Emergence of biosimilar medicines across Europe and in the US brings the promise of new sources of value, as biologic medicines play a significant role in patient care across a growing number of disease areas. The European pathway to approval of biosimilars was developed to improve affordability and access to biological therapies; however, it remains a working progress as understanding on safety issues continue to develop.
Due to the present reality of biosimilar monoclonal antibodies (mAbs) in rheumatology, hospital pharmacists must play an important role in ensuring the safe, effective, and cost-effective use of biosimilars in health systems. This involves educating health care administrators, providers, policymakers and patients about these products.
The prospect of more affordable options that are safe and effective would increase patient access to biologics, free up resources for investment in new areas, and bring relief to pressured healthcare budgets. Overall, however, it is widely recognised across Europe that more awareness of the stringent regulatory approval pathways is needed to build confidence amongst pharmacists and physicians in biosimilars.1,2 This, along with clearer economic and clinical guidance surrounding their use, is necessary to improve understanding of healthcare providers.
Biosimilars in rheumatology
At the end of 2015, there were 41 biosimilar medicines of four key original biologics in the pipeline. Currently, manufacturers have filed marketing authorisations globally for biosimilar versions of the four top-selling biologics in rheumatology.
Samsung Bioepis has filed its biosimilar infliximab with the European Medicines Agency (EMA). This will be the second biosimilar infliximab to be approved in the EU, following the launch of Celltrion’s biosimilar infliximab in 2013.
Samsung Bioepis received a positive assessment of the first biosimilar version of Enbrel by the EMA in November 2015 under the brand name Benepali, and this was approved by the European Commission (EC) in January 2016. This opened the way for the launch of the product across the EU. Furthermore, in December 2015, the EMA accepted Sandoz’s submission for its biosimilar etanercept; in the US, the Food and Drug Administration (FDA) approved Sandoz’s submission for biosimilar etanercept in August 2016.
Late in 2015, Amgen became the first manufacturer to file an application with the EMA and the FDA for biosimilar adalimumab – and there are approximately half a dozen other biosimilars versions of this molecule in late stage development.
Applications have been filed in Europe for Sandoz’s and Celltrion’s biosimilar rituximab. South Korea and Argentina are also assessing marketing authorisation for two different biosimilar versions of Mabthera, by Apogen and Mabion, respectively.
Further biosimilar versions of Simponi (golimumab), and Orencia (abatacept) are also in development. This pipeline represents an opportunity for hospital pharmacists, physicians and patients to ensure greater access to these important treatments.
Change of paradigm in regulatory approval of biologics
The alteration of the manufacturing processes, and introduction of new formulations and new containers and closures might affect the protein characteristics and the impurity content of a medicine during its life cycle. These alterations create a new version of the active substance.3,4 Therefore, the manufacturer must compare the new and old versions of the product and demonstrate to the regulatory authorities that an impact in the clinical efficacy and safety is not likely.
In most cases, this is achieved by physicochemical and structural comparisons, sometimes supplemented by in vitro functional assays. The experience over the last 20 years of validating product and process changes has given manufacturers and regulators the knowledge to reliably compare different versions of a given biological medicinal product.4
The important question is whether an independent biopharmaceutical manufacturer has the technical capability to reproduce entire antibodies. The exhaustive and comprehensive comparability exercise conducted to demonstrate the biosimilarity of infliximab biosimilar Remsima/Inflectra (CT-P13) compared to the reference biological (Remicade) shows that this was possible.5 In this case, the comparability exercise met all the stringent requirements requested for EMA approval and clearly demonstrates that current technology exists to reproduce glycosylated mAbs with a high standard of biosimilarity. Although the methodology of comparability is crucial to the concept of biosimilarity, it is important to note that a comparable drug is not a biosimilar.
A biosimilar drug is compared with a limited historical batch record of the original drug present in the market. Therefore it is necessary to have a clinical development phase to confirm its clinical equivalence to the reference biologic drug.5 Comparability at the pre-clinical level evaluates all mechanisms of action related to the antibody in question in all approved indications. The emphasis in pre-clinical assessment is a central claim when comparing two mAbs, because this methodology is more sensitive to the differences between two molecules than clinical studies in patients. Therefore, the clinical efficacy and safety of a biosimilar mAb can be securely anticipated when the correspondent critical quality attributes (CQAs) are studied in detail by comparability.
Clinical trials aim to confirm the quality, efficacy and safety of the biosimilar mAb and assess whether remaining uncertainties impact clinical outcomes. The two major uncertainties to be evaluated in Phase I and Phase III studies are pharmacokinetics (PK) and immunogenicity.5,6 Although the CQAs that influence pharmacokinetics and immunogenicity were evaluated in pre-clinical studies, the response of the patient to the drug is variable. Thus, a clinical confirmation stage is necessary to conclude that the biosimilar has no clinically significant differences to the reference product in terms of safety, purity, and potency. In conclusion, the change of paradigm in regulatory assessment of biosimilars is to focus on medicine and not on disease.7
Assessing immunogenicity of mAbs
Safety is a major concern when it comes to biologics (including biosimilars) and the most critical safety concern is immunogenicity. Immunogenicity is the ability to induce a humoral and/or cell mediated immune response. The immune response, however, is influenced by many factors including the disease, the drug and the patient. This represents a new issue when considering automatic substitution of originator biologicals and biosimilars.7 The EMA leaves this decision to the respective national authorities. It has been claimed that the switch from the reference product to the corresponding biosimilar may have an impact on the efficacy and safety, namely due to immunogenic responses. During biologic drug substitution, immunogenicity may be, in principle, caused by two mechanisms.
First, the immune system may react to a structural difference between the biosimilar and original products due to the uncovering of antigenic portions of the molecule that would normally be hidden from the immune system. Such a reaction is highly unlikely with licensed biosimilars because the products have been shown to have comparable structure, stability, purity and immunogenicity in pre-licensing clinical trials.2,7 8 Without structural changes to the biosimilar, there is a low probability of humoral response against new B-cell epitopes, which reduces the likelihood of neutralising antibodies against the biosimilar.
The second possibility is that the immunoglobulin class or specificity of anti-drug antibodies will change upon the switch to a biosimilar. T-cell activation is required in both cases. Because activation of T-cells would require recognition of new linear peptide epitopes, this is very unlikely due to the same amino acid sequence and similar post-translational profile of the biosimilar compared to its reference product.2,7–9
Most biologic drugs induce immune responses, which in many cases do not have clinically relevant consequences. Increased immunogenicity has, on sporadic occasions, been associated with manufacturing changes of a given original biological product. A well-known example of these reactions was the increase in antibody-mediated pure red cell aplasia associated with a formulation of Eprex (epoetin alfa) used in patients requiring chronic dialysis.10,11 In this case, a minor manufacturing change was responsible for anti-epoetin alfa antibody responses, probably due to protein aggregation.
The scientific rationale is that aggregates contribute to immunogenicity by breaking B-cell tolerance, leading to activated B-cells that produce antibodies.8,9 Thus, protein aggregation is an important CQA that contributes to the immunogenicity of therapeutic proteins, either by revealing new epitopes or by forming highly repetitive motifs. Over the last 20 years, the regulators were more knowledgeable of protein aggregation/purity and the manufacturers have increased dramatically the sensitivity to detect sources of protein instability due to improved regulatory guidelines. Therefore, compared with original biologics, biosimilars have the advantage of being studied by comparability at the level of CQAs with the reference product. For an original drug, immunogenicity is more complicated and unpredictable to conclude.
Management of clinical and pharmaceutical issues
Once approved as a clinically comparable version of the reference product, the biosimilar should be considered for substitution. For example, in the clinical development of CT-P13, the PLANETAS and PLANETRA extension studies did not show any increases in immunogenicity compared with Remicade.12 However, the ultimate therapeutic responsibility and patient follow-up remain with the treating physician and hospital pharmacist. It is therefore essential to trace the individual batch of any original biologic and biosimilar that was administered to an individual patient.
Pharmacovigilance and traceability are key concepts when managing biologics. For this reason, management plans, including immunogenicity assessments, have been put in place for all biologics, including biosimilars. The goals of such plans are to collect additional information as early as possible to further characterise the risk profile and to inform the safe and effective use of the product.13,14 The EMA recommends that a comprehensive pharmacovigilance plan be submitted as part of the original approval application, taking into account immunogenicity risks identified during product development as well as any anticipated future risks.12 Evaluation of immunogenicity should include immune response case definitions, processing patient samples and support for physicians reporting adverse drug reactions.
Immunogenicity has an important place in biosimilar pharmacovigilance. However, to support clinical decisions in rheumatology, it is less conclusive and should be substituted by the assessment of mAb trough levels and PK analysis. World Health Organization guidelines state that the monitoring period for immunogenicity assessment depends on the intended duration of treatment and the expected time of antibody development.13 A longer period of observation may be necessary to increase accuracy in assessing immunogenicity and the appropriate methodology be weighed to better interpret the data generated, taking into account their limitations.
The challenge of substitution
Building a consensus on substitution practices among physicians, pharmacists and administrative departments in health institutions appears to be very difficult. Country-specific rules on how physicians should approach the issue of biologic and biosimilar interchangeability are inconsistent.15 This means that physicians may be unsure of when it is appropriate to switch stable patients who are already on treatment with a particular molecule, but may be suitable for a more cost-effective version of that molecule. The five major EU markets leave the decision on when to switch patients in the hands of the physician. However the Assistance-Publique Hôpitaux de Paris (AP-HP) has recently shown how it is possible to reach a decision.
The Committee on Medicinal Products (COMED) of AP-HP recently decided that infliximab biosimilars and their originator could be considered therapeutically equivalent and, thus, could be authorised to participate in the same tender.13,14 This tender was only implemented for treatment-naïve patients, as the current French law does not allow switching from brand-name biologicals to biosimilars. In reaching this conclusion, COMED followed a rigorous decision-making process which included the following: a) assessment of the therapeutic equivalence; b) evaluation of the risk management plan for the infliximab biosimilars compared with Remicade; c) assessment of the immunogenicity data; and d) budget impact analysis. In addition to its decision, COMED made two recommendations.
First, that a vital post-approval surveillance of these products should be implemented following the tender; and second, physicians should be encouraged to take part in the registries that will be implemented by the medical disciplines concerned in the AP-HP.
- There is a need to address the problems caused by any concerns voiced by pharmacists and physicians about biosimilars.
- Biosimilar pipelines represents an opportunity for hospital pharmacists, physicians and patients to ensure greater access biologic therapies.
- The change of paradigm in regulatory assessment of biosimilars is to focus on medicine and not on disease.
- Pharmacovigilance and traceability are key concepts when managing biologics and biosimilars, and evaluation of immunogenic responses is critical.
- Biosimilar substitution can be possible with post-approval surveillance and followed by registries that will follow clinical, pharmacokinetic and immunogenic outcomes.
- Smith D, Leane S, Yoshimoto, M. Acceptance of biosimilars across physician specialties. BioTrends Research Group; Aug 2015.
- Weise M et al. Biosimilars: what clinicians should know. Blood 2012;120(26):5111−7.
- Gascón P et al. Clinical experience with Zarzio® in Europe: what have we learned? Support Care Cancer 2013;21(10):2925–32.
- Schellekens H, Moors E. Clinical comparability and European biosimilar regulations. Nat Biotech 2010;28:28–31.
- Dorner T, Kay J. Biosimilars in rheumatology: current perspectives and lessons learnt. Nat Rev Rheumatol 2015;11(12):713–24.
- Ratanji KD et al. Immunogenicity of therapeutic proteins: Influence of aggregation. J Immunotoxicol 2014;11(2):99−109.
- European Medicines Agency. EMA/CHMP/589422/2013. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002778/WC500151490.pdf (accessed September 2016).
- European Medicines Agency. EMEA/CHMP/BMWP/42832/2005 Rev1: Guideline on similar biological medicinal products containing biotechnologyderived proteins as active substance: non-clinical and clinical issues; 18 December 2014. www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf (accessed September 2016).
- Allison ME, Fearon DT. Enhanced immunogenicity of aldehyde-bearing antigens: a possible link between innate and adaptive immunity. Eur J Immunol 2000;30(10):2881−7.
- Boven K et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int 2005;67(6):2346−53.
- Kessler M, Goldsmith D, Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant 2006;21(Suppl. 5v):9−12.
- Braun J, Kudrin A. Switching to biosimilar infliximab (CT-P13): Evidence of clinical safety, effectiveness and impact on public health. Biologicals 2016;44(4):257−66.
- Bocquet F, Paubel P. First monoclonal antibody biosimilars: tackling the challenge of substitution. J Med Econ 2016;19(6):645−7.
- Knezevic I, Kang HN, Thorpe R. Immunogenicity assessment of monoclonal antibody products: A simulated case study correlating antibody induction with clinical outcomes. Biologicals 2015;43(5):307−17.
- Michetti P. A look beyond the biosimilarity of the molecules. J Crohns Colitis 2016;10(2):123−4.