Global policies on pharmacy-mediated substitution of biosimilars: a summary

Abstract:
An extensive overview of policies related to pharmacy-mediated substitution of biosimilars across the world was carried out by Larkin et al. in 2017. The details of this are discussed in this commentary.

Submitted: 17 November 2017; Revised: 28 November 2017; Accepted: 4 December 2017; Published online first: 15 December 2017

Introduction

An extensive overview of policies related to pharmacy-mediated substitution of biosimilars has been carried out by Larkin et al. in their paper ‘Pharmacy-mediated substitution of biosimilars – a global survey benchmarking country substitution policies’ [1]. The paper includes information on 82 countries, which has enabled the authors to provide a global perspective and compare different regions of the world.

The authors find that, in 72% of the countries surveyed, substitution at the pharmacy level does not occur, either because it is not permitted or for other reasons. This was based on data collected by Pfizer company representatives working in the specific countries/areas.

Clarifying the difference: substitution and switching

The paper by Larkin et al. focuses on the policies related to substitution of biosimilars in 82 countries across the globe [1]. Substitution is generally defined as the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber [2]. Within the European Union (EU) most regulatory agencies and organizations representing healthcare professionals and/or patients have taken a position on the use of biosimilars. In general, the positions focus on switching instead of substitution [3]. Switching is defined as a decision made by the prescriber to exchange one medicine for another medicine with the same therapeutic intent. Switching generally involves all the stakeholders: the patient, prescriber, pharmacist and a specialized nurse [2]. It is known that any change to the medication can be met with negative expectations towards the new treatment (nocebo effect) and/or certain adverse events can be falsely related to the change in medication [4]. This stresses the importance of the involvement of the patient in insuring that they are given adequate information on switching and their treatment regimen. Involvement of the patient is specifically important when biological treatment is being administered by the patient himself or herself, e.g. subcutaneous administration in the home setting. This is because the device by which the biosimilar is administered might differ from the device of the reference product and the patient should be instructed how to use the new device.

Recommendations for globally successful biosimilar substitution

In their discussion, Larkin et al. suggest six measures that should be considered by countries that are looking to develop guidance on pharmacy-mediated substitution of biosimilars. The authors believe these are essential if pharmacy-mediated substitution is to occur to safeguard patients and the first measure is to establish a legal framework for substitution. Most of the measures are not specific to substitution but are also applicable to switching and are applicable to all biologicals. This assumption is supported by measure 6, which states that a mechanism should be in place to ensure that patient and physician are informed when a product is substituted. With this measure, substitution is moving towards the definition of switching and this is in line with current practice in the EU [3].

The authors also describe measure 2, which proposes that an additional level of scientific evidence, in addition to the biosimilarity exercise, is required to enable designation as a biosimilar that can be substituted. In this context it is important to stress that a biosimilar approved in a country with stringent regulatory requirements, such as in International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) countries, has shown to be similar to the reference product in terms of quality, biological activity, clinical efficacy and safety. Switching or substitution is therefore considered to be safe. The experience with changes in the production process that all biologicals undergo is also supportive for switching [3]. Additional switching studies face specific challenges related, among others, to the design (single-arm studies versus double-arm studies, one switch versus multiple switches), the endpoint, e.g. immunogenicity, pharmacokinetics, clinical efficacy, and the number of patients to be included [5]. The importance of a stringent regulatory system for biosimilars is supported by measure 5, as proposed by the authors. Measure 5 states that the country in question should actively apply stringent regulatory authority approval requirements for biosimilarity and therefore so-called non-comparable biotherapeutic products cannot be approved.

A robust pharmacovigilance system, as proposed by measure 3, is important for all medicinal products, as is traceability, due to the inherent batch-to-batch variability of biologicals. Several studies have shown that identification of the administered brand can be traced with a certain amount of certainty [6, 7]. These studies showed that identification of the product was possible without the availability of different International Nonproprietary Names (INNs), as has been proposed by the authors. At present it is not clear if different INNs will have a positive influence on traceability and this needs to be investigated further. In addition, several EU states have expressed concern as they think that different INNs could have a negative impact on the trust in biosimilars [8]. Identification of the batch numbers remains a challenge and needs improvement. Vermeer et al. have provided an overview of the challenges related to traceability and conclude that long-term solutions lie in expanding the accessibility to and increasing the electronic exchange of exposure data. This is specifically important to reduce the burden on clinical practice as in the current situation; there is a need to record batch numbers manually in patient dossiers [9].

Measure 4 states that the biosimilar should be approved for all indications of the reference product not protected by exclusivity. However, regulations in the EU state that biosimilar companies are not obliged to apply for all indications, for which the reference product is approved [10]. A reason not to apply for a specific indication can, for example, be that a specific formulation is not produced by the biosimilar company. There is a risk of off-label use, especially in the case of substitution. Switching is expected to reduce this risk of off-label use, as is the implementation of electronic patient files, which can be accessed by the pharmacist during patient care.

Limitations

The authors highlight a number of limitations in their study. For example, country regulations can be different to what happens in actual clinical practice [1]. This is specifically relevant when a prescribed brand is not available and so, in such circumstances, clinical practice can go against country regulations in place as a different medication may be dispensed. In addition, the study does not clarify how different country viewpoints are taken into consideration. It is assumed that legislations are the primary basis for biosimilar substitution but, if there is no specific legislation in place related to the use of biosimilars, information is based on guidelines and viewpoints. This is complicated due to the different roles played by the stakeholders involved in the biosimilar discussion. For example, it is possible that physicians and pharmacists will have different guidelines to payers regarding substitution. This is important when considering the discussions on switching and substitution from reference product to biosimilar and that these are mostly driven by financial concerns and the increasing costs of medical care.

Conclusion

Overall, Larkin et al. have provided valuable data on the substitution policies regarding biosimilars around the globe. In most countries, substitution is not permitted. This is in line with the current thinking in the EU, that involvement of all stakeholders is important during the implementation of biosimilars. This ‘so-called’ practice of switching will help patients, physicians, pharmacists and nurses build trust in biosimilars.

Competing interests: None.

Provenance and peer review: Commissioned; internally peer reviewed.

References
1. Larkin H, Macdonald J, Lumsden R. Pharmacy-mediated substitution of biosimilars – a global survey benchmarking country substitution policies. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(4):157-64. doi:10.5639/gabij.2017.0604.034
2. European Medicines Agency and European Commission. Biosimilars in the EU – Information guide for healthcare professionals. May 2017 [homepage on the Internet]. [cited 2017 Nov 28]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf
3. Kurki P, van Aerts L, Wolff-Holz E, Giezen T, Skibeli V, Weise M. Interchangeability of biosimilars: a European perspective. BioDrugs. 2017;31(2):83-91.
4. Netherlands Society for Hospital Pharmacists. [Toolbox for the implementation of biosmilars]. Dutch. April 2017. [homepage on the Internet]. [cited 2017 Nov 28]. Available from: http://nvza.nl/wp-content/uploads/2017/04/NVZA-Toolbox-biosimilars_7-april-2017.pdf
5. Ebbers HC, Chamberlain P. Interchangeability. An insurmountable fifth hurdle? Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):88-93. doi:10.5639/gabij.2014.0302.02
6. Klein K, Scholl JH, Vermeer NS, Broekmans AW, Van Puijenbroek EP, De Bruin ML, Stolk P. Traceability of biologicals in the Netherlands: an analysis of information-recording systems in clinical practice and spontaneous ADR reports. Drug Saf. 2016;39(2):185-92.
7. Vermeer NS, Straus SM, Mantel-Teeuwisse AK, Domergue F, Egberts TC, Leufkens HG, De Bruin ML. Traceability of biopharmaceuticals in spontaneous reporting systems: a cross-sectional study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases. Drug Saf. 2013;36(8):617-25.
8. GaBI Online – Generics and Biosimilars Initiative. EU majority says same INNs for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Nov 28]. Available from: www.gabionline.net/Biosimilars/General/EU-majority-says-same-INNs-for-biosimilars
9. Vermeer NS, Spierings I, Mantel-Teeuwisse AK, Straus SM, Giezen TJ, Leufkens HG, Egberts TC, De Bruin ML. Traceability of biologicals: present challenges in pharmacovigilance. Expert Opin Drug Saf. 2015;14(1):63-72.
10. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. [homepage on the Internet]. [cited 2017 Nov 28]. Available from: Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf

Author Thijs J Giezen, PharmD, PhD, MSc, Foundation Pharmacy for Hospitals in Haarlem, 20 Boerhaavelaan, NL-2035 RC Haarlem, The Netherlands

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Roundtable on biosimilars with European regulators and medical societies, Brussels, Belgium, 12 January 2016

Author byline as per print journal: Vito Annese, MD, PhD; Cristina Avendaño-Solá, MD, PhD; Professor Ferdinand Breedveld, MD; Niklas Ekman, PhD; Thijs J Giezen, MSc, PharmD, PhD; Professor Fernando Gomollón, MD, PhD; Research Professor Pekka Kurki, MD, PhD; Professor Tore Kristian Kvien, MD; Professor Andrea Laslop, MD; Professor Lluís Puig, MD, PhD; Robin Thorpe, PhD, FRCPath; Martina Weise, MD; Elena Wolff-Holz, MD

Introduction: Biological drugs are improving therapeutic options for many diseases, but access to these therapies is being held back by costs. Biosimilars offer a lower-cost alternative to the corresponding original therapeutic protein, the reference product, with a comparable quality, safety and efficacy. Despite these apparent advantages, arriving at the best solution for patients will need improved communication between regulators and caregivers.
Methods: Representatives from medical societies (European and national) which had issued or published a position paper on biosimilars met with regulators and related experts to discuss recent revisions of the regulatory assessment principles of biosimilars, review the current positions of societies on biosimilars, and improve dialogue between medical societies and regulators on biologicals, notably biosimilars.
Results: The positions of the European regulators and medical societies are slowly converging. While many questions were answered, productive discussions identified areas of disagreement and uncertainties. The results of these discussions will inform debate and decision-making in the participants’ organizations and home countries.
Conclusions: The picture of biosimilars is becoming clearer, and stakeholders are beginning to understand better the basis of biosimilar development, on one hand, and the reasons for concerns, on the other hand. Different stakeholders – patients, doctors, pharmacists, payers – need different information. Above all, this must be a collaborative exercise.

Submitted: 24 January 2016; Revised: 21 April 2016; Accepted: 21 April 2016; Published online first: 4 May 2016

Introduction

Access to biological therapies, despite their clear potential for the treatment of many diseases, is more or less restricted owing to high cost. The problem is likely to continue or even aggravate, as a growing number of biological therapies enter the market. It remains unclear whether healthcare systems will be able to make these therapies widely available. Stakeholders hope that biosimilars will have a significant impact on the sustainability of future pharmacotherapy. Regulators and learned societies, especially medical societies, have prominent roles in guiding the rational use of new medicines, including biosimilars.

European regulators and medical societies were the first to encounter biosimilars, and countries worldwide are looking to Europe for guidance.

The Generics and Biosimilars Initiative (GaBI), with its mission to foster the worldwide efficient use of high quality and safe medicines at an affordable price, organized a roundtable discussion for European regulators and medical societies on biosimilars with the aim of promoting interaction and sharing information in this increasing important area. It is important to respect the expertise and role of each stakeholder in the biosimilar discussion, agree Research Professor and former Chair of the European Medicines Agency’s (EMA) Biosimilar Medicinal Products Working Party (BMWP), Pekka Kurki of the Finnish Medicines Agency, Fimea, and Chair of the Roundtable on Biosimilars, and Dr Robin Thorpe, Deputy Editor-in-Chief of the GaBI Journal, expert of BMWP, formerly Head of Biotherapeutics Group of the UK’s National Institute of Biological Standards and Control and Co-Chair of the Roundtable.

Methods

On 12 January 2016, GaBI held a Roundtable on Biosimilars in Brussels, Belgium, with participation by European regulators and medical societies. The programme offered speaker presentations and parallel discussion groups to provide participants with important and up-to-date information related to many aspects of biosimilars with a focus on the key issues of comparability, extrapolation, interchangeability and substitution, as well as pharmacovigilance. Presentations were in English. The speakers were regulators but not official delegates of any regulatory body.

Results

Differences between regulatory decisions and the recommendations of medical societies
The Roundtable was opened by the Chair, Professor Pekka Kurki, expert of BMWP, with an overview of European Medical Societies’ position papers on biosimilars, see Table 1. Restricting the overview to recent papers that were written in English, he focussed on the concerns and contrasting views contained within these papers with regards to the regulatory decisions. With the growth in biological therapies and the numbers of diseases they treat, there is a steadily growing number of position papers.

Table 1
Overall, Professor Kurki noted that these papers were generally in favour of biosimilars, particularly for new patients. But there were mixed opinions on extrapolation, traceability, interchangeability and automatic substitution. Prescribing by brand name was favoured, and there were concerns over immunogenicity.

The biggest problem for physicians, and therefore for medical societies, is that biosimilars can never be exact copies of their reference products. This was a point made throughout the Roundtable in spite of the fact that minor variation of the physicochemical properties of different versions of the same product is an inherent property of all biologicals. Physicians across the board do not find this straightforward to explain to patients. The problem is particularly evident in a naturally relapsing/remitting disease like rheumatoid arthritis (RA). A patient who starts taking a biosimilar and suffers a relapse of symptoms may well blame the symptoms on the biosimilar, and doctors might not always be confident explaining that this is unlikely – given the comparability studies to which each biosimilar will have been subject.

Professor Kurki noted that it is important to recognize that biosimilars have a proven similarity without being identical to the reference product. According to medical societies, even sophisticated comparability testing, in vitro assays and animal studies cannot fully predict the biological and clinical activity of a therapeutic monoclonal antibody.

According to some position papers, extrapolation of indications approved for the originator drug to completely different diseases and age groups that are not based on adequate preclinical, safety and efficacy data (ideally phase I and phase III trials) should not be performed. In their view, extrapolation from rheumatoid arthritis and ankylosing spondylitis studies to Crohn’s disease (CD) and/or ulcerative colitis (UC) cannot be done unless information on mucosal healing, corticosteroid-free remission or immunogenicity and loss of response in CD or UC patients is provided.

The same concerns apply to paediatric patients. Studies specifically looking at outcomes such as growth and development are welcomed by some medical societies.

One concern shared by all the position papers reviewed by Professor Kurki’s team, was that of physician autonomy. It was important for all medical societies that their physicians could make their own therapeutic choices. ‘That is understandable, and we support that. But there are economic realities, and the question is how to apply prescribing autonomy in the best way for the benefit to patients and healthcare systems,’ says Professor Kurki.

Professor Kurki showed a figure illustrating the difference in development philosophies between biosimilars and the reference product, see Figure 1. Two pyramids (representing biosimilars on the left, and originators on the right) represent the marketing authorization documentation. The pyramid representing biosimilars starts at the base with quality documentation (pharmaceutical documentation), followed by an extensive portion dedicated to comparative in vitro studies, analytical, functional and structural testing side-by-side, and then a limited set of clinical trials, and at the top, the risk management plan (RMP). This is clearly different for the development of a new active substance, he notes. While both pyramids share the pharmaceutical documentation, with standards exactly the same for biosimilars as for new biologicals, the originator also has to investigate the pharmacology, the mode of action and the toxicology of the product. For biosimilars, those are already known. Then there is an extensive set of studies for absorption, distribution, metabolism, elimination and pharmacodynamics (PDs). For biosimilars, it is sufficient to demonstrate a comparable exposure after single or repeated administration. In the case of a new biological, every claimed indication needs to be studied, alongside special groups such as children or patients with organ dysfunction. Finally, as with biosimilars, the RMP needs to be in place.

Figure 1
Our problem, suggests Professor Kurki, is that while the regulators look at the analytical and non-clinical testing and the clinical trials as one package (‘totality of evidence’) when deciding what is a biosimilar, clinicians focus on the clinical part only. This would explain, he suggests, the lack of confidence in comparability, while regulators seem more comfortable because they have been carrying out these studies for over two decades for manufacturing changes. This was discussed in more detail by Dr Niklas Ekman, also of Fimea.

Clinical biosimilar safety and efficacy studies look like typical phase III studies, but they are not; they have special features, e.g. looking at population pharmacokinetics (PKs) or PDs markers. Physicians see the active substance of biosimilar as new active substance, whereas regulators see it as a different version of the same active substance.

For specialists, it is difficult to accept that studies performed in one disease can be applied to another disease with different pathogenic features. Regulators, meanwhile, are more focussed on receptor binding and functional tests of the biosimilar, i.e. the mode of action of the active substance.

Manufacturing and characterization of biologicals
Dr Niklas Ekman, a member of EMA’s BMWP, explained how manufacturing process changes are common for all biologicals, both originators and biosimilars. He pointed to earlier studies showing the number of changes made to the manufacturing process of individual products since their approval [1], see Figure 2, and how manufacturing changes impacted on the glycosylation profile and antibody-dependant cell cytotoxicity (ADCC) of biopharmaceuticals – biopharmaceuticals that, from a physician’s point of view, would have been identical [2]. In other words, after a change in manufacturing process, originator biologicals are also not identical to earlier versions of the same originator biological. The comparability concept and its fundamental importance for the maintenance of safety and efficacy have remained unknown to physicians which may explain their reservations to biosimilars.

Figure 2
Clinical and non-clinical comparability
Professor Andrea Laslop of the Austrian Medicines Agency and a member of the EMA’s Committee for Medicinal Products for Human Use (CHMP), discussed clinical and non-clinical comparability for biologicals/biosimilars. The non-clinical development is based on the 3Rs: Reduce, Refine and Replace, animal studies as much as possible with in vitro data.

Comparability programmes at the clinical level can and must be strengthened by a number of factors, Professor Laslop urged. Comparability testing must use a homogeneous/sensitive population, a sensitive dose (or two doses), an appropriate model and statistical approach, and must use an accurate definition of the equivalence margin. The primary outcome measures need not be the same as those in the originator’s pivotal clinical trials. Orphan drugs raise unique challenges related to small population sizes. These challenges can be resolved in collaboration with regulatory authorities. Importantly, international dialogue between regulators is needed in order to encourage harmonization of regulatory requirements on a global scale. The final goal, says Professor Laslop, is to provide faster access for patients to affordable biological medicines at a sustainable price.

Immunogenicity
Dr Robin Thorpe, a member of EMA’s BMWP, focussed on the issue of immunogenicity. The European Union was the first to put together a guideline on immunogenicity assessment, he noted, and there is a revised version of this guideline due later in 2016. Immunogenicity issues occur all along the life cycle of a product, and particularly when a new therapeutic protein is developed and used for various clinical indications; when a change in process, formulation, or storage conditions is introduced or – notably given the topic of this roundtable – when a biosimilar product is proposed. Assessment requires an optimal antibody testing strategy alongside validated methodologies and reference standards. A better quality such as decreased immunogenicity does not preclude biosimilarity but needs to be justified as it possibly indicates a difference between products.

Extrapolation
Dr Martina Weise of the Federal Institute for Drugs and Medical Devices in Germany and Vice Chair of EMA’s BMWP discussed the principles of extrapolation of indications. Despite being the most contentious issue of biosimilar development, Dr Weise says extrapolation of indications is the single greatest benefit of biosimilar development.

Noting the data presented by Dr Niklas Ekman, see Figure 2, Dr Weise pointed out that extrapolation of data is already an established scientific and regulatory principle that has been exercised for many years, for example, in the case of changes in manufacturing process of originator biologicals. In such cases, clinical data are not required. In the development of biosimilars, clinical data are typically generated in one indication and, taking into account the overall information gained from the comparability exercise, may then be extrapolated to the other indications.

Dr Weise has recently published a paper on the science of extrapolation [3], with her regulatory colleagues, where the authors say they are not aware of any case of a change in the manufacturing process where more than one clinical study was required to compare two versions of the same product and this was sufficient for all approved indications.

Extrapolation must always be appropriately justified, and, where doubt remains, additional functional or clinical data are required for extrapolation to be granted. Dr Weise reminded delegates that scientific evidence and explanation of the reasons for extrapolation granted by CHMP may be found in the European Public Assessment Reports (EPARs).

Interchangeability
Dr Elena Wolff-Holz of Germany’s Federal Agency for Vaccines and Biomedicines, and a memberof EMA’s BMWP, discussed the interchangeability and substitution of biosimilars. She presented findings from a series of small to medium-sized switching studies involving biologicals and biosimilars, none of which showed any safety/efficacy signals that would justify extensive, longer studies.

For example, a Swedish study that investigated switching between the originator and biosimilar of the growth hormone (somatropin) showed no impact on patients’ growth velocity after switching to the biosimilar, see Figure 3 [4]. When a model was used to compare observed versus predicted growth, the predicted levels lay close to the observed data, showing excellent fit. Similar findings were shown for epoetin alfa-containing biosimilars, biosimilar filgrastim, biosimilar insulin glargine, and biosimilar infliximab. She also emphasized the value of EPARs (European Public Assessment Reports) in which results of biosimilars development programmes (epoetin, filgrastim, insulin glargine, somatropin), which included crossover trials with originators, are presented.

Figure 3
Referring back to the point made by Dr Niklas Ekman, see Figure 2, Dr Wolff-Holz reminded participants of the number of post-marketing changes made to biological drugs, notably monoclonal antibodies, without the need for further clinical studies. The regulators recalled only one case where clinical data were requested. The risk of rare adverse effects is best addressed by the RMP, as with any other medicinal product, she concluded.

Pharmacovigilance
Dr Thijs J Giezen, a hospital pharmacist at the Foundation Pharmacy for Hospitals in Haarlem, The Netherlands, and a member of EMA’s BMWP, discussed the safety assessment and risk management of biosimilars. Safety assessment is of paramount importance for biosimilars, with a particular focus on immunogenicity. Major differences in immunogenicity might question biosimilarity, he noted. As with all drugs, pharmacovigilance for originators and biosimilars is vital, and traceability is of specific importance.

When drawing up a pharmacovigilance plan for a biosimilar, post-marketing studies that not only compare safety profiles but also warn against rare adverse events are in a key position. Additional immunogenicity studies may be considered, perhaps in the context of studies that are already underway, for example, rheumatology registries, or – at a company’s own discretion – initiating new studies.

Summary of discussion about the regulatory presentations

Physicochemical and functional comparability
It was asked whether the quality attributes of a biosimilar and its reference product will be compared in the same way as in the PK bioequivalence studies. It was clarified that, for the key quality attributes, the acceptable range is defined by the analysis of variability between batches of the reference product. For other quality attributes, the acceptable range depends on the type of analytical method. Therefore, statistical analyses are difficult to apply. The products are tested side-by-side to reduce variability. If differences are found, they will be judged by prior knowledge of previous analyses of different versions of proteins in the same class, analysing additional batches, and by using orthogonal methods to look at the same characteristics.

Impact of physicochemical and functional differences on safety and efficacy
Analytical comparability leans on the experience gained from studies of different versions of the active substance after a change of the manufacturing process. These changes are very common because the manufacturing processes need to be optimized, their scale is increased and manufacturing sites changed. Some participants were surprised by the variation between different versions of original biological products that have been accepted without clinical data. It was discussed whether clinical data should be requested more often before accepting a manufacturing change. The regulators responded that there is no evidence from clinical trials performed after licensing, such as expansion of therapeutic indications, that the safety or efficacy of current biotechnology-derived proteins would have changed over time significantly. The explanation is that analytical tests are more sensitive than clinical trials for showing differences.

The demonstration of comparability of monoclonal antibodies is challenging because they have several possible modes of action. Binding to the antigen is necessary for function but Fc-mediated functions may have a role as well. Nevertheless, all functions can be measured by in vitro analytical and functional tests. In the discussion, interpretation of these tests, especially the test for antibody-dependent cell-mediated cytotoxicity (ADCC) was discussed. The audience was concerned about the differences that have been demonstrated after manufacturing changes as well as differences between biosimilars and their reference products. In general, the role of Fc-mediated functions in the therapeutic effect is incompletely known. It was argued that it cannot be excluded that observed ADCC differences (~20%) have an impact on the efficacy or safety. Regulators responded that the differences often disappear when different effector and target cells are used or non-relevant antibodies are present. Sometimes the difference appears only in cells that have Fc-receptors with high affinity genotype. Glycosylation patterns that increase ADCC activity may have a clinical impact. Obinutuzumab is an anti-CD20 antibody that was glyco-engineered in order to enhance the binding to FcγRIIIa. As a result, its ADCC activity against different B-cell lines is 5- to 100-fold higher than that of the ‘wild type’ antibody. This antibody has been shown to be more effective than rituximab in depleting malignant B-cells in chronic lymphocytic leukaemia. Against this background, the small difference in the ADCC between the first biosimilar infliximab and its reference product appears insignificant, especially when considering the applied ADCC test using a target cell line that has been genetically modified to be very sensitive for anti-tumour necrosis factor (anti-TNF) effects.

Interestingly, serious problems after manufacturing changes have been associated with the drug formulation rather than the active substance itself. Pure red cell aplasia (PRCA) has been triggered initially by factors in drug formulation but not with the epoetin alfa itself.

Does comparability mean therapeutic equivalence?
It was asked whether there are examples of seemingly perfect analytical comparability but observed clinical differences at the same time or later. More than 200 cases of PRCA were observed in patients treated with the marketed original epoetin alfa after a manufacturing change. Likewise, decreased efficacy and increased reactogenicity have been observed after manufacturing changes of a few vaccines. So far, such differences have not been observed with biosimilars after licensing. One case of PRCA was detected in a clinical trial with a biosimilar epoetin alfa in development. The development was discontinued. Thus, the experience from the reference product and the extensive comparability exercise will help to identify possible problems already in the development phase of a biosimilar.

Can a biosimilar be better than its reference product?
A product cannot be biosimilar if it has inferior safety or efficacy. However, what if the product is superior? A biosimilar may have an improved quality profile, e.g. purity and immunogenicity. Reduced immunogenicity may lead to slower loss of efficacy and, thus, better adherence to therapy by some patients. Thus, the applicant has to justify the difference with regard to safety and efficacy. Increased efficacy is not possible for a biosimilar since it would make it impossible to refer to the documentation of the reference product which is the basis of the abbreviated development. According to the EU legislation, a ‘biobetter’ must be licensed as a new active substance.

Immunogenicity
It was pointed out that, in the future, there will be several biosimilars for the same reference product. This may lead to multiple switches for the same patient over time. Multiple switches are often said to increase the risks of immunogenicity. Should this scenario be tested before licensing of a biosimilar? Regulators responded that immunogenicity of each biosimilar and its reference product will be compared before licensing. For the time being, data from switching biosimilars and the reference product are reassuring. The current view among European regulators is that, once comparable immunogenicity has been demonstrated against the reference product, there is no need to perform specific switching studies.

Extrapolation
How to select the patient population for a clinical efficacy and safety study when the product is used in different diseases and patient populations using different combinations with other products that may interfere with the performance of the tested active substance was also discussed. It was also asked whether all combinations and diseases and dosing regimens should be tested. Regulators clarified that clinical safety and efficacy studies were preceded by PK and PD studies. The developer should not proceed to large clinical trials if comparability is not demonstrated. The safety and efficacy studies should be done in a clinical model that is representative for other models, i.e. therapeutic indications and populations, and which is sensitive for showing differences. The purpose of the safety and efficacy studies is to complement and confirm the comparability demonstrated at the previous steps of development. This approach requires that the clinical endpoints are sensitive to differences. Thus, the primary clinical endpoints selected for demonstration of comparable efficacy are not necessarily the same as those used in the pivotal clinical trials of the reference product at the time of licensing. For example, overall survival rate and time to progression are generally used in oncology to study a product with a new active substance. These endpoints are time related and usually take rather long time for evaluation. Therefore, a more reasonable and sensitive endpoint, such as overall response rate, may be used. Thus, testing in all therapeutic indications, populations and drug combinations is neither necessary nor feasible.

Disagreements on extrapolation
The concern about extrapolation by clinicians is the use of the same biosimilar or a new innovative product, notably monoclonal antibodies, in different diseases in which the mechanism of action is thought to be different. Infliximab, for example, used in rheumatology is thought to act predominantly through the neutralization of soluble and trans-membrane TNFα, whereas in other conditions such as Crohn’s disease, signalling through membrane-associated forms of TNFα and Fcγ receptors that may trigger apoptosis or ADCC may play a more important role.

Regulators responded by pointing out that the different functions of a therapeutic monoclonal antibody are always investigated by in vitro receptor-binding and cell-based functional assays. These assays are more sensitive than clinical trials. Therefore, regulators feel more comfortable than clinicians with the extrapolation of safety and efficacy between different therapeutic indications.

Clinicians pointed out that clinical experience from less formal, e.g. open label, studies will and have already relieved some concerns about extrapolation.

Clinicians are puzzled by the fact that, in case of the first biosimilar infliximab, Canadian regulators, in contrast to their European colleagues, did not accept the extrapolation of safety and efficacy from RA to inflammatory bowel disease (IBD). Does the fact that all therapeutic indications of the reference product were granted in the EU and later by the US Food and Drug Administration (FDA) mean that the future biosimilar infliximabs, or even etanercepts, will get all therapeutic indications of the reference product automatically? The current regulatory view is that the extrapolation is considered on the basis of the comparability exercise of a given product together with the justification by the applicant. Thus, it is a case-by-case decision.

Regulators’ expectation is that biosimilars approved in the EU will have the same therapeutic indications as the reference product. This is desirable from the pharmacovigilance point of view since a restricted set of therapeutic indications may lead to off-label use. Sometimes, the applicant is not seeking for all therapeutic indications because of patents or because of the lack of suitable, e.g. paediatric, formulation.

Off-target effects and biosimilarity
In general, it is a constant feature of clinical science to observe results that were not expected on the basis of previous knowledge. This is, indeed, almost always the situation after licensing of a product containing a new active substance. It was discussed whether unexpected off-target effects could be observed with biosimilars.

The regulators argued that biologicals, by their nature, have less off-target effects than chemicals. The long experience with the reference products helps to understand the effects of the active substance. A biosimilar will have the same effects, both beneficial and adverse, as the reference product. For biosimilars, the issue is whether new, unexpected off-target effects could be encountered in spite of the extensive comparability exercise. The discussion led to the topic of whether a comparable receptor interaction is sufficient to predict similar functional effects or whether differences in the downstream signalling pathways in target cells could be significantly different after the binding of the biosimilar and the reference product in spite of comparable results in functional cell-based tests, e.g. phagocytosis, apoptosis, ADCC. Regulators maintained that it is essential to separate the effects of the product from the responses of different types of target cells that may respond differently to the same signal. In the end, no agreement was reached on the significance of off-target effects with the use of biosimilars.

A possible off-target effect was mentioned in the context of cancer therapy and bone marrow after treatment with biosimilar filgrastim. Reference was made to the study of Brito et al. (Support Care Cancer. 2016; 24(2):597-603) in early breast cancer receiving (neo)adjuvant docetaxel/doxorubicin/cyclophosphamide therapy and prophylaxis with biosimilar, pegfilgrastim or reference filgrastim. The treatments were administered at different consecutive time periods and data were gathered retrospectively. The rate of febrile neutropenia (FN) per patient and treatment cycle was the same in biosimilar and reference filgrastim groups. The rate of FN and severe neutropenia (ANC < 100 cells/μL) was seen in 50% of patients in the biosimilar group but only in 4% in the reference product group. The authors concluded that ‘No differences in biosimilar effectiveness were detected. The clinical relevance of the profound neutropenia found in the biosimilar cohort needs further attention’. Interestingly, no such difference was found in the multicentre, double-blind, therapeutic equivalence study of biosimilar G-CSF versus the reference product in subjects receiving doxorubicin and docetaxel as combination therapy for breast cancer.

Interchangeability
There is some concern in the rheumatology community about the long delay of full publication of the safety results of the long-term extension of the pivotal safety and efficacy studies of the first biosimilar infliximab, especially the study in ankylosing spondylitis (PLANETAS). During the extension, ankylosing spondylitis patients were switched from the reference product to the biosimilar. The switched patients had a higher rate of adverse events and more withdrawals from the therapy. These results have been reviewed by the EU regulators who did not react to the difference, probably because of the relatively small number of patients at the time of the switch and lack of a plausible explanation. A publication featuring the safety data after the switch is pending.

It was pointed out that neither regulators nor prescribers across the Atlantic have a uniform opinion of the interchangeability. This is partly due to different regulatory frameworks in the two areas and partly due to the interpretation of the theoretical basis and available data.

In the EU, interchangeability is within the mandate of the Member States whereas in the US, interchangeability studies are mandatory by legislation. Interestingly, FDA has not published any guidance on how to study interchangeability. This may reflect the scientific problems related to the switching studies.

Pharmacovigilance
It is evident that the root cause of some adverse effects of biologicals, notably immunogenicity, is in the improper handling and storage of biologicals. It is particularly important to maintain the cold chain. This is becoming a challenge also in Europe when the administration and storage of biological medicines is more and more often taking place at home by the patient or caregiver. Innovative auto injectors and packages may mitigate this problem in the future for biologicals, including biosimilars.

Group discussions (summaries from moderators)

The Roundtable ended with three parallel discussion groups, each of which included representatives from regulatory authorities and from medical societies. Groups were asked to discuss physicians’ attitudes to and concerns surrounding biosimilars – comparability, immunogenicity, extrapolation, interchangeability and substitution, as well as pharmacovigilance. Focus discussion topics included the thought process in preparing position papers, the bottlenecks, e.g. training, and the concerns and challenges faced.

Summary of parallel group discussions

Group 1 Summary
Summarized by Professor Fernando Gomollón, MD, PhD; presented by Professor Ferdinand Breedveld, MD
Group 1 identified a remaining doubt among clinicians, which could be reflected in the question: do in vitro tests really predict the appropriateness of extrapolation? After recognizing that this mere concept can be difficult to accept for clinicians, the general agreement of the group was that if a multiple set of well standardized tests, enough data on exposure in a sensible population and previous clinical data are all considered, extrapolation can be seen as a good concept, a real change of paradigm.

Some issues were raised about safety signals in PLANETAS data. For some people, safety data may require more clarification, although the general opinion was that if EMA had considered the signals as non-significant, they were probably not important.

Registries
There was general agreement among group members on the importance of registries. Ideally these should function on a national scale with a core of data that is easy to share between countries. More work on the definition of these registries is clearly needed.

A real philosophical (or pathophysiological, if preferred) question was also raised. Would a knowledge of the exact mechanism of action of a drug in a given disease make it easier to extrapolate? Perhaps in theory, but with the mechanisms of these diseases being so complex, the general agreement is that the EMA road to extrapolation is adequate in the current state of knowledge.

Good research, poor communication
Some open discussion was undertaken on the low opinion that clinical gastroenterologists have for biosimilars (although it seems rather clear that things are changing and opinions improving). The general agreement was that EMA has done really good scientific work with biosimilars, but not communicated their findings effectively. So, communications should be improved and coordinated, with contributions from EMA, scientific societies and other authorities.

Improving patient care
The group found two concepts that needed emphasizing: 1) biosimilars are not easy to approve in Europe; 2) to date, after approval, the safety record of biosimilars in Europe is really quite good (if not excellent).

Finally, the group agreed that cost is the main drive for biosimilars introduction. This should be seen as an opportunity for better patient care, and that negotiation between payers, authorities, clinicians, pharmacists and patients is the best way to implement change.

Group 2 Summary
Summarized by Cristina Avendaño-Solá, MD, PhD; presented by Vito Annese, MD, PhD
In a group that included four regulators, two rheumatologists, two gastroenterologists, one haematologist and one clinical pharmacologist, there was full agreement on the opportunity that biosimilars provide both in increasing accessibility to biological medicines and in decreasing costs. Those costs can then be diverted to other health spending. Cost benefits are, however, more likely to be related to the arrival of competition, which will drive down the price of the originator drugs. Another possible bonus of biosimilars is seen in preliminary data suggesting that biosimilars could be improvements on originators. They might have less impurities, reduced immunogenicity, or be administered by improved devices.

Switching
One concern shared by the group was how to introduce biosimilars in clinical practice. It is difficult to promote switching between originators and biosimilars in a chronically ill patient who is already taking the originator.

There is still some reluctance about the comparability exercise based on a limited number of parameters and limited clinical data. Recognition of the contribution of data post-authorization and the importance of pharmacovigilance are key.

Concerns were raised about interchangeability. There were doubts related to the absence of data and the potential impact of switching on individual patients. It is complicated to demonstrate interchangeability.

There were also concerns about multiple switching and how to preserve pharmacovigilance and immunogenicity monitoring of each specific product.

Benefits of cost cutting
The group recommended increasing the visibility of the usefulness of the money saved through biosimilars. For example, the agreement of using biosimilars in IBD could go hand-in-hand with actions such as providing extra nurses, support to registers and support for therapeutic drug monitoring (TDM). It is important to recognize the value of TDM to guide switching.

Group members recommended revising how systems of price and reimbursement decisions work at the country level. Involving patients in decision-making will increase their awareness of the benefits of biosimilars.

Group 3 Summary
Summarized and presented by Professor Lluís Puig, MD, PhD
Group 3 focused on monoclonal antibodies for the treatment of immune-mediated inflammatory diseases (IMIDs).

The question was raised whether biosimilars will remove inequity of access to expensive drugs. Group members agreed that access should not depend on price. The UK’s National Institute for Health and Care Excellence (NICE) is working to facilitate entry of biosimilars into the market, but faces many obstacles and concerns among patients and clinicians who are dealing with the unknown.

Switching
The group recognized opposition to switching in patients who are doing well. The only reason for them to switch would be cost, and the group discussed the importance of cost, budgeting and patients’ say. Problems arise around the issue of enforced switching without patients’ consent and full knowledge of safety, or physicians’ choice. The pressure is clearly on the physician. In oncology and haematology there is particularly low acceptance of switching.

The question was raised whether switching trials are needed. Available results show no significant change, but perhaps they are unlikely to do so given their design and power limitations.

In Denmark, there is a 69% discount on Remsima, and authorities enforced wholesale switching. Wholesale switching was similarly promoted in Austria.

NOR-switch is a study funded by the Norwegian Government, aimed to compare the originator infliximab (Remicade) and Celltrion’s biosimilar infliximab (Remsima) as regards disease worsening rates across all indications after one year of treatment. Thirty per cent is the expected worsening rate of Remicade, 15% the non-inferiority margin, and 500 patients are the population enrolled.

Safety
The issue of safety monitoring and the need for registries was discussed. The group raised doubts on quality of monitoring, and asked who will pay for it. In most countries it is unrealistic that governments will pay for monitoring.

In the UK, NICE made a formal requirement that prescribers included new patients treated with biosimilars into registries. There is a need for tracking. There is a need to collect the data regardless of how likely it will be to see a result. There are huge methodological challenges with registries.

Extrapolation
The group looked at real-life data from the Czech Republic showing no difference between originators and their biosimilars. The same was shown for paediatric indications. Regulators do not care so much about the disease in which the trials are being made.

There is a very large difference in perception and acceptance between individual countries. In the Czech Republic, physicians today have no objection to switching and extrapolation based on their results. The situation has changed in 2015, based on education and experience.

Biosimilarity exercise
The group discussed how subjects for clinical trials of biosimilars cannot be found in Western Europe; they have early access to potent therapy and do not progress to levels of activity making them eligible for enrolment. Furthermore, the ethics of a clinical trial that does not provide a clinical advantage was discussed.

There was a concern that PK studies in healthy volunteers may not be representative for all indications in which PK may vary. The regulatory view is that the variability in patients is more dependent on confounding factors than on the active substances.

A request was made for further detail or transparency in preclinical data. An understanding of the way regulatory agencies make their decisions is needed, rather than calling for ever-increasing numbers of clinical trials.

Chair’s observations from the group discussions

It was concluded that biosimilars have the potential to increase patients’ access to biological therapy. Clinicians keep asking for more data and tailored information, especially on the safety and practical conduct of the switches between the biosimilar and its reference product. There is a consensus on the need for a better traceability and surveillance of adverse events of all biologicals. Physicians would like to see data of biosimilars in new or established registries.

Information and transparency are the key issues. It is not only data, as information is available, but only scarce information that is tailored towards different groups of stakeholders. Prescribers, maybe even different specialities, need different information, patients, hospital pharmacists and maybe payers as well. This is one of the take home messages – not only for regulators. Regulators will certainly give a signal to agencies and EMA that the emphasis on information should be even more than it is today.

This information should not only be tailored to the different stakeholders, it also should be focused on certain issues. Information available on several interesting factors can be put together as needed for each stakeholder. One of the issues that has been raised is whether physicians can explain the comparability exercise, especially the physicochemical in vitro biological aspect, and how decision-making is based on those tests.

Prescribers need information on extrapolation, they need to explain why therapeutic indications have been granted without clinical trials. This is another message that delegates at the Roundtable will need to bring back to their organizations and agencies.

The structure–function relationship, what can be said from individual results of analysis, how it can be concluded that a difference in an analytical test is not important, all needs to be explained to patients.

The Chair added one particular target for information, namely extrapolation of safety and efficacy. There are not enough regulators to explain to all stakeholders what extrapolation is, what analytical testing is, and so on. This has to be a collaborative exercise. The information received from London or from Brussels, prepared by multi-disciplinary multi-national teams, is very complicated. This information needs to be tailored according to national healthcare providers and society in general.

Physicians at the meeting were of the opinion that the information on the whole development cascade has helped to put the difficult issues, such as extrapolation and interchangeability, into a clearer context. Yet the limited data on the difficult topics, especially on interchangeability, is still of concern.

The presentation on the physicochemical and structural as well as in vitro functional analyses as the basis for comparability of different versions of both the original and biosimilar products and the long experience of these studies helped clinicians understand the concept of biosimilarity. The fact that the original biological products are not, from a physicochemical point of view, the same as at the time of licensing – because they have been subject to many manufacturing changes over their life cycle – was surprising to some delegates. One delegate even went on to say that it was a shame that physicians had not been aware of the manufacturing process change data shown by Dr Niklas Ekman and others, see Figure 2, which might have made switching to biosimilars less worrying. Any differences in a drug are feared, but it is now clear that physicians have been prescribing non-identical versions of the same drug for years.

Perhaps not surprisingly, the group discussions all agreed that the position of the physician is a difficult one when switching patients from the original product to the biosimilar. Physicians must keep up to date with the latest data in this area, and are personally accountable to their patients for their treatment decisions. On one hand, clinicians do not have the possibility to judge all data that were available for regulators at the time of marketing authorization. On the other hand, positive experience from some members of the groups reduced the level of uncertainty and anxiety.

It is not easy for a physician who has had success with an originator drug to switch to a biosimilar for cost reasons. It may be difficult to persuade a patient to switching to an alternative drug because it is cheaper, rather than because it is better. The health service overall stands to gain through cost savings, not the individual patient. Therefore, switching plans should incorporate some extra values for the patients, increasing their awareness of the benefits of biosimilars.

In at least two discussion groups, it became clear that Czech physicians are relatively unconcerned by switching. This was attributed to a successful education campaign, and to not being under cost pressures. Physicians from other countries often described how they felt they were being put under pressure to make cost savings from which they and their patients would not directly benefit. Perhaps learning about biosimilars and what they are, before being put under pressure to cut costs, would have made switching easier to deal with.

Conflict of interest was mentioned in the discussions. Biosimilarity is an area with high commercial interest. The regulators have extremely stringent rules for conflict of interest. Such rules are not possible in the clinic because it would be very difficult to run clinical trials. Nevertheless, relationships with industry should be somehow managed in order to maintain credibility. This is an issue that both regulators and prescribers need to be very much aware of.

The post-marketing follow-up is another area where physicians and regulators have common interests, especially how to make the most of registries. Current registries have been useful but there have been clear drawbacks; they are not available in every country, the ones that exist are useful for certain purposes but they are not compatible with each other, and it can be difficult to get information by pooling the data from different registries.

The national agencies should consider ways to contribute to registries. There are economic issues; who will fund the registries, how will the people who maintain it be reimbursed? This is also a political issue, since people are sensitive with their information/personal data and hence, permission from the patient is needed to use the data. This is an area where collaboration is required, including a strong signal from clinicians and regulators that these data are important for health care and for individual patients.

Traceability was discussed in the context of having several biosimilars, price competition and tendering processes. This situation may lead to multiple switches that should be documented. TDM was considered slightly outside the typical regulatory scope. There is some information in the summary of product characteristics if the company has been able to provide the necessary information. However, usually this is not the case and TDM is more for academics and clinicians who develop these systems.

Costs were not included in the presentations of this meeting although there is no other incentive to use biosimilars than lower price/costs. Physicians may have to change their role in the biosimilar discussion. The positive consequences of the price competition that is triggered by biosimilars needs to be understood. Roundtable Chair Professor Pekka Kurki hoped that delegates did not mind this kind of remark: ‘Economics are there and times will not improve, it will be harder in the future,’ he said. Instead of maintaining a very conservative attitude, there is another option to become active and try to get the best out of this situation, he said. ‘Think what you can do to induce cost savings with your prescription behaviour. There are examples, from the Czech Republic and the UK, as to how biosimilars can help save money that can be used for other purposes.’

Conclusions of the roundtable meeting

The Roundtable Chair concluded that the pleasant and constructive atmosphere of the meeting supported fruitful discussions, and testified for the importance of dialogue between regulators and physicians. Dialogue increases the mutual trust that is needed when new products and concepts are introduced to health care. The story of biosimilars is not yet at its end, this meeting was an interim analysis. Stakeholders need to be vigilant as the story unfolds.

It appears that the information on biosimilars has not been sufficient to satisfy the needs of prescribers. Physicians were interested in the way physicochemical, structural analyses and in vitro functional tests are used to demonstrate comparability and in the definition of acceptable differences. EPARs contain valuable information on biosimilars. However, their value for clinicians would increase if the crucial decisions such as extrapolation would be better justified. The European regulatory network, EMA and national regulatory agencies, need to find solutions to fill the obvious information gap.

Most of the position papers of medical societies were quite conservative and some contained requirements that would make the development of biosimilars unfeasible. It is evident that prescribers and regulators have different understanding of the biosimilar concept. The situation is changing since more information has become available and since experience from countries that have introduced biosimilars in massive scale, including switches, has been reassuring.

As a consequence, biosimilars are seen more often as an opportunity than a threat. A new situation is emerging in which regulators and prescribers can collaborate in planning managed switches and in tailoring information to various stakeholders, patients, pharmacists, payers. Pharmacovigilance was recognized as an important field of collaboration. Adverse effect reporting of biologicals, including the batch numbers, should be intensified. Collaboration between and within healthcare centres and hospitals as well as pharmacies is necessary to ensure traceability and early detection of rare adverse effects. Regulatory authorities may be able to promote the use of registries in monitoring the use of biosimilars.

Prescribers are in an uncomfortable situation when planning switches in individual patients who will not get immediate benefit and who may have concerns in using biosimilars instead of the original product. Payers and hospital administration should consider granting some incentives to healthcare units that will introduce biosimilars to their patients, e.g. the possibility to use the saved money to improve patient care by introducing new therapies.

Closing the meeting, Co-Chair Robin Thorpe explained that an event like this could only be the first step to reaching a consensus. The strength of such a Roundtable format allowed stakeholders from different and sometimes opposing camps – physicians (rheumatologists, gastroenterologists, dermatologists, haematologists, oncologists), pharmacists and regulators – to discuss their principles and concerns openly. Any conclusions from the event can only reflect what was agreed at the meeting, and what was not agreed.

Speaker Faculty, Moderators and Participants

Speakers
Niklas Ekman, PhD, Finland
Thijs J Giezen, MSc, PharmD, PhD, The Netherlands
Research Professor Pekka Kurki, MD, PhD, Finland (Chair)
Professor Andrea Laslop, MD, Austria
Robin Thorpe, PhD, FRCPath, UK (Co-Chair)
Martina Weise, MD, Germany
Elena Wolff-Holz, MD, Germany

Moderators and Co-moderators
Vito Annese, MD, PhD, Italy
Cristina Avendaño-Solá, MD, PhD, Spain
Professor Ferdinand Breedveld, MD, The Netherlands
Professor Fernando Gomollón, MD, PhD, Spain
Professor Tore Kristian Kvien, MD, Norway
Professor Lluís Puig, MD, PhD, Spain

Participants
Miguel Angel Abad Hernandez, MD, Spain, Spanish Society of Rheumatology (SER)
Vito Annese, MD, PhD, Italy, Italian Group for the Study of IBD (IG-IBD)
Professor Federico Argüelles-Arias, MD, PhD, Spain, Spanish Society of Gastroenterology (SEPD)
Cristina Avendaño-Solá, MD, PhD, Spain, Spanish Society of Clinical Pharmacology (SEFC)
Professor Jürgen Braun, MD, Germany, German Society for Rheumatology (DGRh)
Professor Ferdinand Breedveld, MD, The Netherlands, European League Against Rheumatism (EULAR)
Professor Antonio Costanzo, MD, Italy, Italian Society of Dermatology (SIDeMaST)
Professor Maurizio Cutolo, MD, Italy, European League Against Rheumatism (EULAR)
Assistant Professor Marc Ferrante, MD, PhD, Belgium, European Crohn’s and Colitis Organisation (ECCO)
Professor Fernando Gomollón, MD, PhD, Spain, European Crohn’s and Colitis Organisation (ECCO)
Professor Dr Richard Greil, MD, Austria, Austrian Society of Hematology and Medical Oncology (OeGHO)
Barney Hawthorne, DM, UK, British Society of Gastroenterology (BSG)
Ana Hidalgo-Simon, MD, PhD, UK, European Medicines Agency (EMA)
Professor Tore Kristian Kvien, MD, Norway, European League Against Rheumatism (EULAR)
Professor Milan Lukáš, MD, PhD, Czech Republic, Czech Society of Gastroenterology (CSG)
Professor Alexander MacGregor, MD, PhD, UK, British Society for Rheumatology (BSR)
Professor Massimo Massaia, MD, Italy, Italian Society of Experimental Hematology (IESS)
Associate Professor Dan Nordström, MD, PhD, Finland, Finnish Society of Rheumatology (FSR)
Marieke Pereboom, PharmD, The Netherlands
Bea Perks, PhD, UK
Professor Roberto Perricone, MD, Italy, Italian Society for Rheumatology (SIR)
Laura Pirilä, MD, Finland, Finnish Society of Rheumatology (FSR)
Professor Lluís Puig, MD, PhD, Spain, European Academy of Dermatology and Venereology (EADV)
Riccardo Saccardi, MD, Italy, Italian Group for Bone Marrow Transplantation (GITMO)
Professor Maria-Jesús Sanz Ferrando, PhD, PharmD, Spain, Spanish Society of Pharmacology (SEF)
Lasia Tang, BSc, MBA, Belgium

Apologies
Gonzalo Calvo, MD, PhD, Spain, European Association of Clinical Pharmacology and Therapeutics (EACPT)
Professor Marco Matucci Cerinic, MD, PhD, FRCP, honfbsr, Italy, Italian Society for Rheumatology (SIR)
Professor Silvio Danese, MD, PhD, Italy, European Crohn’s and Colitis Organisation (ECCO)
Professor João Eurico Cortez Cabral da Fonseca, MD, PhD, Portugal, Portuguese Society of Rheumatology (PSR)
Professor Maurizio Vecchi, MD, Italy, Italian Group for the Study of IBD (IG-IBD)

Acknowledgement

The Generics and Biosimilars Initiative (GaBI) wishes to thank Research Professor Pekka Kurki for his strong support through the offering of advice and information during the preparation of this Roundtable meeting.

The authors would like to acknowledge the help of all the roundtable speaker faculty and participants, each of whom contributed to the success of the meeting and the content of this report as well as the support of the moderators: Dr Vito Annese, Dr Cristina Avendaño-Solá, Professor Ferdinand Breedveld, Professor Fernando Gomollón, Professor Tore Kristian Kvien and Professor Lluís Puig, in facilitating meaningful discussion during the parallel group discussions, and presented the discussion findings at the meeting.

The authors wish to thank Dr Bea Perks, GaBI Journal Editor, in preparing this meeting report manuscript and providing English editing support on the group summaries and for finalizing this manuscript.

Editor’s comment

The PLANETAS and PLANETRA extension studies including full safety data have been published online in Annals of Rheumatic Diseases after the meeting of Roundtable on biosimilars with European regulators and medical societies: Park W, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis. 2016;0:1-9. doi:10.1136/annrheumdis-2015-208783
Yoo DH, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis 2016;0:1-9. doi:10.1136/annrheumdis-2015-208786

Competing interests: The Roundtable meeting was sponsored by an unrestricted educational grant to GaBI from Hospira UK Ltd.

Provenance and peer review: Not commissioned; internally peer reviewed.

Authors

Vito Annese, MD, PhD
Cristina Avendaño-Solá, MD, PhD
Professor Ferdinand Breedveld, MD
Niklas Ekman, PhD
Thijs J Giezen, MSc, PharmD, PhD
Professor Fernando Gomollón, MD, PhD
Research Professor Pekka Kurki, MD, PhD
Professor Tore Kristian Kvien, MD
Professor Andrea Laslop, MD
Professor Lluís Puig, MD, PhD
Robin Thorpe, PhD, FRCPath
Martina Weise, MD
Elena Wolff-Holz, MD

References
1. Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis. 2013 Mar;72(3):315-8.
2. Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol. 2011;29(4):310-2.
3. Weise M, et al. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191-6.
4. Flodmark CE, et al. Switching from originator to biosimilar human growth hormone using dialogue teamwork: single-center experience from Sweden. Biol Ther. 2013;3:35-43.
5. GaBI Online – Generics and Biosimilars Initiative. Norwegian study may be slowing adoption of biosimilar infliximab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Apr 21]. Available from: www.gabionline.net/Biosimilars/News/Norwegian-study-may-be-slowing-adoption-of-biosimilar-infliximab

Author for correspondence: Research Professor Pekka Kurki, MD, PhD, Finnish Medicines Agency, PO Box 55, FI-00034 Fimea, Finland

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2016 Pro Pharma Communications International

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Safety assessment of biosimilars in Europe: a regulatory perspective

Abstract:
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. Topics discussed include adverse events related to an exaggerated pharmacology, immunogenicity including assay development, extrapolation of indications in relation to safety assessment and pharmacovigilance.

Submitted: 29 August 2014; Revised: 2 September 2014; Accepted: 3 September 2014; Published online first: 5 September 2014

Introduction

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 [16].

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 [913]. 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].

Clinical safety during biosimilar development

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 [1618]. 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 [912]. 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].

Pharmacovigilance

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 [1618]. 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].

Conclusion

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.

Acknowledgement

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.

Disclaimer

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.

Authors

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

References
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2. Giezen TJ, Mantel-Teeuwisse AK, Meyboom RHB, et al. Mapping the safety profile of biologicals: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase. Drug Saf. 2010;33(10):865-78.
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10. Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther. 2002;24(11):1720-40; discussion 1719.
11. Schellekens H. Immunological mechanism of EPO-associated pure red cell aplasia. Best Pract Res Clin Haematol. 2005;18(3):473-80.
12. Schellekens H. Follow-on biologics: challenges of the next generation. Nephrol Dial Transplant. 2005;20 Suppl 4: iv31-6.
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
15. European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005 Rev. 1. 3 June 2013 [homepage on the Internet]. 2013 Jun 19 [cited 2014 Jul 19]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/06/WC500144124.pdf
16. European Medicines Agency. Committee for Medicinal Products for Human Use. European Public Assessment Report Inflectra. 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/002778/WC500151490.pdf
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

Author for correspondence: Thijs J Giezen, PharmD, PhD, Foundation Pharmacy for Hospitals in Haarlem, 24 Boerhaavelaan, NL-2035 RC, Haarlem, The Netherlands

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2015 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Source URL: http://gabi-journal.net/safety-assessment-of-biosimilars-in-europe-a-regulatory-perspective.html


Pharmacovigilance of biosimilars: challenges and possible solutions

Author byline as per print journal: Thijs J Giezen, PharmD, PhD; Sabine MJM Straus, MD, PhD

Abstract: 
Post-marketing surveillance is essential to detect, assess and prevent adverse reactions of chemically synthesized small molecule drugs as well as biologicals, as the full safety profile can only be known after they have been placed on the market. Biologicals have specific characteristics, which pose additional challenges in pharmacovigilance.

Submitted: 18 June 2012; Revised: 16 September 2012; Accepted: 17 September 2012; Published online first: 24 September 2012

Challenges are encountered during the pharmacovigilance of biosimilars, including traceability. These challenges and possible solutions were presented at the Conference of the Drug Information Association (DIA) in Copenhagen, Denmark, in March 2012. This paper provides a summary of the presentation given at the DIA.

Post-marketing collected safety data offers a valuable and necessary complement to clinical trials [1]. This applies to both chemically synthesized small molecule drugs and biologicals. However, compared to chemically synthesized drugs, biologicals have specific characteristics which might complicate their safety assessment: 1) biologicals are often indicated for rare diseases, where it is difficult to include sufficient patients in the pre-approval clinical trials and the continuous assessment of the benefit–risk in the post-marketing setting will be more important [2]; 2) obtaining exposure data after approval can be challenging for biologicals, since they are quite often used only in the hospital setting. Population-based databases mainly include information from general practitioners (GPs) and public pharmacies and will, therefore, contain limited information on patients exposed to biologicals. In addition, biologicals are often used in multiple indications with different dosage regimens. This might further complicate the exposure assessment of biologicals and a different approach towards the estimation of the number of patients exposed is warranted [3]; 3) it is sometimes difficult to define the ‘at-risk window’, which is the period that a certain adverse event should be attributed to the drug, for biologicals, due to their often prolonged pharmacodynamic effects [4]; 4) biologicals are often indicated as second- or third-line therapy limiting their use to patients with more severe disease or worse prognosis after the failure of ‘standard treatment’. In addition, this group of patients is often treated with concomitant medication and is often suffering from other diseases. For this reason channelling bias can easily occur [3]. From the above mentioned, it is clear that pharmacovigilance for biologicals poses additional challenges as compared to small molecules. These challenges apply to all biologicals, including biosimilars. However, for biosimilars additional challenges might be encountered. This paper aims to describe challenges in the pharmacovigilance of biosimilars and provide possible solutions to improve the pharmacovigilance of biosimilars.

Pharmacovigilance of biosimilars

At moment of regulatory approval of a biosimilar there is extensive information available on the reference biological. For the biosimilar specific data is limited to the comparability exercise. It is known that (small) changes in the production and purification process of biologicals can have (major) implications on their safety profile, which will mainly be reflected in an altered immunogenicity profile. It is highly expected that adverse events based on the pharmacology of the biological are similar between biosimilar and reference product. Since the manufacturing process of the reference product is proprietary knowledge, the manufacturer of the biosimilar will not be able to precisely replicate the protein product, which may influence the benefit–risk profile [5]. Due to the known limitations of randomized clinical trials [1], and the abbreviated dossier submitted as part of the marketing application for biosimilars, pharmacovigilance is important to obtain (additional) data on the safety profile of biosimilars. From a regulatory perspective, biosimilars have the same pharmacovigilance requirements as their reference products [6]. Biosimilars should, therefore, submit a risk management plan (RMP) as part of their marketing application and should submit periodic safety update reports on a regular basis post-approval.

Routine pharmacovigilance/spontaneous monitoring
Routine pharmacovigilance includes the collection of spontaneously reported adverse events by healthcare professionals and patients. Limitations of spontaneous reports of adverse events have been widely acknowledged and described and include under-reporting and a difficult to establish causality assessment between the adverse events and the drug of interest [7, 8]. In the case of biologicals and biosimilars some additional challenges might occur in the assessment of spontaneous reports. The issue of identifiability and naming has been described extensively [9]. Since small changes in the production process can alter the safety profile of a biological it is important that an adverse event can be related to a specific biological product. The new pharmacovigilance legislation stresses the importance of traceability and Member States are obliged to implement activities to improve traceability, including collection of the name of the medicinal product and the batch number [6].

Pro-active risk management
Since November 2005 applicants are obliged to submit a RMP as part of their marketing application for all new chemical and biological entities, including biosimilars. In the RMP, the safety profile of the medicine has to be described and pharmacovigilance activities should be proposed to further study safety concerns during use of the drug in the real-world setting and, if considered necessary, additional risk minimization activities should be described.

The safety information included in the RMP of the biosimilar should not only be based on the (limited) experience with the biosimilar from the pre-registration trials but should also be based on experience with the reference product. In this way, the RMP of the biosimilar will contain information on the safety profile, which is as complete as possible. In addition, the need for additional efficacy and safety studies in indications in which the biosimilar has not been studied pre-approval, but that are based on extrapolation, should be evaluated on a case-by-case basis. This is also included in the guideline on similar biological medicinal products containing monoclonal antibodies: 1) safety in indications licensed for the reference biological that are claimed based on extrapolation of efficacy and safety data; 2) occurrence of rare and particularly serious adverse events described for the reference product; and 3) detection of novel safety signals [10].

Immunogenicity, including lack of efficacy, is a safety concern that should specifically be addressed in the RMP and the need for additional pharmacovigilance activities should be clearly evaluated. Immunogenicity studies conducted post-approval should be done on a product specific basis and are especially important in case no long-term immunogenicity data has been obtained pre-approval.

Since biologicals are often used in a hospital setting, it can be expected that databases in which mainly GP and public pharmacy data are collected contain only limited information on biologicals. Drug and disease-based registries have shown to be important tools for the post-marketing collection of safety data for biologicals in general [11, 12]. Biosimilar companies are therefore recommended to participate in already existing registries; this will, for example, improve our knowledge on very rare adverse events like progressive multi-focal leukoencephalopathy.

In case there are risk minimization activities in place for the reference product which can be considered a class effect, these risk minimization activities should be included in the RMP of the biosimilar as well.

Conclusions and recommendations

Pharmacovigilance is an important tool to gain additional knowledge and collect safety data for biologicals and biosimilars due to the limitations of randomized controlled clinical trials. Keywords in the pharmacovigilance of biosimilars are: traceability and pro-active risk management to obtain additional knowledge about the safety of a biosimilar. In this context, immunogenicity is of specific interest and collaboration between companies is encouraged.

For patients

With the recent patent expiration of some biologicals, companies are able to develop so-called biosimilars of follow-on biologics. Biologicals have a very complex production and purification process which is owned by the company of the reference product. Therefore, the biosimilar might be different from the reference product. Although these small differences are mostly not clinically relevant it might, in rare cases, lead to safety problems. Collection of safety data during use by ‘real-patients’ is therefore important as well as the traceability of the biological that has been administered if an adverse event develops [13].

Disclaimer

The views discussed here are personal and not those of the European Medicines Agency, its scientific committees or any other regulatory agency.

Competing interest: None.

Provenance and peer review: Commissioned; internally peer reviewed.

Co-author

Sabine MJM Straus, MD, PhD, Medicines Evaluation Board, Utrecht, The Netherlands; Erasmus University Medical Centre, Department of Medical Informatics, Rotterdam, The Netherlands

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Author for correspondence: Thijs J Giezen, PharmD, PhD, Clinical Pharmacy, Hospital Medical Spectrum Twente, Postbus 50000, NL-7500 KA, Enschede, The Netherlands

Disclosure of Conflict of Interest Statement is available upon request.

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

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Tighter EU rules on pharmacovigilance for biologicals

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