Biosimilar monoclonal antibodies—challenges and opportunities in Europe

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Abstract:
New regulations for the development of biosimilars have been introduced in Europe and a new class of biosimilars – monoclonal antibodies – is expected on the market soon, which will both challenge and benefit our healthcare systems.

Submitted: 3 June 2013; Revised: 16 July 2013; Accepted: 23 July 2013; Published online first: 5 August 2013

Biosimilars are biological medicinal products, which contain a version of the active substance of an already authorized original biological medicinal product [1]. Once the market exclusivity period of the innovator has expired, biosimilars can be approved as copy versions of the originator product according to a specific abridged marketing authorization procedure, which demands the demonstration of similarity in physicochemical characteristics, efficacy and safety, based on a comprehensive comparability exercise. In most cases, biosimilars are manufactured from a separate production line, often by a different company and sometimes using a different expression system.

Consequently, although conditions and operations of production are chosen to be as closely related to the originator’s process as possible, it is clear that no exactly identical copy can be made due to the complex nature of the biological product, and some differences are inevitable. This situation, and the fact that biological products generally have a more complex structure than chemically synthesized substances, calls for regulatory approval and life cycle management that differs from the current approval process for generics.

The EU regulatory system has therefore developed a specific framework of guidelines and standards for the approval and pharmacovigilance of biosimilars. This framework has been laid down in Directive 2001/83/EC [2] and subsequently extended in a growing number of guidelines and authorized products on the market (published on the European Medicines Agency [EMA] website) [3]. Generics are usually approved on the basis of demonstration of bioequivalence with the originator reference product, but a more comprehensive development programme is needed for biosimilars. This involves extensive comparability studies at the level of quality characteristics, biological activity and functional characterization. Non-clinical and clinical data are also needed, normally not only including a comparison of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, but also requiring the demonstration of equivalence in efficacy and comparable safety between the biosimilar and the biological reference product. Details of the studies and data required for marketing authorization are addressed in the EMA guidelines on quality issues and on non-clinical and clinical issues relating to biosimilars, both of which are currently under revision [4, 5], as well as in further product specific biosimilar guidelines [3]. In specific cases, where there is a reliable and validated surrogate PD parameter for demonstration of efficacy, approval can be accepted on the basis of clinical data limited to similarity in PK and PD as well as safety.

In June 2012, the European Commission signalled a change in its position on the use of the reference medicinal product in the comparability exercise [6]. The previous requirement of exclusively using a reference product that had been licensed in the European Economic Area (EEA) has created a significant obstacle to companies pursuing global development. Recognizing these difficulties, EU regulators will now accept pivotal data from comparisons of the new biosimilar product with reference products authorized in regulated markets outside EEA, provided that certain preconditions are met. It is the applicant’s responsibility to establish the bridge from the non-EU to the EU reference product and to demonstrate that the former is representative of the latter. This can be achieved with an additional comparison between the non-EU and the EU reference product, encompassing a thorough comparative assessment at the physicochemical and functional level and, depending on the results, clinical data on the PK and PD profile of both originators. A corresponding wording has been introduced in the revision of the guideline on similar biological medicinal products [1], which was released by EMA on 26 April 2013 for public consultation.

By following the stepwise approach for demonstration of biosimilarity, some differences are already expected at the analytical step of physicochemical and functional comparison. These differences, however minor, may extend into the non-clinical and clinical studies and the challenge is to decide whether they bear clinical relevance. Although current methods for analyzing the structural similarity between originator and biosimilar are extremely refined and sensitive, it is very difficult or almost impossible to determine the clinical consequences of differences based on structural information only. On the other hand, the clinical comparability exercise is the least sensitive method for detecting differences. Even if present, disparities may go undetected in a clinical study of limited sample size, especially when the deviation of the biosimilar from the reference product mostly impacts the safety profile with a difference in immunogenicity or other rare adverse events. Thus, it is the totality of data that will deliver the overall picture of comparability and have to be taken into account in order for the regulator to make a well-informed decision with sufficient reassurance that the scientific standards and regulatory requirements defined for the approval of a biosimilar medicine are met.

Until recently, relatively simple biological compounds such as growth hormone, erythropoietin and granulocyte colony-stimulating factor (filgrastim) have been successfully brought to the market [7]. Nevertheless, following their approval several years ago it took on average another two to four years until they were accepted by the clinical community and the payers’ institutions and subsequently able to penetrate the market [7, 8]. Now, the considerably more complicated monoclonal antibodies are developed as biosimilars by several different enterprises. The dossier for the first of these, the biosimilar monoclonal antibody infliximab, has been filed to EMA for evaluation and received a positive opinion for marketing authorization by the Committee for Medicinal Products for Human Use (CHMP) in June 2013. The same product was licensed in July 2012 in South Korea as Remsima, and two other ‘similar biologics’ monoclonal antibodies, Rituxan (rituximab) and Etacept (etanercept), have been approved by the regulatory authorities in India. However, these marketing authorizations were not granted according to the standards as specified in the EU regulation and as such cannot be seen as true biosimilars in the European regulatory sense [9–11].

Apart from the above-mentioned marketing authorization procedure for a biosimilar infliximab, numerous requests for scientific advice related to biosimilar monoclonals have been discussed in the Scientific Advice Working Party, and recommendations for consistent development programmes have been given by CHMP. This indicates significant activity of the biosimilar industry, and several products providing copies of monoclonal antibodies could obtain approval and enter the market in the coming years.

However, there are further obstacles to overcome before this new class of biosimilars could effectively be used in daily clinical practice. Decisions on reimbursement, often referred to as the fourth hurdle, are the next step and could cause a delay in market access. From the payers’ side, an objection to the price of biosimilars may be expected. The price of Biosimilar monoclonal antibodies is forecast to be 10–30% less than originators [7, 8], which is considered too small for significant savings in healthcare expenditure. Notwithstanding, the replacement of innovator monoclonal antibodies with their respective biosimilar counterparts has been calculated to lead to considerable healthcare cost savings of between Euros 1.8 and 20.4 billion between 2007 and 2020 [8], underlining the importance of biosimilars in preserving the sustainability of our healthcare systems.

Clinicians are reluctant to use, or specifically to switch previously treated patients to, a product they are not sure has been sufficiently tested in patients [12]. This reluctance is all the more likely with biosimilar monoclonal antibodies, where extrapolation between products and between different indications is even more demanding. However, this stance ignores the fact that clinical trials on efficacy and safety comparisons between the biosimilar and the originator have been undertaken, albeit with a smaller sample size than normally expected during development of an innovator product. Several aspects need to be reflected upon and measures taken in order to strengthen this limited set of data. Extrapolation from one indication that has been studied in the clinical comparability exercise to others for which the originator has been previously licensed is more straightforward if the same mechanism of action of the monoclonal antibody is involved. Nevertheless, for some indications, different parts of the monoclonal antibody, e.g. not only Fab fragments, but also Fcγ receptor subtypes; may play an innate role in the mode of action and, in these instances, it is particularly relevant to consider additional results from PD comparisons, in a type of fingerprint approach.

As regards the extent of the safety database, the significance of further collection of post-marketing safety data, of prime importance for immunogenicity, is recognized. In line with the new pharmacovigilance legislation, this set of data will strengthen the ongoing evaluation of risks and thus support the conclusion on the benefit–risk balance. Special emphasis is laid on the traceability of either the originator or the biosimilar used in clinical practice so that the rate and severity of adverse events is identified for each product. Interchangeability cannot readily be concluded at the stage of approval due to a potential difference in rare adverse events, especially in the formation of antibodies against the therapeutic proteins. Traceability will only be possible by means of large databases accrued post-marketing from either specific safety studies or real-world data collection. It should be possible to detect any significant difference in immunogenicity reactions or other untoward effects if marketing authorization holders gather these data effectively and clinicians adhere to the requisite for careful documentation of brand names and batches. In this way, the clinical community will be given sufficient reassurance on the safe use of biosimilars with greater acceptance. It remains prudent, however, to avoid multiple switching between originators and Biosimilar monoclonal antibodies until more extensive clinical experience is available.

Disclaimer

The views expressed in this paper are the personal views of the author and may not be understood or quoted as being made on behalf of the Austrian Agency for Health and Food Safety or the Committee for Medicinal Products for Human Use.

Competing interests: None.

Provenance and peer review: Commissioned; externally peer reviewed.

References
1. European Medicines Agency. Guideline on similar biological medicinal products, CHMP/437/04 Rev 1. 2013 [homepage on the Internet]. 2013 [cited 2013 Jul 16]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf
2. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJL311, 28.11.2001, p. 67) [homepage on the Internet]. 2012 [cited 2013 Jul 16]. Available from: http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83/2001_83_ec_en.pdf
3. European Medicines Agency. Multidisciplinary: Biosimilar – list of scientific guidelines on biosimilar medicines [homepage on the Internet]. 2013 [cited 2013 Jul 16]. Available from: http://www.emea.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c
4. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), EMA/CHMP/BWP/247713/2012 [homepage on the Internet]. 2012 [cited 2013 Jul 16]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/WC500127960.pdf
5. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, EMEA/CHMP/BMWP/42832/2005. 22 Feb 2006 [homepage on the Internet]. 2012 [cited 2013 Jul 16]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003920.pdf
6. European Medicines Agency. European Medicines Agency to accept biosimilar reference medicines sourced outside European Economic Area. 28 Sep 2012 [homepage on the Internet]. 2013 [cited 2013 Jul 16]. Available from: http://www.emea.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/09/news_detail_001615.jsp&;mid=WC0b01ac058004d5c1
7. De Labry AO, Gimenez E, Lindner L, Garcia L, Espin J, Rovira J. Biosimilars in the European market. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(1):30-5. doi:10.5639/gabij.2013.0201.012
8. Haustein R, de Millas C, Höer A, Häussler B. Saving money in the European healthcare systems with biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):120-6.doi:10.5639/gabij.2012.0103-4.036
9. Weise M, Bielsky MC, de Smet K, Ehmann F, Ekman N, Narayanan G, et al. Biosimilars—why terminology matters. Nat. Biotechnol. 2011;29(8):690-3.
10. GaBI Online – Generics and Biosimilars Initiative. How are biosimilars special [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2013 Jul 16]. Available from: www.gabionline.net/Biosimilars/Research/How-are-biosimilars-special
11. Thorpe R, Wadhwa M. Terminology for biosimilars—a confusing minefield. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):132-4. doi:10.5639/gabij.2012.0103-4.023
12. Declerck PJ, Simoens S. A European perspective on the market accessibility of biosimilars. Biosimilars. 2012;2:33-40.

Author: Professor Andrea Laslop, MD, Head of Scientific Office, Austrian Agency for Health and Food Safety, 5 Traisengasse, AT-1200 Vienna, Austria

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2013 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.

Last update: 18/02/2019

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Commentary on the recommendations of the European Society for Organ Transplantation Advisory Committee on generic substitution of immunosuppressive drugs

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Abstract:
In 2010, the Council of the European Society for Organ Transplantation formed an Advisory Committee to formulate recommendations on the use of generic drugs in solid organ transplant recipients. The initiative was taken as a result of concerns regarding generic substitution of immunosuppressive drugs. The recommendations were published in Transplant International, and this paper is a short summary of its contents.

Submitted: 27 March 2013; Revised: 5 May 2013; Accepted: 13 May 2013; Published online first: 20 May 2013

Introduction

Solid organ transplant recipients are treated with immunosuppressive drugs in order to prevent rejection of their grafts. The most frequently used maintenance immunosuppressive drugs in Europe are the calcineurin inhibitors (tacrolimus and ciclosporin), and mycophenolic acid (mycophenolate mofetil). For all three drugs patents have expired and generic formulations have been registered. In 2010, the Council of the European Society for Organ Transplantation (ESOT) formed an Advisory Committee to formulate recommendations on the use of generic drugs in solid organ transplant recipients [1]. The initiative was taken as a result of concerns regarding generic substitution of immunosuppressive drugs. Health insurance companies encourage the prescription of generic drugs, as they have substantially lower prices compared to the original brand-name product. In some countries this led to substitutions by pharmacists, even in patients who had a prescription for a brand name drug. Prescribers felt that they were no longer in control of what drug their patients were taking. Uncontrolled substitutions by pharmacists have been linked to graft dysfunction, and the transplant community approached ESOT, and national transplant societies, which mobilized working groups and advisory committees to formulate guidelines on how to deal with generics substitution [2]. In this paper, the contents of the ESOT guidelines are summarized, as well as some recent developments in this field. For the full text the reader is referred to the original publication [1].

Bioequivalence and generic drugs

Registration of generic drugs largely depends on the demonstration of bioequivalence. The readers of GaBI Journal are very familiar with the design and interpretation of bioequivalence studies, and this will not be further discussed. There are subtle differences in regulatory requirements for bioequivalence between the American (FDA – Food and Drug Administration) and European (EMA – European Medicines Agency) agencies, but by and large the procedures are similar. An important difference however is that in 2010, for narrow therapeutic index drugs, EMA narrowed the 90% confidence interval of the ratio between the average rate and extent of bioavailability of the test formulation and the reference formulation from an interval of 80–125% to an interval of 90–111%, while FDA is still applying the wider interval. For the calcineurin inhibitors the stricter criteria are being applied by EMA, but for mycophenolate mofetil the wider range is still being used, as this drug is not considered to be a narrow therapeutic index drug.

Patients or healthy volunteers

Bioequivalence studies are generally performed in healthy human volunteers with normal renal, hepatic and cardiac function. The results of these studies are extrapolated to transplant populations. Although the smaller between-patient variability in healthy volunteers is an advantage in the detection of small differences in drug bioavailability between different formulations, many transplant physicians would favour bioequivalence studies in the respective patient populations. Some pharmaceutical companies have indeed performed such studies in transplanted patients, not as a regulatory requirement, but to convince prescribers that the generic drug is also bioequivalent to the reference product in their patients. It would offer such companies a marketing advantage, and prescribers would feel more comfortable in prescribing these formulations.

AUC and Cmax

The maximum observed drug concentration (Cmax) and the area under the curve (AUC) are the two parameters used to decide on bioequivalence. In daily practice, however, the immunosuppressive drugs are monitored by measurement of the pre-dose concentration (C0), although some argue that drug concentration measurements at other time points would be more appropriate [3]. Whether or not the correlation between the pre-dose concentration and AUC is the same for generic and reference drug product is not tested. Nevertheless, the same target concentrations for both products are strived for, although prescribers perceive this situation as a lack of evidence. In the ESOT guidelines there is a plea to investigate the relationship between the measured surrogate pharmacokinetic parameter, e.g. C0, or C2, and exposure (expressed as AUC) for the respective formulations. When such data are available, regular drug monitoring can be performed under valid assumptions.

Generic to generic substitution

Regulators claim that based on the demonstration of bioequivalence, the reference drug product and the generic formulation are fully interchangeable [4]. However, following a first substitution from the reference drug product to a generic formulation, subsequent substitutions from one generic drug to another often follow. It is important to realize that generic formulations are not necessarily bioequivalent amongst themselves. Although all generic formulations have been tested against the reference drug product, there is no requirement that generic formulations show bioequivalence with generic formulations that have been registered already. Knowing that the acceptance criteria allow for a difference between reference drug product and generic of 20%, it is theoretically possible that substitution from one generic drug to another leads to a substantial deviation in drug exposure. In the ESOT guidelines this omission in the registration process of generic formulations is highlighted.

Uncontrolled substitutions

When the prescriber has specified a particular brand-name drug and the dispensing pharmacist intends to give the patient something else, both prescriber and patient should be informed and both prescriber and patient should agree. Only then can the prescriber ask the patient to return to the clinic at a shorter time interval, to check drug concentrations and to ensure that the patient is taking the right drug in the right dose. Unfortunately, the prescriber is not always informed, and a reliable system to systematically notify the prescriber of a change in the dispensed formulation is not available. The ESOT guidelines warn of uncontrolled substitutions and recommend that pharmacists contact prescribers before dispensing alternative formulations.

Confused patients

Although brand-name drugs and generic drugs may be interchangeable with respect to their drug exposure and their clinical effects, they can differ substantially in their appearance. Consumers of generic drugs must be prepared to receive pills of a different size, colour, and shape, depending on which manufacturer is supplying their pharmacies. With numerous generic to generic substitutions over a period of time, patients may get confused and make mistakes. Such mistakes may have serious consequences [5]. The ESOT guidelines ask for a system of more uniform drug appearance in order to reduce medical error and promote patient adherence to treatment regimens that involve generic drugs [6].

Conclusion

Immunosuppressive drugs are expensive and life-long immunosuppressive therapy of transplant patients is associated with high financial costs. ESOT is not opposed to the use of generic drugs. ESOT Advisory Committee stressed that savings in the cost of immunosuppressive drugs will benefit health care and society, as long as the overall cost is not increased due to additional patient care and drug monitoring. Uncontrolled substitutions and repetitive substitutions from one generic drug to another should be avoided. The guidelines attempt to regulate the process of generic substitution of immunosuppressive drugs in transplant recipients. This is a vulnerable patient population. The demonstration of bioequivalence is not sufficient to conclude there is unconditional interchangeability [7].

Competing interests: Professor Teun van Gelder has received honoraria, research grants or lecture fees from Astellas, Pfizer, Roche, Sandoz and Wyeth; and is a member of the Dutch Novartis Transplant Advisory Board.

Provenance and peer review: Commissioned; externally peer reviewed.

References
1. van Gelder T; ESOT Advisory Committee on Generic Substitution. European Society for Organ Transplantation Advisory Committee recommendations on generic substitution of immunosuppressive drugs. Transpl Int. 2011 Dec;24(12):1135-41.
2. Harrison JJ, Schiff JR, Coursol CJ, Daley CJ, Dipchand AI, Heywood NM, et al. Generic immunosuppression in solid organ transplantation: a Canadian perspective. Transplantation. 2012 Apr 15;93(7):657-65.
3. Knight SR, Morris PJ. The clinical benefits of cyclosporine C2-level monitoring: a systematic review. Transplantation. 2007 Jun 27;83(12):1525-35.
4. Maliepaard M, et al. Equivalence of generic medicines in general and immunosuppressants in particular – a regulatory opinion on switching of cyclosporin, tacrolimus and mycophenolate mofetil. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(2):86-90. doi:10.5639/gabij.2013.0202.019
5. Greene JA. The substance of the brand. Lancet. 2011 Jul 9;378(9786):120-1.
6. Greene JA, Kesselheim AS. Why do the same drugs look different? Pills, trade dress, and public health. N Engl J Med. 2011 Jul 7;365(1):83-9.
7. Van Gelder, T. Why bioequivalence and unconditional interchangeability of generic drugs are not the same. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(2):83-5. doi:10.5639/gabij.2013.0202.020

Author: Professor Teun van Gelder, MD, PhD, Internist – nephrologist/clinical pharmacologist, Departments of Internal Medicine and Clinical Pharmacology, Erasmus University Medical Center, PO Box 2040, NL-3015 CE Rotterdam, The Netherlands

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2013 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.

Last update: 29/03/2017

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The case for biosimilars–a payer’s perspective

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Biosimilars have the potential for making savings in healthcare costs, and with resource allocation, if competition is permitted at the level of treatment induction.

Submitted: 24 August 2012; Revised: 17 January 2013; Accepted: 4 February 2013; Published online first: 13 February 2013

The last decade or so has seen the introduction of many truly innovative biological pharmaceuticals that have had a profound impact on the treatment of many diseases. This is a welcome development. The future of these biologically produced pharmaceuticals looks bright, with almost 300 monoclonal antibodies alone having international nonproprietary name status, 70 of which also have trade names.

Unfortunately, the companies that have brought these drugs to market have uniformly chosen to sell them at very high prices. This presents healthcare financing systems with a dilemma, for the reasons outlined below.

Biological pharmaceuticals are produced using living cells genetically modified to produce a particular substance. This is a hugely complex process that is only partly controllable. In addition, a variety of different cell types can be used to produce each substance. Together with other manufacturing complexities, biosimilar pharmaceuticals are never completely identical to their reference products. The main consequence, from a payer´s perspective, is that regulatory agencies are unlikely to allow pharmacies to substitute these drugs for the originals.

In Sweden, where generic drug alternatives are available, there is mandatory substitution at the pharmacy level. This means that the pharmacy will substitute a branded product with the cheapest generic drug available within a predetermined substitution group, unless the prescribing physician has indicated a medical reason for not doing so. This has led to a very competitive environment within the generics sector, resulting in substantial price decreases and savings for the healthcare system. By and large, all stakeholders find this arrangement acceptable, since it allows the introduction of new and innovative products at the early end of the product lifecycle. It rests, however, on one fundamental and generally accepted assumption: that generics are perfect substitutes for each other – as well as for the original drug, e.g. 10 mg simvastatin from one source is the same as 10 mg simvastatin from another, regardless of supplier.

Thus, substitutability becomes a central issue if one hopes to induce the same type of competitive dynamics for biological drugs as already exists for generics, even though it is reasonable not to expect the same magnitude of price decreases due to the more complex nature of manufacturing. Biosimilars that have been approved by the European Medicines Agency are approved pharmaceuticals in their own right, having passed a number of rigorous safety criteria and following the same pharmacovigilance rules as originator products, and having demonstrated comparable quality and clinical activity to the reference product.

Introducing a more macroeconomic perspective, the current eurozone crisis and general economic conditions clearly signal that politicians responsible for allocating resources have little room for increases in public expenditure. Indeed, many countries are experiencing decreases in public spending. Thus, barring a major redistribution of resources within the healthcare sector, it is highly unlikely that there will be a major budget increase for pharmaceuticals anywhere within the EU in the short- to mid-term. Payers and industry alike must face up to a largely static pharmaceutical budget (shrinking dramatically in some cases) for the foreseeable future.

Also at stake is the issue of equity. Biological pharmaceuticals are almost always priced at levels that lead to high treatment costs. If a very small number of patients consume large amounts of the resources allocated to pharmaceuticals, this may be perceived as unfair, which in turn is politically sensitive. If the high cost of treatment with biological pharmaceuticals for small groups of patients overwhelms the ability to pay for other treatments for larger patient groups public opinion could become quite negative.

From a payer’s perspective, the case in favour of biosimilars is a strong one. There is a clear incentive to foster a competitive climate for biosimilars, including through allowing substitution at treatment initiation. The potential price reductions can then create room for new products or expanded patient populations or both, given the budgetary constraint. This will certainly be encouraged in Sweden and other countries in Europe and beyond. Although manufacturers of originator products may be opposed to the introduction of biosimilars if profit margins fall, this development should nevertheless be embraced by industry as a whole in order to make room financially for the launch of new and innovative products.

For patients

The increasing popularity of biopharmaceuticals as treatments for a variety of conditions, including chronic illnesses is placing pressure on healthcare systems to make these available to patients. Their high costs, however, are encouraging healthcare providers to look to cheaper similar versions of the same biopharmaceuticals, or biosimilars, as lower cost alternatives. For approval in Europe, biosimilars must compare well in safety and efficacy compared to their reference products. Once on the market, competition between products can lead to a reduction in price for both biosimilars and branded products, which in turn will make them more accessible to the patients that need them [1].

Competing interests: None.

Provenance and peer review: Commissioned; externally peer reviewed.

Reference
1. Class JN, Langis L. A patient-centred paradigm for the biosimilar market. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):17-21. doi:10.5639/gabij.2012.0101.006

Author: Gustaf Befrits, Health Economist, Tandvårds-och läkemedelsförmånsverket (TLV) – Dental and Pharmaceutical Benefi ts Agency, PO Box 22520, 7 Fleminggatan, SE-10422 Stockholm, Sweden

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2013 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.

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Last update: 03/10/2016

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Statin generics: no differences in efficacy after switching

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A study presented at the 2010 Congress of the European Society of Cardiology, had created a considerable stir. Its abstract allegedly showed that the originator drug Lipitor was more beneficial than any of its generic statin equivalents. But, in fact the study merely showed that the different potencies of statins were not taken adequately into consideration during the generics switch. The conclusions underscore that statin generics do have essentially the same safety and efficacy as Lipitor and may have implications for new atorvastatin generics that have recently entered the market and will increasingly be prescribed in future.

Submitted: 27 July 2012; Revised: 3 September 2012; Accepted: 3 September 2012; Published online first: 5 September 2012

A notable abstract on generics substitution of statins was presented at the 2010 Congress of the European Society of Cardiology [1]. Some of the resulting media coverage was equally interesting, stating, for example, that ‘Patients should stay on Pfizer’s Lipitor, and not switch to generics’ [2]. What the abstract predicted was an increased potential risk for serious cardiovascular events following a switch to generic statins. Despite this interesting finding, the question of whether generic statins should be considered inferior to the atorvastatin brand leader, however, can be answered with a resounding ‘No’.

Nonetheless, what may appear initially to be a paradoxical conclusion makes perfect sense when considering that the study’s aim was not to see if generics act differently to branded products. Instead, the study showed that following a government-mandated switch to generic statins in The Netherlands, doctors–intentionally or unintentionally–prescribed inadequate doses of the generic drug when switching. Notably, the Dutch doctors were not prescribing generics with the identical active pharmaceutical substance, but instead were switching from branded atorvastatin (Sortis/Lipitor) to various generic versions with simvastatin. This switch makes sense considering the high costs of originator atorvastatin and the remarkably lower costs of generic simvastatin. However, the change of active substances means that it was not a true generics switch because another active substance was prescribed. More importantly, the two active substances are not of equal potency: atorvastatin is more potent than the same molar quantity of simvastatin [3]. The dose equivalence therefore is set at a ratio of at least 1:2 to 1:4, as indicated in the product information leaflets.

Nevertheless, not all prescribing physicians are aware of this fact, and as a result, 20 mg atorvastatin is often substituted by just 20 mg simvastatin. An analysis of the Dutch database revealed, that out of 39,031 patients, more than a third (33.7%) received less than an equipotent dose of simvastatin after the switch. These figures were calculated under the assumption of a potency ratio of 1:2. If the authors had used a ratio of 1:4, the numbers would have been even higher. Statistical models suggested that this inadequate dosing would lead to a 5.6% increase in LDL-cholesterol levels. This, together with the findings of a meta-regression study [4] showing that every 25 mg/dL (0.65 mmol/L) reduction in LDL-cholesterol lowers the risk of serious cardiovascular events by 14%, indicates that inadequate simvastatin dosing might increase cardiovascular risk by at least 5.5% [1].

It remains uncertain whether these dose reductions were intentional or not. But an intentional dose reduction is unlikely due to the high numbers of patients involved, which does not reflect everyday clinical practice. Worryingly, our conclusion is that a substantial number of switches in The Netherlands were performed by physicians who were unaware of the different potencies of statins. This occurred after a government-mandated change in policy in which physicians would have to justify their prescriptions of branded statins. The result was an economically beneficial increased switch to generics. At the time of the policy change, however, atorvastatin generics were not yet licensed, and so patients were switched to generic simvastatin instead as the available alternative.

Fortunately, this situation has not occurred in Austria, for example. Here, the guideline for economic prescribing [5] stipulates that in the case of two equally effective treatments the cheaper one should be chosen. To do so, Austrian doctors can access an online ‘Info-tool’ [6] which indicates alternatives to an originator product and their prices. This tool takes the potency difference of statins into account correctly. A search for alternatives to atorvastatin, e.g. to Sortis 20 mg tablets, produces a list of several simvastatin generics, all at an appropriate dosage form of 80 mg tablets, some of them even with a score line. This takes into account dose equivalence in the range of 1:2 to 1:4. The product information leaflets affirm the difference in potency: the indicated dosage of atorvastatin for the prevention of cardiovascular disease is 10 mg per day, while for simvastatin it is 20–40 mg per day.

The Dutch study shows the importance of thoroughly checking product information and using additional info-tools. The erroneous switch to less than equivalent doses of simvastatin, two to four times below the recommended dosage, could have been detected and presumably avoided if the prescribing physicians had consulted these resources properly.

In conclusion, the media coverage that generic statins might be inferior per se, and that switching should be avoided, can be refuted. In support of this, a Korean study [7] examined the efficacy of atorvastatin generics to reduce LDL-cholesterol and total cholesterol compared to its atorvastatin originator. Reduction after eight weeks from baseline for LDL-cholesterol was about 44% for the generics and 46% for the originator, showing no significant difference. Corresponding values for total cholesterol were about 30% and 31%, respectively, and not significantly different. In addition, a Slovenian trial [8] similarly revealed that generic atorvastatin leads to an equal reduction in LDL-cholesterol compared to the originator after 12 weeks (37.8% vs 38.4%, p = ns). Both drugs reduced the absolute coronary risk by 13% and 13.3% for the generic and reference atorvastatin, respectively.

These findings are important as a number of atorvastatin generics have recently entered the market that will increasingly be prescribed in future, as was already seen with other drug substances [9, 10], giving assurance to physicians that atorvastatin generics are equally as safe and effective as the originator. Physicians who choose to switch from atorvastatin to simvastatin may do so, but must consider the different potency of these two statins and take care to prescribe the correctly adjusted dose.

For patients

A misunderstood study about the statin drug Lipitor and its generic alternatives caused a media storm, with the notion that generics were inferior. A closer examination, however, reveals that physicians had mistakenly prescribed inadequate doses of the generic drug alternatives, putting patients at higher risk of cardiovascular disease.

Competing interests: None.

Provenance and peer review: Commissioned; externally peer reviewed.

References
1. Liew D, et al. The cardiovascular consequences of switching from atorvastatin to generic simvastatin in the Netherlands. Abstract n° 3562. ESC; 2010 Aug 28–Sep 1; Stockholm, Sweden.
2. Bloomberg News, 2010-08-20 [homepage on the Internet]. Patients should stay on Pfizer’s Lipitor, not switch to generic, study say. [cited 2012 Sep 3]. Available from: www.bloomberg.com/news/2010-08-20/cholesterol-drug-study-shows-heart-risks-in-switch-to-generic-from-lipitor.html
3. Rogers, et al. A dose-specific meta-analysis of lipid changes in randomized controlled trials of atorvastatin and simvastatins. Clin Ther. 2007 Feb; 29(2):242-52.
4. Delahoy PJ, et al. The relationship between reduction in low-density lipoprotein cholesterol by statins and reduction in risk of cardiovascular outcomes: an updated meta-analysis, Clin Ther. 2009 Feb;31(2):236-44.
5. Hauptverband der österreichischen Sozialversicherungsträger [homepage on the Internet]. [Austrian instructions on economic prescribing of medicines (RÖV)]. [cited 2012 Sep 3] German. Available from: www.hauptverband.at/portal27/portal/hvbportal/channel_content/cmsWindow?action=2&p_menuid=58307&p_tabid=4
6. Hauptverband der österreichischen Sozialversicherungsträger [homepage on the Internet]. [Infotool to the Austrian Reimbursement-Code]. [cited 2012 Sep 3] German. Available from: www.hauptverband.at/portal27/portal/hvbportal/emed/
7. Kim SH, et al. Efficacy and tolerability of a generic and a branded formulation of atorvastatin 20 mg/d in hypercholesterolemic Korean adults at high risk for cardiovascular disease: a multicenter, prospective, randomized, double-blind, double-dummy clinical trial. Clin Ther. 2010 Oct;32(11):1896-905.
8. Boh M, et al. Therapeutic equivalence of the generic and the reference atorvastatin in patients with increased coronary risk. Int Angiol. 2011 Aug;30(4):366-74.
9. Baumgartel C, Godman B, Malmstrom R, et al. What lessons can be learned from the launch of generic clopidogrel? Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):58-68. doi:10.5639/gabij.2012.0102.016
10. Baumgartel C. Generic clopidogrel–the medicines agency’s perspective. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):89-91. doi:10.5639/gabij.2012.0102.019

Author: Christoph Baumgärtel, MD, Department Head, Department Safety and Efficacy Assessment of Medicinal Products, Institute Marketing Authorisation of Medicinal Products & LCM, AGES PharmMed–Austrian Medicines and Medical Devices Agency, and Austrian Federal Office for Safety in Health Care, European Expert in Pharmacokinetics Working Party and Safety Working Party of EMA, Member of Austrian Prescription Commission, 5 Traisengasse, AT-1200 Vienna, Austria

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.

Last update: 12/03/2020

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Pharmacovigilance of biosimilars: challenges and possible solutions

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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

References
1. Stricker BH, Psaty BM. Detection, verification, and quantification of adverse drug reactions. BMJ. 2004;329(7456):44-7.
2. Heemstra EH, Giezen TJ, Mantel-Teeuwisse AK, De Vrueh RLA, Leufkens HGM. Safety-related regulatory actions for orphan drugs in the US and the EU: a cohort study. Drug Saf. 2010;33(2):127-37.
3. Giezen TJ. Risk management of biologicals: a regulatory and clinical perspective [dissertation]. Utrecht, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University; 2011.
4. Dixon WG, Symmons DP, Lunt M, Watson KD, Hyrich KL, Silman AJ. Serious infections following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum. 2007;56(9):2896-904.
5. Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19(3):411-9.
6. L348/74 Official Journal of the European Union 31.12.2010.
7. Meyboom RH, Egberts AC, Gribnau FW, Hekster YA. Pharmacovigilance in perspective. Drug Saf. 1999;21(6):429-47.
8. Meyboom RH, Hekster YA, Egberts AC, Gribnau FW, Edwards IR. Causal or casual? The role of causality assessment in pharmacovigilance. Drug Saf. 1997;17(6):374-89.
9. Declerck PJ. Biotherapeutics in the era of biosimilars: what really matters is patient safety. Drug Saf. 2007;30(12):1087-92.
10. Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing monoclonal antibodies. London: European Medicines Agency; May 2012.
11. Zink A, Askling J, Dixon WG, Klareskog L, Silman AJ, Symmons DP. European Biologicals registers: methodology, selected results and perspectives. Ann Rheum Dis. 2009;68(8):1240-6.
12. Curtis JR, Jain A, Askling J, et al. A comparison of patient characteristics and outcomes in selected European and U.S. rheumatoid arthritis registries. Semin Arthritis Rheum. 2010;40(1):2-14.e1.
13. Declerck P. Biologicals and biosimilars: a review of the science and its implications. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):84-8. doi:10.5639/gabij.2012.0102.018

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

Last update: 18/02/2019

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Innovator companies should focus on innovations

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Abstract:
 Despite biopharmaceuticals having an enormous potential value for our health, they have also become a serious threat to our healthcare systems.

Submitted: 22 June 2011; Revised manuscript received: 6 October 2011; Accepted: 11 October 2011

Recombinant drugs, or biologicals as they are widely termed, are highly complex drug substances that have added tremendous treatment opportunities to modern medicine. However, introducing these highly complex molecules into a patient is a high-risk medical intervention, particularly because recombinant proteins have additional immunological risks compared to most, if not all, small molecules. This is certainly the case when an original product is clinically tested in first-in-human trials.  Fortunately, we have learned that the risks far outweigh the benefits for conditions where no other treatments are available.

Most recombinant drugs are very expensive, which can only be explained in part by the costs accrued during their development and manufacture. These costs put a tremendous burden on healthcare systems and it is clear that many patients who could benefit from such therapy with a recombinant drug are left untreated if neither they nor their healthcare system can afford to pay. Some therapies can cost up to Euros 500,000 or more per patient per year of therapy [1]. This cost may be warranted due to the potential benefits the drug can deliver and the initial investment when the medicine is innovative and new, but such high costs cannot be justified in the very long term.

Without a doubt, developing a biosimilar is much more complex than developing a generic version of non-biological drugs [2]. A highly controlled manufacturing process is intrinsically important to biotech medicines as even minor variations in manufacturing or production can result in vastly different products with deleterious, or in some cases highly favourable results, such as better tolerability or efficacy [3].

Once the possibility of efficacious treatment within an acceptable safety profile has been demonstrated, competitors may enter the market, occasionally even while the original molecule is still protected by patents. This is possible because, in many cases, a whole variety of different proteins can solve the same clinical problem.  For example, six structurally very different tumour necrosis factor-alpha antagonists compete in the market for the treatment of chronic inflammatory diseases and several more are in the pipeline [4].  All these molecules are innovations as the molecules are structurally very different, but all have turned out to be reasonably well tolerated and more or less equally efficacious and all were consequently approved by authorities in Europe and the US.

Due to the less stringent regulatory requirements of biosimilars and the time required for research, the price of these can be significantly lower than the innovator. By introducing these less expensive biosimilars into the market, the price of the innovator is also often reduced due to this market competition and is a reasonable tool to keep medicines at an affordable cost.

In my opinion, innovator companies should concentrate on innovations—and the potential for innovation is enormous.  There are many unmet medical needs waiting for innovative intervention options and there is always a potential for improving on the characteristics of the molecules towards second or third generation drugs. This is both an opportunity for seriously ill patients and a chance for our healthcare system as well.

References
1.  Bailey L. An overview of enzyme replacement therapy for dysosomal storage diseases. OJIN. 2008;13(1):3. doi:10.3912/OJIN.Vol13No01Man03
2.  Crommelin D, et al. Pharmaceutical evaluation of biosimilars: important differences from generic low-molecular-weight pharmaceuticals. Eur J Hosp Pharm Sci. 2005;11(1):11-7.
3.  Robinson CJ, Jones C. Quality control and analytical techniques for biopharmaceuticals. Bioanalysis. 2011;3:81-95.
4.  Nam JL, Winthrop KL, van Vollenhoven RF, et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis. 2010;69:976-86.

Author: Professor Theodor Dingermann, PhD, Institute of Pharmaceutical Biology, Biocenter, Gebaeude N230, 306, 9 Max-von-Laue Strasse, DE-60438 Frankfurt/Main, Germany

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.

Last update: 22/06/2020

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