The Breakthrough of Biosimilars: A Twist in the Narrative of Biological Therapy
Abstract
:1. Introduction
Basic Concept
Biosimilars or Not?
2. Regulatory Compliance
2.1. The Evolving Regulatory Landscape of Biosimilars
Comparison of Biosimilar Regulatory Guidelines
2.2. Approval Process for Biosimilars
The US. FDA has approved Ogivri (trastuzumab-dkst) as a biosimilar drug product to Herceptin (trastuzumab). The drug is employed in the treatment of patients with breast or metastatic stomach cancer (gastric or gastroesophageal, junction adenocarcinoma) whose tumours overexpress the HER2 gene (HER2+) [38]. Approval of the product was based on a review of comparibility evidence that evaluated data on its structural and functional characterisation, date from animal studies, clinical immunogenicity data, human pharmacokinetic and pharmacodynamic data, as well asclinical safety and effectiveness data. However, Ogivri is yet to be approved as an interchangeable product with its reference biologic [39]. Common side effects of Ogivri when used in treating HER2+ breast cancer include chills, nausea, rashes, headache, infection, congestive heart failure, fever, insomnia, coughing and diarrhea.Case Study 1
2.3. Extrapolation of Indications of Biosimilars
2.4. Future Perspectives of Biosimilar Evaluation
3. Critical Challenges of Biologics and Biosimilars
- (i)
- Manufacture.
- (ii)
- Naming.
- (iii)
- Packaging.
- (iv)
- Labelling.
- (v)
- Pricing.
- (vi)
- Immunogenicity.
- (vii)
- Pharmacovigilance.
- (viii)
- Interchangeability.
3.1. Manufacture of Biologics and Biosimilars
- (i)
- Defining the target—This involves detecting any variability in the reference target molecule and any corresponding changes in qualitative properties of the drug. Choosing the type of biosimilar to be manufactured follows this.
- (ii)
- Development based on target—The engineering process of the biosimilar is designed to match the criteria of the reference. These criteria include various factors, such as choice of cell line, biological processes, and development.
- (iii)
- Similarity confirmation of the biosimilar—Degree of biosimilarity with the reference assessed via physical, chemical, and biological analyses of the biosimilar.
- (iv)
- Regulatory authorization—Co-operating with relevant regulatory authorities to determine the minimum amount of clinical information required for biosimilarity approval.
- (v)
- Clinical assessment—Conducting clinical trials to confirm biosimilarity and compiling any other information required for commercialization of the biosimilar.
Similarity Confirmation Process for Biosimilars
- (i)
- In-vivo studies: Animal models aid in the comparison in therapeutical activity of the biosimilar and its reference drug in the pharmaceutical form. The information obtained is valuable in deciding on the appropriateness of proceeding to further clinical trials.
- (ii)
- Bioanalytical evaluation: Standard bioanalytical evaluation indicates the need for the product to show a high degree of analytical similitude with their reference. This comparison is done especially in terms of amino acid sequencing and folding, proportion of glycan and non-glycan components in their structure, stability profile, mechanisms of action, and purity. The similarity of the physicochemical and biological properties of biosimilar and reference preparations is demonstrated while using two or more orthogonal analytical methods. Ideal extensive bio analyses reveals negligible or no qualitative/quantitative variations in the functional and structural properties of the biosimilar compared to the originator biologic. Any areas of doubt, termed as “residual uncertainty”, in the efficacy profile of the biosimilar are investigated through PK/PD and immunogenicity studies [43].
- (iii)
- Pharmacokinetic studies: Evaluation and comparison of the rate of drug clearance, effective drug absorption, total drug exposure over time, and drug half-life of the biosimilar product with its reference biologics aid in understanding the pharmacokinetic impact of the drug.
- (iv)
- Pharmacodynamic studies: Data that were obtained from these studies aid in contrasting the reactivities of the biosimilar and its reference. This contrast is mainly done through the design of receptor binding studies and cell assays.
- (v)
- Toxicological studies: The toxicity and immunogenicity between the biosimilar and its reference can be compared via repeat dosage toxicity studies. The data obtained are vital in assessing the safety of the follow on product and its tolerance within the body.
- Phase I: Pharmacokinetic and pharmacodynamics studies.
- Phase II: Dose Finding (DF) trials in order to measure the optimal biological dose.
- Phase III: Studies in all targeted indications and development of a risk-management plan.
In certain cases, challenges emerge in the extrapolation to all clinical indications for biosimilars. An example of this was seen when Health Canada decided to grant approval to the biosimilar anti-TNF antibody, Inflectra (infliximab) for only some of the clinical indications of the reference product, Remicade [61]. Inflectra was approved for use in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis, but not Crohn’s disease or ulcerative colitis. Health Canada proposed that differences of the biosimilar compared to the reference product in in vitro ADCC and binding to the FcγRIIIa receptor had a high chance of correlating with the mechanism of action in Crohn’s disease or ulcerative colitis. In 2013 however, the EMA came to a different conclusion on the same data [61,62]. Inflectra was approved as biosimilar for all eight of the clinical indications of the reference product. According to the EMA, the approval for all clinical indications should be viewed in the context of totality of data on analytical, preclinical, PK, PD and clinical information. Subsequent preliminary clinical studies sufficiently demonstrated the safety and efficacy of the biosimilar in paediatric Crohn’s disease, ulcerative colitis and inflammatory bowel disease [63].Case Study 2
3.2. Naming of Biologics and Biosimilars
3.3. Packaging of Biologics and Biosimilars
3.4. Labelling of Biologics and Biosimilars
3.5. Pricing of Biologics and Biosimilars
Where massive price reductions are not a general expectation with biosimilars, small price reductions can still have a significant impact on healthcare costs. The list price of Basaglar in the US is set at a 15% discount as opposed to Sanofi’s originator insulin glargine, Lantus [80]. This allows for the saving of approximately US$56/month or US$1.86/day for a patient switching from Lantus to Basaglar. This has encouraged insurance companies and pharmacy benefit managers within the US to endorse Basaglar and provide exclusive formulary positioning to Basaglar over Lantus. While this may not be a problem for new patients, the issue of switching rears its ugly head when considering changing stable patients onto a biosimilar insulin. Although the US Food and Drug Administration has issued already issued a draft guidance concerning the interchangeability of biosimilars, it has, still not approved any biosimilar as interchangeable with its reference biologic [71].Case Study 3
3.6. Immunogenicity of Biologics and Biosimilars
Rheumatoid Arthritis (RA) affects approximately 1% of the world’s population, primarily women aged between 30 and 55 years. This disease is indicated by the swelling, stiffness and pain in joints caused by the attack of the immune system on joint linings. RA is responsible for increasing disability to intolerable states among patients within five years of the disease diagnosis. RA patients also have a higher susceptibility to developing cardiovascular diseases, mental health problems and cardiovascular issues. Biosimilars have emerged as a new light of hope in RA treatment and are poised to provide new treatment options against the disease within the coming years [97].Case Study 4
3.7. Pharmacovigilance of Biologics and Biosimilars
Aimovig leads the line in a new class of drugs that are capable of inhibiting the calcitonin gene-related peptide, also known as anti-CGRPs [106]. The biopharmaceutical company Amgen (AMGN) is driven to tap Aimovig’s potential US market of 10 million patients through its indications in preventing migraines. The drug has already been approved and commercialized. Even though investors strongly believe that Aimovig is a promising asset, there have been some challenges. The drug is currently in competition with several other upcoming anti-CGRPs [such as Teva’s (TEVA) fremanezumab], oral anti-CGRPs, and Allergan’s (AGN) Botox. Furthermore, investors are concerned that the anti-CGRP class of medication will be restricted to just chronic migraine or patients that have failed Botox treatment. Initial post marketing surveillance data has been successful in reducing a few of these concerns [107].Case Study 5
- identify, characterize or quantify a safety hazard;
- confirm the safety profile of a medicine; or,
- measure the effectiveness of risk-management measures.
3.8. Interchangeability of Biologics and Biosimilars
The Brazilian health regulatory agency, Agência Nacional de Vigilância Sanitária (ANVISA), follows similar guidelines to interchangeability as that of the European Medicines Agency (EMA) [115]. While guidelines in the US connects interchangeability to substitution within pharmaceutical practice, interchangeability in Brazil constitutes medical practice within the scope of influence of physicians, patients, and Ministry of Health. Currently, ANVISA has not introduced any guidelines which specify the additional data or studies required to evaluate whether the biosimilar is interchangeable with its originator biologic. The present guidelines however dictate that the therapy directed towards the patient should not be switched multiple times between the biosimilar and comparator product for traceability reasons. Brazilian physician communities continue to push for an official interchangeability policy [116].Case Study 6
4. Marketing Perspective of Biosimilars
4.1. Opportunities of Biosimilars in Global Markets
Bevacizumab-awwb (Mvasi) received approval by the US FDA for the treatment of adult patients with certain cervical, colorectal brain, kidney, and lung cancers [121]. This biosimilar is a recombinant IgG1 monoclonal antibody that is capable of binding to vascular endothelial growth factor (VEGF), before inhibiting angiogenesis. Bevacimuzab is the first biosimilar approved in the US for anticancer therapy. Studies that were carried out include structural and functional characterization, data obtained through animal studies, immunogenicity studies, pharmacokinetic and pharmacodynamics profiles and safety and efficacy data.Case Study 7
- (a)
- Cost of the biosimilar—Anticipation of how the market for the corresponding biosimilar will respond to a particular price is key for manufacturers of reference biologics. This enables them to determine the price at which their products should be before patent expiry [123]. Biosimilar manufacturers often target biologics possessing lower prices in order to maintain similar drug costs and levels of profit.
- (b)
- History of the interchangeability of the biosimilar drug—Biosimilars that have a well-documented history of being substituted in place of their reference drug in therapy have a higher rate of acceptance for use in clinical settings and by patients [124]. Biosimilars for products, such as erythropoetins and granulocyte colony stimulating factors, have well-established use in replacement of their references. Therefore, these products have a higher preference by doctors and patients. On the other hand, biosimilars used to treat autoimmune diseases may require sufficient persuasion of clinics and patients for their adoption. This is usually attempted through the demonstration of their safety and interchangeability.
- (c)
- Length of the therapy—Patients are more likely to vouch for those biosimilar treatment strategies that do not encompass a large period of time [125]. Patients tend to favour attaining significant cost savings and lowering the risk factor in being treated with a biosimilar product over the reference biologic.
- (d)
- Patient involvement in choice of therapy—Programs that encourage patient participation on treatment decisions allow for greater confidence in selecting biosimilar options. These programs also allow manufacturers to differentiate their products based on the demands of the patient market. Such strategies require strong evidence of the safety and efficacy of the biosimilar drug. This is required to sufficiently convince patients that biosimilars are a safe, effective, and cost effective option in biologics treatment [126].
- (a)
- Variation in regulations: There is high variability in regulations worldwide, regarding the approval of biosimilars. In Europe, the regulatory pathway is much clearer and more defined. On the other hand, in the US., there are stringent but very broad IP and patent laws, which may lead to a major obstacle in effective marketing leading to patient inaccessibility and increase in cost [130]. Certain countries attempt to produce biosimilars without undergoing the standardized regulatory evaluations in terms of the quality, safety, and efficacy. WHO developed a guideline in 2015 that provides a road-map for the regulatory assessments of such products. Under this guideline, these products are classified as non-original biologics since they have been registered without a comprehensive, head-to-head comparison with a reference biologic [131].
- (b)
- Complexity of manufacture: The manufacturing process of biosimilars tend to be more tedious than that of the reference biologic [1]. This results in increased time, risks, and costs of productions pushing the market prices of these drugs to be higher than expected once they are commercialized.
- (c)
- Greater competition: Biosimilar products face market competition from both “biobetters” (improved versions of the innovator biological molecule engineered in order to improve safety and efficacy) as well as competing brands of biosimilars [132]. Providing sufficient demonstration of the reliability and effectiveness of the biosimilar product is a time-consuming process. Manufacturers of biosimilars with long treatment plans face the burden of keeping their footing with their market rivals.
- (d)
- The need for greater caution during drug substitution: Lack of clear interchangeability guidelines within pharmemerging economies lead to reluctance in physicians to prescribe a particular biosimilar over its reference. This can be resolved by the provision of sufficient assurance of the product’s therapeutic equivalence and safety.
4.2. Strategic Perspective for Biosimilar Market Entry
- (a)
- capacity of the company to fund basic research and promote the development of clinical trials;
- (b)
- accessibility to specific and reliable biosimilar development platforms;
- (c)
- supporting services such as legal expertise and distribution channels to facilitate the entry of the product in the market;
- (d)
- access to a global network of marketing representatives;
- (e)
- lobbying with local regulatory authorities, governments and opinion leaders to allow for the approval of the biosimilar drug as a substitute of the reference product in therapy and to initiate competition between the biosimilar and its reference; and,
- (f)
- experience in the manufacturing of biological and/or biosimilar products.
4.3. The Nocebo Effect of Biosimilars
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
- alpha,
- beta, and
- gamma.
Appendix B
Name of Biosimilar Product | Approved by | Date of Approval | Manufacturer |
---|---|---|---|
Omnitrope | EMA | April 2006 | Sandoz |
Binocrit | EMA | August 2007 | Sandoz |
Epoetin alfa Hexal | EMA | August 2007 | Hexal |
Abseamed | EMA | August 2007 | Medice |
Silapo | EMA | December 2007 | Stada |
Retacrit | EMA | December 2007 | Hospira UK |
Ratiograstim | EMA | September 2008 | Ratiopharm |
Tevagrastim | EMA | September 2008 | Teva |
Biograstim | EMA | September 2008 | CT Arzneimittel |
Filgrastim ratiopharm | EMA | September 2008 | Ratiopharm |
Filgrastim hexal | EMA | February 2009 | Hexal |
Zarzio | EMA | February 2009 | Sandoz |
Nivestim | EMA | June 2010 | Hospira UK |
Remsima | EMA | September 2013 | Celltrion |
Ovaleap | EMA | September 2013 | Teva |
Grastofil | EMA | October 2013 | Apobiologix |
Bemfola | EMA | March 2014 | Finox Biotech |
Accofil | EMA | July 2014 | Accord |
Abasaglar | EMA | September 2014 | Eli Lilly |
Zarxio | US FDA | March 2015 | Sandoz |
Basaglar | US FDA | December 2015 | Eli Lilly |
Benepali | EMA | January 2016 | Samsung Bioepis |
Inflectra | US FDA | April 2016 | Celltrion |
Flixabi | EMA | May 2016 | Samsung Bioepis |
Inhixa | EMA | July 2016 | Techdow Europe AB |
Thorinane | EMA | July 2016 | Pharmathen S.A |
Erelzi | US FDA | August 2016 | Sandoz |
Amjevita | US FDA | September 2016 | Amgen |
Movymia | EMA | November 2016 | Stada |
Terrosa | EMA | November 2016 | Gedeon Richter |
Amgevita | EMA | January 2017 | Amgen |
Solymbic | EMA | March 2017 | Amgen |
Renflexis | US FDA | April 2017 | Merck & Co. Inc. |
Cyltezo | US FDA | April 2017 | Boehringer Ingelheim |
Truxima | EMA | August 2017 | Celltrion |
Mvasi | US FDA | September 2017 | Genentech |
Ogivri | US FDA | December 2017 | Mylan |
Ixifi | US FDA | December 2017 | Pfizer Inc. |
Retacrit | US FDA | May 2018 | Pfizer Hospira |
Fulphila | US FDA | June 2018 | Mylan NV |
Nivestym | US FDA | July 2018 | Pfizer Inc. |
Hyrimoz | US FDA | October 2018 | Sandoz |
Udenyca | US FDA | November 2018 | Coherus BioSciences |
Herzuma | US FDA | December 2018 | Celltrion and Teva |
Ontruzant | US FDA | January 2019 | Samsung Bioepis |
Trazimera | US FDA | March 2019 | Pfizer Inc. |
Eticovo | US FDA | April 2019 | Samsung Bioepis |
Name of Biosimilar Product | Reference Product | Class of Biological Medicine | INN | NN |
---|---|---|---|---|
Zarzio Zarxio | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | X filgrastim-sndz |
Remsima Inflectra | Remicade | Tumor Necrosis Factor (TNF) alpha blocker | Infliximab | X infliximab-dyyb |
Erelzi | Enbrel | Tumor Necrosis Factor (TNF) Žalpha blocker | Etanercept | etanercept-szzs |
Amgevita Amjevita | Humira | Tumor Necrosis Factor (TNF) alpha blocker | Adalimumab | X adalimumab-atto |
Renflexis Flixabi | Remicade | Tumor Necrosis Factor (TNF) alpha blocker | Infliximab | infliximab-abda X |
Cyltezo | Humira | Tumor Necrosis Factor (TNF) alpha blocker | Adalimumab | adalimumab-adbm |
Mvasi | Avastin | Monoclonal Antibody (MAb) | Bevacizumab | bevacizumab-awwb |
Omnitrope | Genotropin | Growth Hormone (GH) | Somatotropin | X |
Binocrit | Eprex | Erythropoietin (EPO) | Epoetin alpha | X |
Epoetin alfa Hexal | Eprex | Erythropoietin (EPO) | Epoetin alpha | X |
Abseamed | Eprex | Erythropoietin (EPO) | Epoetin alpha | X |
Silapo | Eprex | Erythropoietin (EPO) | Epoetin zeta | X |
Retacrit | Eprex | Erythropoietin (EPO) | Epoetin zeta | X |
Ratiograstim | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | X |
Tevagrastim | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | X |
Biograstim | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | X |
Filgrastim ratiopharm | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | X |
Filgrastim hexal | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | X |
Accofil | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | X |
Nivestim | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | X |
Ovaleap | Gonal-f | Follicle Stimulating Hormone (FSH) | Follitropin alpha | X |
Grastofil | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | X |
Bemfola | Gonal-f | Follicle Stimulating Hormone (FSH) | Follitropin alpha | X |
Abasaglar Basaglar | Lantus | Human Insulin Hormone | Insulin glargine | X X |
Benepali | Enbrel | Tumor Necrosis Factor (TNF) alpha blocker | Etanercept | X |
Inhixa | Clexane | Low molecular weight heparin (Anticoagulant) | Enoxaparin Sodium | X |
Thorinane | Clexane | Low molecular weight heparin (Anticoagulant) | Enoxaparin Sodium | X |
Solymbic | Humira | Tumor Necrosis Factor (TNF) alpha blocker | Adalimumab | X |
Truxima | MabThera | Monoclonal Antibody (MAb) | Rituximab | X |
Movymia | Forsteo | Para-Thyroid Hormone (PTH) | Teriparatide | X |
Terrosa | Forsteo | Para-Thyroid Hormone (PTH) | Teriparatide | X |
Ogivri | Herceptin | Monoclonal Antibody (MAb) | Trastuzumab | trastuzumab-dkst |
Ixifi | Remicade | Tumor Necrosis Factor (TNF) blocker | Infliximab | infliximab-qbtx |
Fulphila | Neulasta | Leukocyte Growth Factor | Pegfilgrastim | pegfilgrastim-jmdb |
Nivestym | Neupogen | Granulocyte Colony Stimulating Factor (G-CSF) | Filgrastim | filgrastim-aafi |
Hyrimoz | Humira | Monoclonal Antibody (MAb) | Adalimumab | adalimumab-adaz |
Udenyca | Neulasta | Leukocyte Growth Factor | Pegfilgrastim | pegfilgrastim-cbqv |
Herzuma | Herceptin | Monoclonal Antibody (MAb) | Trastuzumab | trastuzumab-pkrb |
Ontruzant | Herceptin | Monoclonal Antibody (MAb) | Trastuzumab | trastuzumab-dttb |
Trazimera | Herceptin | Monoclonal Antibody (MAb) | Trastuzumab | trastuzumab-qyyp |
Eticovo | Enbrel | Tumor Necrosis Factor (TNF) alpha blocker | Etanercept | etanercept-ykro |
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Regulatory Guideline | Definition |
---|---|
European Medicines Agency (EMA) | A biologic medicinal product similar to another biologic medicine that has already been authorized for use |
World Health Organization (WHO) | A biotherapeutic product that is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product |
United States Food & Drug Administration (US FDA) | A biologic product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between the biologic product and the reference product in terms of safety, purity, and potency of the product |
Biologics and Genetic Therapies Directorate (BGTD) | A biologic drug that enters the market subsequent to a version previously authorized in Canada, with demonstrated similarity to a reference product |
Pharmaceuticals and Medical Devices Agency (PMDA) | A biotechnological drug product developed by a different company, which is comparable with an approved biotechnology-derived product |
Therapeutic Goods Administration (TGA) | A version of an already registered biologic medicine that has a demonstrable similarity in physicochemical, biologic, and immunological characteristics, efficacy, and safety, based on comprehensive comparability studies |
Regulatory Guideline | Preclinical Data | Clinical Trials |
---|---|---|
EMA | Target binding; signal transduction, functional activity/viability of cells of relevance. If in vitro comparability is satisfactory, animal studies may not be required | Comparative PK/PD * studies followed by clinical efficacy and safety trials |
WHO | Receptor-binding or cell-based assays; relevant biologic/PD activity, toxicity | Similar to EMA |
US FDA | Structural analyses, functional assays; animal toxicity assessments, PK/PD, immunogenicity (unless determined not necessary by FDA) | Similar to EMA + Immunogenicity assessment studies |
BGTD | Receptor-binding or cell-based assays; Animal PD and repeat-dose toxicity studies, and other relevant safety observations | Similar to EMA + Immunogenicity assessment studies |
PMDA | Toxicity and pharmacologic assessments, PK, and local tolerance | Similar to EMA + Immunogenicity assessment studies |
TGA | Similar to EMA | Similar to EMA |
Regulatory Guideline | Naming |
---|---|
EMA | Commercial name, appearance, and packaging should differ; INN * should be the same for related biosimilars |
WHO | Changes are being considered to the current policy of using INN |
US FDA | Draft guidance proposes that all biologics be given a four-letter suffix to the INN |
BGTD | Not specified |
PMDA | Non-proprietary name of the reference product followed by “BS” and an abbreviation to reference the manufacturer |
TGA | Australian biologic name without a specific biosimilar identifier suffix (policy is under review) |
INN | Name | Strength | Price | Cost Difference (%) |
---|---|---|---|---|
Filgrastim | Neupogen (Reference Biologic) | 300 mg | $324.30 | 16.21% |
Zarxio (Corresponding Biosimilar) | 300 mg | $275.66 | ||
Filgrastim | Neupogen (Reference Biologic) | 480 mg | $516.45 | 16.22% |
Zarxio (Corresponding Biosimilar) | 480 mg | $438.98 | ||
Infliximab | Remicade (Reference Biologic) | 100 mg | $940/vial | 44% |
Inflectra (Corresponding Biosimilar) | 100 mg | $525/vial | ||
Infliximab | Remicade (Reference Biologic) | 100 mg | $1167.82/vial | 35% |
Renflexis (Corresponding Biosimilar) | 100 mg | $753.39/vial |
Regulatory Guideline | Pharmacovigilance |
---|---|
EMA | Risk management pharmacovigilance plan must be submitted; clinical safety monitored closely after marketing authorization |
WHO | Pharmacovigilance plan submitted with marketing authorization application; describe planned post-marketing activities |
US FDA | Any risk evaluation and mitigation strategy for the reference product applies. Post-marketing studies or additional clinical trials could be mandated |
BGTD | Risk management plan submitted prior to marketing authorization; periodic safety update reports. Serious adverse drug reactions reported within 15 days |
PMDA | Post-authorization safety studies monitored on a continuous basis |
TGA | Risk management plan outlining pharmacovigilance procedures to be implemented submitted with biosimilar application |
Potential Risk Factor | Considerations | Sources of Evidence |
---|---|---|
Risk of product not being approved as per standards in global guidelines supporting biosimilar development | The presence of “non-comparable biologics” (NCBs) in certain parts of the world implies the existence of drugs that have not been directly compared with the reference product according to recognized guidelines and therefore may not meet global standards. Switching scenarios between these types of products and their reference product represent the highest level of uncertainty and risk to patient safety | Approved by Regulatory Authorities in accordance to WHO guidelines on Similar Biotherapeutic Products (SBPs) |
Switching between the reference product and its biosimilar | Regulatory submissions for a biosimilar may sometimes consist of information on substituting the reference product for the biosimilar and/or vice versa. The quantity and type of this information will differ with each submission | For example, public assessment reports from Regulatory Authorities & scientific literature |
Switching between biosimilars | The presence of clinical data directly comparing different biosimilars to the same reference biologic in the similar group of related products is very less likely to exist. This is not a mandate in regulatory filings. Switching between biosimilars represents an unknown, and one that harbours considerable uncertainty | There may be anecdotal or real world data available |
Nature of the product | All biologics display a degree of immunogenicity, however, the nature and consequences of immunogenicity differ based on the product. Information regarding the reference biologic and biosimilar products may be of great assistance in this aspect. For biologics that are substitutes for a naturally-occurring hormone/cytokine/receptor, there is an increased risk of serious consequences, (e.g., if antibodies directed towards native proteins are produced) | For example, public evaluation reports from the related regulatory authorities and scientific literature |
Route of administration and dosing device | Subcutaneous administration shows a greater degree of immunogenicity compared to intravenous administration. Usage of a different dosing device for the biosimilar may potentially increase the uncertainty as patients may be not be sufficiently familiar, when administering the product | Adequate labelling for biosimilar and reference products possessing proper dosing instructions |
Extent and scope of post approval safety data | Where stringent systems for post approval safety monitoring of biologics including biosimilars exist, i.e., in jurisdictions compliant with WHO guidelines, such data may provide reassurance that the real-world use of the product does not result in any unexpected risks | Design and assessment of a risk management plan or evaluation of post marketing safety reports from related regulatory authorities. Overview of publications possessing review of safety data |
Developed Markets | Emerging Markets |
---|---|
Most promoinent biosimilar markets e.g., EU, Japan, USA | Biosimilar markets with little or no presence e.g., China, Russia |
Possess dedicated regulatory pathways | Tend to adopt regulatory pathways already set in developed markets |
Possess stringent, abbreviated approval processes | Approval processes have less stringent comparability guidelines and therefore take lesser time |
Physicians less open on reducing costs of therapy | Physicians more open on lowering the cost of therapy and increasing patient affordability |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Kabir, E.R.; Moreino, S.S.; Sharif Siam, M.K. The Breakthrough of Biosimilars: A Twist in the Narrative of Biological Therapy. Biomolecules 2019, 9, 410. https://doi.org/10.3390/biom9090410
Kabir ER, Moreino SS, Sharif Siam MK. The Breakthrough of Biosimilars: A Twist in the Narrative of Biological Therapy. Biomolecules. 2019; 9(9):410. https://doi.org/10.3390/biom9090410
Chicago/Turabian StyleKabir, Eva Rahman, Shannon Sherwin Moreino, and Mohammad Kawsar Sharif Siam. 2019. "The Breakthrough of Biosimilars: A Twist in the Narrative of Biological Therapy" Biomolecules 9, no. 9: 410. https://doi.org/10.3390/biom9090410