Abstract:
This paper discusses topics covered by the EGA’s April 2015 biosimilars conference, where extrapolation of indications was highlighted as a key issue.
Submitted: 2 July 2015; Revised: 15 July 2015; Accepted: 15 July 2015; Published online first: 28 July 2015
The European Generic medicines Association (EGA) held its 13th EGA–European Biosimilars Group Conference in London on 23–24 April 2015.
The conference was attended by more than 280 delegates from 36 different countries, and included delegates from national and international regulatory agencies, pricing and reimbursement authorities, academia, patient organizations, medical societies and healthcare professionals.
The key topic was ‘the science of extrapolation of indications’ but many related subjects were also covered by the conference including the basic principles of biologicals, the European Medicines Agency (EMA) overarching guideline, harmonization efforts on biosimilar clinical trials, naming/labelling of biosimilars, the World Health Organization BQ (biological qualifier) proposal, strategic approaches for the uptake of biosimilars in France, Germany, Italy, Spain, Sweden and the UK; Norway’s biosimilar infliximab experience [1], and the global view of biosimilars regulatory approval with a focus on Brazil, Canada [2] and the US.
Mr Didier Laloye from Hospira France gave a presentation on behalf of the French generics association GEMME. His presentation, which covered biosimilars uptake in France, highlighted the complexity of the situation in the country regarding reimbursement, pricing, substitution and incentives for biosimilars.
France is the first European country to consider legislation on biosimilars substitution. French legislation allowing substitution of biosimilars was introduced as part of a new law concerning the social security budget (Article 47 of the Law of 23 December 2013) [3]. However, the implementing decree has not yet been published. The French healthcare authority, ANSM (Agence nationale de sécurité du médicament et des produits de santé), recommends that after the first administration of biological product, not to change the product given to the patient, in order to limit the risk of immunogenicity and ensure traceability for pharmacovigilance follow-up. This is also reflected in the law, which states that substitution of biosimilars is allowed only when initiating a course of treatment, if the biosimilar belongs to the same group as the prescribed product (known as a ‘similar biologic group’) and if the prescribing physician has not explicitly prohibited substitution of the prescribed biological by indicating ‘non substiuable’ (non-substitutable) in handwritten characters on the prescription.
A presentation concerning the trends from marketing authorization applications, scientific advice procedures and policies by Dr Peter Richardson, Head of Quality Office, Specialised Scientific Disciplines Department, at EMA, explored the use of statistical methodology for comparative assessment of quality attributes, global development and the increasing use of non-EU comparators, and the variety of clinical approaches proposed to demonstrate biosimilarity. A global development approach was proposed in 75% of the scientific advice requests for biosimilars in 2014.
In a presentation by Dr Jian Wang from Health Canada entitled ‘Biosimilars in Canada: learning from the approval of the first mAb and future outlook’, the reasons for the agency’s refusal to extrapolate inflammatory bowel disease (IBD) indications to the infliximab biosimilar (Remsima/Inflectra) [4] were outlined. Dr Wang explained that extrapolation to indications and uses pertaining to IBD (Crohn’s disease and ulcerative colitis) was not recommended because the comparability between the reference and biosimilar infliximab indicated insufficient similarity between the two products. This arose from the observed differences in the level of afucosylation, FcγRIIIa receptor binding and in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) activity. Furthermore, uncertainty arose since differences were observed in the quality assessment – a lower ADCC activity, interpretation of in vitro test results from all assays was challenging, ADCC mediated effects in certain disease(s) cannot be ruled out, the clinical significance of a lower ADCC activity is still unclear and clinical studies were conducted only in populations where ADCC is unlikely to be involved.
Dr Wang pointed out that ‘based on the same data set, regulatory agencies may render different regulatory decisions. This can happen for both innovator and biosimilar products. He added that ‘further dialogue and harmonization among regulatory agencies on their decision-making could be considered as experience with the scientific and regulatory issues related to biosimilars increases.’
According to Dr Wang, the uncertainties in extrapolation of indications are due to the fact that the ‘scientific and regulatory knowledge and experience are limited in dealing with these types of issues’, and that the ‘pre-submission package was not sufficiently informative in terms of the issue of concern’.
Despite uncertainties on extrapolation of indications in certain circumstances, Health Canada does support extrapolation of indications, and emphasizes that the science of extrapolation is based on the following principles:
Similarity is demonstrated through a detailed and comprehensive comparative product characterization.
There is a thorough understanding of the mechanism(s) of action of the biological product, and the similarities and differences in the mechanism(s) of action that play a role in each of the indicated conditions for which a sponsor applies.
There is an understanding of the pathophysiological process(es) of the indicated diseases, and the differences and similarities between them.
The safety profiles in the respective conditions and/or populations are comparable.
There is adequate clinical experience with the reference drug.
In the session chaired by Dr Sumant Ramachandra on ‘The evolving biosimilar paradigm: from a science-driven conceptual approach to a science-driven knowledge-based approach’ the science of extrapolation was also discussed and highlighted as a critical issue for biosimilars makers.
Competing interest: None.
Provenance and peer review: Article prepared based on research and conference presentations, internally peer reviewed.
Michelle Derbyshire, PhD, GaBI Online Editor
References 1. Asbjørn M. Norway, biosimilars in different funding systems. What works? Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(2):90-2. doi:10.5639/gabij.2015.0402.018 2. Pen A, Klein AV, Wang J. Health Canada’s perspective on the clinical development of biosimilars and related scientific and regulatory challenges. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(1):36-41. doi:10.5639/gabij.2015.0401.009 3. GaBI Online – Generics and Biosimilars Initiative. France to allow biosimilars substitution [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Jul 15]. Available from: www.gabionline.net/Policies-Legislation/France-to-allow-biosimilars-substitution 4. GaBI Online – Generics and Biosimilars Initiative. Subsequent entry biologics approved in Canada [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Jul 15]. Available from: www.gabionline.net/Biosimilars/General/Subsequent-entry-biologics-approved-in-Canada
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Abstract:
The substantial improvement in the power of analytical methods to compare different versions of a given protein molecule should be taken into account when considering the value of clinical studies for designation of biosimilarity. Arguably, demonstration of comparative pharmacokinetic, allied to post-registration monitoring, will provide more discriminatory clinical evidence than large pre-approval therapeutic equivalence studies.
Submitted: 4 August 2015; Revised: 5 August 2015; Accepted: 6 August 2015; Published online first: 19 August 2015
In this issue of GaBI Journal, Gerard et al. conclude that extrapolation to other indications of biosimilars on the basis of throughout analytical characterization of biosimilars can be done [1]. Their message is that the analytical methods available today have evolved enormously compared to the time the first biosimilars came to the market. On analytical grounds it is possible to predict efficacy and safety. Will this have consequences for the registration requirements in the near future?
In 2003, the Committee for Medicinal Products for Human Use (CHMP) came to a positive opinion for the first biosimilar product Omnitrope (genotropin). Legal issues prohibited an approval by the European Commission but the company resubmitted two years later and in 2006 Omnitrope was approved as the first biosimilar biological. This procedure initiated and stimulated the publication of biosimilar European Union (EU) guidelines. The principle behind these guidelines is that similarity demonstration is crucial. Full demonstration of efficacy and safety is no longer required, but a biosimilar application should be supported by an extensive comparability exercise at quality, preclinical as well as at clinical level. The idea behind this approach is that for biologicals comparability is impossible to demonstrate on analytical grounds alone.
Since 2006 several biosimilars have been approved in the EU. Clinical data were limited; studies were often restricted to one indication. This indication is chosen because of being the most sensitive indication to show a potential difference if such a difference really exists. In a few cases clinical data were even more limited to pharmacodynamic data alone.
Since 2006, major advances have been made in analytical techniques, exquisite methods exist nowadays to characterize the primary amino acid sequence, the tertiary conformational structure, post-translational modifications, e.g. glycosylation, and to assess any impurities and degradation products both after release and during shelf life. Biological activity is further compared by in vitro and in vivo activity assays.
These advances in technology have already influenced regulators. Updates of existing guidelines show that regulators keep an eye on new possibilities to show comparability and especially to extrapolate to other indications. The recent clinical EU guideline mentioned that extrapolation should be considered in the light of the totality of data, i.e. quality, non-clinical and clinical data [2]. Gerard et al. highlight the possibilities available today to fully establish analytical comparability with quality tools and receptor assays alone and that these possibilities are able to fully justify extrapolation to other indications. The authors point out that these analytical possibilities are already in place for approved biologicals in case of manufacturing changes. Analytical comparability of the product before and after the manufacturing change is common practice. Only in an exceptional case is a clinical efficacy study performed and seldom is an immunogenicity study initiated.
Extrapolation to all the indications of the reference product is essential to the concept of biosimilarity. It is regrettable that clinicians sometimes have difficulty understanding this extrapolation. It requires a full understanding of all the required analytical, preclinical and clinical study data available. It is the task of regulators to explain and convince the medical community about the background of the approval of biosimilar products, a few have already done so [3].
The present abilities to demonstrate on the analytical level similarity/comparability to the reference product raise the question of whether there is still a need for all the clinical data currently required. How much efficacy and safety will really be needed for the approval of biosimilar products in the future? Would it not be possible to restrict the comparability exercise to analytical and just pharmacokinetic (PK)/pharmacodynamic (PD) data alone? The clinical data currently required are costly and burdensome. Is this compatible with the correct use of our medical resources? Institutional review boards sometimes hesitate to approve these extensive studies with their major burden on patients.
One reason to ask for long-term clinical studies is the risk of unexpected immunogenicity. However, the experience gained during the last 10 years has failed to identify any immunogenicity-related issues for approved biosimilars. In a few cases, quality-related issues were already identified in the preauthorization phase as being potentially relevant for an increased immunogenicity risk. It is possible to identify and control these immunogenicity-related risks for biosimilar candidate product [4]. With the advances in analytical technologies, the risk of incremental immunogenicity can, to a large extent, be avoided by analytical characterization, batch release testing and stability testing. PK/PD studies in volunteers could give valuable information on immunogenicity. Preregistration, short-term immunogenicity testing will also give valuable information. The need for preregistration clinical data should be decided on a case-by-case basis depending on what is known about the reference biological and on available analytical and preclinical data. Accumulation of additional information on longer-term safety, including immunogenicity, is already a standard element of the EU Risk Management Plan in the post-registration phase. Immunogenicity would be much better studied by less costly post-authorization monitoring. These studies will provide a better and more sensitive approach for detecting real world differences in efficacy, safety and immunogenicity and are less costly. Yes, analytical advances are a challenge for regulators. They make it possible to consider requiring much less expensive, preregistration clinical study data.
Competing interest: The author is a member of the Advisory Board of NDA Regulatory Science Ltd.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. 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 Rev1. 18 December 2014 [homepage on the Internet]. [cited 2015 Aug 5]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf 2. Gerard TL, Johnston G, Gaugh DR. Biosimilars: extrapolation of clinical use to other indications. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):118-24. doi:10.5639/gabij.2015.0403.027 3. Fimea. Interchangeability of biosimilars – position of Finnish Medicines Agency Fimea. 2015 May 22 [homepage on the Internet]. 2015 May 22 [cited 2015 Aug 5]. Available from: http://www.fimea.fi/instancedata/prime_product_julkaisu/fimea/embeds/fimeawwwstructure/29197_Biosimilaarien_vaihtokelpoisuus_EN.pdf 4. Chamberlain PD. Multidisciplinary approach to evaluating immunogenicity of biosimilars: lessons learnt and open questions based on 10 years’ experience of the European Union regulatory pathway. Biosimilars. 2014;4:23-43.
Author: Frits Lekkerkerker, MD, Chairman of Medical Ethical Committee Twente, Hospital MST, Postbox 50000, NL-7500 KA Enschede, The Netherlands
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This issue of the journal contains a number of manuscripts that discuss proposals to simplify the evaluation of, and therefore decrease the cost of developing, follow-on biological products. These controversial proposals include extrapolation of indications, abbreviated approval processes in resource-poor countries, biological/biosimilar nomenclature, and patent litigation strategies.
Dr Frits Lekkerkerker, reviews the paper by Gerrard et al. in light of the history of biosimilars in the European Union (EU). He comes to the thought-provoking, controversial conclusion (in agreement with Gerrard et al.) that biological products could be approved for all registered indications for the originator product based only on preregistration studies that demonstrate clinical equivalence using modern preclinical analytical data and pharmacokinetics/pharmacodynamics data plus immunogenicity results in both volunteers and during post-marketing surveillance. Comments from GaBI Journal readers are both expected and welcomed concerning both his conclusions and his claim that modern analytical techniques ‘will provide more discriminatory clinical evidence than large pre-approval therapeutic equivalence studies.’
Drs Robin Thorpe and Meenu Wadhwa provide an editorial response to a Letter to the Editor from Professor Cheraghali published in a previous GaBI Journal issue [1] that proposed implementing alternative approval processes to improve patient access to biological products in resource-poor countries. Drs Thorpe and Wadhwa raise many concerns about the ‘more pragmatic’ method based on ‘a loosely designed and practiced clinical study’ that was proposed in Professor Cheraghali’s letter. They conclude that while alternate proposal methods may be necessary, if countries ‘decide to approve follow-on biological products by procedures that do not comply with the World Health Organization’s (WHO) similar biotherapeutic products (SBP) guidelines [2], then these should not be called biosimilars or SBPs.’
The naming of biologicals/biosimilars is an important, controversial issue. Dr James S Robertson, a member of the WHO’s International Nonproprietary Names (INN) Expert Group, discusses the background and rationale behind the pending WHO proposal to include ‘a novel global and company specific biological qualifier, distinct from the … INN’ as part of the official name of biologicals. This would be an important ‘entirely new, global nomenclature scheme for naming biological active substances’ that deserves careful review by our readers who are encouraged to send their responses to the proposal to both the WHO and GaBI Journal. The WHO proposal is very similar to the US Food and drug Administration’s recently (27 August 2015) released draft guidance [3] on the unique naming of biologicals, which is generating considerable debate. The Editors would welcome comments from our readers about these proposals.
In the first of a planned two part series of Review Article, Mr Brian J Malkin presents a ‘strategic overview’ that compares relevant EU and US biosimilar patent laws and litigation cases. He discusses how these affect the development and approval of follow-on biological products. The paper should be of interest to readers both with and without training or experience in dealing with these legal issues.
A Review Article by Gerrard et al. present data and experience in support of their opinion that for therapeutic proteins and monoclonal antibodies ‘analytical and clinical sciences justify the approval of biosimilars for all the clinical indications of the reference products’ based on demonstrated similarity for a single indication. They argue that advances in the preclinical evaluation of such products justify this approach and claim that ‘failure to extrapolate to all clinical indications would cause confusion and undermine the concept of biosimilars.’ The authors make an important proposal, but their proposal does not discuss some important questions. What would happen if post-marketing data did indicate that safety or efficacy was found to differ for an approved product compared to the innovator when used to treat only one of multiple indications? What should be done with those follow-on products for which the most modern processes were not used for approval? What should be done if an already approved product (either the innovator or its biosimilar) is found to have meaningful differences using a new preclinical test? The paper does not discuss drugs for which even the most modern preclinical testing is inadequate to assure similarity as has been found to be true for some non-biological complex drugs (NBCDs) [4]. Please note that GaBI Journal will soon introduce a section devoted to NBCDs. Readers’ opinions about these questions as well as authors’ proposal are welcomed.
A Review Article by Godman et al. discusses the regulatory and patent issues concerning extrapolation of pregabalin indications. This generic drug product has both an off-patent indication as well as a second, more common, on-patent indication. The manuscript describes the many widely different approaches taken by the many co-authors, working at literally dozens of regulatory groups in a number of European countries, in dealing with these issues. The manuscript demonstrates the important impact of extrapolation of indications has on the use and costs of small-molecule generics. Such extrapolation clearly also has major implications for biosimilars.
Much of the drive to develop follow-on products is related to their potential to decrease healthcare costs. This potential is not always realized as exemplified by the very slow uptake of generic drugs in many countries. An example of this problem is given in the first Perspective paper by Drs Jacques Rottembourg and Jessica Nasica-Labouze. This paper describes the 20-year history of the still limited use of generic drugs in France, ‘a country reluctant to switch to generics’ despite the described efforts of legislators and insurers to encourage this switch. The authors present data on generic drug use and question whether efforts to encourage biosimilar use will meet similar resistance.
A second Perspective paper by Dr Christoph Baumgärtel describes the use of generics in Austria, a country that has had more rapid generics uptake than seen in France but where not all possible savings are being realized. Dr Baumgärtel lists initiatives that could be used to improve generics uptake including education and training, financial incentives, prohibiting originator rebates and free samples in hospitals, and improving counselling and guidance. Dr Baumgärtel suggests that the uptake of biosimilars will also be limited based on the experience with generics.
The delayed uptake of quality follow-on therapeutics is important not only for France and Austria but for all countries. Delayed uptake decreases cost savings that could be used by governments to provide other needed services. It also decreases the incentives needed to encourage pharmaceutical companies to develop less costly, quality products. This is even more important for biosimilars than for generic drug products because of the greater economic, scientific, educational, regulatory and clinical barriers they face.
GaBI conducts educational workshops as one way to meet its objective of providing unbiased education because, as suggested by Dr Baumgärtel, lack of understanding may be one of the barriers to the uptake of adequately tested, high quality follow-on pharmaceuticals. A Meeting Report by myself and GaBI Journal’s Deputy Editor-in-Chief, Dr Robin Thorpe, describes a recent workshop held in Mexico City at which many participants suggested that there is a need for both professional education and consensus guidelines for the best practice regulation, use and monitoring of follow-on biologicals. Providing descriptions of the different regulatory approaches being used by various countries to handle follow-on biological products is a useful step towards the development of such consensus guidelines.
The final paper by Leng et al. in this issue describes the approach being used in South Africa, which ‘follows the same principles as those proposed by the European Medicines Agency, Health Canada and the WHO.’ The authors explain that as of July 2015 not one of a number of follow-on biological products submitted for registration contained data adequate to allow registration as a biosimilar using these guidelines despite the fact that they were registered for use in their countries of origin. This is only one of the problems created by poor quality, but already marketed follow-on biologicals that are not true biosimilars, see the Letter to the Editor by Drs Thorpe and Wadhwa in this issue.
Professor Philip D Walson, MD
Editor-in-Chief, GaBI Journal
References 1. Cheraghali AM. Access to alternative biopharmaceuticals in low- and middle-income countries. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;4:164-5. doi:10.5639/gabij.2014.0304.038 2. World Health Organization. Guidelines on evaluation of similar biotherapeutic products (SBPS). Annex 2, WHO Technical Report Series No 977 [homepage on the Internet]. [cited 2015 Sep 9]. Available from: http://www.who.int/entity/biologicals/publications/trs/areas/biological_therapeutics/TRS_977_Annex_2.pdf?ua=1; 2009 3. GaBI Online – Generics and Biosimilars Initiative. FDA issues draft guidance on naming biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Sep 9]. Available from: www.gabionline.net/Guidelines/FDA-issues-draft-guidance-on-naming-biosimilars 4. Walson PD, Mühlebach S, Flühmann B. First Asia-Pacific educational workshop on non-biological complex drugs (NBCDs), Kuala Lumpur, Malaysia, 8 October 2013. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(1):30-3. doi:10.5639/gabij.2014.0301.010
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Abstract:
In South Africa, medicines are registered and regulated in terms of the Medicines and Related Substances Control Act (Act 101 of 1965), as amended, and the regulations to this Act. A guideline which outlines the quality, non-clinical and clinical requirements for the registration of a biosimilar medicine was first published in March 2012. This guideline was amended in August 2014 to include requirements for registering monoclonal antibody biosimilars.
Submitted: 23 June 2015; Revised: Not applicable; Accepted: 1 July 2015; Published online first: 14 July 2015
Introduction
The South African guideline for the development and registration of biosimilar medicines [1] defines a biosimilar as a biological medicine that is similar, but not necessarily identical, in terms of quality, safety and efficacy to an already registered reference biological medicine. The reference biological medicine is the innovator medicine that is used as comparator in head-to-head comparative quality, non-clinical and clinical studies with the biosimilar product to demonstrate similarity. A requirement for the reference medicine is that it must be registered in South Africa on the basis of efficacy and safety data; however, samples of the reference product used in comparability studies do not need to be procured from the South African market but can be sourced from a country with which the Medicines Control Council (MCC) is aligned. These include countries generally recognized to have stringent regulatory systems such as those forming part of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) regions as well as Australia, Canada and Switzerland.
The guideline for biosimilars applies only to those biologicals composed of well-characterized recombinant DNA-derived therapeutic proteins. It excludes vaccines, even if these are derived from recombinant DNA technology. Guidance for the development and registration of biosimilar monoclonal antibody (mAb) products is set out in an annex to the main guideline document [1].
The South African biosimilars guideline is essentially based on the corresponding guidelines of the European Medicines Agency (EMA) [2] and World Health Organization (WHO) [3]. All three guidelines stipulate that biosimilars, being biological molecules with complex structures, would require proof of efficacy and safety in humans prior to registration. The generic medicines registration pathway used for small well-characterized molecules and which require only the demonstration of pharmaceutical equivalence (comparative dissolution in three pH media) and bioequivalence with the innovator (in the case of most solid oral dosage forms) would not be appropriate. Although the extent of clinical and non-clinical studies required for the registration of biosimilars would be less than for innovator medicines, it will to a large degree be dependent on how well the active ingredient has been characterized and its similarity to that of the reference drug substance. Complete physico-chemical characterization of the active ingredient coupled with a high degree of similarity with the reference substance, using state-of-the-art analytical methods, would require substantially reduced clinical and non-clinical data. This is illustrated in Figure 1, which shows that whereas the amount of quality data are greater than for an innovator product (since it includes a comparability study with the reference besides full structural characterization to the same extent as for the reference), the non-clinical and clinical data packages are significantly less. Specific requirements for quality, safety and efficacy are briefly reviewed below.
Quality requirements
A full quality data package detailing the structural characteristics, chemical and physical properties of the biosimilar active pharmaceutical ingredient (API), its validated manufacturing and control processes and stability profile must be submitted. In addition, the formulation, manufacturing, filling and packaging procedures as well as the stability profile of the final product must also be included. These data for the biosimilar are equivalent in amount and extent to that required for the registration of the innovator. However, apart from the quality data on the biosimilar API and final product, the manufacturer of a biosimilar must also submit data on side-by-side comparability studies that show that the biosimilar and reference products are indeed similar in terms of their structures, chemistry and physical properties. This means that for a biological to be considered a biosimilar, it must have an identical primary structure, i.e. amino acid sequence and disulphide bonding, to the innovator reference substance as the primary structure determines the biological function(s) of the substance [4]. Furthermore, it must be shown to be highly similar in terms of post-translational modifications, e.g. glycosylation, three-dimensional structure, e.g. α-helix, β-sheet, and even impurity profiles, although a product with fewer impurities would be preferred [1, 2]. The comparability studies must be carried out in line with the principles of ICH Q6B [5] as well as ICH Q5E [6].
Non-clinical requirements
Non-clinical studies should be conducted before initiation of clinical investigations. The non-clinical studies should be comparative, and be designed to detect differences between the biosimilar and reference medicine. Ideally, a number of endpoints should be monitored such as pharmacodynamic effects as well as toxic effects as determined in at least one repeat dose study. Toxicokinetic measurements should be included and must involve analysis of immunogenicity as the latter may be of value in demonstrating similarity of immune responses to both reference and biosimilar products. Animal immunogenicity studies cannot, however, serve as alternative to immunogenicity studies in humans. In general, other routine toxicological studies such as safety pharmacology, reproduction pharmacology, mutagenicity and carcinogenicity studies are not required for biosimilar medicines.
The trend nowadays is to move away from animal studies; hence, if the minimum required data can be obtained with in vitro biological assays, then these should be used or considered. Justification will, however, be required.
Clinical requirements
Clinical comparability studies should only proceed after acceptable biosimilarity has been established at a physicochemical level. Non-clinical (or in vitro bioassay) comparability data should support the conclusion of biosimilarity based on physicochemical results. The clinical comparability exercise is a stepwise procedure that should begin with pharmacokinetic (PK) and pharmacodynamic (PD) studies followed by clinical efficacy and safety trials. In general, an equivalence trial design is preferred although other designs could be acceptable if properly motivated and justified. Since the clinical data package for a biosimilar is not as extensive as for an innovator medicine, a patient population that is highly sensitive should be selected and the patient population should be large enough to detect meaningful differences in safety, efficacy and immunogenicity.
Clinical studies should be provided for each indication for which the reference product is authorized. However, in cases where the clinical effects have the same underlying mechanism of action, data from a clinical trial of the biosimilar in one indication may be used to support approval of the biosimilar for other indications for which the reference medicine is approved.
Demonstration of comparable efficacy alone does not constitute clinical biosimilarity; equivalent safety and particularly immunogenicity with the reference medicine are also important. Preregistration safety data, derived from the efficacy trials, should be obtained to address the adverse effect profiles of the biosimilar and reference medicines. Preclinical safety data are, however, not sufficient to identify all potential differences and, hence, post-approval pharmacovigilance must be continued accompanied by the submission of regular periodic safety update reports (PSURs) to MCC. This, in fact, is a condition of the registration of all new biologicals, including biosimilars. A suitable Risk Management Plan (RMP) for monitoring immunogenicity, inherent safety concerns and unknown safety signals that could result from the impurity profile and other properties of the biosimilar, should be submitted at the time of application for registration of the biosimilar product.
For most applications for the registration of a biosimilar, comparative clinical trials will be required. However, in certain instances well-designed comparative PK/PD studies may be sufficient to demonstrate clinical comparability where sufficient justification is provided and certain conditions are met. A critical condition is that at least one PD marker is accepted as a surrogate marker for efficacy and that the relationship between dose/exposure to the biosimilar or reference product and this surrogate marker is validated and well known. Examples include absolute neutrophil count to assess the effect of granulocyte colony-stimulating factor and early viral load reduction in chronic hepatitis C to assess the effect of alpha interferon [1].
Finally, since biosimilars, unlike generics, are not considered identical to their innovator reference products, they are neither interchangeable nor substitutable with their reference products or other medicines of the same class. This is in line with similar approaches of other regulatory authorities, such as EMA [2] and Health Canada [7]. Even the WHO guideline stipulates that biosimilars are not interchangeable with their reference products. Interestingly, a few national regulatory authorities in Europe such as The Netherlands [8] and Finland [9] do allow substitution of biosimilars for their reference medicines, albeit under special conditions. In the case of The Netherlands, substitution is allowed but only with adequate clinical monitoring and after the patient has been informed [8]. In Finland, it is permitted but must take place under supervision of a healthcare professional. In France, provisions in the law that allow the substitution of originators by generics have been adapted to extend to biosimilars; however, it has still to be enacted and consequently has not been implemented yet [10].
Current status of biosimilar registrations in South Africa
As of July 2015, no biosimilars have been registered in South Africa. This is despite several biosimilar applications for products containing erythropoietin, filgrastim and insulin having been received by MCC over the past 10 years. None of those which have been reviewed have complied with the registration requirements for a biosimilar medicine. The major deficiencies identified in these applications included the following:
Poor characterization of the active ingredient. Data presented in the quality part of dossiers did not convincingly prove that the primary structure, including carbohydrate chains in the case of glycosylated proteins, was fully elucidated. Isoform profiles were either not determined or poorly characterized. Similarly, impurities were often not sufficiently described and determined.
Head-to-head comparability studies between the innovator and biosimilar at the quality level were either absent or not comprehensive enough to demonstrate similarity at this level.
Non-clinical studies were in many cases absent without justification.
Clinical studies were either not performed or in cases where such studies were conducted, the data were often not comparative. Where comparative data were submitted, the studies did not provide sufficient evidence to support claims of similarity or absence of differences.
It was clear that many of the biosimilars submitted and which were registered in their countries of origin obtained registration in those countries via a non-biosimilars pathway, i.e. by means of the generics route. Although MCC published its final version of the biosimilars guideline only in 2014 [1], it applied the criteria of EMA and WHO biosimilars guidelines to biosimilar registration applications received prior to 2014. An exception was an application received for the registration of a low molecular weight heparin, enoxaparin, of which the innovator product, namely Clexane® was registered as a pharmaceutical medicine in South Africa. The new enoxaparin application was consequently assessed as a generic drug and was approved as such. No clinical or non-clinical data were submitted with the application. The owner of the Clexane® brand subsequently appealed the MCC’s decision on the grounds that enoxaparin was a biological and that all subsequent enoxaparin applications should be reviewed according to criteria for the registration of biosimilars as opposed to those applicable to generics. The appeal was successful and in August 2009, MCC through the Registrar of Medicines, issued a letter to the industry stating that enoxaparin was regarded as a biological and that clinical data will be required for the registration of all enoxaparin products [11]. Interestingly, the US Food and Drug Administration came to the exact opposite decision and rejected the appeal of the innovator company, which suggests that they may have registered their application of enoxaparin made by Sandoz as a generic drug [12].
Conclusion
The biosimilar guideline of MCC follows the same principles as those of EMA, Health Canada and WHO with respect to quality, safety and efficacy. Although several countries in the European Union now allow substitution of innovator biologicals with their biosimilars, it is unlikely that MCC will revise their guideline to allow substitution in the near future since the local population in South Africa has thus far had no therapeutic exposure to biosimilars.
Disclaimer
The views expressed in this paper are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the Medicines Control Council of South Africa or one of its committees or working groups.
Competing interest: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Henry MJ Leng, PhD
School of Public Health, University of the Western Cape, Private Bag X17, Bellville 7130, South Africa
Khamusi Mutoti, BSc, BPharm Sci
Medicines Control Council, National Department of Health, Private Bag X828, Pretoria 0001, South Africa
Professor Nontombe Mbelle, MBChB, MMed, FC Path (CMSA)
Department of Medical Microbiology, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa
References 1. Medicines Control Council. Biosimilar medicines: quality, non-clinical and clinical requirements. August 2014. Ver. 3 [homepage on the Internet]. [cited 2015 Jun 23]. Available from: http://mccza.com/genericdocuments/2.30_Biosimilars_Aug14_v3.pdf 2. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (EMEA/CHMP/BWP/49348/2005). 22 February 2006 [homepage on the Internet]. 2006 Mar 8 [cited 2015 Jun 23]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003953.pdf 3. World Health Organization. Guidelines on evaluation of similar biotherapeutic products (SBPs) [homepage on the Internet]. 2010 Jun 6 [cited 2015 Jun 23]. Available from: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf 4. Thomas PD, Kejariwal A, Guo N, Mi H, Campbell MJ, Muruganujan A, et al. Applications for protein sequence-function evolution data: mRNA/protein expression analysis and coding SNP scoring tools. Nucleic Acids Res. 2006;34(Web Server issue):W645-50. 5. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised tripartite guideline. Specifications: test procedures and acceptance criteria for biotechnological/biological products. Q6B. Current step 4 version. 10 March 1999 [homepage on the Internet]. 2006 Feb 28 [cited 2015 Jun 23]. Available from: http://www.ich.org/fileadmin/public_web_site/ich_products/guidelines/quality/q6b/step4/q6b_guideline.pdf 6. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised tripartite guideline. Comparability of biotechnological/biological products subject to changes in their manufacturing process. Q5E. Current step 4 version. 18 November 2004 [homepage on the Internet]. 2006 Feb 28 [cited 2015 Jun 23]. Available from: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5E/Step4/Q5E_Guideline.pdf 7. Health Canada. Health Products and Food Branch. Guidance for sponsors: information and submission requirements for subsequent entry biologics (SEBs) [homepage on the Internet]. 2010 Mar 8 [cited 2015 Jun 23]. Available from: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/brgtherap/applic-demande/guides/seb-pbu/seb-pbu-2010-eng.pdf 8. GaBI Online – Generics and Biosimilars Initiative. Dutch medicines agency says biosimilars ‘have no relevant differences’ to originators [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Jun 23]. Available from: www.gabionline.net/Biosimilars/General/Dutch-medicines-agency-says-biosimilars-have-no-relevant-differences-to-originators 9. GaBI Online – Generics and Biosimilars Initiative. Finnish drug regulator recommends interchangeability of biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Jun 23]. Available from: www.gabionline.net/Policies-Legislation/Finnish-drug-regulator-recommends-interchangeability-of-biosimilars 10. GaBI Online – Generics and Biosimilars Initiative. France to allow biosimilars substitution [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Jun 23]. Available from: www.gabionline.net/Policies-Legislation/France-to-allow-biosimilars-substitution 11. Medicines Control Council. Applications for registration of medicines containing enoxaparin [homepage on the Internet]. [cited 2015 Jun 23]. Available from: http://mccza.com/dynamism/default_dynamic.asp?Grpid=25&doc=dynamic_generated_page.asp&categid=169&groupid=25 12. GaBI Online – Generics and Biosimilars Initiative. Good news for biosimilar enoxaparin sodium [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Jun 23]. Available from: www.gabionline.net/Biosimilars/News/Good-news-for-biosimilar-enoxaparin-sodium
Author for correspondence: Henry MJ Leng, PhD, School of Public Health, University of the Western Cape, Private Bag X17, Bellville 7130, South Africa
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Abstract:
Biosimilars are highly similar versions of reference biological products, some with the potential to be deemed ‘interchangeable’ by regulatory bodies, such as the US Food and Drug Administration. Biosimilar patent litigation continues to evolve as biosimilars enter new global markets. This manuscript takes a look at patent litigation strategies in a more developed biosimilars market, the European Union (EU) and compares them to a developing biosimilars market, the US, where the litigation strategies are still unfolding. This manuscript is a first in a two-part series, which will later include patent litigation strategies in Canada and Japan, as well as updates in the EU and the US.
Submitted: 13 June 2015; Revised: 4 August 2015; Accepted: 6 August 2015; Published online first: 19 August 2015
Introduction
The European Union (EU) was the one of the first highly regulated areas to develop a legal and regulatory framework for the approval for highly similar versions of innovator biological products, called ‘biosimilars’ or ‘follow-on biologicals’. While formal consideration of a biosimilar approval pathway began in the EU as early as 2001 [1], the European Commission first amended its market authorization provisions to include ‘similar biological medicinal products’ in 2003 [2], and issued its first general biosimilar guidance in 2005 [3]. The European Medicines Agency’s (EMA) first approval under the new similar biological medicinal product pathway was Sandoz’s somatropin called Omnitrope® in 2006 [4]. The EU currently has 19 biosimilars referencing five innovator biological products [4]. The US biosimilar pathway began in 2010 with the enactment of the Biosimilars Patent Cooperation and Innovation Act (BPCIA) [5] and has one approved biosimilar, Sandoz’s filgrastim-sndz [6] called Zarxio® in 2015 [7]. While the EU’s legal system is complicated by the lack of a unified patent litigation system that requires a multi-country patent litigation approach, the US’s biosimilar patent litigation has been complicated thus far by biosimilar applicants and the reference biological product (RBP) applicants picking and choosing what portion of the default patent litigation exchange system to utilize. Despite the differences between the prevalent litigation tactics in the EU and the US, as biosimilar approvals become more globalized, it will be increasingly important to appreciate these differences and consider how biosimilars patent litigation arguments and outcomes in one venue can benefit and be utilized in other venues, even if in different countries or legal systems.
Biosimilar regulatory overview
The EU and the US have similar regulatory standards for biosimilars that would enable a manufacturer to make a biosimilar product that could in theory satisfy both regulatory standards, assuming that the RBP is the same. In the EU, a biosimilar must demonstrate similar quality and biological activity and demonstrate no meaningful differences in terms of safety or efficacy between the biosimilar and the RBP. EMA develops product-specific guidances through a consultative process that establishes common comprehensive comparability and immunogenicity studies required for biosimilar applicants to demonstrate biosimilarity for approval. As part of these requirements, biosimilar applicants are expected to conduct a product-by-product analysis using state-of-the-art bioanalytics and manufacturing along with clinical and regulatory experiences to support biosimilarity.
In the US, biosimilars must be highly similar to the RBP notwithstanding minor differences in clinically-inactive components. To demonstrate biosimilarity, there must be no clinically meaningful differences in terms of safety, purity, or potency—essentially safety and efficacy. So far, US Food and Drug Administration (FDA) has not developed product-specific guidances, preferring to issue more general guidances related to a product-specific development approach. Instead, each biosimilar product has its own approval requirements, developed in a stepwise approach, following multiple comparisons of the proposed biosimilar product to the RBP using state-of-the-art bioanalytics, where the required clinical studies and other study requirements are determined by how similar the products are as well as the observed bioanalytical differences.
Unique to the US, FDA may determine a biosimilar product is ‘interchangeable’ with the RBP. An interchangeable product may be substituted for the RBP without the intervention of the healthcare provider who prescribed the RBP. FDA may determine that a biosimilar product is interchangeable with the RBP if the biological product meets that highly biosimilar standard above plus: (1) the biosimilar product will produce the same clinical result as the RBP in any given patient; and (2) if administered more than once to an individual, the risk in terms of safety or diminished efficacy or alternating or switching between using the biosimilar and RBP is no greater than the risk of using the RBP without such alternation or switch. But FDA has said that while by law it could accept for filing and review an interchangeable biosimilar application, in practice it would not approve a biosimilar as interchangeable without some confirmatory market evidence. In this context, FDA suggested that perhaps five years of post-approval safety data would be sufficient for an applicant to submit a supplement to its previously approved biosimilar application, requesting a finding of interchangeability. So in the near future, most biosimilar litigation in the US will likely not involve an interchangeable biosimilar product.
EU biosimilar patent strategies
European patent opposition In Europe, the opposition process to a patent granted by the European Patent Office (EPO) is the most common approach for challenging the RBP’s patents. In part, this appears to be because it enables a biosimilar manufacturer to challenge a RBP’s key patents in a single forum rather than multiple nation state patent courts. For example, oppositions were filed for epoetin (RBP Epogen® [Amgen]), filgrastim (RBP Neupogen® [Amgen]), infliximab (RBP Remicade® [Johnson and Johnson/Janssen]), insulin glargine (RBP Lantus® [Sanofi]), and somatropin (RBP Gentropin® [Pfizer]). EPO has 38 contracting states and provides unified patent prosecution and opposition with the option for national patents by applicant choice after prosecution. Oppositions may be filed by any public member(s) except the proprietor within nine months after the patent is granted, which has public notice.
But an opposition has limited grounds to revoke a patent, including: (1) the subject matter is not patentable; (2) the invention was not disclosed clearly or completely enough for one skilled in the art to perform the invention; or (3) the subject matter extends beyond the content of the application filed. From an opposition, there are a number of possible outcomes: (1) the opposition is rejected and the patent is maintained as granted; (2) the patent is maintained in amended form with a new published specification; or (3) the patent is revoked. Initial opposition decisions may be appealed within two months, and countries may have conflicting rules whether they stay, i.e. halt further legal process, national patent infringement actions while an opposition and any associated appeal is pending. The median time for an appeal is close to three years, which is the same approximate median time for an opposition for patents concerning pharmaceutical/biotechnology products.
National patent litigation Concurrently or following an opposition, biosimilars patent litigation may begin in member countries; however, litigation in each county requires detailed knowledge of that country’s national patent litigation procedures. A RBP manufacturer may choose to bring an infringement action or a biosimilar applicant may bring a declaratory judgement action for one or more patent(s) that may be at issue. Given the differences in patent litigation rules and biosimilars regulatory applications, there may be advantages to bring an initial biosimilars patent litigation in the anticipated primary biosimilar markets, the place of business or manufacture of the RBP or biosimilar, or based on a perceived jurisdictional favouritism for the action. For example, Amgen brought its filgrastim patent infringement litigation in Germany, which is the only EU country with separate courts for infringement and invalidity and is preferred for patent enforcement. Teva, on the other hand, brought its declaratory judgement action against Amgen’s patents for the same product in the UK, which has specialized patent courts and a high rate of patent invalidity judgements. Because each country has its own court system where patent holders may enforce their patents, there is the possibility for conflicting patent enforcement decisions in different countries, where RBP and biosimilar manufacturers may pursue national patent litigations in member countries simultaneously or successively.
In this context, biosimilar manufacturers have employed a variety of tactics, depending on a particular member country’s perceived market and the strength of the patents at issue. One option is to wait out key patents to expire in each member country, as Hospira suggested it would do for Remicade® (infliximab) [8]. Another is to launch at risk, which is often considered in The Netherlands and the UK given their higher rate of invalidity decisions and accelerated proceedings with no or lower punitive/treble damages, i.e. damages higher than calculated or treble (triple damages), which is punitive to make up for intentional infringement. In other situations, to avoid a preliminary injunction, i.e. an injunction entered by a court prior to a final determination of the merits of a legal case, to restrain a party from going ahead with a course of conduct or compelling a party to continue with a course of conduct until the case has been decided, issued by the judge ex parte, i.e. without hearing the other side, a biosimilar manufacturer may file a ‘protective letter’ to inform the court beforehand in detail of its non-infringement and invalidity arguments. Such letter may request the court to take account of its arguments and may also request to be heard to prevent the ex parte measure. But it is at the court’s discretion to what extent the court will take account of this protective letter. Biosimilar manufacturers are more likely to consider protective letters in countries where patent proceedings take longer or tend to favour the patent holder, e.g. Belgium and Germany.
Yet other measures seek to avoid disruptive patent litigation prior to product approval or before product launch. For example, Hospira sought to invalidate certain patents for trastuzumab (RBP Herceptin® [Genentech/Roche]) in the UK even before product approval. The primary patent for Heceptin® with a supplementary protection certificate (SPC, a type of extension of the term or expiration date of a patent based on a product approval) expired on 28 July 2014, and two additional dosage and composition patents had been held invalid in an opposition with appeals pending. Hospira challenged those two patents and won a lower court decision in April 2014 [9] and an appeal on February 2015 [10], finding both patents invalid, where it further obtained a declaration of non-infringement for certain trastuzumab formulations. In some instances, a biosimilar manufacturer may also begin its national merit invalidity or non-infringement proceedings early to help prevent preliminary injunctions.
Unitary patent/Unified Patent Court One option that may be possible for biosimilars litigation in the EU in the future is patent litigation in a proposed Unified Patent Court (UPC). The concept is that a unitary patent (UP) will be a single patent with a unitary effect for all contracting states and a unified court system for all patent litigations. Many EU countries have joined the UP/UPC with notable exceptions being Croatia, Poland and Spain. The European Parliament and European Council approved the EU UP package in December 2012, with participating Member States signing the Agreement for a UPC in February 2013. The UPC needs to be ratified by at least 13 signatory states to come into force including France, Germany, and the UK, and has so far been ratified by Austria, Belgium, Denmark, France, Luxembourg, Malta and Sweden. A potential fly in the ointment was an action brought by Spain before the EU Court of Justice, challenging the UP and applicable translation arrangements, which was dismissed on 5 May 2015 [11]. While the UPC is waiting for a final ratification by sufficient Member States, the infrastructure for a UPC is building within the EU.
A UPC has the advantages of one application leading to one patent, with one patent litigation action leading to one decision for all participating 25 states in a streamlined procedure. The streamlined litigation procedure has a series of steps: (1) Written Procedure (two writs per party normally on infringement and two on validity, if included); (2) Interim Procedure (includes all steps to comprehensively prepare the case for an oral hearing including conferences); (3) Preparation for Oral Hearing (all steps to prepare an oral hearing for the panel); (4) Oral Hearing (managed by three judges – two multinational and one non-state national – including witnesses, evidence, pleadings and cross-examination); (5) Decision on the Merits (includes decisions on injunctions, damages, accounting, validity and costs of proceedings); and (6) Appeals (based on points of law and matters of fact brought within two months of decision of the Court of First Instance or within 15 days of an order, where rehearings appear to be exceptional).
At this point, there is no UPC, but when ratified and effective, there will likely be a parallel system structure, i.e. a UPC and a national patent system, which has led to the question whether these will lead to an inadmissible double patent protection. While the new UPC system at this point has no case law, there is already contradictory case law in the participating Member States, leading to some initial uncertainty on how the UPC system will work. Some initial thoughts are that RBP holders will use the UPC system to protect their intellectual property in all participating states and continue to protect EPO and national patents in key markets either for a first litigation or as part of a fall-back plan.
US biosimilar patent strategies
Patent dance The US biosimilar pathway includes new patent litigation provisions (aka ‘the patent dance’) that provide for a default exchange of information leading to at least two distinct phases of patent litigation with possible ramifications for failure to follow this default exchange. The proposed exchange mechanism differs in many ways from Hatch-Waxman patent litigation for small molecule drugs including: (1) there is no book like the ‘Orange Book’ that lists patents including claims to the active ingredient, product, or approved use(s) of the product [12]; (2) there are no patent certifications to FDA indicating potential patent challenges or a 30-month stay options for patent challenges by the RBP holder; (3) it relies on a voluntary exchange of information including the biosimilars application and information that describes the process(es) used to manufacture the biological product in the application and relevant patents as determined by the RBP holder and biosimilar applicant; (4) there are ramifications for not participating in the voluntary exchanges including limited litigation rights; (5) there are relatively short timeframes for the patent exchanges that, when followed, would yield a lengthy cycle before any infringement action after FDA accepts the biosimilar application for filing; (6) it envisions multiple patent litigation cycles following the initial exchange of patent lists, 180 days prior to commercial product launch, and post launch.
When everything is followed as provided in the default pre-approval patent litigation process, the following steps are indicated:
Notifications
– Within 20 days of FDA notification of the biosimilar’s application acceptance, the applicant sends notice of filing and a copy of its application to the RBP holder and such other information that describes the process or processes used to manufacture the biological product that is the subject of such application and may provide to the RBP holder additional information requested by or on behalf of the RBP holder (under statutory or otherwise-agreed-to confidentiality terms).
– Within 60 days, the RBP holder provides biosimilar applicant with a list of all patents for which it could bring a claim of patent infringement and a list of patents it is willing to license to the applicant.
– Within 60 days, the biosimilar applicant provides: (1) its own list of patents that it believes the RBP holder could bring a claim of patent infringement; (2) detailed statements (like in Hatch-Waxman Act) why, claim-by-claim, each patent is invalid, unenforceable, or not infringed by the applicant; (3) may include a statement when the applicant intends to launch, e.g. after expiration of one or more patents; and (4) whether it would consider a license to one or more patents listed by the RBP holder.
– Within 60 days, the RBP holder provides: its own detailed statements why, claim-by-claim, it believes each listed patent is valid, enforceable and infringed by the biosimilar applicant.
Litigation suits
– For 15 days of good-faith negotiations, the biosimilar applicant and RBP holder attempt to agree on a list of patents to litigate prior to product launch as an ‘artificial’ act of infringement, i.e. ‘artificial’ because there is no infringement until a product is marketed, but the litigation proceeds based on the biosimilar applicant’s assertion that it intends to market its biosimilar product, if approved, prior to expiration of one or more patents.
– If they fail to agree, the biosimilar applicant and RBP holder each compile their own list, with the biosimilar applicant responding first, and the RBP holder must reply within five days of provision of the biosimilar applicant’s list.
– The RBP holder’s list may not exceed the number of patents in the biosimilar applicant’s list, and if the biosimilar applicant’s list contains no patents, then the RBP holder may include one patent in the patent litigation list.
– Within 30 days, the RBP holder must bring suit against the biosimilar applicant with respect to the patents included in the lists (a ‘timely infringement suit’ and phase one).
– The RBP holder may only recoup a royalty if:
○ The RBP holder fails to bring a timely infringement suit; or
○ Following a timely infringement suit, the action is dismissed without prejudice or not prosecuted to judgement in good faith.
– Newly issued or licensed patents must be added to the patent lists within 30 days of issuance or licensing.
– The biosimilar applicant must provide 180 days advance notice prior to commercial launch, upon which (as to the patents to the lists as modified by newly issued or licensed patents):
○ The RBP holder or biosimilar applicant can seek a declaratory judgement; and
○ The RBP holder can sue for a preliminary injunction before the date of first marketing (phase two).
Like generic drug patent litigation following the Hatch-Waxman Act, which established a generic drug approval process in the US, US biosimilars patent litigation has been off to a bumpy start. The initial US biosimilars patent litigation actions were filed before the related biosimilars applications were filed, e.g. Sandoz’s version of Enbrel® (etanercept) and Celltrion/Hospira’s version of Remicade® (infliximab). However, both of these actions were denied by the courts because they were premature, so a similar strategy is unlikely to be followed by subsequent biosimilar applicants.
Two other biosimilar patent litigation actions appear to have included some but not all elements of the patent dance [13]. Reasons to avoid the patent dance include: (1) the maximum allotted times for each party in the patent dance may mean 250 days before a lawsuit after FDA has accepted the biosimilar application for filing, but FDA has a 10-month review cycle (~300 days), which could lead to an FDA approval prior to any substantive patent ruling; (2) the proposed confidentiality provisions and need for patent certainty before launch may not be viewed as insufficient for the biosimilar applicant to provide the RBP holder its proprietary application; (3) FDA’s review process appears to be separate from the patent dance; (4) the default patent information and list exchange leading to pre-launch patent litigation is expensive and unproven; (5) following market approval, there still exists the risk of another lawsuit for the marketed product; and (6) the EU model suggests alternative patent challenges via the Inter Partes Review (IPR) mechanism (a post-grant patent challenge at the United States Patent and Trademark Office (USPTO) versus the federal court system) and possibly the International Trade Commission (another type of patent challenge that may provide for an injunction for imported, infringing goods) or wait for relevant patents to expire, i.e. 12-year exclusivity means core patents may have limited life left.
One of the two actions is moving forward on the first FDA-approved biosimilar application, Sandoz’s version of Amgen’s Neupogen® (filgrastim), called Zarxio® (filgrastim-sndz). Amgen filed in a California District Court a lawsuit under California’s Unfair Competition Law and for conversion for failure to follow the default patent information exchange mechanism that would lead to pre-market patent litigation. In the same court, Amgen also moved for a preliminary injunction to prevent Sandoz’s market entry of Zarxio® pending a disposition on the merits. Here, Sandoz failed to provide its biosimilar license application within 20 days of FDA’s notice of filing or other elements of the patent dance, yet ultimately provided Amgen with its biosimilars license application, resulting in the present lawsuit and a separate patent infringement suit for one patent, which has been stayed pending resolution of the procedural patent exchange suit. Sandoz disagreed with the Unfair Competition Law charge, arguing that the provisions of the default patent exchange and pre-market litigation are optional. The California Court denied Amgen’s motion for a preliminary injunction and motion for a judgement on the pleadings. In conjunction with this action, Amgen filed a citizen petition with FDA to request that FDA not file any biosimilar application in its discretion, unless the applicant agreed to follow all procedures under the patent dance. FDA denied this petition on 25 March 2015, pending any contrary outcome in the litigation [14]. Amgen has appealed the lower court’s decision, and the matter is pending in the Federal Circuit, which heard oral arguments on the pleadings on 3 June 2015. The main issues in the case are whether a biosimilar applicant needs to engage in all steps of the patent dance to take advantage of the biosimilars approval pathway, or whether some or all of the steps are optional, and whether a biosimilar applicant can only provide 180-day notice of commercial launch after approval of the biosimilars license application or if notice of an intent to market following application approval is sufficient.
While Celltrion/Hospira failed to meet the standard for a declaratory judgement for several Janssen patents related to Remicade® (infliximab) prior to filing its application, it appears that Janssen has filed a patent litigation suit along with allegations that Celltion/Hospira failed to follow mandatory patent dispute procedures under the BPCIA, demanding that such procedures be followed. In this instance, Janssen has asserted that while Celltrion/Hospira timely provided its biosimilar license application to Janssen and followed some patent dispute procedures, Celltrion/Hospira failed to disclose required manufacturing process information requested by Janssen to develop its list of potential patents to litigate. Janssen has also asserted that Celltrion/Hospira failed to follow procedures under the BPCIA by illegally shortening the patent litigation negotiation process from the list of patents exchanged by Janssen and that Celltion/Hospira failed to provide an effective 180-day notice of commercial launch, because such notice may only be provided after application approval, which has not yet occurred. The issues are therefore similar as with the Amgen v. Sandoz case, namely whether all or some patent dance steps need to be followed according to the BPCIA and what constitutes notice of 180-day advance notice of commercial launch. No dispositive motions have been decided in this case related to these pending issues. And at this point, it is uncertain what information has been exchanged for the two other publicly noticed and pending biosimilar license applications filed by Apotex referencing Amgen’s Neupogen® (filgrastim) and Neulasta® (pegfilgrastim).
Additional considerations
At this point, there appears to be limited patent litigation challenges in the EU with a preference to patent issuance challenges and some limited country patent challenges. There are many unresolved issues. As more biosimilar product applications are filed in the US, will there be greater incentives for testing patents in certain country markets before the US, especially if there is a UP/UPC, or will all major patent litigation continue to be in the US? Once FDA approves interchangeable biosimilars, how will that affect European patent challenges, especially for bridging products, i.e. similar or same biological products marketed in both the EU and the US? Will the Federal Circuit require biosimilar applicants to follow all steps of the patent dance, some of them, or none of them, at the discretion of the parties? Depending on the Federal Circuit’s decision in the Amgen v. Sandoz case, will Congress amend the US biosimilars approval or litigation pathway? Will other tactics that challenge patents outside the US Federal courts such as IPRs in the USPTO or litigation in the International Trade Commission become more frequent strategies similar to how oppositions are used in the EU, because biosimilar patent litigation is too unwieldy? We are just at the tip of the iceberg when it comes to biosimilar patent challenges.
The subsequent manuscript will look at patent challenges in Canada and Japan, along with updates for the EU and the US.
Index of abbreviations/acronyms
IPR – Inter Partes Review A trial proceeding conducted by the Patent Trial and Appeal Board (PTAB) at the United States Patent and Trademark Office (USPTO) to review the patentability of one or more claims in a patent only on a ground that could be raised under 35 U.S.C. §§ 102 or 103, and only on the basis of prior art consisting of patents or printed publications. The PTAB is created by statute and includes statutory members and Administrative Patent Judges. The PTAB is charged with rendering decisions on appeals from adverse examiner decisions, post-issuance challenges to patents, and interferences. UP – Unitary Patent A proposed new type of European patent that would be valid in participating Member States of the EU with such unitary effect registered upon grant, replacing validation of the European patent in the individual countries concerned. The unitary effect means a single renewal fee, a single ownership, a single object of property, a single court (the Unified Patent Court), and uniform protection, meaning that revocation as well as infringement proceedings are to be decided for the unitary patent as a whole rather than for each country individually. UPC – Unified Patent Court A proposed common patent court for participation of all Member States of the European Union that would hear cases regarding infringement and revocation proceedings of European patents (including unitary patents) valid in the territories of the participating states, with a single court ruling being directly applicable throughout those territories. Requesting unitary patents upon the grant of certain European patents will be possible from the establishment of the UPC.
Author’s notes
Patent litigation for this manuscript is used broadly to mean to bring or defend a legal patent action, which may be in a court or before another judicial body, e.g. a patent review board, such as the European Patent Office or the United States Patent and Trademark Office, or another official governmental or quasi-judicial body, where a patent may be enforced or a patent challenged in terms of validity, infringement, or enforceability.
Disclosure of financial and competing interests: The author is an employee of McGuireWoods LLP. The author has no competing interests to disclose for this manuscript. The author wishes to note that he is a licensed patent attorney and also practices food and drug law in the US, not the European Union (EU). As a result, his comments regarding the legal system in the EU are based on his research and not his licensure to practice law in the EU. As noted in the manuscript, litigation in each jurisdiction requires detailed knowledge of that jurisdiction’s litigation procedures and should be in consultation with appropriate counsel.
Provenance and peer review: Commissioned; externally peer reviewed.
References 1.European Medicines Agency. Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. 17 December 2003. EMEA/CPMP/3097/02/Final [homepage on the Internet]. 2003 Dec 22 [cited 2015 Aug 4]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003963.pdf 2.Commission Directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use. J Eur Union. 2003;L159:46-94. 3.European Medicines Agency. Guideline of similar biological medicinal products. 30 October 2005. EMEA/CHMP/437/04 [homepage on the Internet]. [cited 2015 Aug 4]. Available from: http://www3.bio.org/healthcare/followonbkg/GuidelineonSimilarBiologicalProducts.pdf 4.European Medicines Agency. EMA list of approved biosimilars [homepage on the Internet]. [cited 2015 Aug 4]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=WC0b01ac058001
d124&searchTab=searchByAuthType&alreadyLoaded=true&isNewQuery=true&status=Authorised&keyword=Enter+keywords&searchType
=name&taxonomyPath=&treeNumber=&searchGenericType=biosimilars&genericsKeywordSearch=Submit. 5.Patient Protection and Affordable Care Act, Pub.L. No. 111-148, 124 Stat. 119, tit. VII, subtit. A (2010). 6.FDA called this a ‚placeholder nonproprietary name,‛ because FDA is still deciding its nonproprietary naming procedures. 7.U.S. Food and Drug Administration. FDA approves first biosimilar product Zarxio [homepage on the Internet]. 2015 [cited 2015 Aug 4]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436648.htm 8.PR Newswire. Hospira launches first biosimilar monoclonal antibody (mAb) Infectra™ (infliximab) in major European markets [homepage on the Internet]. [cited 2015 Aug 4]. Available from: http://phx.corporate-ir.net/phoenix.zhtml?c=175550&p=irol-newsArticle&ID=2016883 9.British and Irish Legal Information Institute. Hospira UK Limited v. Genentech Inc. [2014] EWHC 1094 (Pat) (10 Apr 2014) [homepage on the Internet]. [cited 2015 Aug 4]. Available from: http://www.bailii.org/ew/cases/EWHC/Patents/2014/1094.html 10.Hospira (UK) Limited v. Genentech, Inc., [2015] EWCA Civ. 57. 6th February 2015 [homepage on the Internet]. [cited 2015 Aug 4]. Available from: http://phx.corporate-ir.net/phoenix.zhtml?c=175550&p=irol-newsArticle&ID=2016883 11.Court of Justice of the European Union. The Court dismisses both of Spain’s actions against the regulations implementing enhanced cooperation in the area of creation of unitary patent protection. Press release no 49/15. 5 May 2015 [homepage on the Internet]. 2015 May 5 [cited 2015 Aug 4]. Available from: http://curia.europa.eu/jcms/upload/docs/application/pdf/2015-05/cp150049en.pdf 12.FDA publishes a ‚Purple Book‛ that includes biologics license applications (BLAs) with interchangeability ratings for biosimilars, approval dates, and product names. 13.Because these litigations are pending and some related court papers have been filed under seal, there is a limited record to ascertain which elements were actually followed. Based on the public filings, it appears that the information exchange was somewhat other than that proposed in the statute, and this article reflects the author’s review of public information available from the associated court dockets as of July 1, 2015. 14.Requests FDA adopt policies and practices in their acceptance and review of biosimilar applications that will provide for the orderly implementation and efficient functioning of the Biologics Price Competition and Innovation Act (BPCIA). FDA Docket No. FDA-2014-P-1771 [homepage on the Internet]. [cited 2015 Aug 4]. Available from: http://www.regulations.gov/#!docketDetail;D=FDA-2014-P-1771
Author: Brian J Malkin, Esq, Senior Counsel, McGuireWoods LLP, Suite 400, 2001 K Street NW, Washington, DC 20006-1040, USA
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Author byline as per print journal: Robin Thorpe, PhD, FRCPath; Meenu Wadhwa, PhD
Abstract:
Comment on the Letter to the Editor by Professor Abdol Majid Cheraghali: Access to alternative biopharmaceuticals in low- and middle-income countries, published in GaBI Journal, 2014;4(3):164-5.
Submitted: 7 June 2015; Revised: 8 June 2015; Accepted: 8 June 2015; Published online first: 22 June 2015
In the above Letter to the Editor of GaBI Journal, it is concluded that although biosimilars offer potentially increased global patient access to biopharmaceuticals due to lowering of prices, this may be problematic in low- and middle-income countries primarily due to local resource limitations and lack of experience.
The author questions the relevance of the World Health Organization (WHO) and European Medicines Agency (EMA) guidance and the applicability of the similarity/comparability concept for development of biosimilars in low- and middle-income countries. He considers that these processes are ‘not feasible’ in such countries and elaborates possibilities for regulatory procedures which could be adopted by them for approval of follow-on biological products, thus, obviating the extensive comparability studies as required by WHO, EMA and many other guidelines. We think that this proposal needs much care and consideration before it is seriously considered. The reasons for this are outlined below.
As the letter states, several follow-on biological products are marketed worldwide. As has been discussed previously, biosimilars approved in the European Union are safe and efficacious. However, some products marketed elsewhere are not. These latter products are not biosimilars as there is no evidence that they have been approved using the biosimilarity approach described in the WHO guideline. Furthermore, evaluation of product characteristics pertaining to their quality has clearly demonstrated that these products differ from the reference product [1, 2]. The letter also states that ‘Most of the guidelines published for regulation of alternative biopharmaceuticals, including WHO guidelines, rely on head-to-head comparative clinical studies for proven similarity between innovator products and alternative biopharmaceuticals.’ Indeed, use of this approach, i.e. showing that the biosimilar and the reference product have very similar safety and efficacy, guarantees the safety and efficacy of true biosimilars as substantiated by the proven excellent clinical record of biosimilars approved using this regulatory process [3, 4]. Additionally, this approach allows extrapolation of the product for various therapeutic indications without the need for clinical trials in each indication providing that the therapeutic acts via the same receptor and the mechanism of action remains the same in different indications [5]. The author should also note that despite 10 years of experience with biosimilars, comparative clinical data is still required by EMA in the revised guideline on non-clinical and clinical issues to ensure that the ‘claimed’ biosimilar has a similar efficacy and safety profile to the reference product [6].
The letter describes the process for marketing authorization approval used in low- and middle-income countries as relying on ‘a loosely designed and practised clinical study’. It is acknowledged that it is now well established that ignoring the need for appropriate assessment of quality, preclinical and clinical performance of biotherapeutics (including biosimilars) can lead to serious clinical problems: a good example of this is the high incidence of PRCA (pure red cell aplasia) development following treatment with the many EPO (erythropoietin) products which are approved in Thailand [7, 8]. In any case, quality assessment, which is the foundation of the biosimilarity exercise, is normally cheaper than conducting clinical trials and so the reason for relying solely on clinical assessment seems illogical. The letter acknowledges that ‘The manufacturing of biopharmaceuticals is somewhat different to that for small molecule chemical medicines, and the procedure is much more sensitive to change in the production process and even environmental factors’. Nevertheless, this again questions the wisdom of not conducting a quality assessment of non-innovator products of any type.
The letter considers that historical experience gained with innovator products can be used to assess possible problems with follow-on products. Although such information (when reliable) can provide a general guide for expected problems, it cannot ensure appropriate clinical safety and efficacy for a new product. This has to be assessed directly, using a proven pathway.
In addition, shortened regulatory processes are proposed involving no head to head clinical trial, no trial at all and reliance on approval followed by phase IV assessment by regulatory agencies. How this latter approach could excuse the pharmaceutical company developing the product from its obligation to guarantee safety and efficacy of their product is not explained nor is how the previously mentioned lack of resources and expertise in low- and middle-income countries would allow it. Although the author is in favour of promoting access to biotherapeutic products (which is laudable), the approaches outlined are not akin to the biosimilar philosophy and also not aligned with the WHA resolution (WHA67.21) ‘Access to biotherapeutic products including similar biotherapeutic products and ensuring their quality, safety and efficacy’.
A request is made in the letter for a ‘more pragmatic’ guideline (perhaps from WHO or regulatory authorities), presumably describing some form of abbreviated procedure for regulatory approval of follow-on products. But, considering the above, how is this possible if safety and/or efficacy are not to be compromised? WHO already has current guidelines for Similar Biotherapeutic Products (SBPs) [9] and Biotherapeutic Products (BTPs) [10] which should be applicable to all biotherapeutic products. In a recent WHO Informal Consultation on the amendment for similar biotherapeutic products of monoclonal antibodies (April 2015) in Geneva, Switzerland, the WHO SBP guideline was reviewed and the consensus opinion was that it did not require revision and should be implemented globally. In addition, WHO is in the process of providing guidance on re-evaluation of products that are currently marketed, but have not been tested thoroughly or do not fulfil current international regulatory standards. This again suggests that existence of low regulatory standards is considered a global problem; reducing such standards has been identified as a threat to public health.
It is clearly the prerogative of regulatory agencies in low- and middle-income countries to adopt appropriate procedures for approval of biotherapeutic products. These need to take account of all relevant factors including clinical safety and efficacy. But if they decide to approve follow-on products by procedures which do not comply with the WHO SBP guideline, then these should not be called biosimilars or SBPs. They should be named in accordance with the process used for their approval.
Competing interest: None.
Provenance and peer review: Not commissioned; internally peer reviewed.
Co-author
Meenu Wadhwa, PhD, Cytokine and Growth Factors Section, Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK
References 1. Meager A, Dolman C, Dilger P, Bird C, Giovannoni G, Schellekens H, et al. An assessment of biological potency and molecular characteristics of different innovator and noninnovator interferon-beta products. J Interferon Cytokine Res. 2011;31(4):383-92. 2. Schellekens H. Biosimilar epoetins: how similar are they? Eur J Hosp Pharm. 2004;10(3):43-7. 3. Thorpe R, Wadhwa M. Terminology for biosimilars – a confusing minefield. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3):132-4. doi:10.5639/gabij.2012.0103-4.023 4. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Giezen TJ, et al. Biosimilars: what clinicians should know. Blood. 2012;120(26):5111-7. 5. Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191-6. 6. 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]. 2014 [cited 2015 Jun 8]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf 7. Praditpornsilpa K, Tiranathanagul K, Kupatawintu P, Jootar S, Intragumtornchai T, Tungsanga K, et al. Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies. Kidney Int. 2011;80(1):88-92. 8. Shin SK, Moon SJ, Ha SK, Jo YI, Lee TW, Lee YS, et al. Immunogenicity of recombinant human erythropoietin in Korea: a two-year cross-sectional study. Biologicals. 2012;40(4):254-61. 9. World Health Organization. Guidelines on evaluation of similar biotherapeutic products (SBPS). Annex 2, WHO Technical Report Series No 977 [homepage on the Internet]. [cited 2015 Jun 8]. Available from: http://www.who.int/entity/biologicals/publications/trs/areas/biological_therapeutics/TRS_977_Annex_2.pdf?ua=1; 2009 10. World Health Organization. Guidelines on the quality, safety, and efficacy of biotherapeutic products prepared by recombinant DNA technology. Annex 4, WHO Technical Report Series No 987 [homepage on the Internet]. [cited 2015 Jun 8]. Available from: http://apps.who.int/medicinedocs/documents/s21514en/s21514en.pdf
Author for correspondence: Robin Thorpe, PhD, FRCPath, Deputy Editor-in-Chief, GaBI Journal
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.
Abstract:
Biosimilars should be approved for all the clinical indications of the reference product based on the totality of the evidence even if there is no clinical safety and efficacy data for each indication. The foundation of biosimilar development is the demonstration that chemical, physical and biological parameters are highly similar to the reference product. Any clinical studies confirm functional sameness rather than establish efficacy and safety de novo since this has already been established with the reference product. However, there is a need to maintain linkage of the biosimilar with the original safety and efficacy data of the reference product in all indications. Reference products are not unchanged throughout the product life cycle due to changes in manufacturing site, scale or process, and new safety and efficacy studies are rarely required. Yet, the reference product retains the same approval in all clinical indications. Most biosimilars will be as close to the reference product as the reference product is to itself after a manufacturing change or even from lot to lot. Thus, analytical and medical sciences justify the approval of biosimilars for all the clinical indications of the reference product.
Submitted: 1 June 2015; Revised: 13 July 2015; Accepted: 13 July 2015; Published online first: 27 July 2015
Introduction
The extrapolation of biosimilar approval for all the clinical indications of the reference product can be justified based on scientific principles that begin with the precept that protein structure dictates function along with the totality of evidence. Biosimilars will be highly similar to the reference product in primary amino acid sequence, tertiary structure and biological activity as determined by rigorous analytical characterization in multiple assays. The biosimilar will have the same receptor or ligand binding and the same mechanism or mechanisms of action as the reference product. Clinical pharmacokinetic (PK) and pharmacodynamic (PD) studies and perhaps efficacy and safety data will confirm the biosimilarity determined at the analytical level. Thus, a biosimilar would have the same clinical performance as the reference for all approved indications.
Biosimilars should be approved for all the clinical indications of the reference product since extensive chemical, physical and biological comparisons demonstrate the same structure and function. There may be minor differences between a biosimilar and reference product that do not result in clinically meaningful differences. These differences are generally relatively small in comparison to product variants generated by post-licensing modifications. This is reflective of the nature of biologicals where no two batches of these products are the same. Likewise, the reference product undergoes changes when the manufacturing process is changed throughout its life cycle. Since the early 1990s, manufacturers have implemented manufacturing changes for protein therapeutics and monoclonal antibodies without the need for clinical efficacy and safety studies. The US Food and Drug Administration (FDA) and reference product sponsors have relied on the analytical characterization and non-clinical demonstration of biological activity as the most sensitive indicators of potential product changes. FDA has many years of experience in evaluation of potential product changes and their clinical impact and has developed guidance on comparability. Sponsors are able to implement process improvements or manufacturing site changes and demonstrate the new product is comparable to the previous product using analytical and non-clinical characterization. There is no change in labelling and the reference product retains all the approved indications. This approach for comparability is directly applicable to biosimilars with analytical characterization being the foundation in establishing biosimilarity.
The approval of a biosimilar for all clinical indications of the reference is also the key to retaining the linkage between the established clinical safety and efficacy of the reference and the projected clinical safety and efficacy of the biosimilar. Biosimilar approval depends on a demonstration that chemical, physical and biological parameters are highly similar to the reference product rather than a full clinical safety and efficacy programme in each indication. Any clinical studies conducted for biosimilars are limited and serve to confirm functional sameness and not to establish efficacy and safety de novo. Efficacy and safety have already been established with the reference product for all indications.
Extrapolation is essential to the concept of biosimilarity. Extrapolation requires an understanding that the biosimilar is sufficiently similar to the reference product using current assays that are highly sensitive and manufacturing process controls that are at least as good as that of the reference products. This ensures that the biosimilar will exert the same clinical effect across all diseases. Failure to extrapolate biosimilar use to all clinical indications of the reference product could create unnecessary confusion and undermine the concept of biosimilarity for physicians and patients. If a biosimilar cannot be approved for all clinical indications of the reference product one would question whether it is actually biosimilar. Extrapolation to all clinical indications is consistent with the globally recognized regulatory principle of comparability for originator/reference products as well as the approach for biosimilars in Europe and with generic drugs in the US.
Manufacture and characterization of therapeutic proteins and monoclonal antibodies
Most products being developed as biosimilars are recombinant proteins. Since 1982, when the first recombinant protein was approved, FDA has reviewed and approved numerous simple proteins, glycosylated proteins, fusion proteins and monoclonal antibodies. While each may be unique in its pharmacology, the methods used for production and purification of most recombinant proteins are similar in many aspects. Many of the host cells, fermentation procedures and purification steps are standard in the industry. The process starts when a human gene specific for a protein is inserted into a host cell to create a master cell bank. Proteins made in bacteria produce non-glycosylated proteins. Proteins made in yeast or mammalian cells, e.g. Chinese hamster ovary cells, can make glycosylated proteins. As the host cell grows and multiplies, it produces the human protein along with its own proteins. Purification is typically done through several chromatography steps. The final formulated protein product is highly purified (generally 95–98% pure).
Biotech products are more like drugs in their characterization compared to other biologicals (vaccines, blood products). While proteins are larger and more complex than most drugs, they are not too complex to be characterized. In fact, FDA approved some very complex products such as enoxaparin and glatiramer acetate as generic drugs without a requirement for clinical efficacy data [1, 2]. FDA has approved hundreds of protein products over the past 30 years that are safe and effective. Analytical tests for proteins are more numerous and sophisticated than those for small-molecule drugs. Typical release tests for a recombinant protein or monoclonal antibody are shown in Table 1. These allow the rigorous assessment of proteins, product-related substances and process-related impurities.
Knowledge base from comparability studies is relevant to evaluation of biosimilars
Most protein therapeutics were originally regulated as biologicals in an era where the process defined the product. In the first decade of recombinant products, it was not certain if changes in manufacturing process would impact the product in such a way to affect clinical safety and efficacy. Therefore, most manufacturing changes required no new clinical data. Sponsors argued that biotech products could be characterized by their chemical, physical and biological attributes. In fact, analytical assessments were more likely to detect product changes than clinical studies because these are more precise, reproducible and more sensitive than clinical studies. There was concurrence from FDA and recognition that recombinant products were distinct from other biologicals in their ability to be characterized. This distinction was a factor in the transfer of review of most recombinant therapeutic proteins in FDA from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER) in 2003.
Demonstration of comparability means that the product manufactured after the manufacturing change is analytically comparable to the product made before the manufacturing change. The expectation is that the product would have the same clinical safety and efficacy. Comparable does not imply identical as minor product changes are sometimes expected. As per the globally recognized regulatory guidance recognized by FDA and other health authorities [3] the standard for establishing comparability is high similarity, which is the same standard as for establishing biosimilarity. The effect of these minor differences is evaluated in in vitro biological activity and sometimes in PK studies. Only rarely, when more notable differences are observed, is clinical data required.
This concept is key for protein therapeutics since most products undergo changes in the manufacturing site, scale or process during the product life cycle. Manufacturers can and do change, e.g. the host cell, fermentation, purification process, manufacturing site; and still have a comparable product without the need to demonstrate safety and efficacy again. Analytical data is more sensitive in the ability to detect potential product changes than clinical trials.
FDA outlined their approach to comparability in the 1996 Guidance: demonstration of comparability of human biological products, including therapeutic biotechnology-derived products [4]. This guidance was released just prior to the approval of Biogen’s Avonex for multiple sclerosis, a hallmark case in comparability studies. After completion of phase III studies, there were internal disputes such that the Avonex master cell bank and product used during phase III were no longer available. Biogen developed a new master cell bank, new manufacturing process and at a new facility. Using analytical comparability studies and PK data, Biogen demonstrated that the new Avonex was comparable to the product used in phase III without the need for new clinical efficacy studies [5]. Avonex is a complex, glycosylated IFN-beta and minor glycosylation changes were noted, but FDA deemed the new product comparable to the investigational product and approved the new product without additional clinical efficacy trials. The use of analytical comparability studies has been possible because the nature of the proteins or monoclonal antibodies can be characterized by analytical methods and advances in analytical techniques allow for sensitive assessment of proteins.
The use of comparability studies has been recognized internationally with the implementation of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) document Q5E: Comparability of biotechnological/biological products [3]. This approach to evaluation of potential product differences after manufacturing changes has served FDA, industry and patients. FDA has more than 20 years experience in evaluation of manufacturing changes, product changes and their potential impact on safety and efficacy. Manufacturing changes over time are a normal part of the biological product life cycle. Physicians are not notified or aware of manufacturing changes or comparability data. There is no change in labelling and the product retains all the approved clinical indications. There is inherent reliance on FDA to review the analytical data to determine comparability.
Characterization of biosimilars
For biosimilars, side-by-side comparisons in multiple analytical assays would be expected. This was outlined in FDA Guidance for Industry: quality considerations in demonstrating biosimilarity to a reference protein product [6]. Different assays are often used to assess the same attribute in an orthogonal approach. Extensive, robust, physicochemical comparisons are made between the biosimilar and the reference, see Table 2 for the list of parameters typically assessed.
Biological activity relevant to the mechanism of action is compared in bioassays, binding assays to receptor or ligand, or possibly enzyme kinetics. Some bioassays may be more relevant than others. When possible, FDA recommends development of bioassays that are sensitive to changes in the functional activities of the product and these assays should be assessed for variability and reliability.
Newer analytical assays available today are more sensitive than those available when the reference product was approved. This is particularly true for characterization of carbohydrates, conformational studies and aggregates. For biosimilars, the site and type of carbohydrate linkage would typically be compared to reference product as well as quantitation of specific carbohydrates and ratios of various glycoforms. For any glycosylated protein the manufacturer would set specifications for major glycoforms and specific carbohydrates.
Conformational analyses are used to compare the three-dimensional structure and folding of the biosimilar and reference products. This analysis is extremely important because the conformational structure affects the functioning of the protein. Conformation is often assessed through circular dichroism, nuclear magnetic resonance, or possibly X-ray crystallography.
There is also more focus on assessment of aggregation today because of the association of aggregation with an increased risk of immunogenicity [7, 8]. With older reference products there may have been minimal attention on aggregation. Aggregates are often monitored by size exclusion chromatography, analytical ultra-centrifugation, light scattering, or field flow fractionation. Specifications are typically set for the level of aggregates and aggregation is followed on stability.
These are general approaches used in characterization of biosimilars. There is no single approach that is applicable to all proteins. There is a higher level of expectation for product characterization for all biotech products today, including biosimilars, than there was for the reference product when it was approved. Demonstration of biosimilarity involves application of this higher level of characterization to both the reference product and biosimilar, and demonstration that any differences observed do not adversely impact efficacy or safety. In addition to the extensive comparison to the reference product, biosimilars would undergo testing for each manufacturing batch after approval. Like all manufacturers, biosimilar sponsors must demonstrate consistency and control over the manufacturing process, comply with Good Manufacturing Practices, and undergo routine FDA inspections.
Biological products have more variability than drugs because they are produced from living organisms. This is especially true for glycosylated products where the ratio of glycoforms can vary from lot to lot and after a manufacturing change. However, there is some microheterogeneity observed even with simple proteins. The range of heterogeneity permitted is limited by specifications based on manufacturing history, which must be approved by FDA. Both the reference product and biosimilar will be held to the same standards.
The FDA requirements for biosimilarity, taken together with greater sensitivity of assays and advances in manufacturing controls, ensures that biosimilars will not have any greater variability than the reference product. Most biosimilars will be as close to the reference product chemically, structurally and biologically as the reference product is to itself from lot to lot. There is undue focus on the fact that biosimilar might be slightly different from the reference product. While this is true for biosimilars, we must also recognize that it applies to biologicals generally and thus, that the reference product is, of necessity, different from itself over time and from lot to lot [9].
For all of the comparisons between a biosimilar with the reference product the term used by FDA and others is ‘highly similar’ instead of the same. This distinction implies that there are differences between the biosimilar and reference product. While this may be true, the term can be misunderstood. Scientists wish to be accurate and because there are minor differences between two products or limitations of the assay we prefer the term highly similar. The notion that the reference product is unchanging over time is not accurate. The reference product is not identical after a manufacturing change or even from lot to lot. It would be highly similar to the previous product. Biosimilar will not have any clinically meaningful differences in safety or efficacy compared to the reference product. We should be cautious that the caveats of our terms do not overshadow the true meaning.
Extrapolation to other clinical indications for biosimilars
The scientific basis for comparability for biotechnology products can be extended to biosimilars. The assumption is that one can change the manufacturing process and still have the same product. With biosimilars, one is not re-establishing the safety and efficacy of the product. That has been established for the reference product. The goal is to demonstrate that the biosimilar is sufficiently similar to the reference product such that it will have no clinically meaningful differences. This is analogous to comparability studies after manufacturing changes in the reference product. FDA’s knowledge base on comparability studies and the impact of manufacturing changes is relevant in the review of biosimilars.
FDA provided guidance on extrapolation of approval across multiple clinical indications for biosimilars [10]. Extrapolation is justified based on similar mechanism of action, target/receptor interactions and molecular signalling; product structure interactions with the target or receptor; PK, expected toxicities and information based on mechanism of action. All of these are recommended for a biosimilar 351(k) applicationA. However, any differences in these factors can be addressed in the context of the totality of the evidence supporting a demonstration of biosimilarity. Thus, the totality of the evidence supersedes these other considerations.
It is a basic tenet of protein chemistry that structure dictates function. A biosimilar is designed to be highly similar to the reference product. Thus, the same structure should equate to the same function. Characterization of a biosimilar includes extensive analytical comparisons with the reference product using orthogonal methods to assess primary amino acid sequence, tertiary structure, post-translational modifications (primarily glycosylation), and assessment of any impurities [1]. In addition, biological activity is compared through in vitro and sometimes in vivo assays. This analytical comparison demonstrating that the biosimilar is highly similar to the reference product is the foundation of biosimilar development and approval. Thus, a biosimilar with highly similar structure, chemical, physical and biological attributes would be expected to produce the same pharmacology and thus highly similar safety and efficacy as the reference in every clinical indication.
The analytical characterization is easier for non-glycosylated proteins than it is for glycosylated proteins. Differences in glycosylation have the potential to affect bioactivity and possibly PK. However, characterization of carbohydrates has significantly improved in recent years. The quantification of specific sugars and the characterization of glycoform species are routine. The degree of carbohydrate characterization for glycoproteins is typically more extensive than what was available when the reference product was approved. As with comparability studies, differences between a biosimilar and reference product can be further analysed in in vitro and in vivo studies. The sponsor should determine if the differences affect the bioassay, binding, or other in vitro measures of biological function as well as PK. For example, any differences in glycosylation might be further assessed to determine if these differences have an impact on bioactivity or PK in comparison with the reference product. A biosimilar would be expected to demonstrate the highly similar bioactivity and PK as the reference product. If regulators determine that these tests are not adequate to confirm safety and efficacy, additional testing may be requested.
Another basic assumption that supports the extrapolation of a biosimilar to all clinical indications is that a biosimilar must have the same mechanism of action as the reference product (to the extent it is known). For most proteins, the mechanism of action depends upon the protein binding to a cell-associated receptor. While the binding of a protein to a receptor may occasionally cause distinct intracellular signalling reactions in different cell types, this receptor interaction is the same in all patients. Thus, the biosimilar would behave like the reference in all clinical indications. Examination of receptor binding is part of analytical characterization of biosimilars.
Mechanism of action is usually characterized by comparison of the biological activity of the biosimilar with that of the reference product. For some biosimilars there may be a need to examine several biological activities when the mechanism of action is pleiotropic or unknown. An advantage of biosimilar monoclonal antibodies is that the mechanism of action is usually well defined. Monoclonal antibodies are developed to a specific target. Thus, the comparison of a biosimilar monoclonal antibody to the reference product in the binding to the target antigen is the primary demonstration of similar mechanism of action.
FDA has stated that extrapolation to other clinical indications may depend on differences in expected toxicities for biosimilars. While biosimilars may have slightly different impurities than the reference product, it is important to remember that for most therapeutic proteins, any toxicity is due to the exaggerated pharmacology of the protein rather than as a result of impurities. The assessment of product related impurities, such as aggregates, which may be associated with increased immunogenicity, are much more rigorously monitored in today’s products than when the reference product was approved. A fundamental principle of biosimilar development is the reliance on the history of safety of the reference product and the known toxicities observed after many years of clinical use. We can also look to the use of biosimilars in Europe where biosimilars have been used for nearly 10 years and there have been no issues of safety unique to biosimilars [11–13]. In each clinical indication, a variety of biosimilars have demonstrated similar safety issues as the reference product, including in the extrapolated indications.
The extrapolation of biosimilars to all clinical indications of the reference product is also justified based on the experience following manufacturing changes made to protein therapeutics. Only rarely are any additional clinical studies required and if necessary would be conducted in a limited number of patients in a single indication. The ‘new’ product retains approval of all clinical indications of the ‘old’ product. The same principles would apply to biosimilars.
The comparability approach currently used by industry and FDA can be shown in several examples. Scientists followed three glycosylated proteins over time and demonstrated changes in darbepoetin alfa (Aranesp), rituximab (Rituxan) and etanercept (Enbrel) over time [9]. Darbepoetin alfa is a glycoprotein that stimulates red blood cells and is indicated for the treatment of anaemia due to chronic kidney disease for patients on dialysis and those not on dialysis [14]. Changes were noted for darbepoetin alfa (Aranesp) over time, with a higher sialylation rate (which affects PK) in batches expiring before April 2010 compared to batches expiring after September 2010. This corresponded with a major process change of Aranesp in 2008 approved by European Medicines Agency (EMA).
Rituximab (Rituxan) is a monoclonal antibody to CD20 antigen and is indicated for use in non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia and rheumatoid arthritis when used with methotrexate for patients who failed anti-TNF therapy [15]. There were changes in glycosylation of rituximab noted in 2009–2010 (reduction in the basic variants, C-terminal lysine and N-terminal glutamine from 30–50% to 10%) [9]. A further change was also found in the amount of fucosylated glycans and G0 glycans with an increase in antibody dependent cellular cytotoxicity (ADCC).
Etanercept is a glycosylated fusion protein that contains a form of the p75 TNF receptor that binds to the inflammatory mediator, TNF. It is indicated for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis [16].
Etanercept (Enbrel) demonstrated major differences in the glycosylation profile and in the amount of basic variants present in the molecule from 2009 to 2010 [9]. These types of changes are not unusual. Enbrel has been manufactured at multiple sites by several sponsors or contract manufacturers [17]. Glycosylation modifications are expected for every change in manufacturing location. Despite changes in these reference products, there was no change in product labelling or marketed clinical indications and no need for additional clinical trials to demonstrate efficacy in any specific indication. Darbepoetin alfa (Aranesp), rituximab (Rituxan) and etanercept (Enbrel) retained all of their approved indications.
Sometimes there are challenges in the extrapolation to all clinical indications for biosimilars. Health Canada decided to grant approval to the biosimilar anti-TNF antibody, Inflectra (infliximab) for only some of the clinical indications of the reference product, Remicade [18]. Inflectra was approved for use in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis, but not Crohn’s disease or ulcerative colitis. Health Canada believed that differences of the biosimilar compared to the reference product in in vitro ADCC and binding to the FcγRIIIa receptor may correlate with mechanism of action in Crohn’s disease or ulcerative colitis.
However, in 2013, EMA came to a different conclusion on the same data. Inflectra was approved as biosimilar for all eight of the clinical indications of the reference product. Their decision was included in Inflectra Assessment Report [19].
‘As part of the comparability exercise it was shown that all major physicochemical characteristics and biological activities of Inflectra were comparable to those of Remicade. The CHMP [Committee for Medicinal Products for Human Use] noted a small difference in the amount of afucosylated infliximab, translating into a lower binding affinity towards specific Fc receptors and a lower ex vivo antibody-dependent cellular cytotoxicity (ADCC) activity in the most sensitive ADCC assay. This difference was, however, not considered clinically meaningful, as it did not affect the activities of Inflectra in experimental models regarded as more relevant to the pathophysiological conditions in patients.’
The EMA decision reflects that the proposed mechanism of action, for various clinical indications is speculative at this point in time and the correlation with in vitro assays is not certain. The approval for all clinical indications should be viewed in the context of totality of data on analytical, preclinical, PK, PD and clinical information. Subsequent preliminary clinical studies have demonstrated safety and efficacy in paediatric Crohn’s disease [20], ulcerative colitis [21] and inflammatory bowel disease [22].
Failure to extrapolate to all clinical indications would cause confusion and undermine the concept of biosimilars
In addition to the scientific justification for extrapolation, it may be fundamental to the implementation and clinical use of biosimilars that they receive approval for all the same clinical indications as the reference product. Failure to do so would undermine the concept of biosimilars and principles of sound science. FDA guidance states that data for a biosimilar ‘should demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components. The stepwise approach should start with extensive structural and functional characterization of both the proposed product and the reference product, which serves as the foundation of a biosimilar development program[me]’ [4]. Based on a sound characterization approach it is expected that all indications will be granted to biosimilars. The foundation of biosimilars is the demonstration of analytical similarity/comparability to the reference products. Any need for clinical data only serves to confirm the expected safety and efficacy. We might expect that sometime in the future, there will not be a need for any safety and efficacy studies for biosimilars, just PK and analytical data. Some might consider safety and efficacy studies in any clinical indication as superfluous and not a good use of medical resources.
Although sponsors are allowed to seek fewer than the full list of approved indications in a biosimilar 351k application, it is not clear under what conditions this would be an advantage for a sponsor or if this is only a hypothetical issue. If after review of the totality-of-evidence, FDA cannot be certain that a product would be effective in all clinical indications, one should question whether it is truly a biosimilar. It would infer different standards for biosimilars with all indications compared to biosimilars with fewer indications.
At this early stage of biosimilar development in the US, physicians and patients need confidence that biosimilars are safe and effective. Too often, physicians are hearing the message that biosimilars will be different from the reference product. There is some microheterogeneity for all biological products, including the reference product. However, the potential differences for biosimilars have been exaggerated with regard to the potential impact on safety, purity and potency [23]. These same concerns do not arise when changes are made to the reference product and are supported by the same test methods as used for biosimilar.
It may be understandable that some physicians and groups have expressed a desire to see clinical data for every indication. That is their realm. However, as stated by FDA, analytical and other non-clinical data is the foundation for biosimilar development and provides more meaningful information compared to clinical studies. Physicians rely on FDA to assess this data and determine the similarity and approvability of the biosimilar. Most clinical trials are unlikely to detect differences in safety, efficacy or immunogenicity between a biosimilar and a reference product. When the expected difference between two products is small, it represents a significant methodological challenge and the size of the trial needed to determine potential clinical differences between the two products would need to be very large (exceeding the size of the clinical trial for the original approval). Even comparative clinical trials between different products present difficulties [24]. Clinical studies cannot be expected to distinguish subtle clinical, safety or immunogenicity differences between two products that are specifically designed to be identical. FDA approval of biosimilars for all the clinical indications of the reference product, using the same scientific approaches used when reference products make post-approval changes, would instill confidence that biosimilars are as safe and efficacious as the reference product.
In Europe, which has approved numerous biosimilars since 2006, all biosimilars are approved for all clinical indications, and all have the same Package Insert (Summary of Product Characteristics). Similarly, in the US all generic drugs have the same Package Insert as the reference product. This is because the biosimilar or generic drug is linked to the clinical data on the safety and efficacy of the reference product. Retention of this linkage of the biosimilar to the long history of safety and efficacy of the reference product in all clinical indications is key. It would be a mistake to use a different approach in the US for biosimilars that would confound the principle of biosimilarity in the medical community. It would be irrational and potentially confusing to healthcare professionals to have some biosimilars approved for only some of the clinical indications of the reference and more confusing still to have various biosimilars each approved for potentially distinct clinical indications. It would be preferable to link each biosimilar with the safety and efficacy data of the reference product for all clinical indications.
In summary, the science justifies the approval of a biosimilar for all the clinical indications of the reference product:
The totality-of-evidence including the demonstration of high similarity with essentially the same chemical, physical, and biological properties as the reference product in addition to PK and PD bioequivalence.
Extrapolation has been applied to essentially all changes made to reference products after approval. Any minor differences between a biosimilar and the reference product can be analogous to the minor product differences observed in the reference product over time and with manufacturing changes. In these situations there is no change in clinical indications.
Approval for all clinical indications retains the linkage between the history of the safety and efficacy of the reference product and the biosimilar.
If regulatory agencies cannot be certain that a product would be effective in all clinical indications, one should question whether it is truly a biosimilar.
A42 United States Code. Regulation of Biological Products. Available from: http://www.gpo.gov/fdsys/pkg/USCODE-2013-title42/html/USCODE-2013-title42-chap6A-subchapII-partF-subpart1-sec262.htm
Competing interest: This manuscript is funded by the Generic Pharmaceutical Association (GPhA). Dr Theresa L Gerrard is a consultant to many biotech companies; confidentiality agreements restrict the publication or use of their names. Mr Gordon Johnston provides consultant services to GPhA on regulatory and policy issues. Mr David R Gaugh is the Senior Vice President for Sciences and Regulatory Affairs of GPhA.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Theresa L Gerrard, PhD, TLG Consulting Inc, 14521 West Salisbury Road, Midlothian, VA 23113, USA
Gordon Johnston, RPh, MS, Gordon Johnston Regulatory Consultants, Olney, MD, USA
David R Gaugh, RPh, Senior Vice President, Sciences and Regulatory Affairs, Generic Pharmaceutical Association, Washington, DC, USA
References 1. U.S. Food and Drug Administration. FDA approves first generic Copaxone to treat multiple sclerosis [homepage on the Internet]. 2015 Jul 13 [cited 2015 Jul 13]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm443143.htm 2. U.S. Food and Drug Administration. Departmen of Health & Human Services. Citizen petition denial letter from CDER to Teva Pharmaceuticals. 16 April 2015 [homepage on the Internet]. 2015 Apr 16 [cited 2015 Jul 13]. Available from: http://www.regulations.gov/#!documentDetail;D=FDA-2015-P-1050-0012 3. European Medicines Agency. ICH Topic Q 5 E. Comparability of biotechnological/biological products. CPMP/ICH/5721/03. June 2005 [homepage on the Internet]. 2006 Mar 7 [cited 2015 Jul 13]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002805.pdf 4. U.S. Food and Drug Administration. Demonstration of comparability of human biological products, including therapeutic biotechnology-derived products. April 1996 [homepage on the Internet]. 2015 Jul 13 [cited 2015 Jul 13]. Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122879.htm 5. U.S. Food and Drug Administration. Avonex. Summary basis of approval [homepage on the Internet]. 1998 Nov 13 [cited 2015 Jul 13]. Available from: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm086056.pdf 6. U.S. Food and Drug Administration. Quality considerations in demonstrating biosimilarity to a reference protein product. April 2015 [homepage on the Internet]. [cited 2015 Jul 13]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf 7. Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501-7. 8. U.S. Food and Drug Administration. Guidance for industry. Immunogenicity assessment for therapeutic protein products. August 2014 [homepage on the Internet]. 2014 Aug 12 [cited 2015 Jul 13]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338856.pdf 9. 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. 10. U.S. Food and Drug Administration. Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. April 2015 [homepage on the Internet]. 2015 Apr 24 [cited 2015 Jul 13]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf 11. Hörbrand F, Bramlage P, Fischaleck J, Hasford J, Brunkhorst R. A population-based study comparing biosimilar versus originator erythropoiesis-stimulating agent consumption in 6,117 patients with renal anaemia. Eur J Clin Pharmacol. 2013;69(4):929-36. 12. Kerkhofs L, Boschetti G, Lugini A, Stanculeanu DL, Palomo AG. Use of biosimilar epoetin to increase hemoglobin levels in patients with chemotherapy induced anemia: real-life clinical experience. Future Oncol. 2012;8(6):751-6. 13. Eisen S. Safety of biosimilars: what you really need to know. DIA presentation 2011 [homepage on the Internet]. [cited 2015 Jul 13]. Available from: http://www.diahome.org/productfiles/25233/2.2%20 sandy%20eisen.pdf 14. U.S. Food and Drug Administration. Package insert Aranesp (Darbepoetin alfa) [homepage on the Internet]. 2015 Jul 13 [cited 2015 Jul 13]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/darbamg091701lb.htm 15. U.S. Food and Drug Administration. Prescribing information Rituxan (Rituximab) [homepage on the Internet]. 2010 Feb 19 [cited 2015 Jul 13]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103705s5311lbl.pdf 16. U.S. Food and Drug Administration. Prescribing information Enbrel® (enteracept) [homepage on the Internet]. 2012 Dec 11 [cited 2015 Jul 13]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103795s5507lbl.pdf 17. Gerrard TL. The science for biogenerics: is it there already? In: Advances in large scale biopharmaceutical manufacturing and scale-up production. 2nd Ed. Washington D.C.: ASM Press; 2007:35-50. 18. Health Canada. Summary Basis of Decision (SBD) for Celltrion’s Inflectra [homepage on the Internet]. 2015 Jul 13 [cited 2015 Jul 13]. Available from: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2014_inflectra_159493-eng.php#non_clinical 19. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Assessment report Inflectra. EMA/CHMP/589422/2013. 27 June 2013 [homepage on the Internet]. 2013 Sep 30 [cited 2015 Jul 13]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002778/WC500151490.pdf 20. Sieczkowska J, Banaszkiewicz A, Plocek A, Jarzebicka D, Gawronska A, Toporowska-Kowalska E, Kierkus J. Assessment of safety and efficacy of biosimilar infliximab in children with Crohn’s disease: a preliminary report. Poster session presentation Abstract:#P430. 10th Congress of European Crohn’s and Colitis Organisation; 18–21 February 2015; Barcelona, Spain. 21. Molnar T, Farkas K, Rutka M, Bálint A, Nagy F, Bor R, Milassin A, Szepes. Z. Efficacy of the new infliximab biomarker CT-P13 induction therapy on mucosal healing in ulcerative colitis patients. Poster session presentation Abstract:#P603. 10th Congress of European Crohn’s and Colitis Organisation; 18–21 February 2015; Barcelona, Spain. 22. Gecse K, Farkas K, Lovasz B, Banai J, Bene L, Gasztonyi B, Golovics P, et al. Biosimilar infliximab in inflammatory bowel diseases: first interim Results from a prospective nationwide observational cohort. Poster session presentation Abstract:#P314. 10th Congress of European Crohn’s and Colitis Organisation; 18–21 February 2015; Barcelona, Spain. 23. Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider C. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191-6. 24. Temple R. A regulator’s view of CER. Clinical Trials. 2011;10.1177/1740774511422548
Author for correspondence: Theresa L Gerrard, PhD, TLG Consulting Inc, 14521 West Salisbury Road, Midlothian, VA 23113, USA
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.
Abstract:
Austria has seen considerable savings with generics, due to its unique pricing system. Generic medicine penetration is, however, not as advanced as in other European countries. Additional savings could be made, provided certain measures are implemented.
Submitted: 27 May 2015; Revised: 5 June 2015; Accepted: 8 June 2015; Published online first: 22 June 2015
Generic medicinal products are subject to detailed authority assessment in Austria, including the thorough examination of safety and efficacy data. The competent medicines authorities in Austria, and in the European Union (EU), will only issue authorization for their respective markets if all applicable legal and scientific requirements are fulfilled. It is now obvious for most experts in the fields of clinical prescribing and dispensing, after more than 30 years of worldwide experience with generics, that generic drugs present a safe and efficacious alternative to established medicinal products [1, 2]. They are rigorously tested and their safety and efficacy is continuously controlled.
In contrast to originator products, which usually undergo an expensive and protracted development that can take up to 15 years, the development of generic drug products is a relatively quick and inexpensive process. This allows generic drugs to be sold at a lower price. In fact, the increased use of generic medicines is essential to sustain healthcare systems faced by an ever-increasing pressure on resources [3, 4]. Ageing populations and the continued launch of new premium-priced medicines, priced at over Euros 70,000 per patient per year or course are some of the factors causing these pressures.
Austrian health insurance will pay for a patient’s medicine if that medicine is listed in the so-called Erstattungscodex (Austrian reimbursement code). The Main Association of Austrian Social Security Organisations decides whether a new product will be listed. To do this, they assess efficacy and value of a new medicine by conducting a pharmacological evaluation, a medical-therapeutic evaluation and a health-economic evaluation. Before a medicine can be listed, its therapeutic value is compared with that of existing medicines, and average prices for those medicines across the EU are taken into account. For generics, this procedure is an abbreviated one and follows fixed, unique rules.
The moment the first generic drug enters the market; it has to be at least 48% below the price of the originator. This price reduction has gradually increased – from 44% in 2004, to 46% in 2005, finally reaching 48% in 2006. If the company that produces the originator wants it to stay in the reimbursement code, it will need to decrease the originator’s price by 30% within three months. When a second generic drug enters the market, it will need to be priced 15% below the price of the first generic drug to become listed; a third generic drug must be priced at an additional 10% below the price of the second generic drug. Remarkably, the price of the originator and also of the first and the second generics must again go down to the price of the third generic drug within three months if they are to stay listed. At this point, prices are 60.2% below the former originator price. However, this does not mean that every product after that will have the same price forever; every marketing authorization holder can, and usually will, lower the price again, to have a prescribing advantage. Further price decreases are often seen down to -80% or -90% of the former starting price of an originator.
It is estimated that Austria currently achieves savings of up to two billion Euros a year thanks to cheaper generics and their price lowering effect on originators [5]. It was reported recently that Austria’s healthcare payers could have saved an additional quarter of a billion Euros in 2011 if physicians had prescribed generics to all patients whenever they were available [6, 7]. This is only theoretical, however, as it would mean a 100% generics penetration rate in the replaceable segment. Taking into account a more realistic generics penetration rate of 75%, a more likely saving would have been Euros 150 million. The generics penetration rate in Austria is currently slightly above 40%.
A new study has again underlined these potential savings for Austria [8]. The nationwide cohort study showed that substituting originators with generics could save up to Euros 72 million in just three therapeutic indications: hypertension, hyperlipidaemia and diabetes mellitus. This study at the Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS) at the Medical University of Vienna, Austria, analysed data collected from 8.3 million people across Austria between 2009 and 2012 (equivalent to 98.5% of the insured population of Austria). The study concluded that potential annual savings of 18% would be possible if generics uptake was stepped up in these three disease areas, which currently cost the annual health budget Euros 401 million.
Health insurance companies spent Euros 231.3 million on anti-hypertensive medicines, Euros 77.8 million on lipid-lowering medicines and Euros 91.9 million on medicines for diabetes. The calculations show that substituting these medicines with cheaper generic versions could have saved Euros 52.2 million (22.6%), Euros 15.9 million (20.5%) and Euros 4.1 million (4.5%) respectively, in costs.
Importantly, some additional measures might be necessary to achieve these ambitious goals in Austria, where the generics penetration rate is currently no better than average compared with other European countries. For example, Austria has not implemented pro-generics measures such as INN (International Nonproprietary Name) prescribing, compulsory substitution, reference pricing, additional copayments for a more expensive product than the referenced price, or financial incentives to prescribers, dispensers or patients. This means that Austria mainly relies on its pricing system and on doctors prescribing generics.
These additional measures must be taken if a higher generics penetration rate and the full savings potential is to be achieved by Austria [5]:
Enhanced training and education of prescribing physicians, dispensing pharmacists and patients
Starting therapies with, and whenever possible, switching therapies to, generic drug products
Creation of a financial incentive system to intensify use of generics
Prohibition of originator rebates in kind and of all forms of free samples of originators in hospitals
Improve counselling and guidance provision by prescribing physicians and dispensing pharmacists to encourage patients to accept generics
It remains to be seen how big the overall savings will be for national health budgets in Austria, not only with generics, but also taking biosimilars into account, as more and more of these products are now entering the market. Globally, it is expected that, over the next 10 years, biosimilars could save more than US&40 billion in health costs worldwide. Biosimilar prices are expected to be 15% to 35% below the originator biologicals prices [9]. The same savings are anticipated not only worldwide, but also just for the US market, suggesting that potential worldwide savings could be considerably higher [10]. Savings of at least Euros 11.8 billion are expected between now and 2020 with the use of biosimilars in Europe alone [11].
Regarding biosimilars, no specific data in this interesting field is yet available for Austria. However, the Austrian Main Association of Social Security Organisations has made it clear that it will price future biosimilars in the same way as they currently price generics, which means that premium priced biotechnology drugs, including monoclonal antibodies, will see pronounced price reductions of 60% or more. Since the question of substitution and switching from an originator to a biosimilar is not yet answered, it is expected that the biosimilar penetration rate in Austria will not, at least to begin with, be as high as that seen with generics. It is expected that only new patients will be started on a biosimilar, since switching for existing patients is not yet fully endorsed [12]. The saving potential in Austria could grow further with the increasing availability of new biosimilars. It is estimated that more than 300 monoclonal antibodies are in development in more than 200 indications, and that more than 20 blockbuster biotech drugs will lose patent protection by 2020. This, coupled with the fact that the use of biologicals is growing at a much higher rate than the overall pharmaceutical market, suggests there will be more room for considerable savings in Austria.
Competing interest: None.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. Kesselheim AS, Misono AS, Lee JL, Stedman MR, Brookhart MA, Choudhry NK, et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA. 2008;300(21):2514-26. 2. Baumgärtel C. Myths, questions, facts about generic drugs in the EU. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):34-8. doi:10.5639/gabij.2012.0101.009 3. Dylst P, Vulto A, Godman B, Simoens S. Generic medicines: solutions for a sustainable drug market? Appl Health Econ Health Policy. 2013;11(5):437-43. 4. Godman B, Shrank W, Wettermark B, Andersen M, et al. Use of generics – a critical cost containment measure for all healthcare professionals in Europe? Pharmaceuticals. 2010; 3(8):2470-94. 5. Baumgärtel C. [Generics in Austria]. Generika in Österreich und ihre Bedeutung für das Gesundheitssystem. AV Akademikerverlag 2013, ISBN-13: 978-3639491265,106-10. German. 6. Austrian Generics Association. [Current prices of medicines]. Arzneimittelkosten in Österreich – aktuelle Zahlen. 2012 Aug 27. German. 7. Baumgärtel C. Austria could save Euros 256 million by using more generics. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):144. doi:10.5639/gabij.2012.0103-4.038 8. Heinze G, Hronsky M, Reichardt B, Baumgärtel C, Müllner M, Bucsics A, et al. Potential savings in prescription drug costs for hypertension, hyperlipidemia, and diabetes mellitus by equivalent drug substitution in Austria: a nationwide cohort study. Appl Health Econ Health Policy. 2015 Apr;13(2):193-205. 9. Biosimilars entering the U.S. market are likely to face multiple challenges. Tufts CSDD. Impact Reports Single Issue. March/April 2015;17(2). 10. GaBI Online – Generics and Biosimilars Initiative. Biosimilars could save US&44.2 billion over 10 years [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Jun 5]. Available from: www.gabionline.net/Reports/Biosimilars-could-save-US-44.2-billion-over-10-years 11. Hausstein R, 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 12. Baumgärtel C. Austria increases dialogue in order to involve physicians more with biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(1):8. doi:10.5639/gabij.2013.0201.003
Author: Christoph Baumgärtel, MD, MSc, Senior Scientific Expert, Coordination Point to Head of Agency, AGES Austrian Medicines and Medical Devices Agency and Austrian Federal Office for Safety in Health Care, EMA European Expert, Vice Chair 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.
Abstract:
A novel global and company specific biological qualifier, distinct from the International Nonproprietary Name (INN), is proposed by World Health Organization (WHO) for all biological active substances.
Submitted: 14 May 2015; Revised: 2 July 2015; Accepted: 6 July 2015; Published online first: 20 July 2015
Introduction to INN
The concept of one single non-proprietary name to be used worldwide for active pharmaceutical substances was established by the World Health Organization (WHO) in 1950, by World Health Assembly Resolution WHA3.11 and became operational in 1953. Since then, there have been more than 10,000 applications for an international non-proprietary name, or INN, as they are commonly called. INNs are intended for use in drug regulation, prescribing, dispensing, pharmacopoeias, labelling, pharmacovigilance and in scientific literature. They are also used by the World Intellectual Property Organization (WIPO), Trademark offices, and Customs and Excise agencies, including the World Customs Organization (WCO).
An INN itself often is an unusual word; this is because the name has information regarding the active substance it represents built into it. Typically, the name begins with a fantasy prefix of one, two or more syllables, followed by a stem suffix. Stems indicate chemical and/or pharmacological relationships and substems that further refine the relationship may be used. Stems do not necessarily exist for every conceivable pharmacological group and when an INN is requested for a new class of drug, a novel suffix is determined which may or may not become established as a stem at a later date. Take the INN alvelestat as an example. From the end of the name moving forwards, it is constructed as follows: the suffix -stat is indicative of an enzyme inhibitor, the middle part -ele- is a substem indicating a subclass of inhibitors, in this case elastase inhibitors, whilst the prefix alv- is the fantasy part that identifies the unique substance represented by the INN. INN and stems have protection within the trademark arena and a list of current stems and substems is issued by WHO [1]. To avoid confusion, which could jeopardize the safety of patients, trademarks should neither be derived from INNs nor contain common stems used in INNs. In contrast to the INN, which is global, non-proprietary, not owned by anyone (including the INN applicant) and applied to the drug substance, medicines usually will also have a company-specific name – the trade name or brand name – that tends to be region-specific, not global, is owned by the company and is applied to the drug product.
INN for biological medicines
Increasingly, INNs are being requested for complex biological drugs. Biological medicinal products are of increased molecular complexity compared to chemical drugs, including structural micro-heterogeneity. For biological drugs there has been a need, not only for new stems but for new naming schemes and policies. These new schemes are provided in the WHO publication ‘INN for Biological and Biotechnological Substances (A review)’ which is updated regularly and available on the WHO website [2].
Currently, there are 11 general policies for specific classes of biological and biotechnological substances. Three particular policies are relevant for this paper – policies for non-glycosylated compounds, for glycosylated compounds and for monoclonal antibodies. For non-glycosylated compounds and specifically non-glycosylated proteins, the naming format is similar to that mentioned above for INN in general, that is identification of the pharmacological group with a stem/substem whilst the specific amino acid sequence, i.e. structure of the protein, is indicated by the fantasy prefix. Thus, the constituent parts of the INN filgrastim are –stim, the stem for colony stimulating factors, -gra- a substem used specifically for granulocyte colony-stimulating factors, and the prefix fil- is a fantasy syllable indicating the specific amino acid sequence of this substance and in this case also the expression system used (bacterial).
For glycosylated proteins, in addition to the naming policy applied to non-glycosylated proteins, differences in the glycosylation (or glycoform) pattern are represented by a Greek letter second word, spelled out in full; for example, there are now nine distinct epoetin INN with the second word Greek letters alfa, beta, delta, gamma, epsilon, kappa, omega, theta and zeta, all having the same amino acid sequence for the protein but possibly differing in their glycosylation profile.
INN for monoclonal antibodies (mAbs) are typically composed of a fantasy prefix, substem 1 to indicate the biological target of the mAb, for example, -t(u)- for tumour targeting mAbs, and -li- for immuno-modulating mAbs; substem 2 to indicate the type or origin of the mAb, for example, -u- to indicate a human derived mAb, and -xi- to indicate a mAb of chimeric origin; and finally the suffix/stem -mab to indicate that it is a monoclonal antibody. Thus, a monoclonal antibody ending in -tuximab would be tumour targeting and of chimeric origin.
Biosimilars and INN
Whilst identical copies of a particular chemical drug are known as generics, the name has not been applied to copies of biological drugs because of the high level of complexity and heterogeneity in their structure such that one manufacturer’s biological drug will not necessarily be fully identical to the same substance from another manufacturer. Instead of the name ‘generic’ a variety of terms has been used including similar biological product (SBP), biosimilar, follow-on product, subsequent entry biologic, me-too, and non-innovator biologic, with no global consensus. All terms tend to be used interchangeably, with ‘biosimilar’ probably being the most common. However, the term biosimilar was originally coined specifically for biological products that have been licensed via a regulatory pathway in which full quality and specific and usually abbreviated non-clinical and clinical studies have demonstrated the product to have a similar quality, safety and efficacy profile to an already licensed reference product, with the reference product itself having been licensed following a full assessment of quality, safety and efficacy, for example, see WHO and European Union (EU) biosimilar guidelines [3, 4]. The frequent but inconsistent and improper use of the term ‘biosimilar’, and other terms, for products where there has been no comparability regulatory exercise causes confusion, is a potential concern for patient safety and efficacy, and can lead to misconceptions in published reports on apparent problems with ‘biosimilars’ [5, 6].
In recent years, there has been debate and mounting concern as to what INN should be given to biosimilars. This reveals a further issue and miscomprehension with biosimilar nomenclature because WHO has no policy on how to name a biosimilar. The concept of biosimilarity is a regulatory procedure and INN are not assigned on the basis of how a medicinal product achieves licensure. Indeed, at the time of an INN application, it is usually not known to the INN Expert Group* what regulatory pathway will ultimately be followed for licensure of the substance. Furthermore, the INN Expert Group does not receive and is not privy to the vast amount of information submitted in registration dossiers; the amount of data submitted in support of a new INN is quite scant and decisions on INN assignment have to be made before full quality, non-clinical and clinical information on the substance is derived.
INN for non-glycosylated proteins follow the approach for small molecule drugs in that following the first INN assignment for a particular amino acid sequence, no further applications are made. For example, for somatropin, a growth hormone derivative, multiple innovator and biosimilar somatropins all use the same INN.
The glycoform profile of a glycosylated protein is dependent on the expression system used to manufacture the protein, the fermentation conditions and potentially also on downstream processing. For an INN application for a glycoprotein, where glycosylation is stated to be different, or where no statement is made regarding glycosylation, the INN Expert Group assumes it to be different, and so a new Greek letter second word is assigned. Regardless of whether a glycoprotein is (eventually) subject to a biosimilar, subsequent entry, follow-on or a stand-alone registration process, assignment of the INN follows the above rule for glycoproteins. It is important to emphasize that the INN for a glycosylated protein reflects the structure and nature of the substance and is not influenced by the status or the pathway followed for its registration with a regulatory authority. Unfortunately, one issue remains and that is how to determine how different is ‘different’. Interestingly, glycoform differences can occur as a result of manufacturing changes to an already licensed glycoprotein but this has not resulted in a change to a previously assigned Greek letter INN.
The Greek letter system has not been without its complications. Janssen-Cilag’s erythropoietin (EPO) Eprex® had been assigned the INN epoetin alfa; this was subsequently licensed within the EU by an innovator stand-alone registration pathway. Despite a distinct glycosylation profile, the EPO biosimilar HX575 (from Sandoz) adopted the same INN of its reference product, epoetin alfa. In Australia, the Therapeutic Goods Administration (TGA) reacted to the distinct glycosylation profile of HX575 and assigned it the ABN non-proprietary name epoetin lambda. Thus, a single biotherapeutic product has a regional non-proprietary INN-like name distinct from the INN used within the EU. Notwithstanding this particular situation, the Greek letter system in general works well.
Pharmacovigilance and INN
A strong and reliable pharmacovigilance and post-authorization risk management system cannot rely solely on the INN. Reporting of adverse events should rely on other characteristics of a drug, such as the brand name of the product, the manufacturer and the batch or lot number as well as the INN. However, a survey of adverse event reporting by physicians in the EU, conducted by the Alliance for Safe Biologic Medicines in 2013, found that 17%, or one in six physicians, still reported only the INN and only slightly over half reported both the INN and the brand name [7]. Also, slightly over 25% of physicians never reported the batch number whilst only 40% always included the batch number in adverse event reports.
Regional nomenclature schemes
Individual regulatory regions are starting to create their own non-proprietary nomenclature schemes for biosimilars. The TGA in Australia plan to add a second word comprising the prefix sim- followed by a fantasy single syllable to each biosimilar. The Japanese Accepted Name (JAN) for biosimilars uses the INN followed (in parentheses) by the name of the reference substance + BS1, BS2, etc. In the US, FDA has given short prefixes to three stand-alone registered biologicals – tbo-filgrastim, ziv-aflibercept and ado-trastuzumab emtansine. For at least the latter product, this was done for safety reasons to distinguish it from the non-conjugated mAb trastuzumab, which itself is a registered drug with a differing dosage profile.
Biological qualifiers
In the face of regional development of nomenclature schemes for biosimilars, and at the request of some regulatory authorities, WHO has proposed the development of a global biological qualifier (BQ) for biological medicines. This would provide a unique identifier for all biological active substances that are assigned an INN; but whereas the INN is a common and public non-proprietary name for a given active substance, the BQ would be applied to a particular manufacturer’s active substance. The BQ would not be part of the INN and it is envisaged that it would enhance identification, prescribing, dispensing and pharmacovigilance of biological medicines.
A draft scheme for such a BQ was published on the WHO website in July 2014 with comments requested from stakeholders by 19 September 2015 [8]. It emphasized that the BQ would not be part of the INN, would be a voluntary scheme, would be applicable to all biological substances, would uniquely identify the manufacturer or the manufacturing site, would be overseen by the WHO INN Expert Group and would be administered by the WHO INN Secretariat. It was proposed that the qualifier itself would consist of a four-letter code generated randomly and would avoid vowels to avoid inappropriate words; this would have the capacity to generate 160,000 unique codes. The draft scheme highlighted that the BQ would be valuable for physicians and nursing staff, pharmacists, regulatory authorities, health authorities and patients.
The Executive Summary of the 59th INN Consultation held 14–16 October 2014 provides feedback from stakeholders on the draft BQ scheme [9]. Over 100 comments were received from a mix of stakeholders, with opinions being expressed both for and against the proposal. Overall it appeared that two-thirds of commentators including those in industry, academics and patient groups expressed some level of agreement. Pharmacist associations were noted as generally not being in favour. The Summary further noted that negative comments appeared to arise from misunderstandings, with a particular area of confusion being the role of the BQ.
A revised draft of the BQ proposal was posted on the WHO/INN website in June 2015 [10]. The new draft emphasises that the BQ is to be applied to all biological active substances that can be assigned INN and not just to biosimilars. A major change in the revised scheme is that the original proposal to apply the BQ to a specific manufacturing site has been withdrawn and instead the BQ applicant ‘is foreseen to be a corporate body that makes or manages the making of a single substance by a single process controlled by the same quality substance globally’. Thus, an active substance manufactured at more than one site (by a single process controlled by the same quality substance globally) will have the same BQ as long as the substance from the different sites is deemed comparable by the regulatory authority(ies) involved. In the event that they are not deemed comparable, a separate BQ would be applied, but the two BQs would be hyperlinked in the WHO BQ database. The nature of the code – a random four-letter code – remains the same, whilst useful tables illustrating how a hypothetical BQ would apply are provided in the updated proposal.
In summary, this proposal would be an entirely new global nomenclature scheme for biological active substances. Will it be used, and by whom? Does it have advantages over existing nomenclature and traceability systems including the INN, the brand name/trade name, the company name, lot or batch numbers, and in the US the national drug code? Whilst there has been good support for the BQ, not all organizations are in favour of it [11]. WHO held a Biological Qualifier Regulatory Forum on 30 March 2015 and a Front Page Meeting with INN Stakeholders on 16 June 2015. Clearly, there is continuing debate over the need for and the format of a novel global BQ.
The INN process is organized and administered at WHO by the INN Secretariat; the INN Expert Group comprises an international group of experts in drugs and drug nomenclature and is responsible for the assignment of INN and the development of INN policy.
Acknowledgements
The author is grateful to Dr Robin Thorpe for critical reading of the manuscript.
Disclaimer
Any views presented in this paper are those of the author only and do not necessarily reflect the position of WHO, the INN Secretariat or the INN Expert Group.
Competing interest: None.
Provenance and peer review: Commissioned; externally peer reviewed.
References 1. World Health Organization. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. 2013 [homepage on the Internet]. 2013 Oct 29 [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/StemBook_2013_Final.pdf 2. World Health Organization. International Nonproprietary Names (INN) for biological and biotechnological substances (a review) [homepage on the Internet]. 2014 Dec 11 [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/BioRev2014.pdf?ua=1 3. World Health Organization. Guidelines on evaluation of similar biotherapeutic products (SBPs) [homepage on the Internet]. 2010 Jun 4 [cited 2015 Jul 2]. Available from: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf 4. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). CHMP/437/04 Rev 1. 23 October 2014. Guideline on similar biological medicinal products [homepage on the Internet]. 2014 Oct 30 [cited 2015 Jul 2]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf 5. 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 6. 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. 7. Dolinar RO, Reilly MS. Biosimilars naming, label transparency and authority of choice – survey findings among European physicians. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):58-62. doi:10.5639/gabij.2014.0302.018 8. World Health Organization. Biological Qualifier. An INN Proposal. Revised draft July 2014 [homepage on the Internet]. 2014 Jul 30 [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/bq_innproposal201407.pdf?ua=1 9. World Health Organization. 59th Consultation on International Nonproprietary Names (INN) for Pharmaceutical Substances. Geneva, 14–16 October, 2014. Executive summary [homepage on the Internet]. 2015 Mar 13 [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/59th_Executive_Summary.pdf?ua=1 10. World Health Organization. Biological Qualifier. An INN Proposal Revised draft June 2015. [homepage on the Internet]. [cited 2015 Jul 2]. Available from: http://www.who.int/medicines/services/inn/bq_innproposal201506.pdf.pdf?ua=1 11. BioPharma. Markets & Regulations. European group criticizes proposed WHO, FDA biosimilar naming schemes. 13 Apr 2015. [cited 2015 Jul 2]. Available from: http://www.biopharma-reporter.com/Markets-Regulations/European-group-criticizes-proposed-WHO-FDA-biosimilar-naming-schemes
Author: James S Robertson, PhD, Member of the WHO INN Expert Group
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Abstract: The first recognized and trusted generic drugs were launched in France in 1995, at the same time that the Prime Minister Alain Juppé introduced his new plan on Retirement and Social Security. It has taken 20 years for generic drugs to become integrated into the pharmacy community, and for acceptance to be reached by pharmacists, physicians and patients. The French Health Insurance Agency can potentially save close to two billion Euros per year, given its continued investment in therapeutic innovation. In the future, biosimilars will not be generics, but their market may, in years to come, play a role similar to that of the generics market.
Submitted: 7 April 2015; Revised: 22 May 2015; Accepted: 24 May 2015; Published online first: 8 June 2015
Introduction
The official pharmaceutical market for prescription products is worth around Euros 28 billion, and generic drugs represent Euros 6 billion, accounting for 22% of the market and around 70% of all substitution products registered to the Generics Repertory.
Definition of a generic drug
Within patent legislation, the term ‘generic drug’ refers to a copy of a listed brand-name drug, whose patent and patent term restoration have expired, making the drug publically usable by any drug manufacturer.
In France, the first legal definition of a generic drug was given by France’s National Office of Fair Trading (Commission de la Concurrence) on 21 May 1981:
‘a generic drug is defined as any copy of an original drug, whose production and marketing are made possible after the expiration of the original drug patent, hence becoming part of the public domain once the legal protection period comes to term. The term ‘generics’ includes drugs sold under a brand name or an invented name, as well as drugs sold under an internationally common or chemically-descriptive non-proprietary name, which must be accompanied by a brand or manufacturer name.’
It was subsequently necessary to define the content and quality of generic drugs more precisely. The order 96–345 of 24 April 1996 introduced the first technical legal definition of a generic drug [1], which corresponds to the European definition as cited in the minutes of the Executive Council of December 1986.
This definition was later used in 1998 in a judgment of the Court of Justice of the European Communities [2], highlighting the unique property of the qualitative and quantitative composition of active principles as well as of the bioequivalence between the original (brand-name) drug and the generic drug. This same definition was further modified in 2004, following a ruling of the Court of Justice of the European Communities [3], this time highlighting the bioequivalence criterion requirement.
In 2005, another legal ruling [4] permitted any drug containing the same active fraction as the brand-name drug (from a therapeutic standpoint) to benefit from a shortened registration procedure. The excipient can, on the other hand, be a different salt, isomer or ester. By focusing on therapeutic effect rather than on molecular structure, the notion of a generic drug became closer to the notion of therapeutic equivalence; that is, with the same qualitative and quantitative effects. The technical rationale behind generic drugs now focused on in vivo results for quality assessment rather than on galenic form for oral administration. On the basis of these legal rulings and the above logic, the Directive 2004/27/CE adopted the extensive definition of a ‘generic drug’, hence, replacing the vague term ‘similar drug’ [5].
This definition is due to be incorporated into the Public Health Code in the section L.5121–1,5°a) [6]. Within this framework, the sanitary authorities will require additional and sufficient proof of the safety and efficacy of a generic drug if its active principle is not identical in pharmaceutical or salt form to the brand-name drug. In France, a Repertory of Generic Groups [7] has been established to allow for easy identification of generics as substitutes to brand-name drugs.
The 1999 Health Insurance Funding Act introduced the notion of right of substitution for pharmacists, as long as the prescriber has not excluded this possibility. In 2008, the prescription of International Nonproprietary Name (INN) drugs became mandatory for all branded pharmaceutical products [8].
A country reluctant to switch to generics
Compared with other high-income countries, e.g. Germany, the UK and the US, France is lagging behind in its introduction of generics to the pharmaceutical market. The first mention of the term ‘generic’ was in 1995 in the Prime Minister’s Health Plan to reduce public health spending:
‘The generic version of a reference branded product is defined as having the same qualitative and quantitative composition in terms of active principles, the same pharmaceutical form and whose bioequivalence with the reference product is demonstrated by relevant studies of bioavailability.’
At that time, pharmaceutical manufacturers considered generic drugs a potential threat to their products and doubted their economic benefit, given the high cost of drugs at the time; the medical profession, with lack of knowledge of health economics, were dismissive of pharmaceutical manufacturers, who they perceived to be rushing into the market to duplicate and exploit the discoveries of others.
Physicians believed that they were still in control of treatment, with the autonomy to choose the molecule, brand and manufacturer of a drug. Pharmacists were strongly opposed to the idea of cheaper drugs, because of the difficulty of stocking larger quantities of drugs, even if greater quantities should be sold, because they would be less profitable. The public, in the meantime, were completely unaware of developments in this area and what was at stake.
The French generics pharmaceutical company Laboratoire Français de Produits Génériques was established in the 1980s but was boycotted by pharmacist unions and by its parent pharmaceutical company Clin-Midy. This boycott of generics was condemned in July 1981 by the French Ministers of Finance, René Monory and after Jacques Delors.
In reality, generic drugs were available before 1995, and were copies of drugs whose patents had expired and which therefore benefited from a simplified registration procedure. Often, those were copies of the original molecule manufactured by the same brand as the original drug once the patent had expired, making them indistinguishable from their brand-name counterparts to both the public and health professionals. These generics were promoted among prescribers and sold under the same brand name by new pharmaceutical companies specially created to sell these generics (at a price lower, about 20%), and not well recognized by major companies at prices slightly lower than the brand-name drug prices. Biogalenique Laboratory was one of these new companies and was controlled secretly by Pierre Fabre Laboratories.
The history of generic drugs in France
Generic drugs first gained real recognition with the announcement of the Retirement and Social Security plan by Prime Minister Alain Juppé on 15 November 1995.
In 1994, Mr Jean Marmot, magistrate at the audit office, became the first President of the Economic Committee for Healthcare Products, the interdepartmental government body in charge of regulating the prices of reimbursable drugs. A fervent supporter of generics, he inspired the provisions of Prime Minister Juppé’s plan before they were even set out, and drew up and signed agreements with pharmaceutical manufacturers to sell their products at 70% of the cost of brand-name drugs, using the INN in exchange for more favourable conditions for accessing the pharmaceutical market for their innovative products. This gave pharmaceutical manufacturers the freedom to fix the prices of their own new products.
This type of agreement ultimately benefitted the public accounts, but also became popular among innovative pharmaceutical manufacturers, without perturbing their brand image, who initiated acquisitions, began to develop a range of generic drugs, or both, often through affiliated companies dedicated to this task. In 1995, for example, Rhône-Poulenc Rorer acquired Biogalenique, later renamed ‘Rhône-Poulenc Génériques’. Sanofi also established a generics department, which subsequently became Ratiopharm. Although the price-agreement policy was instrumental to the emergence of generics, a fundamental element of the market was missing: demand.
The second act was in 1999, when the Chairman of the pharmaceutical unions federation of France (Fédération des Syndicats Pharmaceutiques de France), Mr Bernard Capdeville began campaigning for the ‘right of substitution’. Despite opposition from physicians, and, especially, general practitioners, he lobbied the medical profession and public authorities to support the principle of equal profit margins between generic and brand-name drugs.
Approval of this new measure ensured by all pharmacist unions reduced the potential economic gain of generics for public authorities. The authorities subsequently backed down admitting that they could not move forward without pharmacist support, and agreed to relax the system of ‘smoothed decreasing profit margin’ established in 1990.
In order to calm the strong medical opposition, public authorities restricted the ‘right of substitution’ to ‘generics groups’; that is, the ensemble composed of a brand-name drug and its generics registered by the Drug Agency. Then, all the generics groups were brought under the umbrella of the ‘Generics Repertory’, a unique reference directory used by western countries, which contains more than 1,000 generics groups relating to 370 molecules [9]. In France alone, a generic drug cannot be substituted unless it has been registered with the Generics Repertory. Therefore, even today, high-volume drugs such as paracetamol or aspirin whose generics have existed for a long time, are excluded from the substitution system under the pretext that a unique identifiable brand-name drug able to constitute a generic drug group no longer exists.
At this time, the strategic choice of betting on pharmacists paid off slowly but surely. The generics market took off but with rates of substitution well under the expected 35%. Physicians and patients still remained reluctant to switch to generics, and exercised their right to access original brand-name drugs, with no penalty.
The third act was in June 2002, when the newly constituted government, with Professor Jean-François Mattei as the new Minister of Health, gave in to the demands of the three main physicians unions (MG France, Syndicats des Médecins Libéraux (SML) and Confédération des Syndicats Médicaux de France (CSMF)) to increase the cost of a general practitioner’s medical consultation at Euros 20. Underpinning this was a focus on generics, with physicians requested to stop their active counter propaganda against generics. At the same time, the public authorities significantly increased the discounts agreed by manufacturers to pharmacists and further decreased the smoothed decreasing profit margin. Now it became more profitable for a pharmacist to sell a generic drug than a brand-name drug. The market finally took off and the expected substitution target of 35% was attained.
The fourth act was when the generic drug system was transferred from the government to the Health Insurance System in 2010 introducing innovative new changes in relation to generic drugs. First, an agreement was reached between the French National Health Insurance Agency and pharmacists to increase the substitution target to 80% for 20 of most prescribed molecules on the market, with advantages for pharmacists.
The second change, and one that had the biggest impact of all, was initially implemented by the Regional Health Insurance Agency of the ‘Alpes Maritimes’ region, during spring 2011. Only patients accepting substitution drugs (generics) were permitted to receive an advance on costs. The idea of a ‘third-party payer in exchange for generics’ was the first time that patients considering using generic drugs could benefit financially. This was also effective at the treasury level for accounting reasons, because if the patients wanted the brand-name drug they had to pay it and were reimbursed only three to four weeks after.
This initiative was quickly rolled out to other territories, covering all of France by June 2012: at this point, the plan included all pharmacists, all medical prescriptions, all medical products, and nearly all patients. The possibility of a ‘non-substitutable’ mention for the prescriber remained open but it had to be handwritten and was only applicable per product and not for the entire prescription.
The fifth act was between 2009 and 2012, when two important developments took place. First the French National Health Insurance Agency intervened to fix the depletion of the drug Repertory resulting from the expiration of drug patents for the most commonly used molecules, making them fall in the public domain.
A shift in prescribing was then observed to-wards products of the same therapeutic class as brand-name drugs but which were not generics. This move away from brand-name drugs, which blocked the substitution system, was a result of the weak promotion of generics in favour of competitors’ ‘non-repertory’ products still patented and actively promoted. This observation led to the decision to include prescribing in the scope of the Generics Repertory in the new performance-related pay system established in 2009 as part of the French general practitioner’s performance-related pay contract, and was presented to physicians willing to sign up.
The French National Health Insurance Agency requested general practitioners to meet certain objectives (related to increased prescribing of substitution products for certain classes of commonly used drugs), which, if achieved, would be paid in the form of bonuses. This plan was a great success and was implemented with reinforced objectives, to be later added to the medical agreement under the name ‘Contract for Improvement of Individual Practices’. It was signed by 75,000 physicians and anticipated to make each physician earn up to Euros 5,000 more per year, see Figure 1.
A similar performance-related pay system was implemented for pharmacists through a conventional agreement on 4 May 2012. It included an explicit list of about 30 generic drug groups and set target substitution rates, which varied according to the molecule, and depended on their nature, time spent on the market, and mean age of the patient. Target rates varied between 42% for osteoporosis drugs and 95% for pravastatin. At this stage, the projected goal was a global rate of substitution of 85% by the end of 2012.
Coupled with the reinforcement of the ‘third-party payer in exchange for generics’ system mentioned above, this performance-related pay system was successful; reaching a 12% higher substitution from June 2012, see Figure 2. The rates stabilized at around 70% in cost and around 80% in units, with no observed decrease.
Finally, the sixth act was a ruling on the Bertrand Law (from 29 December 2011), which came into effect on 1 January 2015: the generalization of INN prescriptions recommended by the World Health Organization. This provision further promoted the substitution movement, as long as prescribers possessed the correct prescription softwares, of which 39 were certified by the French National Authority for Health.
Historical lessons learned
The establishment and acceptance of generic drugs in France has been a protracted and cumbersome process compared with other countries, which have had a better take-up of generic drugs.
In countries with multiple insurance systems, either private (the US) or public (Germany and The Netherlands), the initiative to implement generics has always come from the insurers, with efforts primarily focused on convincing patients to accept prescribed generic drugs. The simplest system, known as the ‘reference price’ system, was introduced in Germany and The Netherlands in the late 1980s. This system took the price of generic drugs as the basis for reimbursing the cost of drugs, regardless of whether the patient chose a brand-name drug or the generic drug. A harsher version of this same system was implemented in the US by Managed Care organizations, and involved only reimbursing the cost of generic drugs listed in the formulary for reimbursement; a patient wishing to purchase a brand-name drug would be personally liable for the cost.
In one way or another, the policies that have succeeded in encouraging take-up of generic drugs by the patients are based on demand (prompted or forced), which have led to an immediate acceptance of a generics offer, later regulated by public authorities for clarification and organization purposes.
In France, with its centrally administered economy and mistrust of the market’s inner workings, a policy of ‘offer’ was initially devised, with a subsequent re-worked policy of ‘demand’ only when the former failed to produce results. The government had initially wanted to protect the patient, and, after the failure of the policy between the government and pharmaceutical manufacturers, the French Health Insurance Agency intervened to stimulate demand by offering financial incentives for health professionals and patients. This two-step process would have been fine, had it not taken 10 years to happen.
One of the reasons for this reverse logic is the persistence of an administrative system to fix the price of generics. Public authorities have precluded any system of competition, including between manufacturers, by fixing administrative prices for generic drugs (same prices for all generics belonging to the same group). In other countries, it is rather the competition between manufacturers that is responsible for price reductions, often greater than those obtained through the French public regulation system. This competition also leads to the emergence of global leaders and, in turn, to the delocalization of production sites in low cost locations.
Opening the generics market up to competition is still being debated today, and it has been loudly suggested that public authorities open the call for tender to entrust some pharmaceuticals with the entire market, e.g. statins, proton pump inhibitors, giving the best guarantees, as was the case in Germany and in The Netherlands, reducing prices drastically. The French Health Insurance fund prefers a system of well-advised buyers by making sure that public funds and pharmacists split the profits, a model similar to the UK system.
Ironically, the story of generics in itself demonstrates the paradox that financial incentives do produce results when the main health actors have little interest for health economic questions. Health professionals only agreed to the objective of efficacy because they were offered direct profits. Also patients, forced to switch to generics, responded positively to the ‘third-party payer in exchange for generics’ plan beyond expectations. Generics have therefore highlighted a contradiction in the French healthcare system, displaying an obvious aversion for economic issues while resorting to financial incentives to stimulate the generics market.
The poor handling of the generics issue, particularly in the context of drug dispensing, has been evident through Internet blogs and social networks, where the public has vented its frustration, often with a misinformed view of the subject, and with access to partial information. Such frustration is easily understandable in view of the obvious disregard for the patient’s best interests during implementation of the first generics policy. During that time, health authorities were focused on imposing generics on the physician community against their will via pharmacist arm-twisting, and patients were feeling left out in terms of financial benefits.
Health is priceless, but has its costs. The proclamation of experts that cheaper treatments are as efficient as costly treatments are not ringing true with French consumers, as they are used to intuitively factoring in price as a quality indicator. The questioning of pharmaceutical quality and similarity of generics has become even more widespread following the publication of a heated report from the Academy of Medicine [10]. Its high-level political, scientific and suspicious economic discourse has left the public with mixed feelings about generics.
Will biosimilars follow the success of generics?
The future of generics in France and in developed countries is rather predictable. Generic drugs are about to become everyday drugs prescribed for almost all common diseases in all therapeutic domains. In most cases of common diseases, except for the thyroid disease, the current prescribed drugs are generics, see Table 1.
This situation is likely to last, at least for the next decade or two, until an important pharmaceutical innovation comes along to change the market share ranking of commonly sold molecules in these therapeutic areas. On the other hand, the flood of new generics is bound to dry up as a result of fewer innovations for commonly sold products in the past 20 years (duration of a patent). Therefore, the generics market seems stable for now and the model may spread to other countries where prices will yield under the pressure of payers either through administrative channels (as in western countries) or through competition.
Pharmaceutical research has long shifted from the big domains of traditional common diseases to the exploration of diseases such as cancers, autoimmune diseases and genetic diseases. It is here that true theoretical breakthroughs are needed, with new technological paradigms, e.g. targeted therapy, gene therapy, cell therapy, and that pharmaceutical manufacturers are not afraid to invest money in these. This active investment in innovative technologies is what shapes the market today. Among the top 20 products in the pharmaceutical market, two-thirds are recent high biotechnology products: monoclonal antibodies, antitumour necrosis factor, recombinant insulin, haematopoietic growth factors, granulocyte colony-stimulating factor, and erythropoietins, in addition to targeted anticancer therapies and, more recently, antiviruses.
The question is will this new costly innovation wave, which started in the 1980s and developed over a 20-year period, generate a new wave of generics when patents start to expire? No, it will not. These big molecules, copies of recombinant proteins with lost patents, are difficult to produce industrially from genetically modified live cells and cannot be compared with generics; either legally, medically or economically. Production conditions are such that, in 2005, the European Medicines Agency requested clinical efficacy trials to be conducted for ‘biosimilar’ drugs [11], contrary to generics, in which only a proof of pharmaceutical bioequivalence is necessary. European regulations state that, under certain circumstances, if the reference biological drug is prescribed in several indications, the biosimilar can be used for these same indications, even if it has been tested for only one of them. These products will create a new market for biosimilars, characterized by very different operational rules and by highly specialized high-tech pharmaceuticals. Biosimilars will not be generics, but their market may, in the coming years, play a role similar to the generics market.
Finally, the subject of small complex chemical molecules has been discussed internationally and also at the European level since 2009. These molecules are difficult to manufacture and, even though they may fit the definition of generic drugs, the generics market approach cannot be applied here. These molecules are commonly referred to as non-biological complex drugs [12]. As with biosimilar drugs, these few molecules are quite complex with iron sucrose (not registered in the Generics Repertory) being the main representative member of this class of active principles [13]. They are complex because the structure of these molecules depends partly on manufacturing conditions and is, therefore, specific to each manufacturer. This type of molecule could benefit from tailored registration regulations with appropriate risk-management plans.
Conclusion
With sustained financial means from society and from the French Health Insurance Agency, the savings generated by the use of generic drugs are ensuring better and cheaper access to costly therapeutic innovations for patients. The implementation of generics must hence be perceived as a sign of therapeutic progress and not as an obstacle. It is, therefore, paramount that health professionals unconditionally support all policies in favour of generics from now on, particularly because physicians are the main conduits of information for patients.
Acknowledgement
The authors wish to thank the English editing support provided by Ms Maysoon Delahunty, GaBI Journal Editor, for this manuscript.
Competing interest: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
Co-author
Jessica Nasica-Labouze, PhD, Laboratoire de Biochimie Théorique, IBPC, CNRS, Paris, France & International School for Advanced Studies (SISSA), Trieste, Italy
References 1. Journal Officiel de la République Française du 25 avril 1996 N° 98 page 6311-l’article 23 établit une définition des médicaments génériques et dispose que la publicité qui leur est relative mentionne leur nature de spécialités génériques. 2. CJCE, 3 décembre 1998, AFF, C368-396, Generics et al. 3. CJCE, 29 avril 2004, AFF, C-106/01, Novartis. 4. CJCE, 20 janvier 2005, AFF, C-74/03, Smithkline Beecham. 5. Médicaments génériques et droit de la concurrence, Evgéniya Petrova. Thèse de doctorat en droit des affaires- présentée et soutenue publiquement le 17 juillet 2009 – Université Jean Moulin Lyon 3 – école doctorale de droit. Available from: http://www.acadpharm.org/dos_public/RAPPORT_GEnEriques_VF_2012.12.21.pdf 6. Journal Officiel de la République Française du 27 février 2007 – Loi 2007-248 du 26 février 2007 portant diverses dispositions d’adaptation au droit communautaire dans le domaine du médicament. 7. Article L5121-10 et R.5121-8 du Code de la Santé Publique. Available from:
http://ansm.sante.fr/var/ansm_site/storage/original/application/52e5390a6f9e8580d73bca744a516503.pdf 8. Journal Officiel de la République Française du 26 décembre 2001- Loi n° 2001-1246 du 21 décembre 2001, art. 19-1 (article L5125-23 du Code de Santé Publique). 9. Agence nationale de sécurité du médicament et des produits de santé. Répertoire des Groupes Génériques. 10 avril 2013. 10. Menkes JC. Place des génériques dans la prescription. Académie nationale de Medicine. février 2012. 11. 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. EMEA. 2006 [homepage on the Internet]. [cited 2015 May 22]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003920.pdf 12. Schellekens H, Klinger E, Mühlebach S, Brin JF, Storm G, Crommelin DJ. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol. 2011;59(1):176-83. 13. Rottembourg J, Kadri A, Leonard E, Dansaert A, Lafuma A. Do two intravenous iron sucrose preparations have the same efficacy? Nephrol Dial Transplant. 2011;26(10):3262-7.
Author for correspondence: Professor Jacques Rottembourg, MD, Department of Nephrology, Hôpital de la Pitié, 83 Boulevard de l’Hôpital, FR-75013 Paris, France
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Author byline as per print journal: Brian Godman, BSc, PhD; Michael Wilcock, MPharm; Andrew Martin, MPharm; Scott Bryson, MSc, MPH; Christoph Baumgärtel, MD; Tomasz Bochenek, MD, MPH, PhD; Winne de Bruyn, BSc; Ljiljana Sović Brkičić, MPharm; Marco D’Agata, MSc; Antra Fogele, PhD; Anna Coma Fusté, MSc; Jessica Fraeyman, PhD; Jurij Fürst, MD; Kristina Garuoliene, MD, PhD; Harald Herholz, MD, MPH; Mikael Hoff mann, MD, PhD; Sisira Jayathissa, MBBS, MMedSc (Clin Epi), MD, FRCP (Lond, Edin), FRACP, FAFPHM, FNZCPHM, DClinEpi, DOPH, DHSM, MBS; Hye-Young Kwon, BPharm, MPH, PhD; Irene Langner, MA; Marija Kalaba, MD; Eva Andersén Karlsson, MD, PhD; Ott Laius, PhD; Vanda Markovic-Pekovic, PhD; Einar Magnusson, MD; Stuart McTaggart, MSc; Scott Metcalfe, MBChB, DComH, FAFPHM (RACP), FNZCPHM; Hanne Bak Pedersen, MD; Jutta Piessnegger, PhD; Anne Marthe Ringerud, MPharm; Gisbert W Selke, BSc; Catherine Sermet, MD; Krijn Schiffers, BSc; Peter Skiold, MSc; Juraj Slabý, MD; Dominik Tomek, Pharm Dr, PhD, MPH; Anita Viksna, PhD; Agnes Vitry, PhD; Corinne Zara, MSc; Rickard E Malmström, MD, PhD
Introduction: The manufacturer of pregabalin has a second use patent covering prescribing for neuropathic pain – its principal indication. The manufacturer has threatened legal action in the UK if generic pregabalin rather than Lyrica is prescribed for this indication. No problems exist for practitioners who prescribe pregabalin for epilepsy or generalized anxiety disorder. This has serious implications for health authorities. In Germany, however, historically generics can be legally prescribed for any approved indication once one indication loses its patent. Aim: To establish the current situation with pregabalin among health authorities principally from European countries. Methods: Personnel from 33 regional and national health authorities mainly from Europe, and nine from universities across Europe working as advisers to health authorities or with insight into their activities, were surveyed regarding four specific questions via email to shed light on the current situation with Lyrica and pregabalin in their country. The information collated from each country was subsequently checked for accuracy with each co-author by email and face-to-face contact, and collated into five tables. Results: The scenarios ranged from extending the patent life of Lyrica, e.g. France, endorsing the prescribing of Lyrica for neuropathic pain at the same price as the generic drug, e.g. Catalonia and South Korea, and current prescribing of pregabalin for all indications, e.g. Germany and Serbia. Little activity has taken place in European countries in which generic pregabalin is not yet reimbursed. Conclusion: The availability of generic pregabalin has prompted a number of different activities to be undertaken among the 33 countries and regions surveyed. The situation in Serbia and the historic situation in Germany provide examples of ways to maximize savings once a product loses its patent for at least one indication.
Submitted: 27 March 2015; Revised: 11 June 2015; Accepted: 24 August 2015; Published online first: 7 September 2015
Introduction
The increased use of generic medicines is essential to sustain healthcare systems given the ever-increasing pressure on resources [1–4]. Prices of generic drugs are as low as 2–10% of pre-patent loss prices in some countries [5–7]. Consequently, increased use of generic drugs can generate substantial savings, which can be redirected into funding new valued high-priced medicines [2, 5–12], which is especially important for countries struggling to fund these medicines. A number of strategies globally have been initiated to encourage prescribing and dispensing of generic drugs rather than the originator (brand-name) drug, as well as patented products in a class in which all medicines are seen as essentially similar at therapeutically equivalent doses [4, 8–12].
Increasing use of generic drugs does not appear to compromise care, and many studies have reported little or no difference in outcomes across a range of products and classes [13–18]. In Europe, only generic drugs produced in accordance with the European Medicines Agency’s strict guidelines and definitions [19] are granted marketing authorization.
Well-known and agreed exceptions to generics prescribing or substitution include lithium, theophyllines, some anti-epileptic drugs, modified release preparations and immunosuppressants. In these cases, brand-name prescribing is endorsed [20–23]. Agreed exceptions to generics prescribing, including medicines to treat epilepsy and prevent organ rejection, also exist in Germany and Sweden [6, 24].
A new emerging problem, however, has come to the fore in recent years, concerning the expiry of patents for medicines that have patents for more than one indication, and the threat of legal action by the manufacturer of the originator drug against physicians. This situation occurred recently in the case of pregabalin for the treatment of epilepsy and generalized anxiety disorder (GAD) when the basic patent for pregabalin expired in July 2014 in a number of European countries. The patent for its second medical use, protecting the originator drug Lyrica’s use in treating neuropathic pain, extends to July 2017 in Europe [25, 26]. In the UK, this resulted in the manufacturer of the originator drug (Lyrica) claiming patent infringement and warning doctors not to prescribe the generic drug pregabalin for neuropathic pain [26, 27]. As far as we are aware, this is the first time this has happened, and has serious implications for health authorities.
Prior to this, the originator manufacturer of Lyrica had been fined heavily for promoting gabapentin (prelude to pregabalin) off label for the treatment of neuropathic pain [28–31], although it is now recommended for this indication [32]. In addition, there have been concerns with the methodological limitation of some of the studies of pregabalin in neuropathic pain [33–35]. Pregabalin, for example, is currently not listed in the ‘Wise List’ of Stockholm Metropolitan Healthcare Region because of efficacy and safety concerns compared with other treatments for these conditions [36]. However, there are increasing concerns with the implications of the activities of second use patents with Lyrica [26, 37].
In this paper, historical developments in Germany and the UK relating to this case are examined. Personnel from regional and national health authorities from principally across Europe, and advisers to health authorities working in universities, were then surveyed to ascertain the current situation with pregabalin in their country and to determine the best strategy for maximizing savings for countries once a product loses its patent for any indication.
United Kingdom
In the UK, the international non-proprietary name (INN) prescribing rate is over 80%, and up to 98–99% of non-contentious generic drugs, such as proton pump inhibitors, renin-angiotensin inhibitors and statins, with pharmacists not permitted to substitute an originator drug with a generic drug when the originator drug is prescribed [7, 20, 21, 38].
The UK medicines agency recently issued advice on which epilepsy drugs to prescribe by brand name (originator) and which by INN [39]. Pregabalin was considered suitable for INN prescribing [39], which was endorsed by the originator company stating ‘there will be no clinical superiority of the originator branded medicine Lyrica over generic pregabalin’ [25].
The extended patent for neuropathic pain resulted in the originator company writing to all Clinical Commissioning Groups (CCGs) in England and Health Boards in Scotland in November 2014 pointing out that generics of pregabalin were expected to be approved only for GAD and epilepsy indications, and that the prescribing of generic pregabalin for neuropathic pain could represent ‘off-label’ use. This would be considered a patent infringement constituting an unlawful act, with the originator company reserving all legal rights in this regard [25–27].
The wish of generics companies to make generic pregabalin available in the UK across all indications resulted in a court case, with the originator company as claimant and the Actavis group as the principal defendant [26, 40]. The judge in his deliberations, posted on 21 January 2015, granted Actavis the possibility to launch generic pregabalin and again stated that the best way forward was to try to ensure physicians prescribe Lyrica for the treatment of neuropathic pain and pregabalin for other conditions, including epilepsy [40, 41].
The actions of the originator company are unsurprising. In 2013, global sales of Lyrica generated US$4.6 billion for the company [40]. In the UK, sales of Lyrica increased by 53% between 2011 and 2013 to about US$310 million. It is estimated that 54% of prescriptions in September 2014 were for treating pain, of which 44% was for neuropathic pain [40]. In 2014, sales of Lyrica were GBP 250 million (US$390 million) [26].The potential loss in revenue, therefore, would hugely impact company sales – estimated to be GBP 220 million per year (US$340 million) across all indications assuming high INN prescribing rates and generic drug prices rapidly falling by 90% of the price of Lyrica [7, 42].
In an attempt to preserve sales of Lyrica, the originator company has been proactive in lobbying groups in the UK who could influence physician prescribing, such as the Medicine Management groups within CCGs, the Pharmaceutical Services Negotiating Committee, the General Practitioners Committee of the British Medical Association, and the National Health Service [26, 32, 37, 43–45]. For instance, National Health Service (NHS) England in March 2015 issued advice to all CCGs that within electronic prescription systems there should be a notice or advice box stating ‘If treating neuropathic pain, prescribe Lyrica (brand) due to patent protection. For all other indications, prescribe generically’ [45]. The Pharmaceutical Services Negotiating Committee stated to its members they should be aware that the originator company still retains the indication for neuropathic pain. Members were also made aware that following a high court decision, ‘it was agreed by all parties that the generic [drug] producers would write to CCGs to ensure they were aware that the generic [drug] could not be supplied for the patented indication. A CCG or other party that promotes the supply of generic pregabalin for the patented indication risks facing legal action’ [43].
This situation in the UK has important future implications for generics and biosimilars companies across countries, as it may impede the ability of health authorities to fully realize potential savings from generics and biosimilars once the first indication loses its patent, especially if pharmaceutical companies look to extend the number of indications for their new medicines once launched in an attempt to extend the patent life.
Germany
Germany has taken a different approach to the UK. Currently, nine pregabalin generics are available and reimbursed in Germany (up to April 2015), all of which have the indications for epilepsy and anxiety disorders. The situation, however, is now less clear cut as the originator manufacturer, has taken Ratiopharm, Hexal, 1A Pharma, Glenmark and Aliud Pharma and some Sickness Funds (German payers) to court in an attempt to conserve Lyrica sales for neuropathic pain (up to 10 April 2015) [46]. The legal battle is still ongoing. The originator company’s previous strategy to promote Lyrica was to communicate directly with physicians or via KVs (regional doctors’ associations) by letter, making it clear that Lyrica was the only pregabalin licensed for neuropathic pain [47]. However, these communications were largely dismissed by KVs because the focus was on legal rather than medical issues, and the KVs continued to advise physicians to reach targets of generics prescribing of at least 85%. In addition, the Social Code Book V (SGB V), which is decisive for Sickness Funds, stated in paragraph 129 that generics substitution is possible wherever at least one indication matches [48–50].
The contrast between the situation in the UK and the situation in Germany, and the implications for potential savings when other pharmaceutical products lose their patents for some but not all indications, has led health authorities, across Europe, to review the current status of pregabalin in other countries in order to refine their own strategies if possible.
Aim of study
A qualitative study was undertaken to ascertain the current situation between generic pregabalin and Lyrica among health authorities principally from across Europe. This included a range of Central, Eastern and Western European countries with different epidemiology and funding of health care, as well as policies to enhance the prescribing of generics. This builds on the situation Germany and the UK, and is in line with current recommendations for conducting cross-national research projects [51]. The aim was to maximize future savings for countries once a product loses its patent for any indication.
Materials and methods
Personnel from 33 regional and national health authorities mainly from across Europe, and personnel from nine universities working closely as advisers to health authorities or with insight into health authority activities, were contacted by email to provide answers to the following four questions (up to April 2015):
1. Are you aware of any similar examples to the situation of pregabalin and Lyrica in the UK from other pharmaceutical companies for small molecules once the patent has been lost (biosimilars are a different issue)? If so, what were these and how were they handled (if at all).
2. Was Lyrica reimbursed in your country? If yes, for what indications?
3. Has generic pregabalin been launched in your country/about to be launched? If yes what date (month) and indications?
4. Has the originator company issued a letter to healthcare professionals in your country similar to the letter issued to CCGs in the UK? If yes, what actions (if any) are being taken?
This was supplemented with knowledge from other high-income countries taking different approaches to the availability of generic pregabalin to potentially provide additional examples.
All health authority personnel are involved with either pricing and reimbursement decisions, decisions concerning funding or monitoring the use of medicines, or both, including generics, in their countries and regions. Consequently, it was felt that they would have the most insight into the current situation concerning pregabalin and Lyrica in their countries and regions. European countries included those from Central, Eastern and Western Europe to ensure legitimacy with the findings. Personnel from regions in The Netherlands, Sweden and the UK were also included, as healthcare budgets in these countries are devolved downwards.
The written information supplied by the co-authors and others for each of the questions for each country was collated and summarized by the corresponding author. The summarized information was subsequently checked via email and face-to-face contact with the relevant co-author(s) to ensure the accuracy of the summarized information. The information supplied was subsequently summarized into five categories to improve the interpretation of the findings and the implications for the future, building on the situation in England and Germany.
The five categories included:
Countries in which Lyrica was never reimbursed; consequently generic pregabalin is less of an issue for the originator company, see Table 1.
Countries in which the patent life for Lyrica has been extended, negating the threat from generic pregabalin until all three indications have lost their patent, see Appendix 1.
Countries in which generic pregabalin is currently not reimbursed and the future situation regarding generic pregabalin is unknown, see Appendix 2.
Countries in which generic pregabalin is currently not reimbursed; however, the country is likely to follow the example of either the UK and restrict the prescribing of pregabalin for neuropathic pain, alternatively reimburse pregabalin across all indications, see Table 2.
Countries in which pregabalin is available and reimbursed, see Table 3.
Potential or actual demand-side measures among the health authorities were not broken down into the ‘four Es’: education, engineering, economics and enforcement, as in our previous paper on generic clopidogrel [52]. This is because pregabalin may not be available and reimbursed across Europe and the other chosen countries.
This information was supplemented with a limited literature search for further information about generics generally, pregabalin and the activities of the originator company, including recent court cases, as well as relevant papers known to the co-authors. A similar methodological approach was used when reviewing health authority activities when generic clopidogrel became available [52].
Results
The results of the survey revealed that respondents were typically unaware of similar examples to pregabalin and Lyrica in their countries. For example, generic clopidogrel was reimbursed and endorsed by health authority personnel from across Europe despite generic clopidogrel not including all licensed indications at launch [52]. The main exception was Lithuania, see Table 2, with Glivec and generic imatinib.
The current situation for Lyrica and generic pregabalin among health authorities and health insurance companies across Europe and other selected countries is included in Tables 1–3 as well as Appendices 1 and 2. This also includes additional activities in Scotland.
Discussion
In this paper, we have described the situation across Europe following the launch or imminent launch and reimbursement of generic pregabalin. We were not surprised by the activities of the originator company in the UK in view of the current high levels of INN prescribing, no clinical issues with patients being switched between generic pregabalin or Lyrica across indications, and the high sales of Lyrica globally and in the UK [7, 21, 25, 39, 40, 65].
The threat of legal action against physicians taught to prescribe generically is a major concern among health authorities already struggling to fund increased volumes and new high-priced medicines within available budgets [66]. It also raises issues about off-label prescribing generally and pharmacists checking the use of medication with every patient [37]. Moreover, it would seem that this is the first time that an originator company has threatened court cases against physicians in an extended patent use situation. Previous examples can be found in some countries such as Lithuania, see Table 2; however, no coordinated approach has been taken across countries. These concerns are exacerbated if such activities make European markets unattractive for generics companies, thereby reducing potential savings once a product loses its patent. It is also unhelpful to influence physicians to remember to prescribe different versions of the same molecule for different indications. This could, however, potentially be addressed through increasing use of electronic prescribing support systems. Actions of this nature also impede constructive working relationships between pharmaceutical companies and health service personnel [26].
As seen in Tables 1–3, and Appendices 1 and 2, very different approaches have been taken across countries to the availability of generic pregabalin. In addition to historic approaches taken in Germany, countries such as Czech Republic, Estonia, Republic of Srpska, Bosnia and Herzegovina, and Serbia, see Table 3, are good examples of approaches taken to enhance the prescribing of pregabalin across all indications. The situation in Austria, Poland, and Slovenia will be closely monitored, see Tables 2 and 3, to see if they could also provide examples of potential ways forward to enhance the prescribing of pregabalin across all indications.
Lithuania, Norway and Sweden will also be closely monitored to see whether the originator company will be successful in limiting the prescribing of generic pregabalin in practice to epilepsy and GAD, with Lyrica prescribed and dispensed for neuropathic pain, see Table 2 and Appendix 2. Whether these countries will follow the examples of Bosnia and Herzegovina, Czech Republic, Estonia, Germany (historic), Republic of Srpska Bosnia and Herzegovina, and Serbia, see Table 3, once pregabalin is available and reimbursed remains to be seen.
It is interesting to note the different approaches taken by the originator company to the KVs in Germany initially compared with regional health authorities in England and Health Boards in Scotland, see Table 3. This acknowledges adherence to current stipulations of Social Code Book V serving as an example to other countries worried about such developments in the future, although this is now being challenged.
The introduction of reference priced systems with reimbursement typically just covering the costs of the lowest priced molecule is another way forward, given the extent of internal reference pricing across Europe once multiple sources of a product become available [1]. This works best if originator companies drop their prices to compete; alternatively, the situation is pre-empted as seen for instance in Spain, see Table 3. Alternatively, the price of the originator (brand name) is reduced over time despite the protestations of the originator manufacturer, as seen in South Korea, see Table 3. Difficulties could, potentially occur if reimbursement or substitution for one indication is not recommended, which could occur in Sweden for treatments for epilepsy, see Table 2. This has not currently been a problem in South Korea with multiple pregabalin packs available from different manufacturers, see Table 3. This situation could potentially reduce the attractiveness of the market to generics companies if originator (brand name) manufacturers are happy to drop their prices to those of generics to compete in the knowledge that patients may prefer to stay with the originator if copayments are the same in the absence of any substitution in pharmacies. This is, however, being resisted by the originator company in South Korea, see Table 3.
The developments surrounding Lyrica and generic pregabalin, including potential health authority activities to enhance the prescribing of generic pregabalin, will be closely monitored over the coming months. This will be combined with research on the resultant effect of prescribing and dispensing of pregabalin or Lyrica in practice. The objective will be to provide further guidance to health authorities with their increasing need to maximize savings from generics or biosimilars once they become available for at least one indication. This is essential to maintain the ideals of comprehensive and equitable healthcare especially in Europe.
Conclusion
We have documented different approaches to the availability of generic pregabalin, with countries such as Germany historically having measures in place to enhance the prescribing of generics once at least one indication is off patent. This contrasts with countries such as the UK where generic pregabalin can only be prescribed for some but not all indications. This appreciably reduces potential savings from the availability of generics, which is an increasing concern given ever growing pressures on available resources.
Note from corresponding author
The situation in the UK will now be closely monitored following a recent court judgement post acceptance of the paper overturning the originator company’s patent for pregabalin for pain control; although, this is currently being challenged by the company [67].
Acknowledgements and financial disclosure
We thank Ms Elina Asola for the current information regarding Finland, Ms Laura McCullagh and Ms Susan Spillane for the current information regarding Ireland, and Ms Marie-Camille Lenormand for information regarding France.
All authors wish to thank the English editing support provided by Ms Maysoon Delahunty, GaBI Journal Editor, for this manuscript.
There are no conflicts of interest from any author. However, the majority of authors are employed by ministries of health, health authorities and health insurance companies or are advisers to them. The content of the paper and the conclusions though are those of each author and may not necessarily reflect those of the organization that employs them.
This work was in part supported by grants from the Karolinska Institutet, Sweden.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Brian Godman1,2, BSc, PhD; Michael Wilcock3, MPharm; Andrew Martin4, MPharm; Scott Bryson2,5, MSc, MPH; Christoph Baumgärtel6, MD; Tomasz Bochenek7, MD, MPH, PhD; Winne de Bruyn8, BSc; Ljiljana Sović Brkičić9, MPharm; Marco D’Agata10, MSc; Antra Fogele11, PhD; Anna Coma Fusté12, MSc; Jessica Fraeyman13, PhD; Jurij Fürst14, MD; Kristina Garuoliene15,16, MD, PhD; Harald Herholz17, MD, MPH; Mikael Hoffmann18, MD, PhD; Sisira Jayathissa19, MBBS, MMedSc (Clin Epi), MD, FRCP (Lond, Edin), FRACP, FAFPHM, FNZCPHM, DClinEpi, DOPH, DHSM, MBS; Hye-Young Kwon20,21, BPharm, MPH, PhD; Irene Langner22, MA; Marija Kalaba23, MD; Eva Andersén Karlsson24,25, MD, PhD; Ott Laius26, PhD; Vanda Markovic-Pekovic27,28, PhD; Einar Magnusson29, MD; Stuart McTaggart30, MSc; Scott Metcalfe31, MBChB, DComH, FAFPHM (RACP), FNZCPHM; Hanne Bak Pedersen32, MD; Jutta Piessnegger33, PhD; Anne Marthe Ringerud34, MPharm; Gisbert W Selke22, BSc; Catherine Sermet35, MD; Krijn Schiffers36, BSc; Peter Skiold37, MSc; Juraj Slabý38, MD; Dominik Tomek39, Pharm Dr, PhD, MPH; Anita Viksna11, PhD; Agnes Vitry40, PhD; Corinne Zara12, MSc; Rickard E Malmström41, MD, PhD
1Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden 2Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK 3Head of Prescribing Support Unit, Pharmacy Department, Royal Cornwall Hospitals NHS Trust, Truro, Cornwall TR1 3LJ, UK 4North West Commissioning Support Unit (NWCSU), Salford, Manchester M6 5FW, UK 5NHS Greater Glasgow & Clyde Prescribing Management Group, Glasgow, UK 6AGES Austrian Medicines and Medical Devices Agency and Austrian Federal Office for Safety in Health Care, 5 Traisengasse, AT-1200 Vienna, Austria 7Department of Drug Management, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland 8Utrecht University, Utrecht, The Netherlands 9Croatian Health Insurance Fund, 37 Branimirova, Zagreb, Croatia 10Achmea Zorg and Health, 2 Handelsweg, NL-3707 NH Zeist, The Netherlands 11The National Health Service of Latvia, 31 k-3 Cēsuiela, LV-1012 Riga, Latvia 12Barcelona Health Region, Catalan Health Service, Barcelona, Spain 13Epidemiology and Social Medicine, Research Group Medical Sociology and Health Policy, University of Antwerp, Antwerp, Belgium 14Health Insurance Institute, Ljubljana, Slovenia 15Faculty of Medicine (Department of Pathology, Forensic Medicine and Pharmacology), Vilnius University, Vilnius, Lithuania 16State Medicines Control Agency, Vilnius, Lithuania 17Kassenärztliche Vereinigung Hessen, 15 Georg Voigt Strasse, DE-60325 Frankfurt am Main, Germany 18NEPI – Nätverk för läkemedelsepidemiologi, Sweden 19Department of Medicine, Hutt Valley DHB, Lower Hutt, Wellington, New Zealand 20Institute of Health and Environment, Seoul National University, Seoul, South Korea 21Department of Global Health and Population, Harvard School of Public Health, Boston, MA, USA 22Wissenschaftliches Institut der AOK (WIdO), 31 Rosenthaler Straße, DE-10178 Berlin, Germany 23Republic Institute for Health Insurance, Belgrade, Serbia 24,25Drug and Therapeutics Committee, Unit of Medicine Support, Public Healthcare Services, Stockholm County Council and Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden 26State Agency of Medicines, Tartu, Estonia 27,28Faculty of Medicine, University of Banja Luka, Banja Luka, Republic Srpska, Bosnia and Herzegovina; Ministry of Health and Social Welfare, Banja Luka, Republic Srpska, Bosnia and Herzegovina 29Department of Health Services, Ministry of Health, Reykjavík, Iceland 30Public Health and Intelligence, NHS National Services Scotland, Edinburgh EH12 9EB, UK 31PHARMAC, 40 Mercer Street, Wellington 6011, New Zealand 32Health Technologies and Pharmaceuticals, Division of Health Systems and Public Health, WHO Regional Office for Europe, Copenhagen, Denmark 33Hauptverband der Österreichischen Sozialversicherungsträger, Vienna, Austria 34Section for Reimbursement, Department for Pharmacoeconomics, Norwegian Medicines Agency, 8 Sven Oftedals vei, NO-0950 Oslo, Norway 35IRDES, 10 rue Vauvenargues, FR-75018 Paris, France 36Erasmus University, Rotterdam, The Netherlands 37Dental and Pharmaceuticals Benefits Agency (TLV), PO Box 22520, 7 Flemingatan, SE-10422 Stockholm, Sweden 38State Institute for Drug Control, Czech Republic 39Department of Pharmacology, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia 40Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide SA 5001, Australia 41Department of Medicine Solna, Karolinska Institutet, Clinical Pharmacology Karolinska University Hospital Solna, Stockholm, Sweden
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Author for correspondence: Brian Godman, BSc, PhD, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden
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