunogenicity must be investigated through clinical studies of at least 12 months, including a comparative phase lasting at least 6 months. Finally, the manufacturer must also design a pharmacovigilance programme that will rapidly detect any clinically significant immunogenicity that may emerge over extended time periods.[21,28–30] The application for marketing authorisation of three biosimilar insulin formulations in March 2007 suggested deficiencies in long-term efficacy and inadequate immunogenicity testing.[32–34] The details of these applications were recently reviewed by Kuhlmann and Marre in this journal.[35]
What Clinicians Should Know Before Selecting a Biosimilar Insulin
When contemplating biosimilar insulins, it is important to consider the manufacturer, protein quality and formulation, batch consistency and reliability of supply (table 1).[36,37] Reassurance can be gained from full disclosure of information to the healthcare community about the manufacturing process and about safety testing.
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Table 1. A checklist of issues to consider when selecting a biosimilar insulin product[36]
Manufacturer
v R eputation, reliability, experience with biopharmaceuticals
v Location of manufacture of the medicinal product
v Location of the manufacture of the active drug substance (are third parties involved?)
v Dissemination of safety updates and changes in manufacturing process
Protein quality and formulation
v Bioassays: appropriateness, comparisons with reference product
v Levels of foreign proteins, DNA, pyrogens, endotoxins, aggregates
v Formulation: choice of excipients, stabilisers and preservatives
v Administration device or technique; teaching materials for use of a different administration system
v Shelf life, susceptibility to degradation
v Consistency between batches; appropriate quality controls
Reliability of supply
v Stock position
Clinical efficacy
v Clinical trials carried out with different batches of the biosimilar product itself: adequacy of design, results, consistency and generalisability of results
Clinical safety and tolerability
v Comparison of safety and tolerability profile with reference product
v Precautions or contraindications for use of the biosimilar
v Serious adverse events
v Immunogenicity (especially as compared to reference product); selection of antibody tests
v Post-marketing risk management programmes: required laboratory tests, antibody testing, pharmacovigilance programmes to detect infrequent adverse events
With regard to quality suppliers should be asked for a written statement that covers aspects such as the purity of the biosimilar protein, the upper limits for impurities such as aggregates or endotoxins, differences in isomer pattern, and clinical consequences of any potential differences. In the case of insulin impurities such as desamido forms may arise as by-products of conversion from proinsulin to insulin by removal of the C-peptide and regeneration of the three-dimensional form of the molecule.[31] Moreover, with regard to formulation any differences between the biosimilar and the originator molecule plus choice of excipients, stabilisers and preservatives should be provided, Additionally administration (either device or technique) should be explicit. If the biosimilar is administered by a different method from the originator product, e.g. with a new device, teaching materials should be available to train patients and caregivers to use the different system. It is also important to know the product's shelf life and its susceptibility to degradation if it is stored improperly (for example, if accidentally stored at room temperature instead of being refrigerated).
Quality control to ensure batch-to-batch consistency is paramount with insulin preparations. There should be a guaranteed stock position which will maintain supplies if a newly produced batch fails to meet all the required standards of quality. A sustainable supply chain with reliable transportation conditions should also be established.
Particular attention should be given to any differences in clinical activity, biological activity per unit, relative biological potency and dosage of a biosimilar compared with the originator molecule. The known safety and tolerability profile of the biosimilar, as well as precautions or contraindications for its use, should be comparable with the originator molecule. Because clinical trials which enrol relatively small numbers of patients cannot identify rare side-effects, it is obligatory to monitor safety during the post-approval phase. The use of more than one biosimilar product (for example, a biosimilar insulin and a biosimilar epoetin for the diabetic patient with renal failure) may present an additional layer of complexity regarding safety issues.
Similarly, substituting one insulin for another may require dose adjustment. While the development of antibodies to insulin rarely has major clinical consequences, it may have an impact on efficacy (because higher insulin doses may be necessary) and tolerability (mainly in the form of local injection site reactions). Hence, a biosimilar product should receive thorough antibody tests extending into the post-marketing period.
Summary and Conclusions
Biosimilar products such as epoetin alfa biosimilars are already marketed in the EU, and biosimilar insulins are expected shortly. Patients with diabetes are often candidates to receive both types of products. Therefore, it is imperative for prescribers to be aware of issues presented by biosimilar products, and particularly the special challenges presented by biosimilar insulin. Biosimilars are not interchangeable with the corresponding originator biopharmaceuticals in the same way that non-peptide, small-molecule generic molecules are interchangeable with the original products. Any apparently minor modification in the manufacturing or formulation of a product such as insulin, or in the administration device, has the potential to cause untoward clinical consequences, even if the product appears to be physicochemically equivalent to an accepted reference standard. The consequences are particularly relevant for insulin as the therapeutic window is narrow. For this reason, the EMA has developed robust regulatory requirements before marketing authorisation can be granted for a biosimilar insulin. Prescribers should consider critical issues regarding the manufacture, protein quality and formulation, supply, clinical efficacy, safety and tolerability of biosimilar insulins before substitutin
Sidebar
Key Messages
•Unlike non-peptide small molecule generics, biosimilars are not identical to the originator
•Biosimilar insulins are challenging because insulin has a complex structure and a narrow therapeutic window
•The dosing accuracy of biosimilar insulins depends on the quality of the administration device
•Regarding biosimilars, consider the manufacturer, protein quality, formulation, reliability of supply, clinical efficacy, safety and tolerability
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References
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Abbreviations and acronyms
CHMP, Committee for Medicinal Products for Human Use; CMC, chemistry, manufacturing, controls; EMA, European Medicines Agency; EU, European Union; GCSF, granulocyte colony-stimulating factor; HCP, host-cell protein; IGF, insulin-like growth factor; NPH, neutral protamine Hagedorn; PD, pharmacodynamic; PK, pharmacokinetic; PZI, protamine zinc insulin
Acknowledgment
Editorial support for this article was provided by the medical writing agency PHOCUS and by sanofi-aventis groupe. The opinions expressed in the current article are those of the authors. The authors received no honoraria or other form of financial support related to the development of this manuscript.
Declaration of conflict of interest
IK has been a consultant, speaker and member of advisory boards of various (bio)pharmaceutical companies, which had no influence on the content of this article. TS is an employee of Sanofi-aventis Deutschland GmbH.)
British Journal of Diabetes and Vascular Disease © 2010 Sage Publications, Inc.
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