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Abstract: |
Submitted: 29 August 2014; Revised: 2 September 2014; Accepted: 3 September 2014; Published online first: 5 September 2014
The safety profile of biologicals can often be attributed to: a) adverse events related to an exaggerated pharmacology, and b) immunological reactions, including immunogenicity and infusion-related reactions [1, 2].
Adverse events related to an exaggerated pharmacology can be illustrated by the occurrence of infections during the use of biologicals with a strong immunosuppressive mode of action. Patients treated with tumour necrosis factor alpha (TNF-alpha) inhibitors should, for example, be tested for latent tuberculosis before treatment is initiated due to an increased risk of tuberculosis related to treatment with these agents. TNF-alpha plays an important role in human immune defence against the mycobacterium tuberculosis bacterium. Patients with latent tuberculosis should, therefore, receive anti-tuberculosis treatment before starting treatment with a TNF-alpha inhibitor [1–6].
Immunological reactions are varied, and can include the formation of antibodies, allergic reactions, and administration-site conditions, which are inherent to the biological nature of these agents and the parenteral route of administration. If antibodies are formed they often have no clinically relevant effect, but in some cases they are directed against the administered biological, neutralizing the agent’s effect and in some cases antibodies are not only directed against the administered biological but also against the endogenous available protein. Neutralizing anti-drug antibodies (ADAs) result in a diminished clinical response to the biological, and their presence is reflected in clinical practice by the administration of higher doses and/or more frequent dosing over time. A study by Bartelds et al. found that about one third of patients treated with adalimumab for rheumatoid arthritis developed neutralizing antibodies within three years after the start of treatment [7].
Testing for the presence of neutralizing antibodies is receiving more and more attention in clinical practice, partly as a result of available tests and trained staff able to use them. In addition, ADA has been associated with severe infusion reactions following treatment with monoclonal antibodies [8]. The development of antibodies directed against both the administered biological and the endogenous available protein can be illustrated by the well-known Eprex® case. After a change in the formulation of epoetin-alfa, patients developed antibodies against both the administered epoetin and also against the endogenous available erythropoietin, resulting in a complete depletion of erythropoietin and a serious condition: pure red cell aplasia. As illustrated by the Eprex® case, a change in the production process of a biological might influence the immunogenic potential of that biological, and any change in the production profile should, therefore, be clearly evaluated during the production of all biologicals [9–13]. Several factors are known to influence immunogenicity in clinical practice, including the presence of impurities and/or leachables, and protein aggregation. The subcutaneous route of administration is in general more immunogenic than the intravenous route of administration, and the concomitant use of other immunosuppressive agents is known to reduce the formation of antibodies. Alongside these factors, an individual patient’s genetics and age are known to influence immunogenicity [10, 14]. Adverse events related to the parenteral mode of administration are often reflected in adverse reactions at the site of administration.
Clinical safety is important during the development of a biosimilar. This paper provides an overview of the main aspects related to the safety assessment of biosimilars. The European Medicines Agency’s ‘Guideline for similar biological medicinal products containing biotechnology-derived proteins as active substances: non-clinical and clinical issues’, which is currently under revision, forms the basis for the topics discussed in this paper [15].
Data related to the clinical safety of the biosimilar should be collected during the complete clinical development programme and should be captured during initial pharmacokinetics and/or pharmacodynamics studies and also as part of the pivotal clinical efficacy study [15]. A complete overview of all safety data collected should be submitted to the regulatory authorities for assessment.
Safety related to an exaggerated pharmacology
Adverse events related to an exaggerated pharmacology known for the reference product will also occur during use of the biosimilar. Differences in adverse events related to an exaggerated pharmacology, which can be related to the biosimilar and not to a chance finding, may preclude registration as a biosimilar and should be carefully evaluated in relation to the totality of evidence obtained for the biosimilar.
The safety data available for the reference product should specifically be taken into account and should form the basis for the safety evaluation of the biosimilar [15]. For the infliximab biosimilars Inflectra® and Remsima®, safety issues of special interest were identified which are known safety concerns for the reference product, Remicade®. These safety issues included heart failure, serious infections, serious infusion reactions, delayed hypersensitivity reactions (serum sickness), systemic lupus erythematosus/lupus-like syndrome, hepatobiliary events, demyelinating disorders, haematologic reactions and lymphoma [16–18]. Due to a relatively limited number of patients, the pivotal clinical efficacy study is in general not capable of detecting differences in rare adverse events between the biosimilar and the reference product. However, the equivalence design used for the pivotal clinical efficacy trial of the biosimilar is usually much larger than the superiority trails against placebo that formed the basis for the approval of the reference product. This results in a safety database which is usually sufficient for the assessment of the biosimilar. In addition, adverse events should be compared by type, severity and frequency in order to provide as complete as possible a comparison between the safety profile of the biosimilar and the reference product [15]. A thorough evaluation of the particular cases, in light of the totality of evidence as regards biosimilarity, is needed in case differences are observed between the biosimilar and the reference product; in other words, is a more adverse safety profile scientifically plausible? For the biosimilar infliximab, a numerical imbalance was found in serious adverse events in the pivotal clinical efficacy trial, with a higher incidence of serious infections, including tuberculosis. A thorough review of all the available data suggested that the difference was most likely a chance finding and that this should be further evaluated as part of the risk management plan (RMP). The following arguments were considered:
This example illustrates a challenge in the safety assessment of a biosimilar and the need for a thorough post-marketing follow-up, especially if differences are observed during the assessment of safety data collected throughout clinical development [15, 16].
Immunogenicity assessment
Immunogenicity and other immunological reactions, e.g. infusion and hypersensitivity reactions, are especially important during the development of a biosimilar. As already mentioned in the introduction, a change or a difference in production process might influence the characteristics of the biological and potentially its immunogenic potential – notably, in either an adverse or beneficial way. Since the production process of a biological is proprietary knowledge of a company, biosimilar companies should develop their own production process [9–12]. Assessment of immunogenicity, therefore, already starts during the quality assessment of the biosimilar, where the physicochemical characteristics of the biosimilar and the reference product are extensively assayed, assessed and compared. If differences are found, for example, differences in glycosylation, companies are advised to clearly evaluate these differences in relation to the immunogenic potential of the biosimilar [14].
Immunogenicity assessment is an important part of the clinical development programme and should also be investigated in a comparable way between the biosimilar and the reference product. The amount of immunogenicity data needed will depend on experience gained with the reference product and/or the product class. Immunogenicity data for chronically administered biosimilars should normally be collected pre-licensing for up to one year. However, shorter follow-up might be justified based on the immunogenicity profile of the reference product. If, for example, it is known that immunogenicity for the reference product mostly develops within six months after the start of treatment, collection of immunogenicity data for the biosimilar less than one year pre-licensing may be justified. Immunogenicity data for the additional period, up to one year, could then be submitted post-authorization, if considered necessary by the regulatory authorities [15]. In addition, other aspects related to immunogenicity, e.g. route of administration and/or type of disease; should be included and preferably tested in the most sensitive patient population [10, 14].
Immunogenicity testing of the biosimilar and the reference product should be conducted within the biosimilar comparability exercise by using the same assay format and sampling schedule. The assay used to detect antibodies is an important consideration during the clinical development of a biosimilar and should meet all current standards. Comparison of data obtained for the biosimilar with historical data obtained for the reference product is generally not considered appropriate due to continuing developments in this field.
Assays have over time evolved to be much more sensitive. If one were to directly compare the immunogenicity of a biosimilar measured using a current assay with historical data of the reference product using an outdated assay, then it could appear that the biosimilar exhibits a much higher immunogenicity since the current assay is much more sensitive. This would not result in comprehensive data. Preferably, two assays should be used which are capable of detecting antibodies against both the biosimilar and the reference product. However, if only one assay is used, the assay should be capable of detecting antibodies to the biosimilar. This will provide a conservative comparison between the biosimilar and the reference product, and biosimilar companies should take into consideration that the one assay approach may result in higher antibody levels for the biosimilar as compared to the reference product. Differences found between the biosimilar and the reference product need to be justified in the application dossier. In principle, the incidence of antibodies and antibody titres should be measured and presented [14]. Assessment and interpretation of antibodies in relation to the potential effect on clinical efficacy and safety is important, as illustrated by the development of the infliximab biosimilar. Development of antibodies to infliximab was associated with an increase in the frequency of hypersensitivity/infusion-related reactions in patient groups treated with both the biosimilar and the reference product [16, 17].
In principle, the safety profile of the biosimilar and the reference product should be comparable. This also relates to immunogenicity. However, one exemption might be possible: if a lower immunogenicity is found for the biosimilar, this might not preclude approval as a biosimilar. Reduced development of neutralizing antibodies to the biosimilar could erroneously suggest that the biosimilar is more efficacious than the reference product when analysing the entire study population (since efficacy is less antagonized). The biosimilar company is therefore recommended to perform a subgroup analysis of patients treated with both the biosimilar and the reference product which did not mount an ADA response during the clinical trial. This subgroup analysis could be helpful to establish that the efficacy of the biosimilar and the reference product are in principle similar if not impacted by an immune response. [15].
Extrapolation of indications
Extrapolation of indications is a key aspect in the development and approval of biosimilars in Europe. Safety of the biosimilar should also be taken into account in relation to the mode of action of the biological in different indications. Adverse events related to an exaggerated pharmacology will apparently also occur in different indications of the biological. Immunogenicity is related to different aspects as discussed in the introduction, which might differ between indications, e.g. differences in concomitant medication and/or duration of treatment. Extrapolation of immunogenicity data from one indication to the other should, therefore, be justified based on the knowledge obtained with the reference product and/or product class. In case differences exist, there might be a need for additional immunogenicity studies in one or more specific indications [15].
The safety profile of the biosimilar should be evaluated on an ongoing basis during use in clinical practice. The same rules and obligations apply for biosimilars as for any other biological medicinal product, which means that a RMP must be submitted as part of the application procedure as well as Periodic Safety Update Reports (PSURs) and the collection of adverse events identified and reported after approval.
The RMP of the biosimilar should, as a starting point, be based on the RMP and knowledge obtained with the reference product and should take into account identified and potential risks associated with the use of the reference product. Immunogenicity and infusion-related reactions should specifically be addressed in the RMP and, if needed, additional pharmacovigilance activities to identify these reactions should be described. It is expected that spontaneous reporting of adverse events will generally not be able to detect effects of neutralizing antibodies and therefore other activities should be considered, e.g. measuring neutralizing antibodies in a subset of the population as part of a post-marketing obligation, where deemed necessary. Any specific safety monitoring for the reference product should, in principle, also apply to the biosimilar. In some instances there will be a need to compare certain adverse events of interest between the biosimilar and the reference product. With very rare events, e.g. progressive multifocal leukoencephalopathy during use with rituximab, any case will contribute to the general knowledge about this very rare condition and a comparison will not be possible due to the limited number of cases. Biosimilars are, therefore, encouraged to participate in already existing registries of the reference product.
Several registries are in place in Europe, particularly with biologicals used for rheumatoid arthritis, which have contributed greatly to the general knowledge on the safety and efficacy of the agents during use in clinical practice [1, 15]. The biosimilar infliximab will, for example, perform several post-marketing studies in already existing registries used for RA [16, 17].
Risk minimization measures in place for the reference product should generally also apply to the biosimilar, e.g. a patient alert card for serious infections related to the use of Remicade® is also included in the risk minimization programme of the biosimilar infliximab [16–18]. One exemption to this approach is risk minimization activities in place for the reference product which are specific for the device by which the reference product is administered [15]. The device by which the biological is administered might differ between biosimilar and reference product and might consequently need different educational measures to realize correct use in clinical practice [15].
An important issue related to pharmacovigilance is traceability of the administered biological, which applies to all biologicals and is not specific to biosimilars. Therefore, all appropriate measures should be taken to identify clearly any biological medicinal product which is the subject of a suspected adverse reaction report, with due regard to its brand name and batch number. This not only applies to the collection of spontaneously reported adverse events, but also during pharmacoepidemiological studies, including registries [15].
Safety assessment is an important part of the development of a biosimilar. Safety data should be collected throughout the complete clinical development programme and should be compared between the biosimilar and the reference product. Assessment of immunogenicity is especially important in this context due to the potential impact of changes in the production process and consequently on clinical safety. Differences in the safety profile will question biosimilarity and will require appropriate in-depth assessment and evaluation. A lower immunogenicity of the biosimilar might, however, be acceptable. Extrapolation of safety data from one indication to the other is possible and should be justified, especially with regard to immunogenicity and potential differences in the characteristics of the patient population and the disease in which the biological is used.
The same pharmacovigilance rules apply for biosimilars as for any other biological. Within the RMP the knowledge obtained with the reference product should be the basis for the content of the RMP and the obligatory post-marketing requirements, including risk minimization measures. Traceability is important and measures should be implemented to improve traceability.
All members and experts of the Biosimilar Medicinal Products Working Party (BMWP) of the Committee for Medicinal Products for Human Use (CHMP) are acknowledged for the discussions during the revision of the aforementioned guideline.
The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
Thijs J Giezen, PharmD, PhD
Foundation Pharmacy for Hospitals in Haarlem, 24 Boerhaavelaan, NL-2035 RC, Haarlem, The Netherlands
Christian K Schneider, MD
Danish Health and Medicines Authority, Division of Medicines Licensing and Availability, 1 Axel Heides Gade, DK-2300 Copenhagen S, Denmark, and Twincore Centre for Experimental and Clinical Infection Research, 7 Feodor-Lynen-Strasse, DE-30625 Hannover, Germany
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13. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Eng J Med. 2002;346(7):469-75.
14. European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. EMEA/CHMP/BMWP/14327/2006. 13 December 2007 [homepage on the Internet]. 2008 Jan 10 [cited 2014 Jul 22]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdf
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17. European Medicines Agency. Committee for Medicinal Products for Human Use. European Public Assessment Report Remsima. 27 June 2013 [homepage on the Internet]. 2013 Sep 30 [cited 2014 Jul 19]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002576/WC500151486.pdf
18. European Medicines Agency. Committee for Medicinal Products for Human Use. Scientific Discussion Remicade [homepage on the Internet]. 2005 Aug 12 [cited 2014 Jul 19]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000240/WC500050885.pdf
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Author for correspondence: Thijs J Giezen, PharmD, PhD, Foundation Pharmacy for Hospitals in Haarlem, 24 Boerhaavelaan, NL-2035 RC, Haarlem, The Netherlands |
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Source URL: https://gabi-journal.net/safety-assessment-of-biosimilars-in-europe-a-regulatory-perspective.html
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Abstract: |
Submitted: 9 November 2012; Revised: 12 November 2012; Accepted: 15 November 2012; Published online first: 19 November 2012
In GaBI Journal, 2012, issue 3-4, Dr Carlo Petrini [1] from the Italian National Institute of Health raises an important question–what are the ethical aspects of biosimilars? The participation of a bioethicist in the multidisciplinary debate around biosimilars is most welcome. In fact, ethical issues have been raised on the use of granulocyte colony-stimulating factor (G-CSF, filgrastim) in healthy volunteers by the European Group for Blood and Marrow Transplantation (EBMT) [2] later echoed by the World Marrow Donor Association (WMDA) [3]. The hypothesis is that healthy donors do not have any benefit from donating bone marrow and should therefore receive biosimilar filgrastim only when it has been tested in a clinical study in this particular setting (to confirm its safety), apparently since this indication was obtained by extrapolation of clinical data rather than by a dedicated clinical study, and ‘unexpected toxicity’ could occur [2]. This recommendation implies a notion that one can experience in numerous debates that there is a certain implicit assumption that biosimilars are less safe, or less ‘well tested’. Apparently, this is a good example on how important a thorough understanding of the biosimilar concept is when it comes to ethical considerations. Biosimilars in the EU have to undergo a strictly regulated comparability exercise against the reference medicinal product on the physicochemical, analytical, functional, non-clinical and clinical level [4]. Only if a biosimilar is a close copy of the reference medicine will it be approved as a biosimilar. The mainstay is an extensive comparative characterisation of the biosimilar in all functional aspects of the respective molecule [4]. Clinical data are generated not to re-confirm benefit, but to establish that any small differences that may exist, e.g. due to lack of sensitivity of current methods; do not have any relevant impact on efficacy and safety. This is performed in a sensitive clinical ‘model’ indication that covers these functional aspects. Extrapolation to other indications is then a logical scientific consequence and a sound scientific principle; every indication granted for authorised biosimilars has been ‘actively’ granted based on data or justification. The approval history in the EU clearly shows that not every biosimilar was approved, only those that met the stringent criteria were authorised; and such data were made publicly available also in literature [5, 6]. The safety database for a biosimilar is still considerable and can comprise several hundreds of patients [7, 8]. The question is also what ‘unexpected toxicity’ one would expect, since biologicals mostly have target-mediated toxicity (known from the reference product), and unspecific toxicity would very likely be picked up already in non-clinical and clinical studies before approval. Impurities, which may be able to elicit such unexpected toxicity are tightly controlled as for any other biological, otherwise a biosimilar would not be authorised in the EU, and thus quality concerns are not substantiated. One could say that at the time of approval a biosimilar submits both its own safety data plus the safety data accumulated so far with the reference medicinal product. It is unclear what other unexpected toxicity one could expect.
Dr Petrini takes this (controversially discussed) recommendation by the EBMT up and indicates how multifaceted ethical issues are. One could not agree more – in fact, EBMT recommendation not to use biosimilar filgrastim in this indication has been taken up by national medical societies [9, 10] and there is evidence that biosimilar filgrastims are not, or not widely, used in this indication, and this proves Dr Petrini right – raising ethical questions in the biosimilar debates are multifaceted and, one could add, create further ethical issues. In the 2012, European Generic medicines Association’s conference on biosimilars in London, UK [11], a discussant in one of the panel discussions indicated that medical doctors are in an ethical dilemma due to this recommendation. He said that there is evidence from medical practice with filgrastim biosimilars that they work ‘the same’ as the reference medicines and that money could be saved when using them, but due to the EBMT/WMDA recommendation, physicians cannot use biosimilars in this indication: Would an adverse event occur (and an adverse event would over time inevitably occur – there is no medical intervention without possible side effects!) then the particular doctor would be liable, since he did not follow the EBMT/WMDA recommendation, notwithstanding the fact that the particular adverse event would likely also have occurred with an ‘originator’ filgrastim. This raises another ethical dilemma: Scientifically not well founded concerns result in lack of trust and lack of uptake of medicines that have the potential to result in significant cost savings in the healthcare systems [12]. These financial resources could be used to either provide an effective treatment to more patients as it was possible before, or they could also be used for innovative new additional or alternative treatments that are often inherently expensive.
Interestingly, even we as regulators could see this recommendation not to accept extrapolation of safety data as an ethical dilemma for our approval procedures. Biological medicinal products like filgrastim often undergo changes in their manufacturing process after approval, and regulatory authorities require a ‘comparability exercise’ to prove that the change in the manufacturing process did not have any adverse impact on safety and efficacy [13]. In many cases analytical and functional data from in vitro assays are sufficient to claim this, and this helps maintain the manufacturing process of any licensed biological in line with state-of-the-art manufacturing principles, but certainly one could always start asking questions like: Are we really sure that there are not minute differences between pre- and post-change product that could show unexpected toxicity? How should we then handle a change in the manufacturing process for a licensed filgrastim? Should we demand a safety study also for healthy volunteers, or at least clinical data in any case? This answer has been, and should remain: ‘no’ – this would not necessarily be required from a scientific perspective. One could say that changes in the manufacturing process are not that critical since knowledge with the previous version exists. However, this would be dependent on the type and extent of change. But one could expand this ethical question and take it to a more general level, since this aspect may be the real underlying concern: How to justify authorisation and use of a biosimilar when there is an original product with a huge safety database and experience from practical clinical use? Obviously one can take the question to a more general level: How to justify authorisation of treatment option B with a limited database if there is treatment option A with an already extensive database due to its earlier approval and longer availability on the market? In practical terms, one could make deliberations on the following example from the treatment of rheumatoid arthritis with tumour necrosis factor alpha (TNF-alpha) inhibitors: For example, Remicade (infliximab) was licensed in 1999 for Crohn’s disease on a ‘limited’ database ‘under exceptional circumstances’ [14], and in 2000 for rheumatoid arthritis [15] (NB: example chosen due to availability of publicly available data on patient exposure). Already in 2004, the safety database was considerable: Cumulatively, more than half a million patients had been exposed to infliximab for a total of over a million person-years elapsed since first exposure [16]. Other TNF inhibitors were filed for marketing authorisation later, for example, Simponi (golimumab) or Cimzia (certolizumab pegol) in 2008 [17, 18], that is four years later. While their dossiers contained sufficient number of patients to come to an individual benefit–risk assessment, one could also have asked the aforementioned ethical question in this scenario (if it is valid to ask it for a biosimilar which is highly similar, then one should all the more so ask it for a new active substance where no reference is made and where there are differences between the products): Should we have licensed any other TNF inhibitor, given that others like Remicade, Enbrel and Humira already had a much larger safety database at the time the new ones filed their applications? Should doctors use them, given that there are others already on the market with an ‘established’ database? Should patients be exposed? The answer is clear: Both Simponi and Cimzia were approved for rheumatoid arthritis, based on their individual positive benefit–risk balance, and both have their place in the rheumatological armamentarium, like the other TNF inhibitors. Surely, this parallel to the biosimilars is on one hand not fair, since new active substances in the same class could have particular advantages like easier administration, reduced immunogenicity or others. On the other hand, if safety, and in particular unexpected safety, is a concern, then it is maybe worth exploring it from a bioethical perspective. Biosimilars make reference to an already authorised reference medicinal product and thus do, in this philosophy, not only file for regulatory approval with data generated with the biosimilar, but, as mentioned before, also with all the data generated with the reference medicinal product.
For me personally, the most important ethical question around biosimilars is: Given the strict rules that are applied for their approval in Europe, how ethical is it to question their safety, and can we afford to question it? Apparently, bioethical questions are multifaceted. The participation of bioethicists in this debate is not only welcome – it is urgently needed.
The views expressed in this article are the personal views of the author and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.
Competing interests: None.
Provenance and peer review: Commissioned, internally peer reviewed.
References
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Author: Christian K Schneider, MD, Chairman, Working Party on Biosimilar Medicinal Products (BMWP), European Medicines Agency (EMA), London, UK; c/o Danish Health and Medicines Authority, 1 Axel Heides Gade, DK-2300 Copenhagen, Denmark |
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