Abstract:
How has the European Medicines Agency (EMA) changed its requirements for biosimilars since it first approved biosimilars in 2006? This is the question Dr Martina Weise, Head of Licensing Division at the Federal Institute for Drugs and Medical Devices (BfArM), discussed at the 14th Annual Biosimilar Medicines Group Conference.
Submitted: 1 December 2016; Revised: 8 December 2016; Accepted: 8 December 2016; Published online first: 14 December 2016
The European Union (EU) was the first to establish a legal framework and guidance for biosimilars. The legal framework for approving biosimilars in the EU was established in 2003. This framework means that biosimilars can only be approved centrally via the European Medicines Agency (EMA) and not nationally [1]. The agency first developed guidelines for the approval of biosimilars via an abbreviated registration process during 2005 to 2006, and since then has developed many general and specific guidelines for biosimilars [2]. The initial approach by the agency was science-driven, but with no practical experience a cautious, conservative approach to biosimilars was adopted.
Since those early days EMA has issued new guidelines and updated its existing guidelines based on new evidence and rapid advances in analytical sciences. For example, the sensitivity of mass spectrometry methods to detect peptides has increased rapidly over the past two decades. The detection limit for peptides back in 1990 was only 100 pmol compared to 0.00001 pmol in 2011; representing a 10 million-fold increase in sensitivity in 20 years. The agency has also incorporated learning from both manufacturing process changes and biosimilar product reviews.
In her presentation [3], at the 14th Annual European Biosimilars Group Conference, Dr Martina Weise, Head of Licensing Division at the Federal Institute for Drugs and Medical Devices (BfArM), discussed biosimilars applications reviewed by EMA and the evolving landscape on data requirements to demonstrate biosimilarity in the European Union.
Since EMA started reviewing applications for biosimilars, and up to April 2016, the agency had received 44 marketing autho- rization applications (MAAs). Of these, 13 were still under review and seven had been withdrawn (six for insulin biosimilars and one for an epoetin biosimilar). Up to April 2016 the agency had given a positive opinion for 22 MAAs [of which two were later withdrawn (filgrastim and somatropin)] and a negative opinion for two MAAs (interferon alfa and insulin), see Figure 1.
In May 2016, the infliximab biosimilar Flixabi received approval in the EU [1]. In November 2016, EMA’s Committee for Medicinal Products for Human (CHMP) gave a positive opinion for the teriparatide biosimilars, Terrosa and Movymia, and for the insulin glargine biosimilar Lusunda [4].
Major changes in data requirements, according to Dr Weise, include the choice of the reference product, clearer requirements on quality data, changes in the focus for non-clinical studies, use of a tailored clinical programme, reduced clinical programme, extrapolation and pharmacovigilance.
Reference product
One major change with respect to reference products is that a reference product not authorized in the European Economic Area1 (EEA) may be used for certain clinical and in vivo non-clinical studies if it was authorized based on similar scientific and regulatory standards as those used by EMA and if it is representative of the reference product in the EEA [5]. This is outlined in EMA’s Guideline on similar biological medicinal products (CHMP/437/04 Rev 1. Effective date: 30 April 2015) [2].
The only catch is that applicants have to prove that batches sourced from outside the EEA are representative of the reference medicine authorized in the EEA through an extensive analytical comparison. Bridging data must include a 3-way analytical comparison (structural and functional data) and may include a 3-way pharmacokinetic (PK) and/or pharmacodynamic (PD) comparison.
Requirements for reference products in the EU and US are comparable.
Quality data
No factual changes have been made, but the guidance, which was updated in December 2014 [2], has been made clearer.
Full quality dossier + extensive comparability exercise with the chosen reference product
Use of state-of-the-art, sensitive and orthogonal analytical tools
Amino acid sequence must be the same; small differences in micro-heterogeneous part acceptable with justification
Identify ‘Quality Target Product Profile’ (QTPP) based on characterization of multiple batches of the reference product
Select expression system and adjust manufacturing process to achieve the QTPP
Quality attribute ranges should not be wider than the range of variability of the reference product batches, unless justified
Non-clinical studies
The latest revision to EMA’s Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005 Rev 1) came into effect on 1 July 2015 [2]. The document includes:
Focus on comparative in vitro studies to extensively characterize and compare the function(s) and activity of the molecule
Usually more sensitive to detect differences than in vivo studies
Target binding, e.g. receptors, antigens, enzymes
Signal transduction and functional activity
Risk-based approach for in vivo studies, e.g.
Novel (or not widely used) expression system or excipients
Quality findings of concern or unclear relevance
Tailored clinical programme
According to Dr Weise, the clinical programme for a biosimilar is not intended to show efficacy and safety per se. The endpoints should be sensitive to detect differences in efficacy and may be different from those used in clinical trials with the originator. There has been a clear shift to PD endpoints, examples include:
Magnetic resonance imaging (MRI) endpoint for drugs in multiple sclerosis
Overall response rate for anticancer drugs
Anti-factor Xa (anti-FXa) and anti-FIIa activity for low molecular weight heparin (LMWH)
Absolute neutrophil count (ANC) for granulocyte colony-stimulating factor (G-CSF)
Number of oocytes retrieved for follitropin (IVF)
Glucose infusion rate (in clamp studies) for insulin
Reduced clinical programme
EMA does not require a full clinical dossier for a biosimilar. It is usually possible to carry out one clinical trial in one indication, with the option to extrapolate to other indications of the reference biological.
Clinical trial not needed, if analytical, PK and PD comparisons allow conclusion of similar efficacy and safety and the impurity profile and the nature of excipients of the biosimilar do not give rise to concern
Mentioned in the general guidelines and specifically for insulin and LMWH; planned for filgrastim
Also expected for more complex biologicals with increasing characterizability of their physicochemical and functional properties
Extrapolation
Regarding extrapolation2 of indications for biosimilars, EMA has stated that ‘if clinical similarity can be shown in a key indication, extrapolation of efficacy and safety data to other indication(s) of the reference product may be possible’ under certain conditions [1].
In her presentation, Dr Weise explained that extrapolation:
Should be considered in the light of the totality of data supporting biosimilarity
Changed from ‘situations where extrapolation may be considered’ to ‘situations where additional data may be required’:
If different active sites of the molecule or different receptors involved in different indications
Efficacy and/or safety (immunogenicity) data are not relevant for extrapolated indication(s)
Pharmacovigilance
New pharmacovigilance legislation was adopted by the European Parliament and European Council in December 2010. EMA is responsible for implementing the legislation. As part of its commitments the agency released draft guidance on pharmacovigilance for biologicals in December 2015 for public consultation. This guideline has since been finalized and came into effect in August 2016.
Guideline on good pharmacovigilance practices (GVP)
Product- or Population-Specific Considerations II: Biological medicinal products Effective Date: 16 August 2016 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/08/WC500211728.pdf
The guideline outlines the following:
Risk-management plan obligatory
Needs to be in line with the risk-management plan of the reference product
Deviations in risk-minimization measures or safety monitoring imposed on the reference product must be justified
Encouragement to participate in pharmacoepidemiological studies of the reference product
Ensure product traceability
Product name and batch number should always be recorded
Data from EudraVigilance suggest good identification by brand name
Dr Weise concluded that ‘EMA has shaped biosimilar development globally’, with ‘10 years of safe and effective use of biosimilars in the EU’. Meanwhile the agency is increasingly ‘moving from a science-based concept to a science and experience-based approach’. This, accompanied by the ‘increasing armamentarium and sensitivity of analytical tools allows increased tailoring and reduction of clinical programmes’. Finally, she added that global development is ‘desirable’ but warned that ‘complete alignment of scientific thinking and data requirements may not be achievable’.
1 EEA: European Economic Area, this area includes the 28 EU Member States, plus Iceland, Liechtenstein and Norway.
2 Extrapolation involves extending and applying the data from clinical studies regarding one medical condition to another medical condition.
Disclaimer
The author of the presentation [3] declared that the views and opinions expressed in the presentation were personal views, and may not be understood or quoted as being made on behalf of the CHMP or reflecting the position of the CHMP or any other EMA Committee or Working Party.
Competing interests: None.
Provenance and peer review: Article abstracted based on the presentation of Martina Weise, MD, BfArM, Germany; internally peer reviewed.
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.
This fourth and final GaBI Journal issue of 2016 begins with the paper by Adjunct Professor Pekka Kurki about ‘applying ancient principles in a modern society’ in which he discusses a perspective recently published in our journal from Annese et al. that presented the skeptical views expressed by Italian gastroenterologists concerning extrapolation of indications for infliximab. This paper summarized resistance to extrapolation based on the quote, ‘first do no harm’. In fact, some say Hippocates’ actual quote was, ‘As to diseases, make a habit of two things—to help, or at least to do no harm’. Perhaps another Hippocrates quote is more appropriate, ‘I have clearly recorded this: for one can learn good lessons also from what has been tried but clearly has not succeeded, when it is clear why it has not succeeded. [Hippocrates On Joints, 47. Trans. R. W. Sharples. Science quotes on: Diagnosis (54)]. Both scientific studies and actual clinical experience have shown that the extrapolation that bothers these clinicians has both a solid scientific foundation and extensive and growing clinical and research data yet resistance to it continues. Such resistance is likely to be influenced by the marketing efforts of innovator companies but there are also many other possible reasons, including real concerns for patient safety, distrust of biosimilar manufacturers, regulators, insurers as well as politicians and government bureaucrats. Regardless of the causes those who want to find ways to increase patient accessibility by decreasing the costs of treatment must understand what does and what does not work and to better understand and acknowledge all barriers to the prescribing and use of generics and biosimilars. As the recent UK referendum and US election have shown, ignoring the ‘will of the people’ can have major unwanted consequences. More effective ways must be found to better communicate with, rather than just talk to, all ‘stakeholders’ including the patients who take these medications and the physicians who prescribe and monitor them.
Pharmacists are also important ‘stakeholders’. Professor Philip J Schneider and Mr Michael S Reilly present data gathered using a questionnaire designed and administered by the Alliance for Safe Biologic Medicines (ASBM) to obtain pharmacists’ views on the naming and labelling of biosimilars. While the validity and the ability to extrapolate such questionnaire results beyond those pharmacists who responded is always limited, these data are potentially very important and certainly deserve to be listened to and considered seriously both by those who agree with as well as those who oppose these opinions.
A paper by Khan et al. presents disturbing data collected by the authors on the poor quality control of active pharmaceutical ingredients present in generic medicines sold in Pakistan. The paper raises a significant issue, which is at least in part responsible for the mistrust of the follow-on drug industry by clinicians in both resourcepoor and developed countries. Until all countries have the kind of effective regulation of generic drug products that currently exists in the EU, UK and the US, and/or until the transport and sale of poor quality drugs is stopped, such data will reinforce resistance to the more widespread use of generics as well as to the even more complicated biosimilar medicines.
The economic implications of such resistance to the use of generics is illustrated by the paper by Akku et al. who discuss the difference between potential and actual savings generated by the use of generic oncology drugs in Colombia. The need to replace brand name with less expensive generic oncology drugs is particularly important in resource limited countries such as Colombia but this is also important in resource rich countries because of the obvious life or death consequences of not having such access. However, as illustrated by the data in Colombia, the availability of less expensive but quality generic drug products on the market is necessary but not sufficient to guarantee their use. Similar problems are discussed in a paper by Fatokun et al. that appears near the end of this issue.
A paper by O’Callaghan et al. describes in some detail the structure of and significant progress made by Regulatory Science Ireland (RSI) in improving acceptance of biosimilars through efforts ‘to enhance understanding of biosimilar medicines amongst stakeholders and encourage best practice in the use of these medicines’. RSI is, ‘a voluntary network of interested parties from academia, the Health Products Regulatory Authority (HPRA), pharmaceutical and medical device industries and government agencies’. The authors describe a useful model for others who are attempting to increase the uptake of, and savings generated by, the availability of quality biosimilar (as well as generic) medicines.
Follow-on medicines, whether generics or biosimilars, have clear potential to reduce costs and thereby increase overall access to medicines. However, they can also have ‘value added’ properties for both patients and manufacturers. Dr Fereshteh Barei argues that, ‘High quality, low risk, improved valueadded therapeutics, and super generics/hybrids can ensure con venience, provide increasing patient adherence, efficiency, safety, sustainability, cost-effectiveness, competitiveness and innovativeness’. While not discussed by Dr Barei, similar arguments have been made that follow-on biological drugs can actually be ‘biobetters’. Availability of such improved products might improve acceptance of follow-on products by all stakeholders. However, as pointed out by Dr Barei, development of such products will require, ‘a team effort by innovators, entrepreneurs, regulators, payers and policymakers’.
Another possible way to increase accep tance of follow-on biotherapeutic (and generic) drug products is through the availability of improved pharmacopoeia monographs as discussed by Dr Emmanuelle Charton in a paper addressing the main challenges to developing such monographs as well as how they can be overcome. As a former, long time member of the US Pharmacopeia (USP) I can attest to how important to and yet how underappreciated they are by many clinicians. However, I agree with Dr Charton that well written pharmacopoeia monographs, ‘play a major role in ensuring that medicinal products … meet the same quality standards, thereby contributing to patient safety’. I also feel that all stakeholders would be well served by a better understanding of the methods used to develop and use these monographs as described in this important paper.
Fatokun et al. summarize the data presented in a doctoral thesis that examined, ‘The determinants and characteristics of generic medicines entry following the patent expiration of innovator drug products in Malaysia … The sources of data used … included 22 policy documents, a survey of 13 key informants, a cross-sectional questionnaire of 14 generic medicines manufacturing industries, and panel data analysis of the 12 best-selling single entity prescription drug products that experienced loss of patent protection and subsequent generics entry in Malaysia between January 2001 and December 2009’. The authors propose a number of as yet untested but logical actions they feel would improve the uptake of generic medicines in Malaysia.
The issue ends with a meeting report followed by four abstracted scientific papers. The meeting report is based on the presentation given by Martina Weise, MD, at the 14th Annual Biosimilar Medicines Group Conference in which Dr Weise, Head of Licensing Division at the Federal Institute for Drugs and Medical Devices (BfArM), described her personal views on how the European Medicines Agency has changed its requirements for biosimilars since approving the first biosimilars in 2006. The presentation contains important insight into this important but still evolving process.
The first abstracted scientific content is based on a paper published by Dr Tomaszewski in which a cross-sectional online survey of 781 pharmacists examined the effect of naming on pharmacists’ perceptions and dispensing of biosimilars. The second is an abstract of a paper published by Alessandro Nobili, MD, Head of the Drug Information Service for the Elderly, IRCCS – Istituto di Ricerche Farmacologiche ‘Mario Negri’ that discusses some of the most frequent concerns raised by internists about biosimilars. The third is an abstract of a paper published by Bergman et al. describing an empirical study of the market-based purchasing policies for generic pharmaceuticals used in Sweden. The final abstracted scientific content is of a paper published by Jones et al. that discusses, ‘the strategies used by brand pharmaceutical companies, often in combination, to delay market entry of affordable generic drugs in the US and other countries’ and in which the authors, ‘highlight 10 possible corrective measures based on US legislation that could be applied to remedy the situation in the US’.
I want to end with best wishes for a healthy and happy holiday season and New Year as well as a plea for your manuscripts and input/feedback on the GaBI Journal.
Professor Philip D Walson, MD
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.
Submitted: 1 December 2016; Revised: 6 December 2016; Accepted: 7 December 2016; Published online first: 12 December 2016
In Sweden, the government funds an insurance programme covering 75–80% of the cost of prescription drugs for patients. Since 2002, in an attempt to contain costs, pharmacists have had to inform consumers whether less expensive substitute products are available. Only the cheapest available generic (chemically and medically identical) substitute or parallel imported product will be fully reimbursed.
The Swedish Medical Products Agency is responsible for setting prices of generic prescription pharmaceuticals and regulates delivery and payment in a highly transparent way. Monthly auctions are held for the nominal right to be the sole provider of each substance-strength-form-package size combination, and the nominal right is given to the lowest bidder.
In a detailed empirical study of the Swedish generic pharmaceutical market, Mats Bergman, David Granlund and Niklas Rudholm investigate whether long-term savings can be achieved by increasing the market share of the lowest bidder and seek to determine how the number of firms operating in the Swedish market can influence price [1].
IMS Sweden data were interrogated to identify causal effects of a number of firms. The data covered all off-patent prescription pharmaceuticals sold in the Swedish reimbursement system at Swedish pharmacies between 2006 and 2011. A total of 49,256 observations of actual transaction prices and total national sales related to 169 pharmaceutical substances and over 800 distinct product markets were identified.
The following estimates were made: the effect of the market share of the lowest-priced product on the cost per defined daily dose; the effect of this market share on the number of firms in the market; and the effect of the number of firms on the average costs. Short- and long-term effects on the cost per defined daily dose of increasing the market share of the lowest-priced product were then calculated.
The investigators found that a 1-percentage-point gain in market share of the lowest bidder reduced average costs by 0.3% in the short term and 0.8% in the long term, but also reduced the number of firms by 1%. Reducing the number of firms had a strong positive (and hence counteracting) effect on average prices, i.e. a 1% reduction raises prices by around 1%.
They believe that their findings have potentially important policy implications. They suggest that instead of focusing on a more efficient system for pharmaceutical substitution at pharmacies and increasing the lowest bidder’s market share, more attention should be paid to lowering barriers to entry by, for example, reducing the fees for being active in the market.
They also believe that, although purchase costs will be minimized in the short term by giving the winner full market exclusivity, costs may in fact increase because the market’s equilibrium response is to reduce the number of bidders.
Competing interests: None.
Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.
Maysoon Delahunty, GaBI Journal Editor
References 1. Bergman M, Granlund D, Rudholm N. Squeezing the last drop out of your suppliers: an empirical study of market-based purchasing policies for generic pharmaceuticals. EconPapers. No 116.
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:
European Pharmacopoeia (Ph. Eur.) monographs for biotherapeutic products have existed since the 1990s and remain the publicly available standard defining the quality of these medicines. Continued development of such monographs however faces considerable challenges in the current environment. This manuscript addresses what the main challenges are (complexity of biologicals, setting of specifications, relations with biosimilars) and how they are overcome.
Submitted: 14 November 2016; Revised: 17 November 2016; Accepted: 18 November 2016; Published online first: 25 November 2016
On 27–28 September 2016, the European Directorate for the Quality of Medicines of HealthCare (EDQM) held a major International Conference in Tallinn, Estonia to celebrate the publication of the 9th edition of the European Pharmacopoeia: ‘European Pharmacopoeia: tackling future challenges of the quality of medicines together’ [1]. Among the topics covered in the programme was a workshop on Setting Pharmacopoeial Standards for biotherapeutic products. This manuscript is prepared based on the presentation entitled ‘The role of European Pharmacopoeia monographs in setting quality standards for biotherapeutic products’ at the workshop.
The European Pharmacopoeia (Ph. Eur.) has driven the development, drafting and publication (what we call ‘elaboration’) of monographs for biotherapeutic products for several decades. The value and utility of these monographs have been questioned in recent years, both in the press [2] and in scientific conferences [3–5, Charton E 2016, personal communication, November 17]. Although the discussions have been open and stimulating, the arguments put forward against pharmacopoeial standards for biotherapeutic products have often been either unjustified or based on an incorrect line of reasoning. The aim of this manuscript is to illustrate past and more recent Ph. Eur. achievements in the field of biotherapeutics and provide users of the Ph. Eur. with responses to the questions raised. In doing so, we hope to lay the foundations for future constructive discussions.
Place of the Ph. Eur. within the European regulatory network
The Ph. Eur. lays down common, compulsory quality standards for all medicinal products in Europe. It is mandatory on the same date in 37 European states and the European Union (EU). Some stakeholders opposed to biotherapeutic product monographs stated that individual monographs might exclude products from the market if the requirements of the monographs are not met [2]. Monographs are public standards; therefore, products that do not comply with the monographs and requirements of the Ph. Eur. are normally excluded from the market. However, these standards are not written in stone and a licensing authority may nonetheless decide to accept such products if their quality, safety and efficacy have been demonstrated. The authority should then request revision of the relevant monograph as per EU Directive 2001/83/EC: ‘In cases where a specification contained in a monograph of the European Pharmacopoeia or in the national pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the marketing authorisation holder. The competent authorities shall inform the authorities responsible for the pharmacopoeia in question. The marketing authorisation holder shall provide the authorities of that pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied’.
The legislation therefore includes a mechanism to provide the pharmacopoeia authority with information on the quality of products on the market. Obviously, the Ph. Eur. must keep pace with the needs of licensing, control and inspection authorities in the public health sector, with industrial constraints and with technological and scientific advances. Today, with the rapid rise of biotechnological products, the question of how the Ph. Eur. can best fulfil this need for biologicals has become a burning issue.
How are Ph. Eur. biotherapeutic product monographs elaborated?
There are two procedures for the elaboration of Ph. Eur. monographs: the multi-source approach and the single source approach. The first of these, the multisource approach, which is also called ‘Procedure 1’ or P1 in our jargon, is the classical procedure, by which the Ph. Eur. takes into account the specifications of more than one marketed product in order to produce a single monograph. In this case, elaboration takes place in collaboration with more than one manufacturer. The members of the groups in charge of the elaboration of these monographs include expert representatives of the regulatory authorities, Official Medicine Control Laboratories (OMCLs), industry and academia. Industry, however, has expressed concerns about this multi-source approach, stating that elaborating a monograph based on several products leads the Ph. Eur. to establish a standard of inferior quality, without consideration of the criticality of quality attributes and preclinical/clinical evidence [2]. The EDQM does not share these concerns. As explained before, Ph. Eur. monographs are based on specifications approved by licensing authorities. The EDQM considers, on the contrary, that monographs in a multi-manufacturer situation have multiple advantages, since comparison of different products and procedures provides a forum for consensus and leads to the elaboration of more robust standards. Examples of this are the insulins and somatropin monographs, published in 1992 and 1993 respectively, hepatitis B vaccine published in 1995, interferon alfa-2 in 1998, erythropoietin in 1999, interferon gamma-1b in 2000, molgramostim in 2004, human coagulation factor VIII rDNA, insulin lispro and insulin aspart in 2005, interferon beta-1a and filgrastim in 2009, see Figures 1 and 2. It was only recently, in 2008, that another procedure, known as ‘P4’, was established for the elaboration of monographs on biotherapeutic products. This is a single-source approach, already successfully applied for many years in the field of chemically defined substances. When a monograph is elaborated under the P4 procedure, the relevant Ph. Eur. group collaborates with the innovator while the substance is still under patent protection to ensure that the monograph is ‘up and running’ at patent expiry. Texts are dealt with by a specific group of experts composed only of representatives of national pharmacopoeia secretariats or regulatory authorities. If we look at what has happened in the last three years, see Figure 3, with the exception of follitropin (published in 2014), all new monographs on biotherapeutics have been elaborated under the P4 procedure, i.e. human coagulation factor VIIa rDNA in 2013, insulin glargine in 2014, human coagulation factor IX rDNA in 2014, teriparatide in 2017.
The elaboration of these monographs has not been an easy task. The next part reports the challenges, see Figure 4, we encountered and how they were overcome.
The challenges: complexity of the molecules
One of the concerns expressed by industry [2] about the elaboration of monographs has been that ‘Due to their inherent complexity and interdependence with their manufacturing processes, the quality and consistency of biologicals can only be defined and ensured through individual and comprehensive process- and product-specific control strategies’. The Ph. Eur. has always recognized the complexity of biologicals and, despite this complexity, has nonetheless been able to develop monographs for biologicals such as vaccines or blood products over the past decades. The experts who elaborate the monographs are fully aware of the fact that biologicals consist of complex mixtures of closely related variants, i.e. naturally occurring heterogeneity in glycosylation or other post-translational modified forms; that the manufacturing process is complex and that changes may lead to distinct quality attributes, e.g. glycosylation, charge heterogeneity, chemical modification. As a result, public standard setting for this class of products is a complex and demanding exercise.
The experts have addressed the complexity of biotherapeutic products by introducing a certain degree of flexibility in the monographs. As a result of this, Ph. Eur. biotherapeutic monographs take into account not only biomolecule complexity but also of the potential diversity in biosimilar compounds resulting from the different manufacturing processes applied. This flexibility is visible in the production section, which has been adapted to reflect process-dependent heterogeneity, e.g. glycosylation. As a reminder, statements under the heading Production draw attention to particular aspects of the manufacturing process but are not necessarily comprehensive [6]. They are mandatory requirements for manufacturers, unless otherwise stated.
To give an example, the Ph. Eur. has successfully elaborated a monograph for recombinant human coagulation factor IX rDNA, which is a complex molecule consisting of more than 400 amino acids produced by mammalian cell lines [7]. To address the complexity of the molecule, a glycan analysis was introduced in the production section together with a number of flexibility statements. In the case of rDNA FIX, the glycan profile depends on the manufacturing process. The test prescribes the use of an in-house reference preparation (available only to the manufacturer). Generic methods of analysis are prescribed, for example, the Ph. Eur. general Glycan analysis of glycoproteins (2.2.59); a specific analytical procedure is given as an example and has no mandatory character; finally, the monograph states that acceptance criteria are to be defined in agreement with the competent authority. We consider that the glycan analysis approach taken in this monograph is a means of improving monograph flexibility under well-defined conditions and that it is compatible with the development of biosimilars. This same approach has recently been taken for other biotherapeutic monographs [8–10] to address structural complexity.
At this juncture, it is important to set the record straight about the complexity of biological products argument that has been used against product-specific monographs. The argument refers to a ‘decision of the EDQM in November 2009 to exclude biological products from the scope of Certificates of Suitability of Monographs of the European Pharmacopoeia (CEP) [11]. CEP is used to certify that a product-specific monograph in the Ph. Eur. is able to adequately control the quality of the manufacturer’s pharmaceutical ingredient obtained by a given manufacturing route. The exclusion of biological products supports the idea that compliance with the monograph is not sufficient to ascertain the quality, safety and efficacy of these products’ [2]. However, this argument is not relevant as the lawmakers’ intention clearly was not to restrict the elaboration of monographs. The EU allows for the quality part of the dossier in a Marketing Authorisation Application (MAA) to include, instead of full documentation on the active substance, either reference to an Active Substance Master file (ASMF) or to a CEP. This possibility is not extended to biologicals because the marketing authorization holder (MAH) must have access to complete information concerning the production of a biological substance, without which they are unable to take responsibility for the final product. This is stated in the EMA guideline on ASMF: ‘The MAH applicant for a biological medicinal product could therefore not comply with the requirement to ‘take responsibility for the medicinal product’ without having full and transparent access to these quality-related data. The use of an ASMF would prevent such access, and should therefore not be allowed for biological active substance’ [12]. This is not comparable to the use of a monograph and therefore has nothing to do with the issue of whether or not a monograph can or cannot address the complexity of biologicals.
The challenges: monograph specifications
A second challenge is that because biologicals are complex, they display a large diversity of quality attributes, which in turn can be analysed using a large variety of methods. The authors of monographs are therefore faced with the difficulty of choosing which tests to include in the monograph. This raises the crucial question of how the information required for a public standard should be defined. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) gives us the answer to this question: ‘Specifications are chosen to confirm the quality of the drug substance and drug product rather than to establish full characterization and should focus on those molecular and biological characteristics found to be useful in ensuring the safety and efficacy of the product’ [13]. As previously stated, approved specifications form the basis for monograph elaboration. Monographs are therefore drafted using the information submitted to EDQM by the manufacturer of the substance in question. Unfortunately, the manufacturer’s specifications may not be appropriate for a public standard for a variety of reasons. For example, as part of the testing strategy, specific analyses may be omitted from routine testing or may be performed as in-process control tests and, therefore, are no longer included in the specifications. In addition, if the process is shown to reduce levels of specific impurities to within acceptable limits, routine testing for a specific impurity may not be performed. As a result, further tests may be required. Sometimes, a specific quality attribute may be flagged in the Production Section.
Analytical procedures are part of specifications. One real challenge is the verification of the methods before they are included in the Ph. Eur. The EDQM ensures that the robustness and transferability of future Ph. Eur. methods are verified experimentally. Ph. Eur. methods should include criteria to verify method performance and the EDQM makes sure that these criteria are appropriate. Sometimes, the method can enter the pharmacopoeia without further work. But sometimes the methods are out-of-date or insufficiently robust. In such cases, specific additional instructions may be needed, for example, information that was not necessarily included in a SOP (Standard Operating Procedure). Sometimes the experts may recommend tightening the criteria for verification of method performance. When the method proposed by the manufacturer already exists in the Ph. Eur., the monograph may refer to this method, if appropriate. When a monograph for a closely related substance already exists in the Ph. Eur., this is also taken into consideration to ensure that Ph. Eur. texts remain compatible with each other. For certain tests, experimental verification may go beyond the monograph itself, e.g. peptide mapping by LC-MS to confirm marker peaks in complex peptide maps. In extreme cases, the decision may be taken to use an alternative method but in this event, a complete validation is required. All this work obviously requires considerable input from our expert groups and the EDQM laboratory. Close collaboration with the manufacturer is therefore essential in order to find the best way forward for public standard setting.
The EDQM is always extremely grateful to the manufacturers who have chosen to collaborate with the Ph. Eur. on the elaboration of its public standards.
The challenges: biosimilars
The reader may find it surprising that the development of biosimilars has created yet another challenge to be overcome by the groups responsible for elaborating biotherapeutic product monographs. This is mainly due to the mistaken belief that the Ph. Eur. monographs can be used to demonstrate biosimilarity. The following information will hopefully clarify any misunderstandings or misuse of Ph. Eur. monographs. Firstly, reference standards described in pharmacopoeial monographs and reference products necessary for the demonstration of biosimilarity are frequently confused. Ph. Eur. reference standards are not intended to be used as reference (comparator) products in the context of applications for biosimilars, rather they are supposed to be used within the scope of Ph. Eur. monographs (see Ph. Eur. Chapter 5.12) and within this scope only. Secondly and most importantly, compliance to a monograph does not mean demonstration of biosimilarity. The EMA guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues states that comparison of the biosimilar to a publicly available standard, e.g. a pharmacopoeial monograph, is not sufficient for the purposes of comparability [14]. The unfortunate misuse of monographs in this respect has had a negative impact on the acceptance of monographs for biotherapeutic products by some stakeholders [15].
In current debates, we should bear in mind that the Ph. Eur. is a set of public standards providing harmonized quality requirements for medicinal products throughout Europe: it is used by all. The process by which the product is being approved (generics/biosimilars) is not taken into consideration when drafting a monograph. On the other hand, biosimilars are a type of product that were established to avoid unnecessary repetition of preclinical and clinical studies. The regulatory pathway to be followed is defined in appropriate guidelines. Biosimilars are developed by companies and evaluated by licensing authorities, whether or not a compendial standard exists.
However, there has been some concern that monographs could actually hold up the regulatory process [2]. The EDQM totally refutes this statement: as far as biological products are concerned, the Ph. Eur. is elaborated based on licensed products and since authorization takes place before the monograph is elaborated, there is simply no way the monograph could delay product authorization. Moving on to biosimilars, 18 of the 21 biosimilar products approved in Europe are covered by a Ph. Eur. monograph and there is no evidence to suggest that the monographs have delayed their authorization. If we look at the timeline, see Figure 5, the EMA biosimilar guidelines were established in 2003. The first biosimilar to be approved was somatropin in 2006. The first erythropoietin (EPO) biosimilar was approved in 2007, and since that time, four more EPO biosimilars have been approved. Both somatropin and EPO are covered by monographs. The EPO monograph has even been revised to accommodate the glycan distribution of one of these biosimilars. And then there is filgrastim, for which a monograph was published in 2009. The first filgrastim biosimilar was approved in 2008 and since then, seven other filgrastim biosimilars have been approved. Since all these biosimilars have been approved, one thing is certain: individual monographs have not blocked the licensing approval of these biosimilars. If we take a closer look at the present situation, see Figure 6, it is obvious that increasingly often, the monograph elaboration and biosimilar approval processes progress together. This is the case, for example, for insulin glargine and follitropin.
An etanercept biosimilar was approved in early 2016. At the same time, a monograph for this substance was under enquiry in Pharmeuropa [9]. The outcome of the enquiry has been very positive, with comments received from both regulatory authorities and industry: these comments have been addressed and the monograph is soon to be published in the Ph. Eur. During the same period, a monograph on pegfilgrastim was published and here as well, input from industry has been extremely constructive. The monograph itself is still being discussed as technical issues have arisen. In the meantime, at least three pegfilgrastim biosimilars are under assessment and many biosimilar manufacturers are requesting scientific advice for their products. This is a very strong indication that there is a pressing need for a public standard for pegfilgrastim.
To summarize, it has proven possible to overcome the challenges linked to the complexity of biologicals and to elaborate biotherapeutic product monographs. However, the success of the monograph elaboration process depends on the willingness of manufacturers to provide the information and candidate reference materials required for the process. This has proven to be more problematic since the advent of biosimilars, probably due to misunderstandings about the role of Ph. Eur. monographs in European legislation on biotherapeutic products.
Conclusion and way forward
Individual monographs play a major role in ensuring that medicinal products throughout Europe meet the same quality standards, thereby contributing to patient safety. From a quality and standardization standpoint, biotherapeutic substances should not be viewed any differently from any other substance for which a monograph exists. The Ph. Eur. will continue to fulfil its mission with regard to setting quality standards for biologicals; the question is how this role can be played.
The EDQM wishes to warmly thank all the manufacturers who contribute to the elaboration of monographs by sharing information on the quality part of their dossiers to serve as future public standards. The EDQM would also like to take this opportunity to draw attention to the outstanding work carried out by its experts in the complex exercise of monograph elaboration and hopes that, through debate and open dialogue, will identify how best to continue the work of standardization for biotherapeutic products.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. Council of Europe. European Pharmacopoeia prepares for the future through exchange with stakeholders [homepage on the Internet]. [cited 2016 Nov 17]. Available from: https://www.edqm.eu/en/news/european-pharmacopoeia-prepares-future-through-exchange-stakeholders 2. IFPMA & European Generic Medicines Association. Reflection Paper. The role of product-specific monographs for biotherapeutic products in pharmacopoeias future role of product specific monographs stakeholders. 3 October 2014 [homepage on the Internet]. [cited 2016 Nov 17]. Available from: http://www.ifpma.org/wp-content/uploads/2014/10/IFPMA_EGA_-_Future_Role_of_Product_Specific_Monographs_vFinal_01.pdf 3. Plenary Session: Role of monographs for biotechnological products. CMC Strategy Forum Europe; 23–25 April 2012; Berlin, Germany. 4. Roundtable Session: Product specific monographs. WCBP 2015, 19th Symposium on the Interface of Regulatory and Analytical Sciences for Biotechnology Health Products; 27–29 January 2015; Washington DC. 5. Session: Implications of product specific monographs for biotherapeutic products. WCBP 2016, 20th Symposium on the Interface of Regulatory and Analytical Sciences for Biotechnology Health Products; 26–28 January 2016; Washington DC. 6. Council of Europe. General notices, General chapter 1. Ph. Eur. 8th Edition Strasbourg, France. 7. Human coagulation factor IX (rDNA), concentrated solution, monograph 2522. Ph. Eur. 8th Edition. Strasbourg, France: Council of Europe 2016. 8. Council of Europe. Human coagulation factor VIIa (rDNA), concentrated solution, monograph 2534. Ph. Eur. 8th Edition. Strasbourg, France. 9. Etanercept, monograph 2895. Pharmeuropa. 2016;28(2). Available from: http://pharmeuropa.edqm.eu/home/ 10. Infliximab, monograph 2928. Pharmeuropa. 2016;28(4). Available from: http://pharmeuropa.edqm.eu/home/ 11. Council of Europe. Public Health Committee. Resolution AP-CSP (07) 1. Certification of suitability to the monographs of the European Pharmacopoeia (revised version). Adopted by the Public Health Committee (Partial Agreement) (CD-P-SP) on 21 February 2007 [homepage on the Internet]. [cited 2016 Nov 17]. Available from: https://www.edqm.eu/medias/fichiers/cep_procedure_revised_version.pdf 12. European Medicines Agency. Guideline on active substance master file procedure. 31 May 2013. CHMP/QWP/227/02 Rev 3/Corr* [homepage on the Internet]. [cited 2016 Nov 17]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129994.pdf 13. European Medicines Agency. ICH Topic Q 6 B. Specifications: test procedures and acceptance criteria for biotechnological/biologicalproducts. September 1999. CPMP/ICH/365/96 [homepage on the Internet]. [cited 2016 Nov 17]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002824.pdf 14. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). 24 May 2012. EMA/CHMP/BWP/247713/2012 [homepage on the Internet]. [cited 2016 Nov 17]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/WC500127960.pdf 15. Ian Schofield. Poor biosimilarity practices, impurities and new technologies debated at European Pharmacopoeia Event. The Pink Sheet. 2016 Oct 6.
Author: Emmanuelle Charton, PhD, Head of Division, European Pharmacopoeia Department, European Directorate for the Quality of Medicines and HealthCare, 7 Allée Kastner, CS 30026, FR-67081 Strasbourg, France
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Submitted: 28 November 2016; Revised: 29 November 2016; Accepted: 30 November 2016; Published online first: 5 December 2016
In the journal Blood, Jones et al. [1] discuss strategies used by brand pharmaceutical companies, often in combination, to delay market entry of affordable generic drugs in the US and other countries. They highlight how these strategies may be mutually beneficial to the parties concerned but are anticompetitive and act against public interest by driving up drug prices to the detriment of many patients who cannot afford to pay for treatments.
The first strategy used by brand pharmaceutical companies is a ‘pay-for-delay settlement’, whereby generic competitors who challenge the patent are offered a lucrative sum (often exceeding potential profits) for delaying market entry and withdrawing any patent litigation. This ensures a longer period of exclusivity to the patent holder. A reverse situation also occurs where the generic competitors pay the patent holder a sum to enter the market. Either way, Jones et al. argue that the losers are the patients as affordable drugs move further out of their reach.
According to the ‘Drug Price Competition and Patent Term Restoration Act’ (Hatch–Waxman Act), brand companies can produce authorized generic versions of a drug during the first-filing generic drug’s 180-day exclusivity period. Authorized generics are produced by brand pharmaceutical companies, often in conjunction with other companies, and are given a different name and priced lower at generics prices. Generics companies are sometimes granted intellectual property to allow market entry early. Pay-for-delay settlements can also include promises not to introduce authorized generics that would compete with the generic drug company’s version.
Although the production of authorized generics offers consumers a short-term reduction in price (4–8% in retail prices and 14–17% in wholesale prices), Jones et al. believe that authorized generics are a ‘coercive tool’, as they can affect first-files long-term revenues by up to 63% in the 30 months thereafter. They also believe that these settlement tactics can create a brand monopoly (the generics company agreeing to delay market entry and the brand company agreeing not to introduce authorized generics during the exclusivity period).
Product hopping is another tactic used by brand pharmaceutical companies, also known as ‘forced switching’ or ‘evergreening’. This occurs just before patent expiry and involves the brand company substituting the existing drug with a non-therapeutically different reformulated version, i.e. slow-release given once daily rather than two tablets daily. Heavy marketing aimed at doctors, patients, or both, then ensues to encourage the switch to the new drug, and the old drug may be withdrawn. The upshot of this is that once the generic drug version enters the market, pharmacist substitution for the new branded version is impossible because, in accordance with state law, dosage strength and other characteristics must be bioequivalent. This strategy has often been used in conjunction with pay-for-delay settlements to buy extra time to engineer the switch to the reformulated version. In the long term, the generics competitor will not be able to benefit from automatic substitution according to state laws.
According to a report for the US Senate Committee on Health, Education, Labor and Pensions on personal drug importation and public health, international online pharmacies are as safe as domestic ones for personal use; however, in the US, drugs valued at US$2,500 or less must be destroyed ‘in the interests of public safety’ in accordance with Section 708 of the Food and Drug Administration Safety and Innovation Act (FDASIA) to discourage patients obtaining the same drugs in cheaper markets, such as Canada.
Lobbying, branding and aggressive advertising are well established marketing strategies used by pharmaceutical companies. On a wider, more aggressive, scale brand pharmaceutical companies have been acquiring competitor companies and immediately hiking up drug prices. As Jones et al. point out, such marketing strategies have become a general trend ‘abandoning the dual mission of social corporate responsibility to both help patients and make profit in favour of a mission to maximize profits at any cost’.
A European Commission (EC) report found that, between 2000 and 2008, 22% of settlements in the European Union involved payments from the brand to the generic company, and a restriction on generics entry, although this figure had decreased to 8% by 2014. The EC has been clamping down on individual companies deemed to be violating the ‘proper functioning of normal competition’. Canada has taken an equally firm stance on reverse payment settlements. Jones et al. also allude to a report by the Canadian Competition Bureau, which states that it would consider applying civil and (for a more limited category of behaviour) criminal liability to reverse-payment settlements.
Jones et al. highlight 10 possible corrective measures based on US legislation that could be applied to remedy the situation in the US: these include allowing Medicare to negotiate drug prices, monitoring and penalizing pay-for-delay strategies that are anticompetitive, and allowing transportation of drugs across borders for personal use. The essence of these measures, they conclude, is simple: ‘reduce the cost of drugs and improve patient access and treatment security’.
Competing interests: None.
Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.
Maysoon Delahunty, GaBI Journal Editor
References 1. Strategies that delay or prevent the timely availability of affordable generic drugs in the United States. Blood. 2016;127(11):1398-402.
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.
Submitted: 21 November 2016; Revised: 22 November 2016; Accepted: 24 November 2016; Published online first: 30 November 2016
Authors from the IRCCS – Istituto di Ricerche Farmacologiche ‘Mario Negri’, Milan, Italy discuss some of the most frequent concerns raised by internists (doctors of internal medicine) about biosimilars [1]. They also try to explain the scientific principles underlying the biosimilar concept established in Europe that allows for the licensing of biosimilars in the European Union.
While the demonstration of bioequivalence is sufficient for small molecule generic drugs, this approach is not scientifically applicable to biosimilars. Generics must demonstrate that the active ingredient of the generic drug is the same as that of the originator drug. Therefore, internists and patients can expect that generics will have the same properties, the same efficacy, and the same safety characteristics as the originator product.
In contrast, biologicals are usually large, complex molecular structures derived from or produced in living organisms, making them very difficult to replicate. Even for the originator biological, small changes in the manufacturing process can cause changes in the final product, making things even more complicated for potential biosimilars. Therefore, biosimilars of such molecules can only be similar, but not identical, to the originator and are also subject to different related post-translational processes. This is of concern for physicians, who worry that if a reference product and its biosimilar are not structurally identical they might not be therapeutically equivalent.
The development process for a biosimilar ensures a comparable risk-to-benefit balance compared with the originator biological. Thus, based on an extensive developmental programme there is no scientific reason to consider that a biosimilar would be different from the originator when used in clinical practice according to the approved indication. Moreover, according to the available evidence and pharmacovigilance network, there are no grounds to believe that the use of a biosimilar carries more risk for the patient than the use of an originator biological. Internists should be also reassured with regard to immunogenicity and safety issues. It is well known that the problem of epoetin antibody-induced pure red cell aplasia (PRCA) was first recognized after the formulation of the originator epoetin Eprex (epoetin alfa) was changed [2].
Furthermore, there is a need for the dissemination of clear information about existing guidelines, access to unbiased information and educational interventions regarding the clinical utility of biosimilars. The aim of this should be to help internists to improve their knowledge and to implement the use of these medications in clinical practice. In Europe, there is a clear gap between the regulatory decisions that govern biosimilar approval and the recommendations of medical societies. The fact that the views of medical societies, whose members are the physicians that will prescribe biosimilars, disagree with those of regulators, may hold back biosimilar uptake [3].
The need for the benefits of biosimilars to be communicated has also been highlighted at a biosimilars roundtable organized by GaBI (Generics and Biosimilars Initiative) in Brussels, Belgium on 12 January 2016. Representatives of medical societies attending the biosimilars roundtable concluded that, while the European Medicines Agency (EMA) has carried out important work looking at extrapolation and investigating the safety of biosimilars, their findings have not been communicated effectively [4, 5].
One of the main expected benefits of the introduction of biosimilars is a reduction in costs and as a consequence to extend the access to new innovative biotherapeutic drugs. Despite this aim, the scientific principles used for defining comparability are the same as those applied to an already approved originator biological after a significant change in its manufacturing process. Starting from this evidence, internists should only prescribe medicines for which the quality, safety and efficacy have been demonstrated according to state-of-the-art science and technology, irrespective of whether they are originator biologicals or biosimilars.
The future development of biosimilars will depend on the definition of reliable parameters of interchangeability and will require further advances in knowledge on the characterization of the molecules. Internists, as well as other clinicians, along with healthcare providers and patients, will play a key role in determining how biosimilars are integrated into clinical practice.
In order to facilitate understanding, the authors also list a number of ‘essential references’ for internists concerned about biosimilars.
Essential references
European Medicines Agency. Scientific guidelines on biosimilar medicines. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c#Productspecificbiosimilarguidelines
European Medicines Agency. Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: quality issues, December 2003 (CPMP/BWP/3207/00/Rev 1*). Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003573.pdf
European Medicines Agency. Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. December 2003. (CPMP/3097/02). Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003963.pdf
This guideline has been replaced in November 2007 by Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process: non-clinical and clinical issues. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003935.pdf
European Medicines Agency. Concept paper on extrapolation of efficacy and safety in medicine development. 19 March 2013. EMA/129698/2012. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129285.pdf
European Medicines Agency. CHMP assessment report. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-Variation/human/000278/WC500153233.pdf
European Medicines Agency. Assessment report for Aranesp. 3 July 2008. EMEA/478499/2008. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_–_Assessment_Report_-_Variation/human/000332/WC500026148.pdf
Competing interests: None.
Provenance and peer review: Article abstracted based on published research paper [1] by Dr Alessandro Nobili, MD, Head of the Drug Information Service for the Elderly, IRCCS – Istituto di Ricerche Farmacologiche ‘Mario Negri’; edited by Michelle Derbyshire, PhD, GaBI Online Editor; internally peer reviewed.
References 1. Pasina L, Casadei G, Nobili A. Biological agents and biosimilars: essential information for the internist. Eur J Intern Med. 2016;33:28-35. 2. GaBI Online – Generics and Biosimilars Initiative. Epoetin alfa and pure red cell aplasia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Nov 22]. Available from: www.gabionline.net/Biosimilars/Research/Epoetin-alfa-and-pure-red-cell-aplasia 3. GaBI Online – Generics and Biosimilars Initiative. Biosimilars: clinicians and regulators need to talk [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Nov 22]. Available from: www.gabionline.net/Biosimilars/Research/Biosimilars-clinicians-and-regulators-need-to-talk 4. GaBI Online – Generics and Biosimilars Initiative. Biosimilars: the benefits need to be communicated [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Nov 22]. Available from: www.gabionline.net/Biosimilars/Research/Biosimilars-the-benefits-need-to-be-communicated 5. Annese V, Avendaño-Solá C, Breedveld F, Ekman N, Giezen TJ, Gomollón F, et al. Roundtable on biosimilars with European regulators and medical societies, Brussels, Belgium, 12 January 2016. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(2):74-83. doi:10.5639/gabij.2016.0502.019
Disclosure of Conflict of Interest Statement is available upon request.
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Submitted: 21 November 2016; Revised: 22 November 2016; Accepted: 24 November 2016; Published online first: 30 November 2016
A study of pharmacists investigated their perceptions of biosimilar naming conventions and the impact it might have on their dispensing habits [1]. The study found that pharmacists had a preference for distinguishable names. However, using the same names for interchangeable biologicals would make pharmacists more likely to dispense biosimilars.
A growing number of biosimilars are set to hit the US market in the coming years. The increase in availability of such agents is being met with a number of questions regarding the regulations that will govern them. The US Food and Drug Administration (FDA) has attempted to answer some of these questions, including those related to biosimilar naming. The agency issued draft guidance on the non-proprietary naming of biological products in August 2015 [2]. However, the guidance continues to be in flux and does not address naming for products given an interchangeable designation.
This study was carried out jointly by the Academy of Managed Care Pharmacy (AMCP) and the Hematology/Oncology Pharmacy Association (HOPA). It aimed to determine pharmacists’ perceptions of biosimilar naming conventions and the impact it might have on pharmacists’ confidence to dispense biosimilars. In addition, the study aimed to measure the burden that is created by laws and regulations requiring pharmacists to complete post-dispense notifications.
The cross-sectional survey of 781 pharmacists was conducted using an online survey software program. Participants reported preference for the use of a non-proprietary base with a designated suffix (48.1%) compared to the use of a non-proprietary base alone (26.3%), non-proprietary base plus a prefix (14.2%), or a unique brand name (11.4%). This preference, however, did not correlate with confidence levels reported when dispensing a biosimilar in place of the reference biological, with the largest percentage of participants reporting high levels of confidence when the products shared the same non-proprietary name (62.9%). This suggests that sharing the same non-proprietary name may improve pharmacist confidence in biosimilars at the point of dispensing. The majority of participants (64.9%) also expected an increased burden when required to provide a post-dispense notification to prescribers when dispensing biosimilars.
The preference for unique names for biologicals correlates with a survey carried out on pharmacists in the US by the Alliance for Safe Biologic Medicines (ASBM) [3]. That survey found that the majority of responders (68%) thought that FDA should require a distinct non-proprietary scientific name for every biological product – originator or biosimilar. While a total of 77% of respondents thought that a manufacturer-specific suffix should be included in the name of each biological product [3].
The issue of naming for biologicals is a contentious one. Advocates for distinct names include the Biologics Prescribers Collaborative (BPC) and the ASBM. The Generic Pharmaceutical Association (GPhA), on the other hand, believes that different names could ‘erect barriers to patient access to new, more affordable medicines, and jeopardize their safety’; whilst the AMCP has said that distinct names could result in ‘lower market adoption and cost-savings’ from biosimilars [4].
The GPhA has also pointed out that Europe has approved biosimilars with the same non-proprietary names as their reference biologicals for more than six years in a system that has proven effective. Biosimilars have also been successfully tracked in the marketplace using their brand name and other identifiers currently in place for product recognition, meaning a separate non-proprietary name is not necessary for keeping track of biosimilars once they are on the market [5].
The World Health Organization (WHO) has proposed a Biological Qualifier (BQ) that would be used in conjunction with the international non-proprietary name (INN) and would consist of a random alphabetic code, made up of four random consonants [5]. The International Generic and Biosimilar medicines Association (IGBA) has expressed concerns, however, that the WHO proposal is ‘meaningless, unmemorable, confusing [and] unnecessarily complicated’. It also believes that retrospective application of BQs to already authorized products may lead to discrimination and be anticompetitive [6].
The ASBM also believes that the use of four-digit codes that are memorable and logical would better promote manufacturer accountability, giving Zarxio (filgrastim-sndz) as an example. The FDA draft guidance proposes a meaningless four-letter suffix. This, says the ASBM, ‘creates an unnecessary barrier to the use of distinguishable suffixes’ [4].
In the survey carried out by the AMCP and HOPA, when asked directly, pharmacists reported preference for a non-proprietary proper name with a designated suffix for biosimilars. However, use of such a naming strategy was associated with a decrease in confidence of substituting a biosimilar for the originator biological. The author therefore concluded that this may impact the ‘willingness of some pharmacists to dispense biosimilars’ or may result in pharmacists transferring this lower level of confidence in the product to the patient. ‘This effect will be minimized if interchangeable biologics share the same nonproprietary name as the reference biologics’. Additional research is needed to determine the overall impact this may have on the actual use of biosimilars.
Competing interests: None.
Provenance and peer review: Article abstracted based on published research paper [1] by Dr D Tomaszewski, edited by Michelle Derbyshire, PhD, GaBI Online Editor; internally peer reviewed.
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Author byline as per print journal: Joan O’Callaghan, BSc Pharm; Sean Barry, PhD; Una Moore, PhD; Margaret Bermingham, PhD; J Michael Morris, PhD; Frank Hallinan, PhD; Brendan T Griffin, PhD
Abstract:
Regulatory Science Ireland (RSI) is a voluntary network of interested parties from academia, the Health Products Regulatory Authority (HPRA), pharmaceutical and medical device industries and government agencies. RSI is conducting a research project, the objective of which is to enhance understanding of biosimilar medicines amongst stakeholders and encourage best practice in the use of these medicines.
Submitted: 26 October 2016; Revised: 26 October 2016; Accepted: 27 October 2016; Published online first: 31 October 2016
Regulatory Science Ireland
The ever increasing complexity of healthcare products requires a data driven, evidence-based approach to their regulation. The European Medicines Agency (EMA) has identified regulatory science as a key driver to meet its mission of fostering ‘scientific excellence in the evaluation and supervision of medicines’ [1]. Regulatory science is becoming increasingly important as an approach to how medicines are developed and regulated. EMA recognizes this fact and recommends that regulators work closely with academia, industry, expert patient groups and others in order to support developments in this area [2].
Regulatory Science Ireland (RSI) is an integrated Irish response to global regulatory science initiatives. The group is composed of interested parties from the Health Products Regulatory Authority (HPRA), academia, pharmaceutical industry, medical devices industry and government agencies, see Figure 1. RSI is contributing to the regulatory science effort by conducting research, provision of educational materials and organization of regulatory symposia. Efforts such as these will help improve regulatory understanding among all stakeholders and will ultimately be of real benefit to patients.
Why is RSI focusing on biological and biosimilar medicines?
A biological medicine is a medicine that contains an active substance made by a biological process or derived from a biological source. The standards for the quality, safety and efficacy of biological medicines are complex and it is essential that healthcare professionals involved in their clinical use and supply are appropriately informed of their unique characteristics. Biosimilar medicines are biological medicines which contain a version of the active substance of an already authorized biological medicine (reference medicine). Manufacturers of biosimilar medicines must perform an extensive head-to-head comparability exercise with the reference medicine and demonstrate to regulators that the biosimilar medicine has similar quality, safety and efficacy to the reference medicine such that there are no clinically meaningful differences between the two.
The biosimilar approval process is based predominantly on evidence generated from the quality and preclinical comparability exercise. The extent of clinical data needed to demonstrate similarity in addition to the quality and non-clinical data is tailored to each product on a case-by-case basis and is considered confirmatory in nature. Therefore depending on the nature of the product, the clinical data can range from limited to extensive. Reliance on quality evidence over clinical evidence may be an unusual concept for those that know a biosimilar medicine is ‘similar but not identical’ to the reference medicine. The biosimilar medicine may also be licensed in therapeutic indications for which no specific clinical trials have been conducted. This is commonly referred to as indication extrapolation and is only approved by regulators after comprehensive scientific justification which includes consideration of the mechanism of action in each indication.
A key output from the RSI biosimilar project is to identify and implement mechanisms to increase the understanding of how these medicines are regulated and used amongst healthcare professionals, patients and healthcare providers.
HPRA guide to biosimilar medicines
Prior to commencement of the RSI biosimilar project, the HPRA was already engaged in activities to facilitate knowledge transfer concerning biosimilar medicines to stakeholders. In 2015, the HPRA published a guide to biosimilar medicines [3]. This guide is targeted primarily at healthcare professionals but is also relevant to patients, manufacturers, distributors and those involved in hospital procurement. Some of the drivers for producing the guide are outlined in Table 1.
The guide provides an overview of how biosimilar medicines are regulated and outlines the difference between a biosimilar medicine and a generic (chemical) medicine. Topics such as pharmacovigilance considerations, adverse drug reaction reporting, prescribing, and interchangeability are also addressed. A public consultation process was undertaken before finalization of the guide which allowed the HPRA to gather feedback from stakeholders as to whether it provided enough relevant information to meet their needs. Comments from stakeholders were considered and incorporated as appropriate. While the publication of such guidance documents can help in addressing some of the misconceptions surrounding biosimilar medicines, the HPRA is continuing in its efforts to bridge the information gap on biosimilar medicines by providing dedicated resources to the RSI Biosimilar Research Project.
RSI Biosimilar Research Project
Biosimilar medicines were highlighted as being a key area of interest for the development of the regulatory science knowledge base in Ireland and therefore a biosimilar research project was launched as one of the first major projects for RSI. The project, which has been ongoing since January 2016, involves a collaboration between the HPRA and University College Cork (UCC). The research is also supported by the Irish Pharmaceutical Healthcare Association (IPHA). A project advisory panel meet quarterly to share ideas about the direction of the research. In addition to HPRA and UCC, the advisory panel consists of stakeholders from industry, industry representative bodies, a patient representative and government agencies.
The project focuses on a number of specific objectives relating to enhanced pharmacovigilance and traceability of biological medicines and the need for procurement/purchasing procedures to appreciate the difference between biosimilar medicines and generic medicines.
The project objectives include:
Peer-reviewed scientific publications on biosimilar medicines – particularly concerning the practical considerations for healthcare professionals
Conducting surveys of healthcare professionals on perspectives and understandings of issues relating to biosimilar medicines
Development of training materials and online resources
Participation in outreach activities, e.g. running short training courses, information days, invited lectures
Research activities are conducted independently by the HPRA and UCC which ensures the generation of unbiased neutral information relating to the use of biosimilar medicines by healthcare professionals.
Survey of physicians
An early goal of the project is to evaluate the level of understanding about biosimilar medicines amongst Irish healthcare professionals. In May 2016, a link to an online questionnaire was circulated to medical specialists (predominantly hospital consultants in specialities that use biological medicines) and general practitioners (GPs). The objective of this survey was to explore physician’s perspectives and understanding of issues relating to biological and biosimilar medicines. The questionnaire addressed topics such as familiarity with the term ‘biosimilar’, implications of shared international non-proprietary names, pharmacovigilance recording practices, prescribing behaviours, attitudes to pharmacist led substitution and specific concerns relating to biosimilar medicines. The results from the survey are currently being analysed and will shortly be submitted for publication.
Stakeholder engagement
Many medical specialists in Ireland are members of professional societies. Societies, whose members are likely to be involved in the prescribing of biological medicines, have facilitated the research by distribution of the online questionnaire to their members. Continued engagement with the societies is envisaged after publication of the survey findings.
Engagement with GPs has been facilitated by the Irish College of General Practitioners (ICGP). The ICGP is the professional body for general practice in Ireland and its members and associates account for over 85% of practising GPs. The College agreed to distribute the questionnaire to its membership and organized a speaking slot for RSI at an educational conference organized for their members.
Pharmacists have been kept informed of key aspects of biosimilar regulation and their use in clinical practice via RSI presentations at continuing education events and publication of papers in national pharmacy journals (Irish Pharmacy News and the Hospital Pharmacist News). An article highlighting the importance of traceability of biological medicines has been published on the RSI website [4]. Pharmacists were informed of this material via a newsletter distributed by the Pharmaceutical Society of Ireland.
The RSI project team also aims to facilitate knowledge transfer to patient communities. Representatives from various patient organizations have been made aware of the project at a recent event on ‘Biologicals and Biosimilars’ organized by the Irish Platform for Patients’ Organisations, Science & Industry (IPPOSI). IPPOSI has also conducted a recent survey of 150 arthritis patients [5]. The findings suggest that awareness and understanding of biosimilars amongst patients is low. Respondents also felt that there was limited access to patient friendly, easily understandable information about biological and biosimilar medicines. This identified need has resulted in the RSI publication of a patient Q & A which can be found on the RSI website [6]. It is planned to produce a short informative video to accompany the Q & A. Once finalized the materials will be publicized to relevant patient organizations.
Ongoing activities
Materials generated from the project will be available for download from the RSI website (www.regulatoryscienceireland.ie). Research findings will be disseminated to healthcare professionals, patients, payers and policymakers. Outreach activities will continue as the project gains momentum and it is planned to organize and contribute to future events involving key stakeholders.
Conclusion
Since its inception, RSI has made significant progress in increasing the awareness and understanding of the regulation, prescription and use of biosimilar medicines in Ireland. However, a level of misunderstanding around the whole area still persists. Through our future research, outreach programmes and engagement activities, RSI plans to bridge the knowledge gap between industry, regulators, healthcare professionals and patients, and contribute to the safe and effective use of biological medicines in Ireland.
Acknowledgements
Regulatory Science Ireland acknowledge the financial support provided by the Irish Pharmaceutical Healthcare Association and the Health Products Regulatory Authority for the conduct of this research.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
Authors
Joan O’Callaghan1,2,3, BSc Pharm Sean Barry1, PhD Una Moore1, PhD Margaret Bermingham2, PhD J Michael Morris3, PhD Frank Hallinan2,3, PhD Brendan T Griffin2,3, PhD
1Health Products Regulatory Authority, Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2, Ireland 2School of Pharmacy, Cavanagh Pharmacy Building, University College Cork, Cork, Ireland 3Regulatory Science Ireland, c/o School of Pharmacy, Cavanagh Pharmacy Building, University College Cork, Cork, Ireland
References 1. European Medicines Agency. Road map to 2015 [homepage on the Internet]. 2010 [cited 2016 Oct 26]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/01/WC500101373.pdf 2. European Medicines Agency. EU Medicines Agencies Network Strategy to 2020 [homepage on the Internet]. 2015 [cited 2016 Oct 26]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/12/WC500199060.pdf 3. Health Products Regulatory Authority. Guide to biosimilars for healthcare professionals and patients [homepage on the Internet]. 2015 [cited 2016 Oct 26]. Available from: https://www.hpra.ie/docs/default-source/publications-forms/guidance-documents/guide-to-biosimilars-for-healthcare-professionals-and-patients-v2.pdf?sfvrsn=18 4. Regulatory Science Ireland. Pharmacovigilance considerations for biological medicines [homepage on the Internet]. 2016 [cited 2016 Oct 26]. Available from: http://www.regulatoryscienceireland.com/pharmacovigilance-of-biological.html 5. IPPOSI. IPPOSI patient survey [homepage on the Internet]. 2016 [cited 2016 Oct 26]. Available from: http://www.ipposi.ie/images/Appendix_I_-_graphs_from_survey_v5.pdf 6. Regulatory Science Ireland. Biosimilar medicines: what patients should know [homepage on the Internet]. 2016 [cited 2016 Oct 26]. Available from: http://www.regulatoryscienceireland.com/biosimilars.html
Author for correspondence: Joan O’Callaghan, BSc Pharm, Research Scientist, Regulatory Science Ireland, Health Products Regulatory Authority, Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2, Ireland
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.
Author byline as per print journal: Shyam Akku, MD; Amit Garg, MD; Suhas Khandarkar, MPharm
Introduction: Majority of the Colombian population has become health insured leading to improved healthcare access in the country. Healthcare expenses have risen drastically, and cancer is responsible for the major disease burden. An option to reduce cost burden is to replace the use of originator drug products with generic formulations which are considered to be bioequivalent to the originator drugs and cost much less.
We conducted a cost-minimization study for Colombia to assess the savings that could be achieved with the use of generic formulations of three anticancer drugs, namely bortezomib, decitabine and capecitabine as compared to their originator products. Methods: We compared the prices of originator and Dr Reddy’s Laboratories Ltd generic equivalents of bortezomib, decitabine and capecitabine in Colombia for the year 2015. Prices of originator drugs were obtained from SISMED (Sistema de información de Precios de Medicamentos – Drug Price Information System), the prices of generic drugs were provided by Dr Reddy’s Laboratories Ltd. Cost savings were estimated in value and percentages. Results: The study showed the substantial savings of 63% (US$4.68 million) with bortezomib, 26% (US$0.29 million) with decitabine, and 46% (US$1.50 million) with capecitabine from Dr Reddy’s Laboratories Ltd generics as compared to their originator branded medicines. Conclusion: Considering the high economic burden of cancer and high prices of originator anticancer drugs, our study highlights the need to replace the originator branded medicines with the generics. This will not only improve the patient access to medications but also be beneficial for the insurance payers in Colombia, thereby improving the overall healthcare system in the country.
Submitted: 19 October 2016; Revised: 18 November 2016; Accepted: 21 November 2016; Published online first: 28 November 2016
Introduction
Colombia is an upper-middle income country with over 48 million people, as reported by the World Health Organization (WHO) in the year 2015 [1, 2]. Over the past few years, Colombia has undergone various demographic and epidemiological changes viz. fall in total fertility rate from 3.24 children per woman in 1985 to 2.3 in 2013 while life expectancy has increased by four years over the period of 2000 to 2012; mortality rates have also declined from 1990 to 2012, e.g. under-five mortality rate: 35 vs 17 per 1,000 live births, maternal mortality ratio: 100 vs 83 per 100,000 live births [2, 3]. Overall, healthcare expenditure has increased drastically in Colombia. According to WHO, around US$962 per capita were spent on health expenditure in 2014 which accounted for 7.2% of gross domestic product (GDP) in the country [1, 3].
Non-communicable diseases account for 71% of total deaths in Colombia, and cancers constitute 17% of the total deaths [4]. Out of all the cancers, breast, stomach and colorectal cancer are three of the five most prevalent forms in Colombia accounting for 7%, 13.1% and 8.5% of total cancer mortality, respectively. Besides these, blood/bone marrow cancers (9.9%) are also responsible for high burden of cancer-related deaths in the country (leukaemia 4.9%, multiple myeloma 1.2%, non-Hodgkin lymphoma 3.4%, and Hodgkin lymphoma 0.4%) [5].
However, launch prices for the anticancer drugs have substantially increased over time. Anticancer medicines rank first in terms of global spending in the pharmaceutical market (US$91 billion in 2013). According to a recent study in the US, the average price of an anticancer drug is US$65,900 in 2013, while the average survival benefit is 0.46 years [6]. Overall, the economic burden due to cancer cost US$290 billion in 2010 with the greatest share of the medical costs (53%). In fact, economic burden of cancer is estimated to be US$8.3 trillion between the period 2011-2030 [7]. The economic burden of cancer per patient ranged from US$0.54 in India to US$4.32 in China, US$7.92 in South America, US$244 in Japan, and US$460 in the US [8].
At present, majority of the Colombian population is covered under health insurance (85% in 2008 and 97% in 2010) [3, 9]. This has secured the general population and increased the access to health care. However, health care in Colombia is in jeopardy as it faces financial constraints. One of the reasons attributed for this condition is high drug expenditure in the country. Colombia is believed to be one of the highest payers for drugs in the world due to extensive use of expensive originator drugs rather than generic molecules. Thus, there is a need to replace the originators with generic molecules in Colombia to bring down the overall healthcare economic expenditure [9].
A recent cost-minimization study conducted by Alexandra et al. (Essential Medicines and Pharmaceutical Policies, World Health Organization) across 17 countries showed that substantial savings can occur by switching the purchases from originator medicines to generics. These savings ranged from 11% for beclomethasone inhaler to 73% for ceftriaxone injection [10]. Keeping in mind the high cost of anticancer drugs, we conducted a pharmacoeconomic study to estimate the savings that could be achieved with the use of generic formulations of anticancer drugs – bortezomib, decitabine and capecitabine – in comparison to their originator brands in Colombia.
Methods
Rationale Pharmacoeconomics identifies, measures and compares the costs of various drug therapies to the society and the healthcare system. It helps the clinicians, health-payers, and other decision-makers to assess the costs and outcomes of various treatment options via cost-minimization, cost-benefit, cost-effectiveness and cost-utility analyses [11–13]. The choice of the analysis depends upon the clinical situation to be evaluated and the question being asked. Cost-minimization analysis compares the costs of treatments having similar outcomes and aims at identifying the most economic option available. On the other hand, cost-benefit analysis compares the costs and benefits of treatments that have different outcomes and the outcome is measured in monetary value. Cost-effectiveness analysis compares the costs per standardized units of effectiveness for treatments that have different outcomes. Cost-utility analysis compares the costs per quality-adjusted life years for treatments that have different outcomes. Thus, of the different pharmacoeconomic methods, cost-minimization analysis is the one that compares the two interventions when the clinical outcomes of both are equivalent [12]. This means that if the two drugs are equivalent to each other in terms of clinical and humanistic outcomes, e.g. generics and originator molecules, this method can be viable in making a decision with respect to the cost of the drug in order to choose the economical one [11].
Literature evidence clearly shows that generic molecules are equivalent to the originator drugs in terms of outcomes. As per the US Food and Drug Administration (FDA), generic drugs are approved only when they are bioequivalent to the branded drugs, and have demonstrated similar quality and performance [14]. Several systematic reviews have shown that cardiovascular and neurological generics are as clinically effective as the branded drug products [15–17]. Therefore, we chose the cost-minimization study to compare the costs of generic and originator products of three anticancer drugs namely bortezomib, decitabine and capecitabine in Colombia. Our study is further supported by a recent cost-minimization study that was conducted across 17 countries to estimate the savings that could be achieved by switching the use from the originator to generic drugs [10].
Study methods In our cost-minimization study, we compared the prices of originator and Dr Reddy’s Laboratories Ltd (DRL) generic drugs of bortezomib, decitabine and capecitabine in Colombia. For originator products, price data was obtained from the SISMED (Sistema de información de Precios de Medicamentos – Drug Price Information System), Colombia. SISMED is an information system that provides the necessary data to analyse and control the drug prices in Colombia, and thus, helps in the regulation of the pharmaceutical market in the country.
The mean unit price of originator drugs was calculated for the year 2015. On the other hand, prices of generic drugs were provided by DRL. To estimate the maximum cost savings that could be generated if the originator branded medicines consumed were purchased at the price of generics, mean prices of originator brands and the price of generics were applied to the volume of originator branded medicines consumed. All the prices were calculated in US dollars to avoid any fluctuations in the currency value throughout the year 2015.
Results
Our study showed high costs of the originator products as compared to the generic molecules for all the three anticancer drugs. The originator drug of bortezomib cost US$7.48 million, decitabine US$1.12 million and capecitabine US$3.27 million. On the other hand, the generic bortezomib costed only US$2.80 million, decitabine costed US$0.83 million and capecitabine costed US$1.78 million, see Figure 1.
In total, a saving of 63% was achieved with the use of the generic form of bortezomib, 26% with decitabine, and 46% with capecitabine as compared to the originator drugs. Complete results for the three drugs are depicted in Table 1.
Discussion
Our study is based on estimating the total savings that could be obtained by replacing the originator drugs of bortezomib, decitabine, and capecitabine with their DRL generic forms.
All these three drugs have gained a rational place in the treatment of various cancers and thus are commonly used. Bortezomib (as a single agent or in combination) is the preferred regimen for the treatment of multiple myeloma, both in the primary therapy as well as maintenance therapy, and used in relapsed patients. Also, it is approved as a second-line treatment for mantle cell lymphoma [18, 19]. Decitabine has been approved and used for the treatment of myelodysplastic syndrome and acute myeloid leukaemia [20, 21]. Capecitabine is used in the management of gastric, breast and colorectal cancer [22–25]. Moreover, all these three drugs have shown to confer cost savings in comparison to other anticancer drugs in their respective indications [26–35]. Therefore, using these drugs will not only help in the treatment of various cancers but can lead also to substantial cost savings.
Regarding the efficacy of generic medicines, it is well-proven that generics are bioequivalent to the originator drugs [14–17]. In fact, the Clinical Guidelines Committee of the American College of Physicians advises that clinicians should prescribe generic medicines in place of the expensive branded drugs. Generic medicines are not only associated with substantial cost savings, but also provide long-term adherence to the treatment [36].
Taking into account the field of oncology where medications are highly expensive, generics can play a very important role [37]. Generic imatinib is estimated to cost less than US$1,000 per year within the next two years, while the average wholesale price of the branded imatinib is currently US$145,750 [38]. An Indian study showed that anticancer generics cost 8.9% to 36% of the branded originator medications (irinotecan 8.9%, paclitaxel 23%, docetaxel 24%, oxaliplatin 32% and gemcitabine 36%), and around US$843 million were estimated to be the potential yearly savings. All these studies highlight the need for generics substitution which can generate enormous cost savings and increase the access to cancer treatment globally [39]. Therefore, low- and middle-income countries like Colombia can improve the access to cancer medications by using the generic drugs.
Conclusion
This study highlights the substantial cost savings that could be achieved by replacing the originator drugs of bortezomib, decitabine, and capecitabine with the DRL generic formulations in Colombia. This can be very helpful for the insurance payers and bring a positive reform in the Colombian health care.
Competing interests: All authors are employees of Dr Reddy’s Laboratories Ltd. Financial support was provided by Dr Reddy’s Laboratories, Hydrabad, India.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Shyam Akku, MD Amit Garg, MD Suhas Khandarkar, MPharm
Dr Reddy’s Laboratories Ltd, 8-2-337, Road No. 3, Banjara Hills, Hyderabad – 500034 AP, India
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Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs. 2010;70(5):605-21. 17. Dentali F, Donadini MP, Clark N, Crowther MA, Garcia D, Hylek E, et al. Warfarin Associated Research Projects and Other Endeavors (WARPED) Consortium. Brand name versus generic warfarin: a systematic review of the literature. Pharmacotherapy. 2011;31(4):386-93. 18. Anderson KC, Alsina M, Atanackovic D, Biermann JS, Chandler JC, Costello C, et al. NCCN guidelines insights: multiple myeloma, version 3.2016. J Natl Compr Canc Netw. 2016 Apr;14(4):389-400. 19. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines). Non-Hodgkin’s lymphomas. Version 4.2014 [homepage on the Internet]. [cited 2016 Nov 18]. Available from: https://www.nccn.org/about/nhl.pdf 20. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines). Myelodysplastic syndromes. 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NCCN clinical practice guidelines in oncology (NCCN guidelines). Breast cancer. Version 1.2015 [homepage on the Internet]. [cited 2016 Nov 18]. Available from: http://www.cjcpt.org/files/2015/03-06/2015-NCCN/2015%20NCCN%20%E4%B9%B3%E8%85%BA%E7%99%8C-V1.pdf 25. Ajani JA, Bentrem DJ, Besh S, D’Amico TA, Das P, Denlinger C, et al. Gastric cancer, Version 2.2013: featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2013;11(5):531-46. 26. Hornberger J, Rickert J, Dhawan R, Liwing J, Aschan J, Löthgren M. The cost-effectiveness of bortezomib in relapsed/refractory multiple myeloma: Swedish perspective. Eur J Haematol. 2010;85(6):484-91. 27. Lancaster S. Bortezomib: the evidence of its clinical impact in multiple myeloma. Core Evid. 2006;1(4):265-77. 28. LeBlanc R, Hollmann S, Tay J. Canadian cost analysis comparing maintenance therapy with bortezomib versus lenalidomide for patients with multiple myeloma post autologous stem cell transplant. J Popul Ther Clin Pharmacol. 2016;23(1):e103-13. 29. Garrison LP Jr, Wang ST, Huang H, Ba-Mancini A, Shi H, Chen K, et al. The cost-effectiveness of initial treatment of multiple myeloma in the U.S. with bortezomib plus melphalan and prednisone versus thalidomide plus melphalan and prednisone or lenalidomide plus melphalan and prednisone with continuous lenalidomide maintenance treatment. Oncologist. 2013;18(1):27-36. 30. Wiles S, Kabalan M, Sharma R, Shatzel J, Pang J, Yi D, et al. Decitabine is more cost effective than standard conventional induction therapy in elderly acute myeloid leukemia patients. Blood. 2013;122(21):2699. 31. Pan F, Peng S, Fleurence R, Linnehan JE, Knopf K, Kim E. Economic analysis of decitabine versus best supportive care in the treatment of intermediate- and high-risk myelodysplastic syndromes from a US payer perspective. Clin Ther. 2010;32(14):2444-56. 32. Ho MY, Chang AY, Ruan JY, Cheung WY. Population-based cost-minimization analysis of CAPOX versus modified FOLFOX6 in the adjuvant treatment of stage III colon cancer. Clin Colorectal Cancer. 2016;15(2):158-63. 33. Lin JK, Tan EC, Yang MC. Comparing the effectiveness of capecitabine versus 5-fluorouracil/leucovorin therapy for elderly Taiwanese stage III colorectal cancer patients based on quality-of-life measures (QLQ-C30 and QLQ-CR38) and a new cost assessment tool. Health Qual Life Outcomes. 2015;13:61. 34. Tse VC, Ng WT, Lee V, Lee AW, Chua DT, Chau J, et al. Cost-analysis of XELOX and FOLFOX4 for treatment of colorectal cancer to assist decision-making on reimbursement. BMC Cancer. 2011;11:288. 35. Perrocheau G, Bennouna J, Ducreux M, Hebbar M, Ychou M, Lledo G, et al. Cost-minimisation analysis in first-line treatment of metastatic colorectal cancer in France: XELOX versus FOLFOX-6. Oncology. 2010;79(3-4):174-80. 36. Choudhry NK, Denberg TD, Qaseem A. Clinical Guidelines Committee of American College of Physicians. 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Author for correspondence: Shyam Akku, MD, Manager – Global Medical Affairs, Dr Reddy’s Laboratories Ltd, 8-2-337, Road No. 3, Banjara Hills, Hyderabad – 500034 AP, India
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.
Author byline as per print journal: Professor Philip J Schneider, MS, FASHP; Michael S Reilly, Esq
Introduction: To date, the US Food and Drug Administration (FDA) has offered only draft guidance on the naming of biosimilar medicines. The Alliance for Safe Biologic Medicines (ASBM) has asked pharmacists for their views on the labelling and naming of biosimilar medicines. Study objective: To determine the opinions of pharmacists about labelling and naming of biosimilars. Methods: A total of 3,525 pharmacists in the US were invited to complete a survey on the naming and labelling of biologicals. Responses were received from 849 pharmacists, of which 401 completed the survey. Of the pharmacists who completed the survey, 60% worked in hospitals or the healthcare system, 40% worked in retail. Pharmacists were asked for their feedback on a recent FDA non-proprietary biologicals naming proposal. They were also asked what information they would like to see included in a biological product label in order to choose between multiple biosimilars and their reference products. Results: Of the 401 pharmacists who completed the survey, 68% responded that FDA should require a distinct non-proprietary scientific name for every biological product – originator or biosimilar – approved by them. A total of 77% of respondents thought that a manufacturer-specific suffix should be included in the name of each biological product. Respondents considered the following as very important for label inclusion: clinical data to support whether or not the product was a biosimilar and whether or not the biosimilar and originator are interchangeable. Noting that the drug was a biosimilar was considered the most important; whether or not it was interchangeable was slightly less important. Conclusion: A total of 401 pharmacists (11.4% of all those invited) completed the survey. The respondents comprised of 241 hospital pharmacists (60%) and 160 retail pharmacists (40%). Of these the majority of total respondents (68%) think that originator biological and biosimilars should have distinguishable non-proprietary scientific names and 77% think the name should include a unique, distinguishing suffix specific to the manufacturer for future product approval.
Submitted: 28 September 2016; Revised: 28 October 2016; Accepted: 31 October 2016; Published online first: 14 November 2016
Introduction
The market uptake of biosimilars in the US and worldwide will depend on regulatory policies [1], for which an agreed naming and labelling system will be important [2]. A survey of the views of European physicians on familiarity of biosimilar medicines demonstrated the need for distinguishable non-proprietary names to be given to all biologicals [3]. This has been supported by a number of discussions surrounding the development of clear regulation in this area [4–7], and a number of countries across the globe from Latin America [8, 9], Australia [10] and beyond; have called for specific nomenclature to be developed. The results of these surveys reinforce the value of a global naming policy for biologicals and the importance of the World Health Organization (WHO) moving forward with its biological qualifier proposal.
Since the US Food and Drug Administration (FDA) has only distributed draft guidance on the naming of biological medicines [11] and biosimilar labelling [12, 13], feedback from the pharmacists who prepare and dispense them is also important in determining how these drugs are regulated. In Europe, product labelling is seen as important to build user confidence in biosimilars [14]. In response to concerns in Europe, the Alliance for Safe Biologic Medicines (ASBM) invited 3,525 pharmacists in the US to complete a survey that included questions related to the information that could be included in a label, such as whether or not the product was a biosimilar; what analytical/clinical data and clinical similarity data should be present; post-marketing data; approved and non-approved indications; data source; and whether or not it was interchangeable/substitutable.
FDA has proposed a new policy that would require every biological – whether originator or biosimilar – to have a distinct non-proprietary scientific name. Both pharmacists and prescribers concluded that FDA was right to require a distinct non-proprietary scientific name for every biological product – originator or biosimilar – that FDA had approved.
Methods
In 2015, the ASBM invited 3,525 pharmacists in the US to complete a survey on the naming of biological medicines and biosimilar labelling [15], including feedback on FDA draft guidance on non-proprietary biologicals naming [11]. A total of 849 pharmacists replied (a response rate of 24%). Of these, 448 pharmacists were screened out predominately for their lack of knowledge on biologicals or did not complete the survey. A total of 401 pharmacists (11.4% of all those invited) completed the survey, and are collectively termed ‘respondents’. Pharmacists were reimbursed US$22 for completing the survey.
Pharmacists were recruited from a large, global panel of healthcare professionals and were either employed in a hospital/health system pharmacy (60%) or retail pharmacy setting (40%). All 401 pharmacists that completed the study had dispensed biological medicines and had been in practice as a pharmacist for one year or more, see Figure 1.
Pharmacists were asked what information they would like to see included in a biological product label in order to choose between multiple biosimilars and their reference products. Data were analysed using MS Excel, and checked manually.
Results
Use of biological product reference material by pharmacists The majority (64%) of pharmacist respondents were very familiar with the FDA ‘Orange Book’ [16], that is, the resource for Approved Drug Products, with Therapeutic Equivalence Evaluations. The ‘Orange Book’ is a reference that identifies drug products approved on the basis of safety and effectiveness by FDA. One third (29%) of pharmacists refer to this at least weekly, 24% monthly, 6% daily, with the rest referring to it less frequently. In contrast, 28% of respondents had never heard of the FDA ‘Purple Book’ [17], that is, the resource for Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations, and almost 80% of respondents never or infrequently used or referred to it. Information contained in the Purple Book is designed to help enable a user to see whether a particular biological product has been determined by FDA to be biosimilar to or interchangeable with a reference biological product. The results from the survey are outlined below and presented in Tables 1 and 2. Only 2% of pharmacists used the Purple Book daily, 7% of pharmacists used it weekly, 12% of pharmacists used it monthly, 30% of pharmacists used it rarely, and 49% of pharmacists never used the Purple Book at all.
Knowledge of biosimilars Survey participants were asked how familiar they were with biosimilar medicines with the following question:
‘Biosimilar medicines are intended to be copies of already approved biological medicines. They are referred to as “biosimilar” rather than “generic” because they will be similar, but not identical to the product they copy. How familiar are you with biosimilar medicines?’
Of the pharmacists who completed the survey, 57% of respondents said that they were familiar with biosimilars having a basic understanding and 35% said they had a complete understanding. Hospital pharmacists included in the survey reported being the most familiar with biosimilars, with 44% saying they had a complete understanding, while only 23% of retail pharmacists reported having a complete understanding.
Pharmacists were asked about their knowledge of the approval process for biosimilars using the following question:
‘Originator medicines are approved by the US Food and Drug Administration based on an evaluation of clinical data that demonstrates a medicine is safe and effective for the specified indication and data must be provided for every indication. The approval pathway for biosimilars is different than for originator medicines. Are you aware a biosimilar medicine may be approved for several or all indications of the reference product on the basis of clinical trials in only one of those indications?’
The responses suggest that overall knowledge among respondents was good with 86% answering yes (91% hospital pharmacists are more likely to respond ‘Yes’ versus 78% retail pharmacists). When asked if they thought that their understanding of the biosimilar approvals process was acceptable, there was a consensus that this was ‘acceptable’ (27%) or at least ‘somewhat acceptable’ (51%).
Naming knowledge The survey participants were asked questions about their knowledge of the naming of biosimilars and what this meant about how these products could be used. Most respondents (63%) indicated that if biological medicines have the same non-proprietary scientific name, this would imply that the products are identical, with 68% hospital pharmacists are more likely to answer ‘Yes’ versus 57% retail pharmacists. Those respondents would expect the same results from biological medicines with the same non-proprietary scientific name. The majority of respondents (58%) believed that products sharing non-proprietary scientific names could be safely switched from a reference biological medicine to its biosimilar during a course of treatment and the same result would be expected with either of the products. When the same non-proprietary scientific name is used in two biological medicines, 55% of respondents would also assume that the medicines had both been approved for the same indications.
Naming requirements When questioned about how biological naming should be regulated, the majority (68%) of the respondents thought that each product – originator or biosimilar – should have a distinct/unique non-proprietary scientific name. Furthermore, 77% of respondents thought the suffix on a biological medicine name should indicate its manufacturer, rather than a random suffix in future product approvals.
Biosimilar labelling A total of 58% of respondents thought that it was very important that a product label for a biosimilar clearly indicates that it is a biosimilar. They also agreed that labels should include an explanation as to what a biosimilar is. Analytical information resulting from biosimilarity studies should be included, as should any clinical data submitted to FDA and any post-marketing data. There was also a consensus that the label should include reference to the brand name of the originator product.
Participants felt strongly that it should be clear and explicit on the label if a biosimilar product has not been approved for all indications approved for use of the reference product. The label should clearly distinguish data generated from the use of the biosimilar sponsor and that generated by the originator sponsor, and that it is clear which indications were studied with the biosimilar sponsor and which indications were approved based on extrapolation from studies of the reference product. Respondents also felt that labels should clearly include all relevant data used to establish similarity and clearly indicate if the biosimilar is interchangeable with a reference product.
Discussion
The results of this survey of pharmacists are consistent with the results from a survey of physicians in Europe [3]. In both surveys, respondents believed that products sharing a non-proprietary name could be considered identical, could be expected to produce the same results, could be used interchangeably and would be approved for all the indications of the reference product.
Many of the findings in this study support a recent survey sponsored by the Academy of Managed Care Pharmacy (AMCP) [18]. In the AMCP study, more than 60% of participants (62.3%) reported preferring a biosimilar naming convention that uses either a designated suffix (48.1% of all participants) or prefix (14.2% of all participants). Of the 48.1% who would prefer a designated suffix, the vast majority (83.4%) wanted a suffix that was based on the name of the manufacturer. In this survey, 77% of pharmacists expressed a preference for a suffix based on the manufacturer.
To date, FDA is yet to finalize its guidance for the naming of biologicals and labelling of biosimilars. This is a fast-evolving area – following publication of its draft guidance in 2015 and 2016 [11, 12], FDA issued a request for comments on expanding the number of suffixes that biosimilars makers could propose. The request was swiftly withdrawn; following what FDA said was an administrative error [19]. Some have speculated that the agency wanted to extend the comment period, which was originally in July 2016.
The results from surveys like the one described here will aid in the development of a clear and comprehensive system to promote the safe and effective use of biologicals and biosimilars, and as a result facilitate consumer confidence and market uptake in the US.
Conclusion
The pharmacists responding to this survey reported having a good overall knowledge of biosimilars and their approval process. The results suggest that when a biosimilar and the reference product share the same non-proprietary scientific name, it could lead to confusion among pharmacists. This is because two products sharing a non-proprietary name could be considered identical, be expected to produce the same results from both drugs, be used interchangeably, and be approved for all of indications of the reference product. As these are assumptions that cannot be made with biosimilars, pharmacist respondents agreed that all biological products should have unique names and that clear and explanatory labelling of these products should be required.
In general, all issues raised with regards to labelling were considered by pharmacist respondents to be very important for label inclusion. This means that they are supportive of biosimilar products being labelled specifically as such, with the clear inclusion of what a biosimilar product is. There should also be clear information about the analytical studies and clinical studies used for the approval of the product. In cases where the biosimilar is not approved for all indications of the reference product, this should be clearly indicated where these indications are based on extrapolation of the indications approved for the reference product, and whether the biosimilar is interchangeable.
Key points of the 2015 pharmacists naming and labelling survey
All items queried in the labelling survey were considered very important for label inclusion
The fact that a drug was a biosimilar was considered the most important; whether or not it was interchangeable was slightly less important.
68% of pharmacist respondents thought FDA should require a distinct non-proprietary scientific name for every biological product – whether originator or biosimilar – that FDA had approved. 23% of pharmacists did not, and 8% had no opinion.
77% of pharmacist respondents would prefer a suffix on the non-proprietary name, which is indicative of the product’s manufacturer; only 8% of pharmacists had no opinion. 15% of pharmacists thought a random suffix that does not indicate the manufacturer – as recently proposed by FDA – would be best.
Funding sources
The Alliance for Safe Biologic Medicines (ASBM) is an organization composed of diverse healthcare groups and individuals – from patients to physicians, innovative medical biotechnology companies and others – who are working together to ensure patient safety is at the forefront of the biosimilars policy discussion. The activities of ASBM are funded by its member partners who contribute to ASBM’s activities. Visit www.SafeBiologics.org for more information.
Disclosure of financial and competing interests: Mr Michael S Reilly, Esq, Executive Director, is employed by ASBM.
Professor Philip J Schneider is a member of the International Advisory Board of ASBM since 2012 without compensation. From September 2014, Professor Schneider has been the Chair of the International Advisory Board and is paid a small stipend for that role.
This paper is funded by ASBM and represents the policies of the organization.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Professor Philip J Schneider, MS, FASHP
Associate Dean, College of Pharmacy, University of Arizona, Phoenix Biomedical Campus 3384, 1295 N Martin, PO Box 210202, Tucson, AZ 85721, USA
Michael S Reilly, Esq
Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
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BiologicApplications/Biosimilars/ucm411418.htm 18. Tomaszewski D. Biosimilar naming conventions: pharmacist perceptions and impact on confidence in dispensing biologics. J Manag Care Spec Pharm. 2016;22(8):919-26. 19. GaBI Online – Generics and Biosimilars Initiative. FDA withdraws biosimilar suffix proposal aplasia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Oct 28]. Available from: www.gabionline.net/Guidelines/FDA-withdraws-biosimilar-suffix-proposal
Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
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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:
Physicians are pondering the clinical use of biosimilars. A reliance on clinical trials is deeply rooted in the modern healthcare system, whereas comparability and totality of evidence remain unknown concepts. This editorial explores these ideas, with reference to a case study of Italian gastroenterologists.
Submitted: 24 October 2016; Revised: 1 November 2016; Accepted: 1 November 2016; Published online first: 7 November 2016
Europe’s healthcare systems are facing ever-increasing costs. Biologicals, a group of biotechnology-derived therapeutic products, are driving the increasing costs of pharmacotherapy. Unless these increasing costs can be contained, the use of new biological medicinal products could be restricted, even in the wealthiest European Union (EU) Member States.
One means of avoiding such price hikes is developing drugs that are equivalent to brand-name products, but without the patent. Copies of biological products are known as biosimilars. In the EU, cheaper copies of some of the best-selling ‘blockbuster’ biologicals, such as etanercept, infliximab (tumour necrosis factor-alpha [TNF-α] inhibitors used to treat autoimmune diseases such as arthritis) and insulin glargine (a long-acting insulin analogue) have been licensed. Biosimilars to other blockbuster biologicals are in the evaluation or development phases [1]. In the EU, biosimilars are developed according to stringent regulatory requirements and those licensed have been shown to be safe and efficacious after over a decade of use.
In principle, biosimilars have the potential to reduce costs and increase access for important medicines. However, the adoption of biosimilars has faced barriers within the healthcare system. With the exception of infliximab, most of the blockbuster biological drugs are used outside of hospitals, within the community. Thus, physicians are in a key position for increasing the use of biosimilars. Illustrating this point, the paper recently prepared by Annese et al. [2] describes use of biosimilars in the Italian healthcare system, including the difficulties doctors face in accepting biosimilars which often bring economic relief but no direct clinical improvements over existing drugs.
The authors also discuss the Italian health insurance system, which provides pharmacotherapy for citizens. In this system, neither physicians nor patients have an incentive to prescribe and use biosimilars. The system is also fragmented and the use of biosimilars varies between regions. Such variation is difficult to explain by medical or scientific reasons. Together, the lack of incentives and lack of coordination between different regions hinder the rational use of biosimilars. Sadly, this situation is not unique to Italy – healthcare systems across the EU have been poorly prepared for the entry of biosimilars.
As in most EU Member States, the substitution of biosimilars at the pharmacy level is not permitted in Italy. Thus, the decision to initiate treatment with a biosimilar or to switch treatment from the originator drug (reference product) to a biosimilar is normally made by hospitals or individual physicians and patients. The Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) states in its recent concept paper that biosimilars are safe and efficacious and that a switch from a reference product to its biosimilar copy is possible, but leaves the responsibility for the decision to individual physicians [3]. In contrast, local medical societies, such as Italian Society of Rheumatology, Italian Society of Dermatology, and Italian Group of Inflammatory Bowel Disease, are less positive regarding the use of biosimilars, especially when it comes to blockbuster monoclonals, such as those used to treat autoimmune diseases [4, 5]. Thus, on the whole, Italian physicians, like many of their colleagues in other EU Member States, appear to distrust licensed biosimilars.
The paper of Annese et al. illustrates the dilemma from the point of view of gastroenterologists. On the one hand, it is acknowledged that biosimilars may enable cost savings, improve access to treatment and promote sustainable health care. On the other hand, local medical societies and individual physicians are reluctant to recommend the use of biosimilars.
The willingness of Italian gastroenterologists to accept the biosimilar concept was tested after the launch of the first biosimilar monoclonal antibody, infliximab, in Italy. The sore points for clinicians were the extrapolation of safety and efficacy from another therapeutic indication (rheumatoid arthritis) to inflammatory bowel disease (IBD) and the interchangeability of biosimilars and their reference products. Italian gastroenterologists insist that clinical trials must be performed in IBD, even if comparability has been demonstrated on physicochemical, structural, functional, pharmacokinetic, safety and efficacy levels in rheumatoid arthritis.
However, there is good evidence for the interchangeability of biosimilars. Several small, mainly uncontrolled studies have not raised concerns. The preliminary results of a large controlled Norwegian switch study (NOR-SWITCH) of biosimilar infliximab in its major therapeutic indications, including IBD, indicate no significant differences in safety and efficacy to the reference product [6]. These findings, along with the good safety record of EU biosimilars, suggest that biosimilar and reference products can be switched safely.
These results may not satisfy all gastroenterologists. However, it is extremely difficult to detect small differences in drug activity due to the fluctuation in disease course and pharmacokinetics within an individual patient, as well as variation between production batches of biological products. A demonstration of the lack of such minor differences would require very large studies and make biosimilar development unfeasible. Thus, one has to rely on comparability based on the totality of evidence from physicochemical, structural and functional tests as well as from limited clinical studies. Furthermore, Italian gastroenterologists are reluctant to switch a patient to a biosimilar if their disease is being well controlled with the reference product. This is another blow to biosimilars, because a switch to biosimilar infliximab only makes clinical sense in patients who already respond to infliximab therapy.
According to Annese et al., the patient should be informed that the safety profile of a biosimilar is less well known than that of the reference product. They also refer to legislation that requires physicians to choose the safest alternative product. Taking this advice literally would limit prescriptions of not only biosimilars but also generic (small molecule) drugs.
European regulators maintain the position that biosimilars contain a new version of the active substance of its reference product, just as a manufacturing change will create a new version of a biological product. Thus, the fact that the original infliximab has had more than 30 changes to its manufacturing process without any supporting clinical safety and efficacy studies is difficult to reconcile with the Italian position towards biosimilars, which are developed according to the same principles of comparability.
To support their conservative approach to biosimilars, Annese et al. refer to Hippocrates’ oath cited as ‘first, do not harm’. Some scholars of ethics say that Hippocrates actually said, ‘above all, do not harm more than succour’. The situation becomes even more complex if one considers biosimilars at an interpersonal level. Vaccines provide an extreme example of the problem of the concept ‘first, do not harm’. It has been argued that the benefits to the many outweigh the harms to the few [7]. With biosimilars, the harm would be theoretical and the benefit economical.
The current circumstances, whereby the physician is part of the healthcare system and where responsibility for the sustainability of health care, including the costs of pharmacotherapy, lie on administrative and political levels, which is very far from the circumstances that prevailed during Hippocrates’ time. For biosimilars, prescribers need to balance the theoretical harm to patients with the concrete benefit of improving access to medicines. What would Hippocrates’ advice be today – to do nothing or act?
Annese et al. insist that the choice of the therapy, originator or biosimilar, should be left to the physician and the patient. Because of the slow uptake of biosimilars, this view has already been challenged and even overruled in several countries, including some regions in Italy that have issued administrative orders to prescribe biosimilars [2]. A massive and almost complete switch from the original (reference) infliximab product to its biosimilar copy took place in Denmark in 2015, following the recommendation of an official body [8]. Only 11 adverse effects related to the switch of more than 90% of patients treated with the reference product to a biosimilar infliximab were reported even after a stimulated reporting.
It seems clear that healthcare systems will gradually adopt biosimilars, including the switches from the reference products to biosimilars. The important question is: will physicians be part of the solution or part of the problem?
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. European Medicines Agency. Applications for centralised marketing authorisation [homepage on the Internet]. [cited 2016 Nov 1]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000169.jsp&mid=WC0b01ac0580a45420 2. Annese V, Gabbani T, Annese AL. Biosimilars in Italy: a gastroenterologist’s view Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(3):131-3. doi:10.5639/gabij.2016.0503.033 3. Italy’s AIFA outlines challenge of sustainable innovation, proposes important pro-biosimilars change, second concept paper. IHS Markit. 2016 Jun 16. 4. Annese V, Vecchi M. Italian Group for the Study of IBD (IG-IBD). Use of biosimilars in inflammatory bowel disease: statements of the Italian Group for Inflammatory Bowel Disease. Dig Liver Dis. 2014;46(11):963-8. 5. Fiorino G, Girolomoni G, Lapadula G, Orlando A, Danese S, Olivieri I, et al. The use of biosimilars in immune-mediated disease: a joint Italian Society of Rheumatology (SIR), Italian Society of Dermatology (SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG-IBD) position paper. Autoimmun Rev. 2014;13(7):751-5. 6. Moe L. Nor-Switch: – Safe switch to biosimilar. Dagens Medicin. 2016 Oct 17. 7. Sokol DK. First do no harm revisited. BMJ. 2013;347:f6426. 8. Danish Medicines Agency. Special focus on reported adverse reactions to biological medicines and biosimilars. 2016 [homepage on the Internet]. [cited 2016 Nov 1]. Available from: https://laegemiddelstyrelsen.dk/en/news/2016/~/media/FF5865ABAC6D492AB650739216D65DCB.ashx
Author: Adjunct Professor Pekka Kurki, MD, PhD, University of Helsinki, 19 Lukupolku, FI-00680 Helsinki, Finland
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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.
GaBI Journal is an independent and peer reviewed academic journal. GaBI Journal encompasses all aspects of generic and biosimilar medicines development and use, from fundamental research up to clinical application and policies.
