Biosimilar.pptx
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Bio similar and innovators - the battle of the two is a long story . In this presentation am trying to explain the merits nd demerits of each with available evidence
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Biosimilar.pptx
- 1. Biosimilar Dr .Raju Nair Mitera Hospital Kottayam Kerala India
- 2. 1995 1930’s Horse PMSG Pig FSH Pituitary FSH u-hMG u-FSH r-hFSH 1950 1980 1960 Antibodies Local, systemic reactions Local rections & potentiel side effects CJD Lunenfeld. RBM Online 2002;4(suppl 1):11 Discovery Timelines: Gonadotropins 1946
- 3. The Move From Urinary FSH to rFSH • Better ovarian response. • Lower FSH doses. • Fewer dosage adjustments. • Shorter treatment time. • No risk of contamination / infection.
- 4. Gonadotropin • Advantages of recombinant FSH • High purity • High specific FSH activity (about 10,000 IU/mg protein) • Identical amino-acid sequence to natural FSH • No contamination with urinary proteins of undetermined origin • No LH activity • Good source control, providing good batch-to-batch consistency • Disadvantages of urinary FSH • Variable purity • Variable specific FSH activity • Amino-acid sequence of more acid profile as in postmenopausal women • May contain >95% proteins of urinary origin • There is always some LH contamination • No absolute source control, resulting in batch-to-batch inconsistency. • Collection of urine is cumbersome
- 5. Concerns About Batch to Batch consistency
- 6. Comparison – Batch to Batch Consistency Urinary gonadotropins (-20%,+25%) Follitropin alfa (2%) 1. Bassett et al. Reprod Biomed Online 2005;10:169–177; 2. Driebergen et al. Curr Med Res Opin 2003;19:41–46
- 7. 1. Bassett et al. Reprod Biomed Online 2005;10:169–177 2. Driebergen et al. Curr Med Res Opin 2003;19:41–46 Conventional Bioassay High variability (~20%) in vivo (rat) Novel analytical method Physiochemical technique Minimal batch-to- batch variability (1.6%)1,2 Gonadotropins: an overview Product Quality: Filled by Mass (FbM)
- 8. R-FSH • Better ovarian response. • Lower FSH doses. • Fewer dosage adjustments. • Shorter treatment time. • No risk of contamination / infection • More oocytes • Better quality embryo with HMG ? • More or less equal pregnancy rates
- 9. What are Biosimilars? Biosimilar designates a copy version of an approved original biologic medicine (innovator or reference product) whose data protection has expired. Ranke M.B. Horm Res 2008;69:22–28 Approval of biosimilar products does not substantiate interchangeability with reference products Biosimilars are Only “Similar” to innovative reference products, Not Identical biologicals that contain essentially the same API as an original biomedicine, and that share its quality, safety and efficacy, may be developed: the so-called similar biologic medicines, or biosimilars
- 10. Changes in the manufacturing process alter the characteristics of biological drugs Mellstedt et al. Ann Oncol 2008 Cloning and protein expression Possibly same gene sequence Possibly different vector Different cell expression system Protein production, purification and validation Different cell line, growth media and method Different cell line and growth media Different operating procedure Different binding and elution conditions Different methods, reagents and reference 6 The Process Is the Product “It is Impossible to replicate same product using a different process”
- 11. Sources of variation between manufacture of innovator biopharmaceutical and Biosimilars Cell Expansion Cell Production in bioreactors Recovery through filtration or centrifugation Purification through chromatography Characterization & Stability Purified Bulk Drug 11 Different cell line, growth media, method or expansion Different cell line, growth media, bioreactor conditions Different Operating conditions Different binding & elution condition Different methods, reagents, reference standards Sources Of Variation Horm Res 2008;69:22–28 Impact of small differences in either biological or manufacturing process could lead to potentially serious safety issues for patients and different clinical efficacy
- 12. Full development process to generate a recombinant (12 years) 12
- 13. Immunogenicity: a problem to be resolved Bioquality, Biosimilar Special Edition 2012 Much work still needs to be done in order to prove that biosimilars are as safe and effective as their originator products -- Int Urol Nephrol (2007) 39:261–266
- 14. Concerns Loss of efficacy Immune effects such as anaphylaxis or allergic reactions Can be severe and potentially lethal Nephrol Dial Transplant (2006) 21 [Suppl 5]: v9–v12; NATURE BIOTECHNOLOGY 2004;22(11):1357-9 Even if the biosimilar product has the same gene sequence, vector, host cell line, culture conditions and purification methods as the innovative protein, it can still differ substantially in its biological and clinical properties.
- 15. Figure 1 Reproductive BioMedicine Online 2017 3581-86DOI: (10.1016/j.rbmo.2017.03.020) Copyright © 2017 Reproductive Healthcare Ltd. Terms and Conditions
- 16. Biosimilars are not the same…. • Definition: “biopharmaceutical drug designed to have active properties similar to one that has previously been licensed.” • "copycat drug makers use an innovator's research data to make biosimilars“ – Oxford Dictionaries Biosimilars are not like Generics – they are not identical but similar, because biosimilars are produced using different cell lines and production processes Biosimilars are approved following an abbreviated process – they thus, lack the extensive clinical and in-market data of the originator drug – Much smaller number of patients included in phase III trial (~150-250) – Need only to show comparable effect / non-inferiority within margin – Pharmacodynamic studies are generally not required, the equivalence of biological effect is not established Given that biosimilars are permitted to be different from the originator drug, they have a different safety & efficacy profile – Monitoring required by EMA as long-term efficacy and safety is unproven 1
- 17. Advantages ?? • The lower investment needed for biosimilar development compared with the original drug, along with increased competition resulting from biosimilars entry into the market, has led to a reduction of the average price of biologic drugs that may contribute to optimizing healthcare expenditure as for the experience gained in other therapeutic areas (Flodmark et al., 2013; Tsao et al., 2014). • Treatments such as IVF may also benefit from such trends (Foxon et al., 2015; Ripellino et al., 2015) and, therefore, patient access to infertility care will ultimately improve (Aitken, 2016).
- 18. • Biosimilar recombinant follitropin alfa preparations versus the reference product (Gonal-F®) in couples undergoing assisted reproductive technology treatment: a systematic review and meta- analysis Chua et al. Reproductive Biology and Endocrinology (2021) 19:51
- 20. Objective • Live birth has been increasingly identified as the standard clinical approach to measure the success of infertility treatment • Since regulatory approval of biosimilar preparations is governed by a distinct pathway which varies between countries, it is important from a physician and patient perspective to consider all available evidence to evaluate if clinically meaningful differences exist in quality, safety, or efficacy outcomes after use of biosimilar preparations in comparison with the reference product
- 21. Study _ meta-analysis • 292 records • 17 RCT • Primary outcome • Live birth • Clinical pregnancy • Ongoing pregnancy
- 27. Biosimilars are not the same….. • They are not identical but similar, because are produced using different production processes. Biosimilar are Not Generics •Small number of patients in phase II-III trials •Only show comparable effect/ non-inferority •Pharmacodynamic studies are generally not required, the equivalence of biological effect is not established Biosimilars lack of extensive clinical data •Given that biosimilars are permitted to be different from originator drug, little differences generated a different safety & efficacy profile •Close monitoring required by EMA as long-term efficacy and safety is unproven Biosimilar have different Safety & Efficacy
Editor's Notes
- Discovery timelines of urine-derived and human recombinant gonadotropins Over the years, the development of preparations containing FSH has been guided by a quest for control over variability derived from the drugs. The journey began in 1930, when Cole and Hart showed that product derived from pregnant mare serum had potent gonadotrophic activity. When this product failed to produce consistent results and induced adverse events, pig and sheep extracts were utilized by Mazer and Ravetz in 1946. Gemzell and Bettendorf introduced the use of pituitary FSH between 1958-1963. With the discovery of 12 CJD cases, potentially linked to the use of PFSH, the product was discontinued. In 1961 Lunenfeld reported the first successful pregnancy using hMG developed by Donini. This product’s purity was 5%. Urofollitropin was developed in 1966, using affinity purification processes. It contained 1 IU LH/75 IU FSH and 95% contaminants. Once monoclonal antibody technology was applied, highly-purified urofollitropin was developed, resulting in a product with specific activity of 9000 IU/mg protein, compared to 100-150IU/mg protein seen with the former generation of gonadotropins. In the early 90s, the first pregnancies were reported following development of the fourth generation of gonadotropin products, recombinant FSH.
- The conventional method used to quantify the activity of FSH in gonadotropin products is the Steelman–Pohley assay, which is an in vivo rat bioassay. As well as being costly and subject to ethical concerns related to the use of animals, this technique has an inherent variability of up to 20%. In 2003, Driebergen et al. demonstrated the batch-to-batch consistency of r-hFSH (follitropin alfa) in terms of specific activity, isoform pattern and sialylation profile. Following this, a novel physiochemical method was developed for measuring FSH content (by protein mass).
- © Merck KGaA Darmstadt/Germany
- What are biosimilars? Reference Ranke M.B. New Preparations Comprising Recombinant Human Growth Hormone: Deliberations on the Issue of Biosimilars.Horm Res 2008;69:22–28
- Biological drugs the final product, with the potential to affect therapeutic efficacy and safety in the clinic. are never entirely reproducible. The manufacturing process for biological drugs is highly complex and dependent on living cells. Even small changes in the manufacturing process or production conditions can affect Differences may be introduced at virtually every step of the manufacturing process, from the initial protein source to the extraction/purification stage, as illustrated in the slide. 1. Mellsted et al. Ann Oncol 2008;19:411419
- ELUTION -To extract (one material) from another, usually by means of a solvent. How does a reference or innovator differ from Biosimilars? A Biosimilar is defined by characteristics related to both the molecule (product-related) and its manufacturing process (process-related) . Both need to be adequately addressed . The higher complexity of biopharmaceuticals relates not only to the manufacturing process but also to the substances themselves Biosimilars should have full knowledge of replicating the innovator’s manufacturing process right from Full chemistry and manufacturing data , Physico-chemical properties, Biological activity , Purity and impurities. (as they will not have access to the original proprietary knowledge owned by innovators) Reference Ranke M.B. New Preparations Comprising Recombinant Human Growth Hormone: Deliberations on the Issue of Biosimilars.Horm Res 2008;69:22–28
- The science behind the differential regulatory requirements for biosimilar, original biologic and generic medicines. The basis of the demonstration of equivalence between a biosimilar and the reference product relies on the physicochemical and biological activity comparability assessment (quality module). This is represented in the figure by means of a wider basal layer (dark red bottom layer). Conversely, the main demonstration of a favourable risk-to-benefit balance of an original biological resides in the late clinical trials in patients (dark blue top layer). Finally, given the fact that the active pharmaceutical ingredient (API) of a chemically-synthesized medicine can be virtually identically replicated, the generic development pathway may be considerably abridged (as represented by narrow green layers). In addition to the pre-authorization studies, an active pharmacovigilance program needs to be set for biosimilars approval as for any new biological or chemical entity. PK = pharmacokinetic. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
- Biosimilars are SIMILAR, not THE SAME Biosimilars are approved following an abbreviated process, therefore have a different safety and efficacy profile.