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Biosimilars
- 1. BIOSIMILARS - Dr. Chandini - Moderator: Dr. Chandralekha
- 2. Overview ▪ Introduction ▪ Definition ▪ Differences b/w biosimilars & generics ▪ Regulatory approval ▪ Examples ▪ Potential concerns ▪ Conclusion
- 3. Introduction ▪ Biological drugs – essential part of modern pharmacotherapy ▪ 1st developed in 1980s – Recombinant technology ↓ Complex proteins (eg. monoclonal Abs) (DNA manipulation in bacteria, yeast or mammalian cells)
- 4. ▪ Other eg – cytokines, hormones, interleukins, human insulins, clotting factors, enzymes, vaccines, cell & tissue based therapies. ▪ Up to 50% share in global pharmaceutical market in the next few years.
- 5. • What is a Biological agent? aka Biopharmaceutical. “any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of disease or injuries of man”
- 6. What are Biosimilars? ▪ A biologic medical product which is almost an identical copy of an original product that is manufactured by a different company. ▪ Biosimilars (Europe) = Follow-on biologics (USA) ▪ Officially approved versions of original "innovator" products. Manufactured when the original product's patent expires.
- 7. • 1st biosimilars approved by EMEA (2006) - Omnitrope : biosimilar to Genotropin Valtropin : “ “ Humatrope • US-FDA: Zarxio (filgrastim-sndz) – 2015 Recomb forms of Somatostatin
- 8. • India: 1st ‘similar biologic’ – 2000 (for Hep B vaccine), according to GaBI • One of the leading contributors. (50 biopharmaceutical brands approved) • Affordability & easy accessibility good reputation among healthcare professionals.
- 9. Why biosimilars are not generic drugs? Generic drugs Biosimilars • Chemical & therapeutic equivalents of chemical drugs. • Structure: smaller, less complex, 1D • Molecular weight: low • Copies of existing biological medicinal products or protein drugs • Large & complicated (100-1000x), 3D • High
- 10. Generic drugs Biosimilars • More stable • Route: Oral • Manufacturing process: less complex • Registration procedure: simple (ANDA) • Sensitive to changes in physical conditions • Injected/Inhaled • complex, lengthy & expensive (require different cell lines) • Complicated (EMEA/FDA)
- 11. Regulatory approval ▪ Stringent criteria – quality, safety & efficacy. ▪ Feb’06: EMEA – guidelines on clinical, nonclinical & quality expectations. ▪ Approved biosimilars of - Somatropin (omnitrope, valtropin) - Epoietin (abseamed, binacrit etc) & - G-CSF(ratiograstim, biograstim, tevagrastim)
- 12. EMEA guidelines
- 13. • Feb’12: FDA – 3 draft guidance documents - Scientific Considerations - Quality Considerations - Questions and Answers (regarding Implementation of the Biologics Price Competition and Innovation Act of 2009) • India: lacks specific guidelines unrestrained flooding of biosimilars
- 14. Nonclinical testing • Extensive in vitro & in vivo investigations. • Eg. 1st monoclonal Ab biosimilar approved CT-P13 (Infliximab) - molecular structure - product stability & quality - binding affinities forTNF-α - PK & toxicity profile (10 & 50mg/kg in rats)
- 15. Clinical evaluation • Aims - to resolve slight differences arising in previous steps of the development process. - to confirm comparable clinical performance between the biosimilar & reference products (immunogenicity, PK equivalence, & therapeutic equivalence) • Eg. HX575 - bioequivalent (PK & PD) to epoetin based on a study in 80 healthy subjects.
- 16. Biosimilar product Reference product INN Indication Approval date Omnitrope Genotropin Somatotropin (GH) GH deficiency Hypothalam ic disease April 2006 Valtropin Humatrope Abseamed Epogen/ Procrit Epoetin alpha Chemothera py-induced anemia August 2007 Epoetin alpha Hexal Anemia associated with CKD Binocrit blood transfusion
- 17. Biosimilar product Reference product INN Indication Approval date Biogastrim Neupogen Filgrastim Cancer Sep 2008 Ratiogastrim Hematopoietic stem-cell transplantation Sep 2009 Nufil Grafeel India Inflectra Remicade Infliximab Ankylosing spondylitis Sep 2013 Remsima Crohn’s, Ulcerative colitis, psoriasis, RA July 2012
- 18. Biosimilar product Reference product INN Indication Approval date Reditux Rituxan/ Mabthera Rituximab NHL, CLL, RA India Cresp Aranesp Darbepoeti n alpha ESA for anemia d/t CKD , In chemotherapy 2010 (India) Silapo Dec 2007 • Other eg – biosimilars for Enbrel (etanercept), Herceptin (trastuzumab), Humira (Adalimumab), Neulasta (pegfilgrastim) etc.
- 19. Potential concerns 4 major concerns – Safety Substitution Naming Labeliing
- 20. Safety ▪ Biosimilars – only ‘similar’, not identical ▪ Safety profile of biosimilar not identical to that of reference product. ▪ Eg. Valtropin (biosimilar GH) has different precautions & warnings than Humatrope (ref product) - d/t different cell lines used to produce both drugs (Valtropin – yeast, Humatrope – E.Coli )
- 21. • Immunogenicity - unique safety issue • Rarely Ab-related reactions – serious & life- threatening. • Various potential consequences of immunogenicity – - loss or enhancement of efficacy - neutralization of a native protein - general immune effects (allergy, anaphylaxis, serum sickness)
- 22. • Eg. the complication of epoetin therapy - Pure red cell aplasia. assoc with specific formulation of epoetin α (Eprex) ↓ production of neutralizing antibodies against endogenous epoetin (Eprex – human albumin stabilizer replaced by polysorbate 80 & glycine ↑ immunogenicity) • Recomb IFNs neutralizing Abs ↓ its own production
- 23. • Recent EMEA guidelines – Preclinical data insufficient to demonstrate immunologic safety of some biosimilars. • Pharmacovigilance is mandatory - type of A/E - data about drug (proprietary name, international non-proprietary name & dosage given)
- 24. Substitution ▪ Principle behind substitution of traditional chemical drugs - original drug & its generic are identical & have the same therapeutic effect. ▪ Chemical generics - automatic substitution is appropriate & can produce cost savings
- 25. • Same rules cannot be applied to biotechnological medicines - not identical - ↓ safety of therapy/ cause therapeutic failure. • Uncontrolled substitution confound accurate pharmacovigilance. (A/E ascribed to wrong product) • Awareness among prescribers & pharmacists necessary
- 26. Naming ▪ INN - technical name for the medical products ▪ Chemical generics assigned the same name ▪ Biosimilars require unique INNs - facilitate prescribing & dispensing of biosimilars & also aid in precise pharmacovigilance.
- 27. Labelling Labels of originator & biosimilar products must be different. Product characteristics Reference products Data for approval Unique safety data Substitution advice
- 28. Conclusion ▪ Biotechnological medicines - important part of future healthcare ▪ Biosimilars - ↑ availability - alternative Rx options - ↓ direct costs of therapies
- 29. ▪ Biosimilars never identical to reference products - Substitution rules must be different for generics & biosimilars ▪ Biosimilars differ from reference products - efficacy - safety - immunogenicity
- 30. References 1) Khraishi, M., Stead, D., Lukas, M., Scotte, F., & Schmid, H. (2016). Biosimilars: A multidisciplinary perspective. Clinical Therapeutics, 38(5), 1238-1249. 2) Misra, M. (2012). Biosimilars: Current perspectives and future implications. IndianJournal of Pharmacology, 44(1), 12-14. 3) Nowicki M. Basic facts about biosimilars: Review. Kidney Blood Press Res 2007;30:267–272 4) Ventola CL. Biosimilars: Part 1: Proposed Regulatory Criteria for FDA Approval. Pharmacy andTherapeutics. 2013;38(5):270-287.
Editor's Notes
- Biopharmaceutical drugs have become an essential part of modern pharmacotherapy. Biologics were first developed in the 1980s using recombinant techniques to copy or improve on naturally occurring complex peptides, proteins, and glycoproteins.1,3,4 Since then, even more complex products, such as monoclonal antibodies, have been produced in living organisms through the manipulation of the DNA in bacteria, yeast, or mammalian cells.
- Other Examples include biological proteins (cytokines, hormones, interleukins, human insulins and clotting factors), enzymes, vaccines, cell and tissue based therapies. Biopharmaceuticals have potential to reach up to 50% share in global pharmaceutical market in the next few years.
- According to the U.S. Federal Code of Regulations (CFR), the definition of a biologic is “any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of disease or injuries of man (fig) This illustration depicts the markedly greater structural complexity of the biologic agent erythropoietin, compared with aspirin, a conventional, small-molecule chemical drug.
- What Are Biosimilars? The expiry of patent protection and regulatory data protection for certain biotechnological medicines has led to the development of what are called biosimilars. A biosimilar is a biologic medical product which is almost an identical copy of an original product that is manufactured by a different company.[1] The term ‘biosimilars’ is in use in the European Union but in the US the term ‘follow-on biologics’ is much more popular. Biosimilars are officially approved versions of original "innovator" products, and can be manufactured when the original product's patent expires.[2] Reference to the innovator product is an integral component of the approval. It is important to state that biosimilars are not (bio)generics. Biosimilars are attempted copies of existing biological medicinal products or protein drugs. However, they are made with a different cell line and a different manufacturing and purification process, and the final product is not identical. the first biosimilars entered the market in 2006 after having been approved by the European Agency for the Evaluation of Medicinal Products (EMEA). Those first biosimilars were Omnitrope (biosimilar to Genotropin) and Valtropin (biosimilar to Humatrope) [9, 10] Also multiple biosimilar products are under development. (*genotropin & humatrope – recomb forms of somatotropin)
- the first biosimilars entered the market in 2006 after having been approved by the European Agency for the Evaluation of Medicinal Products (EMEA). Those first biosimilars were Omnitrope (biosimilar to Genotropin) and Valtropin (biosimilar to Humatrope) [9, 10] Also multiple biosimilar products are under development. The 1st BS product approved in USA by the US-FDA – Zarxio (filgrastim-sndz)
- Acc to Generics & Biosimilars Initiative (GaBI), the 1st “similar biologic” was approved & marketed in Inidia in 2000 for a Hep B vaccine - some 15 years before the US approved its 1st bs. At present, India is one of the leading contributors in the world biosimilar market. India has demonstrated the greatest acceptance of biosimilars, which is reflected from over 50 biopharmaceutical brands getting marketing approval. Owing to affordability and easy accessibility, biosimilars have established a good reputation among healthcare professionals.
- Why biosimilars are not generic drugs? It is important to state that biosimilars are not (bio)generics. Biosimilars are attempted copies of existing biological medicinal products or protein drugs. However, they are made with a different cell line and a different manufacturing and purification process, and the final product is not identical. Generic drugs are characterized by their chemical and therapeutic equivalence to the branded, original, low molecular weight chemical drugs whose patents have expired. These are approved through simplified registration procedure as abbreviated new drug application (ANDA), with demonstration of bioequivalence. [5] However, it is not possible to employ the same standards for the evaluation or appraisal of biosimilars, as there are various differences between chemical generics and biosimilars. Biologics are much more complex than conventional “chemical” drugs because they are larger and have more complicated structures This is reflected by the huge differences in a molecular weight of the molecules. The typical biologic drug is 100 to 1000 times larger than small molecule chemical drugs The former also possesses a fragile 3-dimensional structure unlike the well-characterized 1-dimensional structure of chemical agents (chemical formula) which in most cases is easy to reproduce [
- . Chemical drugs are also much more stable whereas biological drugs are sensitive to changes in physical conditions which require not only strict control of the manufacturing process but also appropriate storage at pharmacies and by the patients. Most chemical drugs are taken orally but almost all biologics are injected or inhaled because, as proteins, they are very sensitive to enzymatic degradation in the gastrointestinal tract. Manufacturing biotechnological medicines is complex, lengthy and expensive. Each manufacturer must make their own unique cell line which is a clone to a single cell.
- Regulatory approval Unlike chemical generics, the biosimilars require more stringent criteria for the evaluation of quality, safety and efficacy. In May 2004, the European parliament issued recommendations for regulatory approval of biosimilars. In February 2006, EMEA released guidelines containing details of clinical, nonclinical and quality expectations for biosimilars. Based on these guidelines, EMEA has approved biosimilars of somatropin (omnitrope, valtropin), epoietin (abseamed, binacrit, hexal, silapo, retacrit) and G-CSF(ratiograstim, biograstim, tevagrastim). [17],[18] EMEA has rejected marketing applications for aplheon, the biogeneric of interferon, due to the concerns over manufacturing technique and quality control. [17],[18] The application of biosimilar Marvel Insulin was also disapproved because of inadequate data to prove similarity with innovator product.
- In February 2012, the FDA issued three draft guidance documents regarding the regulatory requirements for biosimilars:4,14–16 Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 In India, the specific guidelines for approval of biosimilars are lacking. [4],[18] Thus, there is unrestrained flooding of biosimilars in Indian market.
- Nonclinical Testing Extensive in vitro and in vivo investigations are undertaken before a biosimilar enters the next clinical evaluation step. the first monoclonal antibody biosimilar approved in Europe, the infliximab biosimilar CT-P13 underwent comprehensive nonclinical testing.13 Similarity of CT-P13 to reference infliximab was shown for molecular structure, product stability and quality, and binding affinities for soluble monomeric and trimeric forms of tumor necrosis factor-α and transmembrane tumor necrosis factor-α. 17 Additionally, the PK and toxicity profile of CT-P13 did not significantly differ from that of the reference product when both products were administered to rats at doses of 10 and 50 mg/kg
- Clinical evaluation According to the EMA, the aims of clinical evaluation are to resolve slight differences potentially arising in previous steps of the development process and to confirm comparable clinical performance between the biosimilar and reference products. with a focus on immunogenicity, PK equivalence, and therapeutic equivalence/ Eg. HX575 was deemed pharmacokinetically and pharmacodynamically bioequivalent to the reference epoetin based on a study in 80 healthy subjects.
- By definition biosimilars will only be similar but not identical to the product they seek to copy. In biotechnological medicine, each product has a unique safety profile. The best example to illustrate that the safety profile of the biosimilar will not be identical to that of the reference product is that the recently approved biosimilar growth hormone Valtropin has different precautions and warnings than its reference product Humatrope. This is a likely consequence of the different cell lines used to produce both drugs (yeasts in the case of Valtropin and Escherichia coli in the case of Humatrope)
- Immunogenicity is the unique safety issue of biotechnological medicines. All therapeutic proteins have the potential to induce antibody responses. In many cases, no clinical consequences are found but in rare cases an antibody-related reaction can be serious and even life-threatening. There are various potential consequences of immunogenicity such as loss or enhancement of efficacy, neutralization of a native protein and general immune effects (allergy, anaphylaxis, serum sickness)
- Eg. The complication of epoetin therapy, i.e. Pure red cell aplasia - increase in number of cases of pure red cell aplasia associated with a specific formulation of epoetin alfa. [9],[10] This episode made the world to look at biosimilars with caution. The immunological form of pure red cell aplasia was caused by the production of neutralizing antibodies against endogenous epoetin. Most of the cases occurred in patients treated with Eprex, the biosimilar of epoetin alfa, produced outside of the United States. The most likely cause was subtle changes in the manufacturing process. In the formulation Eprex, the human albumin stabilizer was replaced by polysorbate 80 and glycine. Polysorbate 80 is supposed to have increased the immunogenicity of Eprex. In another study, many patients treated with recombinant interferons demonstrated the presence of neutralizing antibodies that significantly suppress their own production.
- The recent EMEA (European Medicines Agency) guidelines on comparability of biosimilars state that preclinical data may be insufficient to demonstrate immunologic safety of some biosimilars. to minimize the risk of such unexpected reactions an appropriate pharmacovigilance is mandatory. The adverse drugs reactions monitoring data should be exhaustive, including the type of adverse event and data about drug such as proprietary name, international nonproprietary name (INN) and dosage given.
- Substitution the common notion of most practicing physicians that medicines with the same molecular structure are the same and therefore can be safely substituted. not every patient can tolerate well every medicine based on the same chemical compound. The principle behind substitution of the traditional chemical drugs is that the original drug and its generic are identical and have the same therapeutic effect. For majority of chemical generics, automatic substitution is appropriate and can produce cost savings.
- However, the same substitution rules cannot be applied since biotechnological medicines are not identical & may decrease the safety of therapy or cause therapeutic failure. The uncontrolled substitution of biosimilars also confounds accurate pharmacovigilance. If an adverse event emerges after switching from innovator biopharmaceutical to its biosimilar without documentation of product change, the event will not be able to be associated to a specific product or it will be ascribed to a wrong product during pharmacovigilance assessment. The prescribers and pharmacists should be aware of it and avoid this inappropriate substitution.
- Naming INN is the technical name for the medicinal products. The generic adaptation of chemical medicines is assigned the same name, as they are identical copies of the reference products. However, the biosimilars require unique INNs, as this would facilitate prescribing and dispensing of biopharmaceuticals and also aid in precise pharmacovigilance.
- Labelling labels of originator and biosimilar products should be different. A summary of product characteristics should be transparent and clear. Reference products should be defined. Also data for approval should be described. Furthermore unique safety data should be included and substitution advice should be provided.
- Conclusion Biotechnological medicines will become an important part of the future healthcare landscape. With patent expiration of innovator products, the biosimilars will increasingly become available. Biologics – and properly regulated biosimilars – will increasingly become available, will provide patients and doctors with alternative treatment options and most likely will make it possible to decrease the direct costs of therapies and increase their availability to the patients. Biosimilars are expected to be an essential component in reducing health care costs and enhancing patient access to important, often lifesaving medications
- Substitution rules between originator and biosimilar products must be different than in the case of generic substitutions as such products are never identical. Awareness of the deviations between biosimilars and innovator products in terms of efficacy, safety and immunogenicity is essential for proper prescription and safety of the patients.