Author byline as per print journal: Jon SB de Vlieger, PhD; Professor Gerrit Borchard, PharmD, PhD; Vinod P Shah, PhD; Beat Flühmann, PhD; Sesha Neervannan, PhD; Professor Stefan Mühlebach, PhD
Abstract:
Comment on the Regulatory paper by Dr Falk Ehmann and Dr Ruben Pita: The EU is ready for non-biological complex medicinal products, published in GaBI Journal, 2016;5(1):30-5.
Submitted: 4 October 2016; Revised: 20 October 2016; Accepted: 24 October 2016; Published online first: 31 October 2016
It is with great interest that we read the publication entitled: ‘The EU is ready for non-biological complex medicinal products’ by Dr Falk Ehmann and Dr Ruben Pita published in GaBI Journal 2016 [1]. In this GaBI Journal paper the authors of the European Medicines Agency (EMA) express their personal view on the policies that the European Union (EU) and EMA have been developing with regard to the regulation of non-biological complex drug (NBCD) products in the EU and on a global scale. The full definition of NBCD products, among which a substantial number of nanomedicines are found, is stated in their paper. As the publication refers to several papers co-authored by us, please allow us to make some comments on the message presented by Drs Ehmann and Pita.
It is a laudable and appreciated initiative of the authors to provide their personal view on the regulatory aspects of NBCD products. The text clearly describes the current framework in which the EU and EMA operate, as well as the global initiatives to harmonize the regulation of NBCD products. However, we would like to ask that the authors consider some points to further the discussion regarding the suitability/degree of adaptation of this regulatory framework in practice and make some recommendations. Our comment is based on the fact that the debate on scientific evidence and understanding of these drugs of high complexity and their related in vivo profiles are still ongoing, which render the selection of appropriate evaluation tools difficult. In our comment we follow the same section headings as used by Ehmann and Pita.
Re: Marketing authorization procedures and the legal basis of submission In several European countries, nano-similars (follow-on versions of nanomedicines and falling under the NBCD definition) have received marketing authorization following national procedures allowing for different appreciation of the complexity leading to different outcomes. Over time, the outcome of clinical studies from independent sources published in reputable journals became available [2–4]. They clearly showed differences in clinical performance between the innovator and follow-on products. Although these findings may have contributed to the generation of EMA referral and reflection papers [5, 6], it did not lead to clear actions of the competent authorities, e.g. to inform the medical community about therapeutic inequivalence. This aspect is of highest importance as such follow-on medicinal products are put on the market mainly to obtain established therapeutics in a ‘generic version’ allowing drug accessibility at a lower price. Given the assumed comparability of quality, safety and efficacy, substitution or interchange may be possible without notification of healthcare professionals or the patient. For NBCDs and their ‘similars’, this does not only interfere with traceability of the dispensed drug product but also has therapeutic consequences for the patient as clinical evidence has shown.
In our view, the approval process of follow-on versions of NBCD products should follow (being mandatory and not optional) the centralized procedure where the combined competence of the large network of EMA experts is directly available, as is the case for biosimilars. This approach guarantees the application of up-to-date scientific knowledge and evaluation tools. Moreover, drafting EMA reflection papers for the approval of NBCD product families such as liposomes, glatiramoids, iron-colloidals and others stimulates discussion and hopefully leads to the introduction of validated preclinical models and/or a request for the performance of clinical studies, if deemed necessary in NBCD guidance protocols. Last but not least, the outcome of independent research showing lack of equivalence of NBCD follow-on versions requires actions from the side of the competent authorities. For example, EMA may follow the example set by the US Food and Drug Administration (FDA) by performing Generic Drug User Fee Amendment (GDUFA) type programmes, including supporting scientific investigations on NBCD related topics [7].
Re: Harmonization of requirements across regions Ehmann and Pita mention current initiatives to harmonize EMA and FDA technical requirements for follow-on medicinal products. For outsiders it is difficult to judge the extent of progress as little information is brought into the public domain. Both EMA and FDA claim that regulatory decisions regarding equivalence should have a strong science base. However, Lipodox, the follow-on version of Doxil (doxorubicin-liposomes) which received marketing approval in the US failed to do so in Europe. Another example is the follow-on versions of low-molecular weight heparins. They are not considered biologicals in the US, but are in Europe, where they are seen as biosimilars. Published reflection papers (EMA) and (draft) guidance documents (FDA) reflect close views from both sides of the Atlantic Ocean but are not always aligned [8, 9]. The World Health Organization (WHO) has taken the initiative to draft a WHO regulatory protocol for biosimilars [10], but has not started such an initiative for NBCD follow-on products. Ehmann and Pita mention other bodies as well (International Pharmaceutical Regulators Forum [IPRF] and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH]), but no concrete results have been reported so far. The scientific basis for regulatory protocols for NBCD products should be further developed with a global discussion platform enabling an open exchange among experts in the field. Special emphasis should be put on the identification of the physicochemical parameters leading to clinically meaningful differences. In Europe, relevant clinical differences of the performance of supposedly equivalent nanomedicine follow-on products compared to the originator drug were described (see above). Very little, however, is known about the experience in other parts of the world. But would this problem be restricted to Europe? Very unlikely so! Here again, one should strive to create a database filled with data on the (pre)clinical outcome of therapy using NBCD follow-on products from all over the world, and published in reputable journals.
Conclusions
In our opinion, the title of the Ehmann and Pita article should be accompanied by a question mark. In principle, EMA may have the legal basis to deal with NBCD products and their follow-on versions, but in practice there is a list of desiderata. On the top of this list are: 1) Strengthening the science base in the public domain to demonstrate equivalence of these products, for Europe as well as for the rest of the world; 2) Taking appropriate actions and guidance when therapeutic inequivalence of products has been proven; 3) Intensifying global harmonization efforts of reflection papers/guidance documents; and 4) Assisting in and support of educational actions to spread awareness and increase knowledge on the topic especially towards healthcare professionals to eventually assure optimal patient benefit by rational and correct drug treatment.
In our view, a harmonized regulatory approval pathway similar to, but distinctly separate from, the ‘biosimilarity pathway’ should be considered. Because of the complex nature of NBCD products, a stepwise comparison of test to reference drug with respect to analytical characterization, animal studies and clinical studies is essential. This will facilitate the assessment of therapeutic interchangeability.
Authors’ comment
The views expressed are those of the authors and should not be understood or quoted as being made on behalf of or reflecting the position of the individual organizations or the NBCD Working Group as a whole.
Competing interests: Authors are Steering Committee members of the NBCD Working Group hosted at the Dutch not for profit organization Lygature, The Netherlands.
Provenance and peer review: Not commissioned; internally peer reviewed.
Authors
Jon SB de Vlieger, PhD
Lygature, 6 Jaarbeursplein, NL-3521 AL Utrecht, The Netherlands
Professor Gerrit Borchard, PharmD, PhD
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, 1 Rue Michel Servet, CH-1211 Geneva, Switzerland
Vinod P Shah, PhD
Pharmaceutical Consultant, 11309 Dunleith Place, North Potomac, MD 20878, USA
Beat Flühmann, PhD
Vifor Fresenius Medical Care Renal Pharma Ltd, 37 Rechenstrasse, PO Box, CH-9001 St Gallen, Switzerland
Sesha Neervannan, PhD
Allergan Plc, RD2-3 A, 2525 Dupont Drive, Irvine, CA 92612, USA
Professor Stefan Mühlebach, PhD
Vifor Pharma Ltd, 61 Flughofstrasse, PO Box, CH-8152 Glattbrugg, Switzerland
Department of Pharmaceutical Sciences, Pharmacenter, University of Basel, 50 Klingelbergstrasse, CH-4056 Basel, Switzerland
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.
The informed, appropriate use of follow-on pharmacological agents can provide significant cost savings for patients and payers. These savings can then be used by governments and patients to increase access to health care. However, the actual savings realized depend on a complex series of factors including how ‘similar’ the products actually are to the innovator products they compete with, at what per cent of the innovator products’ costs they can be purchased, and whether they are prescribed by physicians, accepted by patients, and their costs reimbursed by payers. This issue of GaBI Journal contains a number of manuscripts that illustrate the huge differences in uptake, acceptance and use of follow-on products, both generics and biosimilars, as well as the many methods used to increase their use taken in both different countries and in different regions of the same countries.
The Letter to the Editor by de Vlieger et al. concerns a paper previously published in GaBI Journal 2016 [1] on the European Medicines Agency’s regulatory approach to non-biological complex drugs. This is an important, still evolving, but very important class of agents for which (as is very well explained in the letter) there are still many unclear or unresolved, yet clinically important, regulatory and scientific issues remaining to be clarified.
In Commentary, Mestre-Ferrandiz et al. from the Office of Health Economics in London, UK discuss barriers to the uptake of biosimilars and propose concrete steps that could be taken to overcome these barriers. Based on research published elsewhere by this group they ‘recommend a policy which provides: (1) incentives for budget holders to use safe and effective lower-cost products; (2) market support to collect real world outcomes evidence to increase prescribers’ confidence in biosimilars’.
In the Review Article that follows, Siu and Wyatt present in a not so brief ‘overview of … regulatory, reimbursement, clinician, and patient perspectives’ concerning the still very limited use of subsequent entry biologics (SEBs) in Canada. They conclude that, ‘More support is needed in order to allow stakeholders to fully comprehend the concept of SEBs so that these therapies can be properly evaluated and utilized’.
The lack of such ‘support’ is perhaps responsible for the understandable, relatively slow uptake of high quality, well-studied follow-on biologicals, i.e. true biosimilars, given that the development, testing, regulatory approval of biosimilars are all still relatively new to physicians, payers, regulators and patients. It is less clear however why the use of well-defined, relatively easily characterized, non-biological, generic medicines are not better understood or more widely used. The Review Article by Fontolan et al. documents the rather low and highly variable use of generic medicines in various regions of Italy. The authors claim, based on a summary of questionnaire data they collected, that the low uptake of generics is the result of a series of barriers that result ‘mainly because general practitioners are uncomfortable with generic medicines companies, in particular those whose chain of production is unclear to them’. The authors propose, based on an analysis of the potential economic effects of various changes, that to overcome this problem there needs to be, ‘a clear and definitive commitment of companies to increase production in Italy; a system with equal opportunities for all pharmaceutical companies, with the removal of the obstacles to growth; and an initiative … to promote … reindustrialization processes’. While the economic effects of such changes were well described, it is less clear how much effect they would have on physician, patient or pharmacist’s acceptance or behaviours.
A Perspective paper by Dr Benedicte Lunddahl, discusses a Danish perspective on biological and biosimilar pharmacovigilance programmes that provide the ‘support’ for the uptake of follow-on products. There are many differences between Denmark and Italy other than just size, but the uptake of both generics and follow-on biologicals has been much greater in Denmark than in Italy and many other European Union countries. The differences may be related to the fact that the Danish Medicines Agency has focused on, and continues to evaluate the effectiveness of ‘the pharmacovigilance of biologicals and is implementing an action plan jointly with a working group comprising representatives from the Danish Medical Association, the pharmaceutical industry and the five Danish Regions’. These programmes include attempts to simplify and encourage adverse event reporting, initial and continuous dialogue with all ‘stakeholders’ including patients, and attempts to raise ‘awareness on biosimilarity through targeted information’.
The next Perspective paper by Dr Mathias Flume ‘describes prescription standards and approaches to manage the uptake of biosimilars in Westphalia-Lippe’, Germany. Dr Flume describes how successful Germany in general and this region in particular have been in increasing biosimilar TNF-alpha uptake and argues that this success has been the result of, ‘intensified reporting and increased information supplied to physicians’. This claim is similar to that of Dr Lunddahl in Denmark.
The need to provide the ‘support’ mentioned by Siu and Wyatt, including the targeted, unbiased information distributed in Denmark, is illustrated by the slow uptake of oncology biosimilars in Canada. Two quotes from the Perspective paper by Ms Cherie C Severson from Canada are especially revealing, ‘it is time to re-examine the use of biosimilars in our province and understand if the potential risks outweigh the benefit of cost savings’ and ‘the general consensus regarding the use of biosimilars is to take baby steps’. The author cites problems with interchangeability to answer the question, ‘If biosimilars are more cost-effective and are proven to be safe and equally efficacious while ensuring positive outcomes for patients, the question remains why they are not being utilized more often?’ However, biosimilar interchangeability is a complex, and very separate issue from the use of these products, especially in treatment naïve subjects as discussed in the paper. More widespread use of biosimilars, both in oncology and other patient populations will clearly require greater dissemination of unbiased information to all healthcare practitioners, including the causes of variability in efficacy, immunogenicity and toxicity in both innovator and follow-on products, if the reluctance to use these products is ever to be overcome. The smaller the ‘baby steps’ are, the more limited opportunities to save money and expand access will be and there is growing evidence and real-life experience suggesting that the reluctance to change is seldom justified.
Practitioners’ reluctance to use biosimilars is also evident in the next Perspective paper by Annese et al. who discuss Italian gastroenterologists’ concerns about extrapolation of indications for anti-TNF products. Such concerns should at least be partially lessened by the fact that a growing number of studies have failed to find evidence of any danger posed by the extrapolation of indications when it is based on scientifically valid considerations and common mechanism of action. However, despite recently reported study results that support such extrapolation, the authors express concerns about switching inflammatory bowel disease patients from an innovator product to a biosimilar. They point out that, ‘according to Hypocrates’ oath, doctors are committed to primum non nocere; this means they must know and reiterate information surrounding the safety, efficacy and reliability of any new treatment option to their patients’. However, doctors also have a duty to consider health care availability.
The next paper by my co-editor Dr Robin Thorpe and myself, is a Meeting Report of another GaBI Journal educational conference, this one in Ankara, Turkey that brought together academics, practitioners and regulators to discuss best practices for the evaluation, approval, use and monitoring of biosimilars. These educational conferences are attempts by GaBI to meet its goal of providing unbiased educational information on these topics.
The next Meeting Report summarizes a presentation given by Dr Steven Kozlowski of the US Food and Drug Administration (FDA) at the 2016 Generic Pharmaceutical Association Biosimilars Council Conference held on 6−7 September 2016 in North Bethesda, Maryland, USA. Dr Kozlowski outlined the FDA’s approach to biosimilarity and interchangeability and included the FDA’s ‘definition of biosimilarity, its step-wise approach to the approval process and factors/issues that should be considered when providing scientific justification for extrapolation’.
A Special Report summarizes in detail Dr Leah Christl’s important presentation on FDA’s draft proposal for the naming and labelling of biologicals that is available for public comments.
The final paper is another Special Report summarizing a study by Mr Edward Kong from the Yale University’s Department of Economics in which a ‘discreet game model’ identified, perhaps not surprisingly, the size of the firm, the total available market revenue and the amount of competition as the main factors influencing a manufacturer’s decision to enter a biosimilar market. The effects of financial subsidies, incentives and fixed taxes on competition were also examined.
The editorial staff and I welcome comments from both our readers and our authors about any of the manuscripts or opinions expressed in this and other GaBI Journal issues including comments on how the FDA approach either does or does not deal with their concerns.
Professor Philip D Walson, MD
Editor-in-Chief, GaBI Journal
Reference 1. Ehmann F, Pita R. The EU is ready for non-biological complex medicinal products. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(1):30-5. doi:10.5639/gabij.2016.0501.008
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: Vito Annese, MD; Tommaso Gabbani, MD; Antonio Luca Annese, MD
Abstract:
The introduction of biological therapy has revolutionized the paradigm of treatment in the last two decades. This is expected to lead to corresponding amelioration of the course of several immune-mediated diseases, including inflammatory bowel diseases (IBD). However, this may come with an appreciable increase in expenditure on drugs. Due to ongoing patent expiry of some biologicals, the introduction of biosimilars is creating the opportunity for substantial financial savings to be made, leading to easier, wider and earlier access to therapy for some patients, and possibly to changes in resource allocation by health services. However, the complexity and potential immunogenicity of the first monoclonal biosimilar of infliximab introduced to the market, and the extrapolation of its indications to all diseases approved for the originator, despite the absence of controlled trials in all diseases at time of market authorization, have initially raised concerns in the scientific community. In Italy, the uptake of this biosimilar (CT-P13) is already close to the European mean, although the utilization and regulation at regional levels is highly heterogeneous.
Submitted: 1 September 2016; Revised: 4 October 2016; Accepted: 6 October 2016; Published online first: 19 October 2016
Introduction
In recent years, biologicals have gained significant traction in the pharmaceutical industry, and by 2020 they are predicted to generate US$290 billion in revenue, covering about one third of the pharmaceutical market [1]. In addition, approximately half of sales come from 11 biologicals that face loss of exclusivity over the next seven years [2]. For these reasons, it is expected that the worldwide biosimilars market will reach US$25–US$35 billion by 2020 [3]. This, along with the increasing worldwide focus on improving healthcare access and the reducing cost of care, make biosimilars attractive, but they are also a challenge for stakeholders.
Since the approval of the first biosimilar in the European Union (EU) in 2006, 21 biosimilars have now been approved [4], at least 13 are under evaluation [5] by the European Medicines Agency (EMA), and there are many others in the pipeline globally [6]. In major markets like the EU, regulators and payers have recognized the potential financial benefit of biosimilars and are driving their uptake. The introduction of CT-P13, the first monoclonal antibody (mAb) of biosimilar infliximab on the market, and the forthcoming arrival of many others, has stimulated a great debate and some concerns in the scientific community. The regulatory processes of agencies in the EU and the US (based on what are known as comparability exercises) are rigorous and strict. They are similar to the processes that originator products are subject to following manufacturing changes. The focus of concern is largely on extrapolation to all the indications of the originator, despite the fact that controlled clinical trials of the biosimilar having been performed for only some indications.
In this paper, the Italian National Health Service’s situation and position is analysed. Specific emphasis is given to the gastroenterologist’s perspective, a year after the introduction of CT-P13 for the treatment of inflammatory bowel disease (IBD).
The Italian healthcare system
After World War II, the healthcare system in Italy was funded by health insurance from ‘sickness funds’. As there was a substantial difference in the coverage provided by different funds, and a large proportion of population were uninsured, in 1978, the Servizio Sanitario Nazionale (SSN – Italian National Health Service) was established. As a result, health care is now provided to citizens and residents with universal coverage and receives tax funding through a mixed public-private system. The system is highly decentralized, with 20 Regional Health Authorities (RHAs) which are responsible for planning healthcare services and allocating financial resources. In principle, local autonomy implies stronger financial accountability, which means that regions develop different economic strategies.
Data regarding the evaluation of the performance of the healthcare system are complex and discordant. In Bloomberg’s 2015 ranking of countries with more efficient healthcare systems, Italy is ranked sixth, with a life expectancy of 82.29 years (−0.6 relative to the previous year), cost as per cent of the gross domestic product of 9.02% (+0.12% relative to the previous year), and cost per capita of US$3,155 per person (+US$123 relative to the previous year). However, in the same year, according to the Euro Health Consumer Index, Italy was 22nd in Europe, whereas the OECD (Organisation for Economic Co-operation and Development) survey scored Italy as fourth for life expectancy and 18th for cost expenditure.
The uptake of biosimilars in Italy
The substitution and interchange of biosimilars with biological reference products at the pharmacy level is not permitted by the Italian pharmaceutical system due to possible differences between such products. The official position of AIFA (Agenzia Italiana del Farmaco, Italian Medicines Agency), is that biological medicines and biosimilars cannot be approached in the same way as other generic medicines, with respect to their therapeutic substitutability.
AIFA published a new concept paper on biosimilars for public consultation on 16 June 2016 [7]. This is the second such concept paper issued by the agency, the previous report having been published in 2013. Importantly, although the main elements of the paper are consistent with AIFA’s initial report, the agency did not make any specific reference to prefer the use in the treatment-naïve patients in the second paper. With respect to this, the last concept paper states that all patients should be considered appropriate for treatment with biosimilars. In the latest report, AIFA has now concluded that using a biosimilar instead of the originator is a possibility that should be left to the clinical judgement of the doctor involved. AIFA also concludes that biosimilars offer a favourable opportunity to develop a competitive market, and to aid in the rationalization of public spending.
However, within the biological class, there are ‘simple products (first generation)’ and ‘complex products’ (second-generation) [8]. Here, ‘simple’ refers to those with less structure, instability and changeability, e.g. growth hormones, epoetins and granulocyte colony-stimulating factor (G-CSF); and ‘complex’ refers to monoclonal antibodies [9]. The latter are characterized by greater structural complexity; they are derived from a more complex manufacturing process, which in turn, leads to a higher probability of post-translational changes; and they perform a more critical curative function, as in the case of adjuvant oncology therapy. In the case of biosimilar registration of monoclonal antibodies, it is challenging to assume total overlap and interchangeability with the originators unless post-marketing studies and consistent pharmacovigilance data confirm this in a real world, evidence-based, context.
Based on the 2016 IMS Health report [5], the uptake of ‘simple’ biosimilars in Italy in 2015 ranged from 23% for human growth hormone, to 88% for G-CSF, compared to their originators. However, there were pronounced differences across the country, mainly due to different strategies and regulations at regional levels. In general, Italian gastroenterologists were not impacted by the first ‘wave’ of biosimilars, with the exception of few epoetin prescriptions.
The first mAb biosimilar in Italy
In February 2015, the patent for infliximab expired in Italy and two CT-P13 products, based on the same documentation, are now on the market: Remsima (Celltrion Healthcare Hungary Kft, HU-1023 Budapest) and Inflectra (Hospira UK Limited, Maidenhead, UK). As the infliximab indications approved by EMA are: rheumatoid arthritis (RA), ankylosing spondylitis (AS), adult and paediatric Crohn’s disease (CD) and ulcerative colitis (UC), psoriatic arthritis (PsA), and chronic plaque psoriasis (CPP), the infliximab biosimilar has therefore been licensed for all of these indications. Although biosimilars may lead to significant cost savings, larger access to biologicals and a sustainable level of care in immune-mediated diseases, there was a lack of confidence in the use of biosimilar infliximab for IBD treatment at the time of its launch [10], and concerns had been raised by several national [11] and international societies [12] with regard to extrapolated indications, and especially to switching from the originator.
To date, no randomized controlled trials are available for the use of CT-P13 for treatment of IBD. A randomized, double-blind, parallel group study, the NOR-SWITCH study [ClinicalTrials.gov identifier: NCT02148640], is currently underway in Norway. The purpose of this study is to assess the safety and efficacy of switching from infliximab to the Remsima biosimilar treatment for all indications for which the originator is approved. It has been designed as a non-inferiority study with an estimated completion in May 2016 with the first report due in October 2016. The primary outcome desired is to evaluate the occurrence of disease exacerbation (Δ 30%) in a time frame of 52 weeks. Another study, sponsored by Celltrion, has been designed to assess non-inferiority in efficacy, and to assess overall safety of CT-P13 compared to infliximab in patients with active CD, up to week 54 [ClinicalTrials.gov Identifier: NCT02096861]. This study that enrolled 214 patients will also provide information about switching from infliximab to CT-P13, and from CT-P13 back to infliximab; the study enrolment is now closed, but no data are available yet.
Despite the limited trial data available at present, the uptake of CT-P13 in Italy in 2015, compared to the originator, is already 11%. This is close to the EU mean of 13%, which takes into account 78% uptake in Poland and 100% in Bulgaria [5]. This result has been obtained despite a great heterogeneity of regulation between the 20 RHAs in Italy, which is likely due to either the finances of the local health systems and what is available for pharmacologic expenditure, or more rapid decision-making of some local stakeholders. In two regions, Piemonte and Tuscany, a strict prescription rule has been issued requesting over 65% and 95% of CT-P13 utilization against the originator, respectively. In nine regions across the country, a specific recommendation to use the CT-P13 in all naïve IBD patients has been announced. In the remaining regions there is no specific advice, but it is suggested that patients naïve to anti-TNF products are prescribed the biosimilar in at least 10% of cases. This situation is confusing for doctors and for patients who are often treated in a tertiary referral centre, not in their home region.
The diseases treated with the infliximab biosimilar by gastroenterologists, namely UC and CD, lack a clear-cut effect biomarker, such as haemoglobin or glycaemia. As a result, once starting the therapy with the biosimilar or switching from the originator, a period of months must pass before the clinician might realize that the biosimilar is not working effectively, or is causing a loss of the previously acquired efficacy. Due to the lack of information on efficacy and safety in IBD sufferers and the limited published open label studies [13], a prospective multicentre trial on the use of CT-P13, the PROSIT study, has been promoted by the Italian Group for the study of IBD (IG-IBD). This cohort is still recruiting patients via their web-based platform, and preliminary data were presented at the 2016 European Chron’s and Colitis Organisation (ECCO) [14] and Digestive Disease Week (DDW) meetings. Data from approximately 400 patients, of whom approximately 100 switched from infliximab, so far appear to demonstrate a comparable efficacy and safety when compared to the originator. It is important to note that this was an investigator-driven, non-sponsored trial and to partake, patients signed an informed consent. Paradoxically, the investigators themselves initially had little information on the efficacy or safety profile of CT-P13 for IBD treatment.
It is important that drug safety information is conveyed to patients. Regulations surrounding the compulsory black triangle (included on drug labelling for all new products), apply to both new originator biologicals and newly marketed biosimilars; however, originator biologicals, already on the market, are exempt from needing to include this marker and from being subject to additional monitoring, as they have been on the market for many years and have a proven safety profile. When faced with the choice of new versus old products, doctors must inform the patient when there is no evidence suggesting inferior safety or efficacy of the biosimilar, and also clarify if there are other available drugs with the same active ingredient and a safety profile that is more comprehensively known. However, Italian law unquestionably assigns the final decision over which treatment is administered to the health service operator (not the patient), with the preferential treatment option being that safest for the patient and the operator is completely liable for the choice of treatment adopted. In this context, it is worth noting that, of a sample of 150 gastroenterologists who took part in the IG-IBD’s online anonymous survey, only half responded that they feel completely free to decide whether or not the infliximab biosimilar should be prescribed (Annese V 2016, personal communication, October 3).
In view of the arrival of other biosimilars of infliximab, and in the near future those of adalimumab, it is critical that patients and clinicians retain the freedom of choice over therapy adopted, especially in cases where patients are doing well while receiving a specific drug, either originator or biosimilar. In the future, we may see that there are many biosimilars of the same originator on the market, and that every 6–12 months a new, less expensive biosimilar will be added or, paradoxically, we may see the originator becoming the more economic treatment option. Either scenario could lead to the situation of multiple possible treatment switches.
Conclusion
The ‘biosimilar era’, unlike the non-biological one, is still in its infancy and is likely to increasingly dominate the market. There is no doubt that manufacturing processes and reverse protein engineering have made substantial progress in the last decade, and that the new generation of biologicals and biosimilars are much more completely investigated and evaluated by regulatory agencies globally. This should result in fewer impurities, less heterogeneity among batches and higher consistency. However, according to Hippocrates’ oath, doctors are committed to ‘primum non nocere’ or ‘first, do no harm’; this means they must know and reiterate information surrounding the safety, efficacy and reliability of any new treatment option to their patients. Although the cost and cost-effectiveness of health care are important, patients facing more complex and potentially life-threatening diseases, especially when they are doing well with a specific treatment (either originator or biosimilar), have the right to receive all available information concerning the potential consequences of switching once or multiple times whenever a new, less expensive compound is being considered for use.
Conflict of interest: None.
Provenance and peer review: Commissioned; externally peer reviewed.
Co-authors
Tommaso Gabbani, MD
Antonio Luca Annese, MD
Department of Emergency, Unit of Gastroenterology, Careggi University Hospital, 3 Largo Brambilla, IT-50134 Florence, Italy
References 1. Di Biasi S. Searching for terra firma in the biosimilars and non-original biologics market: insights for the coming decade of change. Pharmaphorum. 2014. 2. Lawrence S, Lahteenmaki R. Public biotech 2013 – the numbers. Nat Biotechnol. 2014;32(7):626-32. 3. Deloitte. Biosimilars in global markets [homepage on the Internet]. [cited 2016 Oct 4]. Available from: http://www2.deloitte.com/us/en/pages/life-sciences-and-health-care/articles/gx-winning-with-biosimilars-oppties-global-mkts.html 4. GaBI Online – Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Oct 4]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe 5. IMS Health. The Impact of Biosimilar Competition. June 2016 [homepage on the Internet]. [cited 2016 Oct 4]. Available from: https://www.imshealth.com%2Ffiles%2Fweb%2FIMSH%2520Institute%2FHealthcare%2520Briefs%2FDocuments%2FIMS_Institute
_Biosimilar_Brief_March_2016.pdf&usg=AFQjCNHR4wvboi0hCXU745cW2lt_tiJYiQ&sig2=MJFX-U_SUZtov7QUZtfGEg 6. Global biosimilars pathway and clinical development activity: where are the biosimilars hotspots? Genetic Engineering & Biotechnology News. 2014. 7. Agenzia Italiana del Farmaco. Secondo concept paper AIFA su farmaci biosimilari. 15 June 2016 [homepage on the Internet]. [cited 2016 Oct 4]. Available from: http://www.agenziafarmaco.gov.it/it/node/20049/ 8. Gascon P. The evolving role of biosimilars in haematology-oncology: a practical perspective. Ther Adv Hematol. 2015;6(6):267-81. 9. Pasina L, Casadei G, Nobili A. Biological agents and biosimilars: essential information for the internist. Eur J Intern Med. 2016;33:28-35. 10. Danese S, Fiorino G, Michetti P. Viewpoint: knowledge and viewpoints on biosimilar monoclonal antibodies among members of the European Crohn’s and Colitis Organization. J Crohns Colitis. 2014;8(11):1548-50. 11. 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. 12. Danese S, Gomollon F, Governing Board and Operational Board of ECCO. ECCO position statement: the use of biosimilar medicines in the treatment of inflammatory bowel disease [IBD]. J Crohns Colitis. 2013;7(7):586-9. 13. Ben-Horin S, Casteele NV, Schreiber S, Lakatos P. Biosimilars in inflammatory bowel disease: facts and fears of extrapolation. Clin Gastroenterol Hepatol. 2016 May 20. pii: S1542-3565(16)30212-9. doi:10.1016/j.cgh.2016.05.023. [Epub ahead of print] 14. Fiorino G, Manetti N, Variola A, et al. Prospective observational study on inflammatory bowel disease patients treated with infliximab biosimilars: preliminary results of the PROSIT- BIO cohort of the IG-IBD. J Crohns Colitis. 2016;10(Suppl 1):S376-7.
Author for correspondence: Vito Annese, MD, Department of Emergency, Unit of Gastroenterology, Careggi University Hospital, 3 Largo Brambilla, IT-50134 Florence, Italy
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
A study of the factors influencing generics makers’ decision on whether to enter a specific market found that firm size, market revenue and expected competition all had an effect. Market size was also positively associated with the entry of more generics. The effect of a financial subsidy on generics entry was also investigated.
Submitted: 27 September 2016; Revised: 29 September 2016; Accepted: 3 October 2016; Published online first: 17 October 2016
Prescription drug spending is estimated to have accounted for 16.7% of the US$2.7 trillion spent on healthcare in 2015.
In theory, an increase in the use of generics should help to reduce overall drug expenditures. However, growth in spending on medicines in the US increased by US$46.2 billion, or 12.2%, over 2014 levels, reaching US$425 billion in 2015 [1]. This increase comes despite a simultaneous growth in spending on generics, which increased by US$7.9 billion (7.4%) to US$114.1 billion in 2015.
One possible explanation for the increase in spending on medicines could be a lack of price competition between generics makers. This could be due to insufficient generics makers entering certain drug markets. A possible deterrent to entry could be the expected competition from other generics makers. This so-called ‘competitive effect’ is an important, however, complex factor for policymakers to understand. Competitive effects are challenging to identify, especially when considering that since markets with many generics makers (and therefore more competition) are usually profitable for many different reasons.
Mr Edward Kong, Research Assistant at the Yale University, Department of Economics, carried out a study into the factors that influence a generics maker’s decision to enter a specific market [2].
The decision of whether to enter the market for a particular drug is complex and strategic, and the factors that influence firms’ entry decisions are not fully understood. In the generics industry, larger markets have been documented to support more generics entrants. It has also been found that firms tend to enter markets for drugs that are similar to those for which they have previous experience. It has been estimated that experience in a drug market can reduce a firm’s cost of entering a similar market in the future by 7% on average. This supports the hypothesis that specialization allows firms to mitigate the risk of over entry (a phenomenon where multiple firms enter the same market and all make reduced profits).
In his approach Mr Kong uses a static model of generics entry based on discrete-choice. His model assumes that firms only have incomplete information about their competitors and allows for firm heterogeneity. It includes market size as an important regressor and assumes that entry decisions are made simultaneously across firms in a ‘one-shot game’ for each market. The competitive effect is estimated in a discrete game model, which allows the importance of competition to be established relative to other factors such as market size.
Data on generics entry and revenue data for abbreviated new drug approvals (ANDAs) for high-revenue drugs approved between 2004 and 2014 was included in the analysis. Data was collected from the US Food and Drug Administration’s (FDA) Orange Book, market revenue data from the Top 100 Drugs list from Drugs.com and firm revenue data.
The results showed that market size is positively associated with the entry of more generics. ‘This effect is strong and robust to the inclusion of controls for the ‘age’ of the market and later new drug application (NDA) approvals.’ The results showed that ‘a 1% increase in sales predicts a significant increase of about three generics entrants (ANDAs), or equivalently, 11 drug products’. Mr Kong concluded that ‘market size is an important predictor of generics entry’.
Factors affecting a generics maker’s decision to enter a specific market were found to include firm size (measured as firm revenue), market revenue and expected competition (other generics entries). In fact, the effect of expecting an additional competitor was found to be similar to a US$540 million decrease in market revenues of the brand-name product.
Mr Kong found that ‘the expectation of one additional competitor reduces the probability of entry by 10% on average’. On the other hand, a US$1 billion increase in market revenue increased the likelihood of a generics firm entering the market by 18.4% on average.
The effect of a financial subsidy on generics entry was also investigated. In the US the 180-day period of exclusivity carries a significant financial incentive, as it allows the generic drug to temporarily operate as a duopoly with the brand-name drug. Consequently, according to Mr Kong, many firms seek ‘Paragraph IV’ entry.
Mr Kong found that when using his discrete game model, giving a subsidy to all generics makers resulted in an increase in competition. ‘With a subsidy, all firms have more incentive to enter, but they also realize that the equilibrium probability of competitor entry has also increased, which tapers the overall effect of the subsidy.’ He also found that a fixed tax on entry, although reducing entry, also reduced competition, therefore having less effect on decreasing entry than expected.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
Michelle Derbyshire, PhD, GaBI Online Editor
References 1. GaBI Online – Generics and Biosimilars Initiative. Spending on medicines in the US increases again in 2015 [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Sep 29]. Available from: www.gabionline.net/Reports/Spending-on-medicines-in-the-US-increases-again-in-2015 2. Kong E. Estimating competitive effects in firm entry with applications in the generic pharmaceutical industry. Yale University Department of Economics; 3 April 2016.
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.
Introduction: Canada is among the leading spenders in pharmaceuticals. Based on projected figures, the cost of pharmaceuticals is expected to rise by another 6–12% by 2023. Approximately CAN$4.6 billion of healthcare funding is spent on biological drugs (including growth factors and monoclonal antibodies) which are commonly used in the setting of haematology and blood and marrow transplant. Aim: As healthcare funds become more scarce, a need to investigate cost-effective alternatives at both the federal and provincial levels to provide cancer care is imperative. Discussion: Biosimilars, also known as ‘subsequent entry biologics’ (SEBs), are cheaper alternatives to biological drugs. Biosimilars have been utilized in many European countries for years with significant cost savings and no significant reporting of adverse events. In Canada, there is a reluctance to use biosimilars due to the potential risk of adverse effects which can occur if the biosimilar is interchanged with the originator product. In keeping with this reasoning, Alberta’s stance is against substitutability or interchangeability of biosimilars/SEBs with the reference product. Conclusion: For the benefit of cost-effective, quality cancer care, it is time to re-examine the use of biosimilars in our province and understand if the potential risks outweigh the benefit of cost savings.
Submitted: 30 August 2016; Revised: 13 September 2016; Accepted: 14 September 2016; Published online first: 27 September 2016
Based on a trade agreement with the European market, Canadian drug costs are among the highest in the world, second to the US [1]. In addition, through the Comprehensive Economic Trade Agreement (CETA) with the European Union, Canadian pharmaceutical costs are expected to increase further by another 6.2–12.9% by 2023 [1]. One class of drugs which erodes our healthcare dollars is biologicals [2]. Biologicals are relatively large complex molecules [drugs] synthesized from living organisms or their products, especially a human or animal protein, such as a hormone or antitoxin, that is used as a diagnostic, preventive, or therapeutic agent [3]. Examples of biologicals include interferons, interleukins, monoclonal antibodies, growth factors, vaccines and some polypeptides [3]. The present drug expenditure on biological medicines in Canada is valued at CAN$4.6 billion [4]. According to Betito, spending on biologicals has increased by more than 200% in less than a decade [4]. While biologicals represented only 1% of (benefit) claims in 2015, they accounted for nearly 21% of total prescription drug spending [4]. These figures are significant to provincial and Canadian healthcare systems in settings such as haematology and blood and marrow transplant where often biologicals such as filgrastim are commonly used. Although essential to many cancer treatments, biologicals are expensive treatments and pose a great burden on healthcare expenditure. The need for more cost-effective measures is imperative to healthcare systems, insurance providers, healthcare providers and patients. One cost-effective strategy is the use of biosimilars [5].
What are biosimilars?
Biosimilars, also referred to as ‘subsequent entry biologics’ (SEBs), are not generic drugs. They are manufactured from living organisms and although similar to their originator drug, biosimilars/SEBs are not identical in composition [5, 6]. They are rigorously evaluated on a case-by-case basis prior to regulatory approval [5, 6]. Regulatory bodies provide approval based on robust comparability exercises demonstrating similarity with the originator product [5, 6]. Similarity is demonstrated on the basis of biochemical characterization, i.e. purity, chemical identity, protein structure and receptor on/off kinetics, biological activity and clinical similarity for at least one indication [5, 6]. Biosimilars/SEBs must demonstrate that the mechanism of action and the receptor involved being identical to those of the originator [6]. They are further evaluated to ensure safety, efficacy (through pharmacodynamics and pharmacokinetics testing) and cost benefit [6]. The significance of implementing the use of biosimilars in Canadian cancer care systems relates to cost savings and easier access to pharmaceuticals and treatments for Canadian cancer patients. If biosimilars are more cost-effective and are proven to be safe and equally efficacious while ensuring positive outcomes for patients, the question remains why they are not being utilized more often?
Interchangeability of biosimilars versus the originator biological
The use of biosimilars in Canadian provinces continues to be controversial. Some of this controversy stems from the uncertainty of whether biosimilars/SEBs are considered interchangeable with the originator biological. Varying definitions of the word ‘interchangeable’ may occur in different countries and differing regulatory bodies. ‘Interchangeability’ refers to a biological product which is a biosimilar to the reference product; it is expected to produce the same clinical result as the reference product in any given patient and the risk in terms of safety and diminished efficacy of switching back and forth with the reference product, is not greater than the risk of using the reference product without any such switch occurring [7, 8]. Although Health Canada has the authority to approve the use of biosimilars on a case-by-case basis, the authority to decide whether a biosimilar is substitutable or interchangeable with the reference biological lies at the provincial level and differs from province to province [8]. In the US, generic medications are often interchangeable meaning they can be switched back and forth (at the pharmacy level) with the reference product during the course of a patient’s treatment [7]. This can be done at a lower cost without any long-term adverse effects. However, biosimilars are not generics, they differ slightly in composition and must be deemed ‘interchangeable’ with their reference product via US Food and Drug Administration (FDA) approval before they can be substituted without the consent of the prescribing physician [8]. Health Canada does not deem a drug interchangeable [8]. Once again, this is a decision made at the provincial level and it is up to prescribing physicians to make this decision [8]. This is due to the fact that the composition of a biosimilar is not exactly alike as their reference product leading to a risk of an adverse effect occurring [8]. At this time, Health Canada does not support the substitutability of an SEB for a brand-name biological [9] at the pharmacy level. Alberta shares Health Canada’s position and is the only province that has taken the stance against substitutability or interchangeability of biosimilars/SEBs due to the potential risk of adverse effects in the long term [9].
The occurrence with Erythropoietin
One example why certain provinces are reluctant to use biosimilar products is the adverse effect which occurred with the biological drug erythropoietin (EPO) [8]. Erythropoietin is used to stimulate the production of red blood cells in patients with treatment induced anaemia and other chronic disorders. After almost a decade of using two different EPO’s on the Canadian market, a number of patients across the country developed an antibody-mediated immune response causing pure red blood cell aplasia [8]. After further investigation it was discovered that the adverse effect occurred for only one of the EPO’s on the Canadian market suggesting both EPO’s were not interchangeable [8]. The purpose of this paper is not to discuss the details of the issues surrounding EPO. It is however to highlight that the concern of a similar occurrence happening with the use of a biosimilar exists in Canada at both the federal and provincial level.
Appreciably, this concern is understandable; the affordability of biological pharmaceuticals is inevitably rising and therefore other viable options need to be examined. One Canadian study reports the cost saving for the use of switching to an SEB EPO in a nephrology setting is between CAN$35–CAN$50 million dollars annually [10]. Furthermore, the projected cost savings between 2015–2019 are estimated to be approximately CAN$221 million [10]. The question which remains is what is the risk of an adverse effect in the long term occurring and does this risk outweigh the benefit of cost savings?
The impact on the use of biosimilars The answer to this is not certain in Canada. It is well documented that biosimilars have been used in the European market for years and continue to currently be in use [10, 11]. The cost savings reported related to the use of biosimilars in different European countries is astronomically beneficial [11]. According to the European Commission, since Europe introduced biosimilars back in 2006, there have been no reports of untoward effects or unexpected adverse events compared with the originator products [12]. Biosimilar filgrastim commonly used in the setting of haematology and blood and marrow transplant is reported in the European market as leading the way when it comes to market penetration, reaching market shares as high as 60–80% across Europe [11]. Between 2008–2014, nine different versions of biosimilar filgrastim have been licensed and all but one is in use in Europe [11]. One was removed for commercial reasons [11]. One biosimilar granulocyte colony-stimulating factor (G-CSF) also known as Zarzio recently approved in the US in the setting of haematology and blood and marrow transplant is used in over 40 countries worldwide [13]. In fact, it is considered the number one biosimilar filgrastim used globally [13]. The reluctance in healthcare providers, although slowly dissipating, still exists. In March of 2016, Health Canada approved the first SEB/biosimilar of Neupogen named Grastofil [4]. Although it is up to each provincial government to decide if they will approve the use of Grastofil and whether it can be interchangeable with the originator product, it appears at least the movement toward implementing the use of biosimilars may be slowly shifting. The impact of these decisions being made at the provincial level suggests that all Canadians may not have the same access to these pharmaceuticals, possibly delaying treatment due to economic reasons. One Alberta physician believes that biosimilars should not be interchangeable [due to safety reasons] [9]. The same physician believes a solution to this issue is that governments should add biosimilars/SEBs onto their [formulary] plans while still covering biologicals [9]. Thus, placing only biological naïve patients on biosimilars so that the risk of adverse effects in the long term is not an issue and similarly, patients who are currently on innovator biologicals would not receive biosimilars [9]. Although this may not reduce the cost of biologicals as much as it could, it may be a step in the right direction towards relieving a currently overstretched healthcare budget and achieving access for some patients in the province.
The general consensus regarding the use of biosimilars is to take baby steps. The need to examine alternatives to reducing healthcare costs demonstrates Canadian healthcare providers’ commitment to fiscal responsibility whilst still ensuring safety, efficacy and quality care. Although biosimilars have been in use in the European market for 10 years and more recently in the American market (such as Zarzio), Canadian provinces continue to evaluate and re-evaluate the safety, cost benefit and general access for the public [11]. With more experience and understanding from the European and American markets, it appears that a shift in Canadian thinking (and other countries) related to the use of biosimilars may be occurring. In March 2016, Apotex launched the first biosimilar/SEB approved in Canada named Grastrofil [4]. This will impact the setting of haematology and bone marrow transplant as Grastrofil is a biosimilar growth factor used to treat neutropenia [4]. The decision of whether this Canadian approved biosimilar will be in the formulary in each province is currently individualized, meaning only certain patients will have access to the biosimilar. Currently, Alberta does not support the interchangeability of SEBs/biosimilars with the originator [9]. Therefore, the benefits for haematology and blood and marrow transplant patients including lower cost, faster access to treatment and overall quality of care could be compromised if the perspective is not re-evaluated [9]. Since formulation of the pan-Canadian Pharmaceutical Alliance (pCPA) in 2010, all 13 provinces and territories including the federal government have joined as of January 2016 [14]. The pCPA strives to negotiate pharmaceutical costs at a national level and as of April 2016 have released some guiding principles through beginning policy frameworks and national processes concerning the consistent negotiations of biosimilars/SEBs in Canada [14]. The leaders of the alliance admit that much work still needs to be done before a more comprehensive policy framework can be cemented [14]. Therefore, the decisions related to the interchangeability of biosimilars with the innovator biological will remain at the provincial level. We will have to wait for each province to reveal their decision if biosimilars such as Grastofil will become formulary and how that decision will impact haematology and blood and marrow transplant patients and cancer care as a whole.
Competing interests: The author declares that she has no financial or other disclosures to report for this paper.
Provenance and peer review: Not commissioned; externally peer reviewed.
References 1. Lexchin J, Gagnon MA. CETA and pharmaceuticals: impact of the trade agreement between Europe and Canada on the costs of prescription drugs. Globalization and Health. 2014;10:30. 2. Dörner T, Strand V, Cornes P, Goncalves J, Gulacsi L, Kay J, et al. The changing landscape of biosimilars in rheumatology. Ann Rheum Dis. 2016;75(6):974-82. doi:10.1136/annrheumdis-2016-209166 3. Morrow T, Felcone LH. Defining the difference: what makes biologics unique? Biotechnol Healthc. 2016;1(4):24-9. 4. Betito E. Launch of key biosimilar medicine to help save healthcare budgets. CNW. 2016 Mar 31. Available from: http://www.newswire.ca/news-releases/launch-of-key-biosimilar-medicine-to-help-save-healthcare-budgets-574119711.html 5. Severson C. The role of biosimilar granulocyte colony stimulating factor (GCSF) Zarzio for progenitor cell mobilization and the treatment of therapy-induced neutropenia in adult hematopoietic stem cell transplantation, Can Oncol Nurs J. 2015;25(4):443-8. 6. Bonig H, Becker PS, Schwebig A, Turner M. Biosimilar granulocyte-colon-stimulating factor for healthy donor stem cell mobilization: need we be afraid? Transfusion. 2015;55(2):430-9. 7. US Food and Drug Administration: Protecting and promoting your health. Christl L. FDA’s overview of the regulatory guidance for the development and approval of biosimilar products in the US [homepage on the Internet]. [cited 2016 Sep 13]. Available from: www.fda.gov 8. Klein A, Wang J, Bedford P. Subsequent entry biologics (biosimilars) in Canada: approaches to interchangeability and the extrapolation of indications and uses. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(3):150-4. doi:10.5639/gabij.2014.0303.033 9. Milne V, Laupacis A, Tierney M. Regulators grapple with Canada’s first generic biologic drug. Healthy Debate. 2015 Jan 25. Available from: http://healthydebate.ca/2015/01/topic/seb-biosimilar-biologics 10. Biosimilars by region: Canada. Quintiles. Available from: http://www.quintiles.com/microsites/biosimilars-knowledge-connect/biosimilars-by-region/canada 11. Biosimilars by region: Europe. Quintiles. Available from: http://www.quintiles.com/microsites/biosimilars-knowledge-connect/biosimilars-by-region/europe 12. European Commission. Consensus Information Document. What you need to know about biosimilar medicinal products [homepage on the Internet]. [cited 2016 Sep 13]. Available from: http://www.medicinesforeurope.com/wp-content/uploads/2016/03/biosimilars_report_en.pdf 13. GaBI Online – Generics and Biosimilars Initiative. Biosimilars of filgrastim [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Sep 13]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-of-Filgrastim 14. How the pan-Canadian pharmaceutical alliance works. 2016 May 6. Benefits Canada. Available from: http://www.benefitscanada.com/benefits/health-benefits/how-the-pan-canadian-pharmaceutical-alliance-works-81307
Author: Cherie C Severson, RN, MN, CON(C), BMTCN, Calgary, Alberta T3K 5S3, Canada
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:
The US Food and Drug Administration (FDA) outlines its approach to biosimilarity and interchangeability at the 2016 Generic Pharmaceutical Association Biosimilars Council Conference. Topics covered include the FDA definition of biosimilarity, its step-wise approach to the approval process and factors/issues that should be considered when providing scientific justification for extrapolation.
Submitted: 22 September 2016; Revised: 27 September 2016; Accepted: 29 September 2016; Published online first: 12 October 2016
In his presentation at the 2016 Generic Pharmaceutical Association (GPhA) Biosimilars Council Conference, which was held in North Bethesda, USA on 7–8 September 2016, Dr Steven Kozlowski, Director of the Office of Biotechnology Products at the US Food and Drug Administration (FDA), outlined the agency’s view with respect to biosimilarity and interchangeability [1].
The Biologics Price Competition and Innovation Act (BPCI Act) of 2009 creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product.
FDA finalized its two overarching guidance documents on scientific and quality considerations in demonstrating biosimilarity, as well as two further guidances on questions and answers for biosimilars and formal meetings between FDA and sponsors in 2015 [2]. The agency has subsequently released further draft guidance documents. These cover subjects including clinical pharmacology data, reference product exclusivity, additional biosimilars questions and answers, non-proprietary naming [3], labelling, and implementation of the ‘Deemed to be a License’ provision of the BPCI Act. FDA also expects to issue draft guidances on both biosimilarity and interchangeability in the near future [4].
According to Dr Kozlowski, the goal of an FDA review of a biosimilar is to demonstrate biosimilarity between the proposed product and a reference product. The goal is not to independently establish the safety and effectiveness of the proposed product.
FDA defines biosimilarity as:
•that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and
•there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency of the product.
FDA has indicated that biosimilarity must first be established before any studies into interchangeability can be performed. Once biosimilarity has been established drugmakers can then decide whether to further pursue interchangeability or not. This approach, however, has raised questions as to what would happen if a product was deemed not interchangeable [5].
A biologicals application [351(a)] is a ‘stand-alone’ application that contains all information and data necessary to demonstrate that the proposed product is safe, pure and potent. In contrast, an application submitted under section 351(k), i.e. for a biosimilar, needs to demonstrate that the proposed product is biosimilar to the reference product. For licensure, a proposed biosimilar relies on (among other things) comparative data with the reference product, as well as publicly-available information regarding FDA’s previous determination that the reference product is safe, pure and potent.
When considering biosimilars applications, FDA has stated that it will consider the totality of the data and information submitted in the application and that it intends to use a risk-based approach to evaluate all available data and information submitted.
To prove analytical similarity the agency considers the following to be important:
• Extensive structural and functional char-acterization
• Understand the molecule and function
• Identify critical quality attributes and clinically active components
• Understand the relationship between quality attributes and the clinical safety and efficacy profile aids ability to determine residual uncertainty about biosimilarity and to predict expected ‘clinical similarity’ from the quality data.
A step-wise approach should then be used to generate data and evaluate residual uncertainty. In this way analytical studies should be followed by animal studies, then clinical PK/PD (pharmacokinetic/pharmacodynamic) studies, then clinical immunogenicity assessment and finally additional clinical studies.
With respect to extrapolation, FDA guidance outlines factors/issues that should be considered when providing scientific justification for extrapolation including, for example:
• The mode of action(s) in each condition of use for which licensure is sought
• The PK and bio-distribution of the product in different patient populations
• The immunogenicity of the product in different patient populations
• Differences in expected toxicities in each condition of use and patient population
• Differences between conditions of use do not necessarily preclude extrapolation
As of 31 July 2016, 62 programmes were in the Biosimilar Product Development Program. The agency has also received meeting requests to discuss the development of biosimilars for 20 different reference products.
Competing interests: None.
Provenance and peer review: Article prepared based on the presentation of Dr Steven Kozlowski, US FDA; internally peer reviewed.
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Abstract:
Biosimilars of tumour necrosis factor-alpha (TNF-α) inhibitors, such as infliximab or etanercept, have recently entered the market. The management of these new products by the healthcare systems differ between European countries, and there may be regional differences within countries. This paper describes prescription structures and approaches to manage the uptake of biosimilars in Germany. Findings show that, through intensified reporting and increased information supplied to physicians, their uptake is strongly supported.
Submitted: 10 August 2016; Revised: 27 September 2016; Accepted: 30 September 2016; Published online first: 14 October 2016
Biological pharmaceuticals have become increasingly important in medical treatment over the past 15 years [1]. They have opened up relevant, new treatment options in many areas, including oncology and nephrology, and also in anti-inflammatory treatment.
Anti-inflammatory biologicals are commonly offered as original preparations with annual treatment costs of more than Euros 20,000 per patient in Germany [2]. As a means of managing this financial burden on the healthcare system, and to finance new medications, it is important to have alternative treatment options available following patent expiry, and to use these actively. This paper describes how this process has occurred to facilitate the use of biosimilars, and also presents the current prescribing governance of tumour necrosis factor-alpha (TNF-α) blockers.
Biosimilars have a comparable pharmacologic effect to their respective reference products. However, neither biosimilars nor sequential batches of the same reference product exhibit a 100% identical structure. A highly differentiated approval process has therefore been established for biosimilars in Europe, through the European Medicines Agency (EMA), which ensures the quality, efficacy and also the comparability of biosimilars with their reference products.
This paper focuses on regional experiences in Westphalia-Lippe, part of the German Federal State North Rhine-Westphalia. Currently, this region has seven million patients with statutory health insurance (SHI). The number of people in Germany with SHI is 70 million and this region represents approximately 11% of the German population [3].
At a regional level, the first approved biosimilars, such as epoetins, were actively managed. The response to these new products in this case study region was positive, and a significant proportion of prescriptions were switched to biosimilars without any problems being reported. The proportion of biosimilar prescriptions is, on average, over 60% today [4]. Of particular importance to governance are biosimilars of the TNF-α inhibitors, infliximab and etanercept, which have been available since 2015 and 2016, respectively. Regionally, the prescribing cost for infliximab in 2015 was almost Euros 30 million in Westphalia-Lippe. This presents an important saving potential, as the sum is only 1% of the regional overall pharmaceutical budget. Regional prescription management attempts to take advantage of potential savings, especially if they are achievable without changing treatment paradigm or quality. As such, biosimilars represent a simple and proven opportunity for savings here.
Regional experiences with TNF-α biosimilars
At a regional level, we have long been working with quotas for biosimilars, such as epoetins, somatropins, introduced since 2006. Historically, this has worked well with biosimilar epoetins prescribed by nephrologists or oncologists. Currently, TNF-α biosimilars are also primarily managed with quotas in this case study region. However, challenges occurred with physicians, who include gastroenterologists, dermatologists and rheumatologists, as they had no experience of prescribing biosimilar infliximab.
Assessment of new biosimilar management in this region today is therefore limited by comparison to the experience of the management of biosimilars that have been available for a longer time period. Here, in the case study region, we have established different methods of actively informing doctors and supporting market entry by providing extensive information to physicians and conducting regular reporting, it has been possible to gain a high acceptance for the prescribing of biosimilars. From our perspective, this supports the hypothesis that doctors have a high level of trust in the decisions made by approval authorities like EMA. Issues, such as the extrapolation of indications, were practically irrelevant at a regional level. On the other hand, there was a high level of sensitivity among doctors to the available information on savings potentials in relation to reference products.
Figure 1 displays the fast uptake of infliximab biosimilars prescriptions, but also marks the significant regional differences.
Nationwide observations, see Figure 2, show relevant differences in the prescription patterns. These are taken from ZI, an official scientific institute of the German physicians associations which also analyses prescription data from public pharmacies for SHI patients [5, 6]. It is an official and accepted source of information in Germany. We believe that active management and transparent information, inthe case study region, arethe main reasons for high biosimilar uptake. Other regulations in place to manage prescriptions are similar in all the federal countries of Germany, which is thought to be a cause of lower relative uptake.
Initial experience of managing the biosimilar etanercept indicates that a solid foundation has previously been laid by providing broader information and allowing for successful management of biosimilars in general. As a result, etanercept biosimilars are prescribed significantly more often in the case study region, see Figure 3.
Conclusion
The prescription uptake of TNF-α biosimilars shows regional differences. Experiences in Westphalia-Lippe indicate that practical information and management of biosimilars can enable a high level of acceptance and prompt switching to biosimilars in practice. Initial data on etanercept seem to reflect uptake levels of infliximab that was introduced successfully at an earlier date.
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
References 1. Schwabe U, Paffrath D. Arzneiverordnungs-Report 2015. Springer-Verlag Berlin Heidelberg; 2015. p. 24-5. 2. Schwabe U, Paffrath D. Arzneiverordnungs-Report 2015. Springer-Verlag Berlin Heidelberg; 2015. p. 513. 3. GKV-Spitzenverband [homepage on the Internet]. [cited 2016 Sep 27]. Available from: https://www.gkv-spitzenverband.de/presse/zahlen_und_grafiken/zahlen_und_grafiken.jsp#lightbox 4. GKV-Spitzenverband. Rahmenverträge zur Arzneimittelversorgung. Rahmenvorgaben nach § 84 Abs. 7 SGB V. Arzneimittel – für das Jahr 2017 vom 30 September 2016. Page 11 [homepage on the Internet]. [cited 2016 Sep 27]. Available from: https://www.gkv-spitzenverband.de/krankenversicherung/arzneimittel/rahmenvertraege/rahmenvertraege.jsp 5. ZI – Zentralinstitut für die kassenärztliche Versorgung [homepage on the Internet]. [cited 2016 Sep 27]. Available from: http://www.zi-berlin.de/cms/index.php 6. AG Pro Biosimilars. Grafik des Monats Juli 2016. [cited 2016 Sep 27]. Available from: http://proBiosimilars.de/presse/grafik-des-monats-juli-2016/
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Abstract:
There is considerable concern and debate over the naming of biologicals and labelling of biosimilars. To ensure that patients receive the safest and most effective treatment, it is paramount that clinicians, prescribers and patients themselves have the relevant information regarding drug treatment. In response to concerns over how biologicals and biosimilars should be named and labelled, the US Food and Drug Administration has issued two sets of guidances that are set to pave the way for consistent and unified product naming and labelling.
Submitted: 7 September 2016; Revised: 15 September 2016; Accepted: 20 September 2016; Published online first: 3 October 2016
Pharmaceutical naming convention: the background
The World Health Organization (WHO) established the use of international non-proprietary names, or INNs, that are assigned to active pharmaceutical substances, in the 1950s. These INNs are used in drug regulation, prescribing, labelling, dispensing, pharmacopoeias, pharmacovigilance and in scientific literature. For chemical pharmaceuticals, the assignment of INNs has been relatively straightforward to date [1].
In general, an INN will contain some information related to the active substance in the product and, as such, the word it forms will be uncommon or unfamiliar. It is typically made up of a prefix of up to three syllables, which is followed by a suffix. The suffix is also a stem that indicates any chemical and/or pharmacological relationships between products. Additionally, there may be sub-stems that give further drug-relationship information. When new drugs are developed that do not belong to a known stem, a new suffix is created [1].
Biological drugs, or biologicals, are complex biological molecules. As a result, these have required the creation of new stems and new naming methods or guidelines. The process of naming biosimilars has further increased naming complexity and to date, many different and inconsistent conventions have been applied worldwide [2]. Often, a biosimilar may share the same name as the reference product, and this, together with naming inconsistencies, has led to concern over the strength of the INN system currently in place [2].
US FDA naming and labelling guidances
The US Food and Drug Administration (FDA) has issued two draft guidance documents [3–5] in which it outlines how non-proprietary (un-trademarked) biological products should be named, and how biosimilar products should be labelled. At present, the guidances are not finalized and FDA is receiving input from a variety of stakeholders prior to finalization.
This paper summarizes the draft naming and labelling guidances and has been prepared based on the presentation of Dr Leah Christl from FDA [6].
Biological nomenclature and FDA
FDA aims to introduce the use of proper names for all biological products [3]. Through this, the use of designated suffixes for individual biological products, irrespective of their licensure pathway, is hoped to become routine in ordering, prescribing, dispensing, record-keeping and pharmacovigilance practices. This nomenclature is outlined in detail below. It is also thought that this will aid in prevention of the development of inaccurate perceptions related to the safety and efficacy of such products that can arise from knowledge of their licensure pathway.
FDA position on ensuring product safety
Product safety is of paramount importance in the treatment of patients. FDA has outlined that it is vital that originator biological products, related biological products and biosimilar products can be distinguished. This is because related biological products may be licensed for different indications, and biosimilar products are not always licensed for all originator indications. In addition, related biological products and biosimilar products may not be licensed for all the routes of administration and may be packaged in different delivery systems, e.g. pre-filled syringe instead of a vial, to that of the originator product is.
Through the inclusion of FDA designated suffixes, inadvertent substitution of products can be avoided. FDA states that the products will be distinguishable and so, only products that have been approved as interchangeable biologicals or biosimilars for a particular indication, will be used when switching treatments. This will also avoid any accidental alternating between different biological products that share the same name.
FDA position on enhancing product pharmacovigilance
Pharmacovigilance practices monitor the effects of products after licencing. This ensures that previously unreported adversities can be identified, monitored and evaluated. Traditionally, products are identified by proprietary name, non-proprietary name, manufacturer, national drug code (NDC) number, lot number, and billing codes. However, for both active and passive pharmacovigilance, it can be difficult to track adverse events and determine the product manufacturer, site of production, or lot, when a biological product has the same proper name as other biological products. Through the application of proper names, as described by the FDA guidance [3], the designated suffixes are hoped to facilitate the precise identification of a biological that has been associated with any adverse events. This will ensure improved knowledge and understanding of safety issues and allow for a more targeted agency response.
FDA proposal for standardized nomenclature of biologicals
FDA defined how biologicals should be named in the draft guidance: Nonproprietary Naming of Biological Products [3]. This draft guidance states that each product will have a proper name that is made up of a core name, hyphenated to a suffix that is composed of four lowercase letters:
Proper name: core name + suffix
The core name is shared among biological products that contain related drug substances, e.g. filgrastim, epoetin alpha, in a similar manner to the stems of INNs. The four lowercase letters that make up the suffix should be unique to the product and not have any known meaning.
For example, for products that share the fictitious core name biologicamab, the proper names would be as follows:
• Originator biological product: biologicamab-cznm
• Related biological product: biologicamab-rzbh
• Biosimilar product: biologicamab-hixf
In addition to the requirements of the suffix as outlined above, FDA has laid out guidelines for what the suffix should not contain or resemble. It should not be in any way promotional, and as such have the potential to be misleading in terms of safety and efficacy. It is also important to ensure that suffixes are not to be confused with other elements of a prescription and therefore should not be the same, or too similar to, other abbreviations used in clinical and medical practice. They should not contain or imply any drug name or core name that has already been designated by the United States Adopted Name (USAN) council. To further reduce the risk of any potential medical or prescription errors, the name should not contain, or be similar to, the name of any other drug product currently on the market, nor should it have a suffix too similar to any other product’s suffix designation.
FDA proposes that this convention should be applied to all biological products licensed under the Public Health Service (PHS) Act. As such, this would include both previously licensed and newly licensed products, together with innovator, related biological and biosimilar products. However, there is still some debate surrounding whether the non-proprietary name of an interchangeable product should have a unique suffix, or share that of its reference product.
Within the draft guidance, FDA put forward some product exceptions that would not need to use the naming convention. These are outlined by this statement: ‘The draft guidance does not apply to biological products for which a proper name is provided in the regulations, e.g. 21 CFR part 640, or to certain categories of biological products for which there are well-established, robust identification and tracking systems to ensure safe dispensing practices and optimal pharmacovigilance (ISBT 128 for cord blood products)’ [6].
The need for regulated biologicals labelling
There is also concern over the labelling of both biologicals and biosimilars. With respect to biosimilars, new and consistent methods of naming need to be devised in order to avoid incorrect drug administration, increase pharmacovigilance and also facilitate education of biosimilar usage. Product labelling exists to communicate information related to a product’s safety and effectiveness to healthcare providers. It is thus vital that it is clear, understandable and specific, to ensure adequate treatment.
The educational requirement has been evidenced in a number of studies, including a recent survey in which physicians in Europe were questioned on their familiarity with biosimilar medicines [7]. The outcome of the study highlighted the need for distinguishable non-proprietary names to be given to all biologicals, including biosimilars. This is of particular importance as biosimilars differ from reference products in their structures but the active substance of a biosimilar has the same amino acid sequences [8]; and may not be approved for all the indications approved for the reference product. This is of particular importance for clinicians and patients who are considering switching drugs, and correct and adequate information on labels will facilitate a safe switch.
Labelling biosimilars in Europe
Biosimilar use was approved in Europe prior to approval in the US. However, no naming convention or labelling outline for biosimilars has been established in Europe to date. In 2015, a survey was conducted by the European Association for Bioindustries (EuropaBio) in which physicians expressed an explicit desire for more information to be displayed on the labels of biosimilar products [9]. In February 2016, a multi-stakeholder meeting was held by the European Biopharmaceutical Enterprises (EBE) and EuropaBio, in which aspects of the requirements for consistent and understandable labelling of biosimilars were discussed. Again, a major focus of this meeting was to ensure that clinicians, prescribers and/or patients receive adequate information to ensure safe and efficient use of the drug products [10].
Labelling biosimilars in the US
FDA biosimilar labelling guidance The general principles behind prescription drug labelling are to provide a summary of the essential scientific information needed by healthcare practitioners for the safe and effective use of a drug, and the labelling reflects FDA’s finding of safety and effectiveness for the drug under the labelled conditions of use and facilitates prescribing decisions, thus enabling the safe and effective use of drugs and reducing the likelihood of medication errors.
Biosimilar products are developed to demonstrate biosimilarity to reference licensed products. As such, data supporting the licensure of biosimilars would generally not be designed to independently demonstrate safety and efficacy. In March 2016, FDA issued a draft guidance on Labeling for Biosimilar Products [4]. FDA has outlined recommendations for the product labelling of biosimilars pertaining only to the prescribing information to ensure patients are well-informed with regard to the products available to them. In the draft guidance, it is proposed that those submitting biosimilar product applications under section 351(k) should develop draft labels which incorporate the data and information from the reference product labelling, with the addition of any biosimilar product-specific modifications, specific labelling recommendations for interchangeable biological products are not provided in this guidance.
Biosimilarity statement FDA has recommended the inclusion of a biosimilarity statement. This should be on the line immediately beneath the initial US approval date in Highlights, that informs the product is biosimilar to the reference product. A sample of such a statement is given below:
‘BIOSIMILAR PRODUCT’S PROPRIETARY NAME (biosimilarproduct’s proper name)] is biosimilar* to [REFERENCE PRODUCT’S PROPRIETARY NAME (reference product’s proper name)] for the indications listed.’ (1).
The asterisk is to draw attention to the footnote that states:
*Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product.
The guidance also indicates that the statement should conclude with a cross-reference to the INDICATIONS AND USAGE section ‘(1)’ the Full Prescribing Information, which contains further, more detailed information.
Example of the statement of a fictitious product NEXSYMEO:
NEXSYMEO (replicamab-cznm) is biosimilar* to JUNEXANT (replicamab-hjxf) for the indications listed. (1)
Specific recommendations for labelling of biosimilar The relevant data and information from the reference product labelling that should be incorporated into the biosimilar product labelling will depend on whether the applicant is seeking approval for all conditions of use, e.g. indication(s), dosing regimen(s), or fewer than all conditions of use of the reference product for the biosimilar product. As such, FDA makes further recommendations to take this into account in the biosimilar labelling.
For biosimilar containing certain differences to the reference product, the labelling may include information specific to the biosimilar product in which differences in administration, preparation, storage, or safety information that do not otherwise preclude a demonstration of biosimilarity. A biosimilar product label may also include its conformity to the Physician Labelling Rule (PLR) and/or the Pregnancy and Lactation Labelling Rule (PLLR), as reference product labelling may not be required to conform to these requirements.
Where the biosimilar product labelling is based on the reference product labelling, text can be similar but need not be identical and should reflect the currently available information necessary for the safe and effective use of the biosimilar product.
Use of biosimilar/reference product name and core name in labelling As is outlined for all biological products identification, the proper names will be composed of the core name and a unique suffix. Identification of a specific product, whether that be by biosimilar product name, reference product name or core name, will be dependent on the context in which the information is presented.
Use of biosimilar/reference product name If the biosimilar product has a proprietary name, FDA recommends that the proprietary name be used.
If a proprietary name is not available for the biosimilar product, the biosimilar product’s proper name (the non-proprietary name designated by FDA in the licence for a biological product licensed under the PHS Act) should be used.
FDA recommends the use of the biosimilar product name in circumstances that:
– information described is specific to the biosimilar product, for instance, the sections of INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, DOSAGE FORMS AND STRENGTHS, DESCRIPTION, and HOW SUPPLIED/STORAGE AND HANDLING.
– directive statements and recommendations for preventing, monitoring, managing, or mitigating risks, for instance, statements typically included in the BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS sections.
FDA states that the reference product’s proper name should be used when clinical studies or data derived from studies with the reference product, e.g. adverse reactions, clinical studies, are described in the biosimilar product labelling.
Use of core name FDA also outlined that the core name should be used in labelling when overall risks and benefits profile of the reference product is also relevant to the biosimilar product. This should include the risk of any adverse reactions or effects seen following administration of the reference product, even if these are not known to be observed with the biosimilar product.
In the labelling section, when a risk applies to both the biosimilar product and reference product, FDA advises that the core name of the reference product be used with the addition of the word ‘products’, i.e. replicamab products, to imply that the information is relevant to both products. This would be included in sections such as a boxed warning, contraindications, warnings and precautions, adverse reactions (post-marketing experience).
Use of more than one product name FDA notes that there are circumstances in which it may be necessary to use more than one form of the product identification approaches in the labelling to accurately convey information. An hypothetical example where the use of the three naming approaches is presented below:
Replicamab products can cause hepatoxicity and acute hepatic failure. In clinical trials of replicamab-hjxf, 10% of patients developed elevated ALT or AST greater than three times the upper limit of normal and 5% progressed to acute hepatic failure. Evaluate serum transaminases (ALT and AST) and bilirubin at baseline and monthly during treatment with NEXSYMEO …’
When considering which name to use – biosimilar product name, reference product name or core name – FDA advises:
‘All text in biosimilar product labeling, even sections that have been based on reference product labeling, should be carefully evaluated for the most appropriate product identification approach.’
FDA’s opinion of their labelling approach
With respect to FDA’s approach on biosimilar labelling, Dr Leah Christl, Associate Director for Therapeutic Biologics and lead of the Therapeutic Biologics and Biosimilars Staff in the Office of New Drugs, stated ‘We think that our approach to biosimilar labeling will be truly beneficial to healthcare providers as they consider prescribing options and the risk–benefit decisions for their patients. The biosimilar labelling guidance has been issued in draft to provide an opportunity for public comment and we hope to hear from the various stakeholder communities – industry, healthcare providers and patients. We will review and consider all of the comments received as we work to finalize guidance on this topic’ [11].
Summary
In recent years, the naming of biological and biosimilar products has become increasingly complex and is inconsistent throughout the world. This has also led to confusion over how such products should be labelled, and there is particular concern over differentiation between biosimilar products and their reference products in labelling.
FDA has issued two draft guidance documents in which they outline the proposed methods for biological product naming and biosimilar product labelling. The guidances are comprehensive and convey clear instructions for naming and labelling, to facilitate the use of these products and ensure correct administration to patients. They aim to be able to give all required information to clinicians and patients to ensure the safe and effective use of products.
At present, the guidances are in draft format and FDA hopes to receive feedback on them from a variety of stakeholders before the nomenclature and labelling guidelines are finalized.
Competing interests: None.
Provenance and peer review: Article prepared based on the presentation of Dr Leah Christl, US FDA; internally peer reviewed.
Alice Rolandini Jensen, MSci, GaBI Journal Editor
References 1. Robertson JS. The challenges of nomenclature – INN, biosimilars and biological qualifiers. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):110-2. doi:10.5639/gabij.2015.0403.025 2. Alexander EA. The biosimilar name debate: what’s at stake for public health. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(1):10-2. doi:10.5639/gabij.2014.0301.005 3. U.S. Food and Drug Administration. Guidance for industry. Nonproprietary naming of biological products. August 2015 [homepage on the Internet]. [cited 2016 Sep 15]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf 4. U.S. Food and Drug Administration. Guidance for industry. Labeling for biosimilar products. March 2016 [homepage on the Internet]. [cited 2016 Sep 15]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf 5. GaBI Online – Generics and Biosimilars Initiative. FDA issues draft guidance on naming biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Sep 15]. Available from: www.gabionline.net/Guidelines/FDA-issues-draft-guidance-on-naming-biologicals 6. Christi L. U.S. Food and Drug Administration update: implementation of the Biologics Price Competition and Innovation Act of 2009. 14th Annual Biosimilar Medicines Group Conference; 28-29 April 2016; London. 7. Dolinar RO, Reilly MS. Biosimilars naming, label transparency and authority of choice – survey findings among European physicians. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(2):58-62. doi:10.5639/gabij.2014.0302.018 8. Kurki P. Biosimilars for prescribers. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(1):33-5. doi:10.5639/gabij.2015.0401.008 9. GaBI Online – Generics and Biosimilars Initiative. Doctors want more details in biosimilars labelling [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Sep 15]. Available from: www.gabionline.net/Biosimilars/Research/Doctors-want-more-details-in-biosimilars-labelling 10. EuropaBio 2015 [homepage on the Internet]. [cited 2016 Sep 15]. Available from: http://www.europabio.org/healthcare-biotech/publications/results-first-ever-european-biosimilars-labelling-survey 11. U.S. Food and Drug Administration. Christi L. From our perspective: biosimilar product labelling [homepage on the Internet]. [cited 2016 Sep 15]. Available from: http://www.fda.gov/Drugs/NewsEvents/ucm493240.htm
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Abstract:
This paper discusses the findings and summary of items covered in the First Turkish interactive workshop on regulation and approval of similar biotherapeutic products/biosimilars, in which structure–function was highlighted as a key issue.
Submitted: 4 June 2016; Revised: 7 September 2016; Accepted: 15 September 2016; Published online first: 28 September 2016
Introduction
This interactive workshop was held on 2–3 March 2016 at the Hacettepe University in Ankara, Turkey using an almost identical format to what was used in prior educational workshops as reported in GaBI Journal. For more details of methods and case presentations, see the published report of the First Latin American educational workshop on similar biotherapeutic products [1] and the First MENA educational workshop on regulation and approval of similar biotherapeutic products/biosimilars [2].
The workshop was organized in collaboration with the Faculty of Pharmacy, Hacettepe University. Presentations were made by both international speakers as well as local academic faculty, clinicians and Turkish regulators. After the formal presentations (as done in the prior two workshops referenced above), the audience was presented with data for two semi-fictional follow-on biotherapeutic products, one a recombinant human erythropoietin (EPO) and the other a monoclonal anti-TNF antibody. The audience was divided into groups; each of which was asked to discuss specific questions about the potential approval of one of the two proteins under the direction of two to three local, university faculty and regulatory experts. The list of speakers and the slides they presented and the slides used to summarize the quality and clinical trial performance of the two products, are all available on the GaBI Journal website (www.gabi-journal.net/about-gabi/educational-workshops).
Summaries of parallel working group discussions are presented below.
Group 1 and 2 Summary
Groups 1 and 2, who were assigned to evaluate the EPO product, chose to work together rather than separately. The specific questions they were asked and an edited simplified summary of their responses are presented in Table 1.
General summary information of Group 1 and 2 discussions is presented in Table 2.
Discussion/Conclusion of Group 1 and 2
EPO is one of the important glycosylated therapeutic proteins. Glycosylation patterns have effects on immunogenicity and half-life of therapeutic proteins by influencing the active clearance of a protein. Glycosylation is dependent on the number of sialic acid residues attached to the protein molecules. Glycans and sialic acids have effects on receptor binding and serum half-life. Serum half-life of the therapeutic proteins increase when the number of sialic acid residues increases. Glycosylation increases blood half-life but decreases receptor binding.
After manufacturing changes such as manufacturing site and method, the influence of in vitro potency activity should be evaluated. As sialic acid content and lactosamine extension is increased, serum half-life of the product is extended but receptor-binding affinity is decreased. Although the pharmacokinetic profile of the product could be estimated since the serum half-life of the product is known; potency values in patients could not be presumed because of the small differences which have an effect on receptor binding. Some bioassay parameters such as receptor binding and cell proliferation studies should be evaluated for estimating potency values in patients. Sialic acid content differences may increase potency values. Thus, increasing the degree of sialylation and glycosylation decreases the renal clearance rate and can increase EPO in vivo activity.
The structural characteristics of the therapeutic product such as glycosylation and product or process related impurities have effects on quality and immunogenicity of the protein product. Clinical immunogenicity is a key factor to determining safety and efficacy of biosimilars. It is important to note that only clinical studies are appropriate for detecting immunogenicity and for evaluation of clinical safety, at least 12 months of human immunogenicity data should be obtained.
Group 3, 4 and 5 Summary
The three groups who evaluated the IgG1 anti-TNF monoclonal antibody SBP candidate did so separately. The specific questions they were asked followed by the edited, simplified summaries of their individual group responses are presented in Table 3.
Group 4 included further summary information, see Table 4.
Discussion/Conclusion of Group 3, 4 and 5
Despite the large and growing number of products being approved and marketed worldwide as ‘biosimilars’, there continues to be a lack of consensus concerning the best practices for the evaluation, approval, use and post-marketing surveillance of follow-on biologicals. While there were areas of general agreement in the case evaluations done by the participants in this workshop, there were many differences in participants’ responses and opinions from the participants concerning whether these two fictitious follow-on biologicals were qualified to be called biosimilars. This has also been seen in GaBI’s similar workshops.
These differences are likely a reflection of the fact that this is a relatively new area of pharmaceutical science and both the number of products and the information becoming available about the proper definition, approval, monitoring, substitution and switching of follow-on biological products are increasing rapidly. The lack of consensus suggests that academics and regulators, as well as prescribers and patients, need to be provided with the training and unbiased information needed for them to properly approve or regulate, prescribe, or use follow-on biological products, i.e. biosimilars.
Speaker Faculty and Moderators
Speakers Dr Elwyn Griffiths, DSc, PhD, UK
Professor Dr Ibrahim C Haznedaroğlu, Turkey
Dr Sundar Ramanan, PhD, USA
Dr James S Robertson, PhD, UK
Dr Robin Thorpe, PhD, FRCPath, UK (Chair)
Dr Meenu Wadhwa, PhD, UK
Çisem Başak Budak, Turkey
Professor Philip D Walson, MD, USA/Germany (Co-Chair)
Moderators and Co-moderators
Dr Aydan Eratalay, PharmD, PhD
Bilgen Beldüz, MSc
Dr İsmail Burak Bal
Professor Dr Nazan Bergişadi, PhD
Fikriye Handan Çelikel, MSc
Assistant Professor Dr Devrim Demir Dora, PharmD, PhD
Professor Dr Türkan Eldem, Dr Nat Sci
Professor Dr R Neslihan Gürsoy, PhD
Dr Enes Karabulut, MD
Professor Dr Nefise Ozlen Şahin, PhD
Professor Dr Semra Şardaş
Professor Dr Sevda Şenel, MSc, PhD
Gökçe Yildirim
Editor’s comment
Assistant Professor Dr Devrim Demir Dora of Faculty of Pharmacy/Department of Pharmaceutical Biotechnology at Hacettepe University and Dr Aydan Eratalay from the Turkish Medicines and Medical Devices Agency had read the report, provided the discussion/conclusion of Group 1 and 2 and revised content of Table 2.
Professor Dr Sevda Şenel of Faculty of Pharmacy/Department of Pharmaceutical Technology at Hacettepe University had reviewed Group 3 discussions detailed in Table 3, and confirms that the summary reflects perfectly what has been discussed and decided.
Professor Dr R Neslihan Gürsoy of Faculty of Pharmacy at Hacettepe University had read Group 4 report detailed in Table 3, and commented that it was well prepared.
Professor Dr Türkan Eldem of Faculty of Pharmacy/Department of Pharmaceutical Biotechnology at Hacettepe University had reviewed Group 5 discussions detailed in Table 3 and made a few updates.
Acknowledgements
The Generics and Biosimilars Initiative (GaBI) wishes to thank Professors Bülent Gümüşel and Neslihan Gürsoy of the Hacettepe University for their strong support through the offering of advice and information towards the development and preparation of this interactive workshop.
The authors would like to acknowledge the help of all the workshop speaker faculty and participants, each of whom contributed to the success of the workshop and the content of this report, as well as the support of the moderators and co-moderators: Dr Aydan Eratalay, Bilgen Beldüz, Dr İsmail Burak Bal, Professor Dr Nazan Bergişadi, Fikriye Handan Çelikel, Assistant Professor Dr Devrim Demir Dora, Professor Dr Türkan Eldem, Professor Dr R Neslihan Gürsoy, Dr Enes Karabulut, Professor Dr Nefise Ozlen Şahin, Professor Dr Semra Şardaş, Professor Dr Sevda Şenel, Gökçe Yildirim, in facilitating meaningful discussion during the parallel case study working session, presented the discussion findings at the workshop and contributed in the finalization of this Meeting Report.
Competing interests: The workshop was sponsored by an unrestricted educational grant to GaBI from Amgen Inc.
Provenance and peer review: Commissioned; internally peer reviewed.
Co-author
Robin Thorpe, PhD, FRCPath
Deputy Editor-in-Chief, GaBI Journal
References 1. Walson PD, Thorpe R. First Latin American educational workshop on similar biotherapeutic products, Mexico City, Mexico, 20 January 2015. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):143-8. doi:10.5639/gabij.2015.0403.031 2. Walson PD, Thorpe R. First MENA educational workshop on regulation and approval of similar biotherapeutic products/biosimilars, Dubai, United Arab Emirates, 1 September 2015. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(4):173-7. doi:10.5639/gabij.2015.0404.039
Author for correspondence: Professor Philip D Walson, MD, Editor-in-Chief, GaBI Journal
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Abstract:
Biological molecules represent a significant portion of therapies utilized in Canada. Biosimilars, also known as subsequent entry biologics (SEBs) in Canada, are highly comparable versions of the originator products. Over the next few years, a number of patents for innovator biologicals will expire in Canada and this creates a tremendous opportunity for the entrance of SEBs. In Canada, SEBs must first be evaluated via Health Canada’s SEB regulatory pathway. Following approval, SEBs must also be assessed for cost-effectiveness by the national health technology assessment agency, Canadian Agency for Drugs and Technologies in Health (CADTH) under the Common Drug Review (CDR) or pan-Canadian Oncology Drug Review (pCODR) processes. CDR and pCODR provide reimbursement recommendations to the provincial/federal public drug plans and cancer agencies. At the time of this writing, multiple SEBs have been approved by Health Canada. Although SEBs are approved after thorough evaluation by regulatory agency, there are concerns expressed by various medical communities, specifically regarding issues of indication extrapolation and interchangeability. The purpose of this paper is to provide a brief overview of the current status of SEBs in the Canadian context, as well as potential lessons that can be learned from European authority on SEBs.
Submitted: 16 August 2016; Revised: 1 September 2016; Accepted: 1 September 2016; Published online first: 14 September 2016
Introduction
Biologicals are a class of drug that is derived from living organisms [1]. The majority of biologicals are utilized in the areas of oncology, inflammatory diseases and diabetes [2–4]. According to a recent report published by the University of British Columbia, the per capita spending on biologicals for inflammatory conditions alone in Canada have more than doubled from CAN$18 in 2007–2008 to CAN$45 in 2012–2013 [5], which contrasts with relatively stable overall per capita spending for all prescription drugs (CAN$661 and CAN$656 in 2007–2008 and 2012–2013, respectively) [5]. In 2010, spending on biologicals was approximately CAN$3 billion, which constituted 14% of the Canadian pharmaceutical market. It is expected to grow to about 20% by the end of the decade, creating substantial financial impact for public and private payers.
A large number of patents for high cost innovator biologicals are set to expire in Canada within the next 10 years, e.g. Avastin, Herceptin, Humira, Lucentis, Rituxan. This will lead to the rapid development of subsequent entry biologics (SEBs). For a review of the current list of innovator biologicals set to expire in Canadaand SEBs in development, please refer to a report published recently by the Canadian Agency for Drugs and Technologies in Health (CADTH) [6]. Introduction of SEBs may lead to increased access for many patients, although SEB developers face many challenges prior to having their products reach patients. This paper provides an overview of the current regulatory and health technology assessment (HTA) environments for SEBs in Canada,positions of various medical and disease associations, as well as lessons that can be learned from Europe to increase uptake of SEBs. Please note that the terms ‘biosimilar’ and ‘SEB’ will be used interchangeably in this paper.
Regulatory framework for SEBs in Canada
Federal Around the time of the approval of the first SEB in the European Union (EU) (Omnitrope) in 2006, Health Canada released an SEB Factsheet [1], which signalled the development of the first SEB regulatory guideline in Canada. In March 2010, the Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs) was released [7]. The term ‘subsequent entry biologic’ is defined as ‘a biologic[al] drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic[al] drug. An SEB relies in part on prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to the reference biologic[al] drug and which influences the amount and type of original data required’.
Because biologicals are produced in living organisms, and they are highly sensitive to process changes, it is virtually impossible to make identical copies of these protein-based therapeutics. Therefore, an important consideration for SEBs is that they are not ‘generic biologicals’. Many characteristics associated with the market authorization process use for generic pharmaceutical drugs do not apply. As a result, SEBs cannot be considered pharmaceutically or therapeutically equivalent to the reference biological products.
Under the Health Canada SEB pathway, the SEB manufacturer presents a reduced clinical and non-clinical package to show that the SEB is highly comparable to the reference biological via a series of comparability exercises, e.g. analytical testing and biological assays. This is particularly important for SEB manufacturers since additional clinical/non-clinical requirements would add significant time (7–8 years) and cost (US$100 million to US$250 million) to develop an SEB compared to small-molecule generics (US$1 million to US$4 million) [8]. As discussed later, the importance of demonstrating physicochemical and in vitro functional comparability between the SEB and the reference biological is also a key for the approval of indication extrapolation (the granting of indication approved for the reference biological to the SEB without conducting clinical trial for that indication).
In December 2015, Health Canada issued a consultation to stakeholders on a revised Information and Submission Requirements for Subsequent Entry Biologics (SEBs) guidance documents [9, 10]. Key revisions included addition of further guidance with respect to considerations in the selection of a reference biological drug; additional detail with respect to considerations when performing non-clinical and clinical studies for SEBs, including discussion with respect to immunogenicity, the use of the most sensitive population in clinical trial design and a new section on extrapolation; and a new section which promotes early consultation with Health Canada, as well as the launch of three-year pilot for SEB Scientific Advice Meetings to allow for discussion of an SEB with Health Canada early in the development process [9]. The latter addition is very much similar to the European Medicines Agency’s (EMA) scientific advice and protocol assistance process [11], suggesting Health Canada’s continuing effort to harmonize its SEB regulatory process with other international agencies.
Health technology assessment of SEBs in Canada
The Canadian drug plan market is a mix of public and private systems. Public drug plans make extensive use of HTA as part of the reimbursement decision-making process. Eligible non-cancer prescription drugs approved by Health Canada are reviewed by the Common Drug Review (CDR) and the Institut national d’excellence en santé et en services sociaux (INESSS; province of Quebec only) [12, 13]. In contrast, eligible approved cancer drugs are reviewed by the pan-Canadian Oncology Drug Review (pCODR) [14]. INESSS also reviews eligible cancer drugs. Both the CDR and pCODR are part of the CADTH that provides reimbursement recommendations that are considered by participating public drug plans. The province of Quebec does not participate in the CDR and the pCODR process.
In the fall of 2009, CADTH initiated a pilot project specific to the submission and evaluation of SEBs due to the different regulatory data requirements (CDR Update – Issue 59, released 30 June 2009). The purpose of the pilot project was to determine the requirements for SEB submissions, establish a review framework, and learn about Health Canada’s approach. The pilot project was to be evaluated after three SEBs had been reviewed and stakeholders’ feedbacks were to be sought at the end. The first SEB submitted under this pilot process was Omnitrope, see extended discussion that follows. However, four years later, no other SEBs had been submitted; and because multiple SEBs with indication extrapolation were imminently expected, CADTH terminated the pilot project and began a new consultation with stakeholders to develop a new standardized procedure and process in the fall of 2013 [15]. As a result of theconsultation process, a new Common Drug Review Procedure and Submission Guidelines for Subsequent Entry Biologics was issued in March 2014 [16]. The submission requirements for SEBsrepresent a significant deviation from the existing requirements for non-SEB products.
According to CADTH, CDR recommendations for SEBs will be based on: i) patient and public perspectives on the impact of the drug; ii) safety, efficacy and effectiveness of the drug compared to alternatives; iii) therapeutic advantages relative to current accepted therapy; and iv) cost and cost-effectiveness relative to current accepted therapy [17]. CADTH also noted that while the new procedure is not a pilot project, it would evaluate the process after a few submissions. And as with Health Canada, the CDR does not issue statements regarding interchangeability. Interestingly, however, in recent recommendations for the SEBs Grastofil (filgrastim) and Basaglar (insulin glargine), the CDR’s Canadian Drug Expert Committee (CDEC) noted that patients being treated with the reference biological should be considered for switching to SEB after a discussion between patients and physicians [18, 19].
Currently, pCODR does not have a separate procedure and process in place for the submission and evaluation of SEBs. However, since pCODR is also under the jurisdiction of CADTH, it is expected that the process will be similar to that of the CDR.
Pan-Canadian Pharmaceutical Alliance (pCPA)
In August 2010, the Canadian Premiers announced the pCPA initiative at a meeting of the Council of Federation (COF). The pCPA is a process under the COF’s Health Care Innovation Working Group (HCIWG). The intended goal of the pCPA is to combine the purchasing power of public drug plans across multiple jurisdictions in order to ensure benefits are cost-effective, and to increase access to drug treatment options across jurisdictions. In addition, the pCPA also serves to reduce duplication of negotiations and to address the issue of inconsistent drug listing decisions across the country that were the results of each jurisdiction making individual decisions. All provinces (excluding Quebec) and Yukon (territory) were part of the initial alliance [20]. However, Quebec announced their intention to join the pCPA [21] and have done so.
Formally, the pCPA negotiations are conducted on brand-name drugs and generic drugs. As the pCPA process does not preclude existing evidence-based drug reviews, only (branded) drugs that have been assessed by the CDR and pCODR and received generally positive, i.e. not ‘Do Not List’, recommendations would be considered for negotiations. It should be noted that province-territory specific review may occur following the recommendations of CDR or pCODR in the absence of the pCPA process [22].
Very recently, pCPA released a ‘Subsequent Entry Biologicals (SEBs) First Principles’ document [23]. This document represents a starting point for the pCPA’s engagement with stakeholders to develop a more comprehensive SEB policy framework. Major principles include:
• All SEB and reference biological manufacturer proposals will only be considered through the national pCPA negotiation process rather than individual or selected jurisdictions
• Consistent with its mandate that includes increasing patient access to clinically and cost-effective drug treatment options, the pCPA will encourage a competitive environment that includes SEB market growth and is conducive to long-term cost reductions and sustainability for public drug plans
• The introduction of an SEB must provide a reduction in the drug’s transparent price to benefit all Canadians
• Proposals from reference biological manufacturers will only be considered if they:
• Provide overall national value to public drug plans and do not result in incremental costs to individual jurisdictions
• Provide at least similar overall value compared to the SEB, and must include similar or better transparent price reductions if equivalent listing status is sought
Provincial/Federal formularies
To date, there have been no published submission and evaluation processes specific to SEBs that are available to the public at both the provincial and federal drug plans. However, we believe that many jurisdictions are actively evaluating and adopting their existing submission guidelines to meet the unique aspects posted by SEB submissions.
Brief overview of SEBs evaluated in Canada
Omnitrope (Sandoz Canada) Omnitrope is an SEB of the recombinant growth hormone (GH) somatropin (somatotropin; marketed as Genotropin by Pfizer Canada) produced in Escherichia coli indicated for the treatment of GH deficiency in children and adults [24]. It was the first SEB to receive regulatory approval by Health Canada. Omnitrope was filed during the period in which Health Canada was developing its SEB guideline, as such, it provided the regulatory agency the opportunity to gain the experience needed to validate the concepts and principles behind SEBs [25, 26].
Several issues were encountered during the evaluation of the file and Health Canada had to exercise a certain degree of flexibility in the evaluation of the first SEB. First, Genotropin was used as the reference biological, which at the time, while authorized, was not marketed in Canada. Following a series of discussions, along with the availability of an extensive set of comparability data as well as other reasons, Health Canada eventually accepted the use of Genotropin as a comparator. Second, a reduced preclinical package was accepted in which full pharmacodynamic studies were accompanied by reduced toxicology information but no pharmacokinetic information was provided. Third, while Health Canada preferred equivalence trial, it accepted a complex and non-conventional crossover study as a pivotal trial.
At the time of filing, no trials submitted for Omnitrope were conducted in adults; however, it was considered acceptable to extrapolate the indication of GH deficiency to adults based on the molecule’s mechanism of action, disease pathophysiology, as well as the suitability of the adult study population with GH deficiency since childhood. Health Canada also requested post-marketing commitments that included long-term follow-ups and safety considerations. Overall, the combination of several critical elements led to the regulatory approval of Omnitrope for both the evaluated and extrapolated indications [25, 26].
Consistent with Health Canada policy, and the fact that the reference biological Genotropin was not marketed in Canada at the time, no statement regarding interchangeability and substitution of Omnitrope was made.
Approximately two months following regulatory approval, Omnitrope was submitted to the CDR for HTA. Since the SEB evaluation framework was still in development, a typical recommendation was not given, instead, an ‘Advice’ was issued [27]. In the report, the Canadian Expert Drug Advisory Committee (CEDAC) of the CDR advised the ‘drug plans [to] consider a similar reimbursement policy for Omnitrope as for other growth hormone products’.
Table 1 lists the provincial and federal public reimbursement statuses of Omnitrope. Results indicate that all provinces provide coverage for Omnitrope. Although Omnitrope is not listed on the Non-Insured Health Benefits (for First Nations) Drug Benefit List, it is likely reimbursed on a case-by-case basis. At least two provinces (Prince Edward Island and Saskatchewan) explicitly stated that Omnitrope is not interchangeable.
Inflectra/Remsima (Celltrion Healthcare Co Ltd) Regulatory background Inflectra/Remsima, developed as CT-P13 by the Korean company Celltrion, is an SEB of the monoclonal antibody (mAb) against the tumour necrosis factor-alpha (TNF-α), infliximab (marketed as Remicade by Janssen). CT-P13 was the first mAb SEB approved by Health Canada and Celltrion received regulatory approval (notice of compliance; NOC) for Remsima in January 2014 [28]. Hospira Healthcare Corporation, following a subsequent licensing agreement with Celltrion, received an NOC in June 2014 as the manufacturer for CT-P13 under the brand name Inflectra [29]. However, as a result of legal proceeding initiated by Janssen in July 2014, the NOC granted to Hospira was quashed in March 2015 [30]. Although Hospira remains the marketer of Inflectra in Canada, the change in NOC status serves as an inconvenience from a logistical perspective and this highlights one of the ways that innovator companies are dealing with competitors.
At the time of regulatory submission, the finalized version of the Guidance for Sponsors had already been published [7]. Because CT-P13 is a mAb, the processes involved in demonstrating its biosimilarity to Remicade was far more complex compared to Omnitrope [26, 28, 29]. The pivotal trials submitted for regulatoryevaluation included a single phase III therapeutic ‘equivalence’ trial conducted in rheumatoid arthritis (RA) patients and a single phase I pharmacokinetic trial conducted in ankylosing spondylitis (AS) patients, both against Remicade. In Europe, CT-P13 was approved by EMA for the two evaluated indications and was also granted authorization for six other indications (psoriatic arthritis, psoriasis, adult and paediatric Crohn’s disease, as well as adult and paediatric ulcerative colitis) based on extrapolation. In contrast, Health Canada only approved the evaluated indications and two of the extrapolation indications of psoriatic arthritis and psoriasis [28, 29, 31, 32].
Several contentious issues arose surrounding the regulatory approval of CT-P13. Specifically, there were questions regarding whether RA was a sensitive enough disease model for detecting therapeutic differences between products, in part, due to the concomitant use of the immunosuppressive methotrexate [33, 34]. Furthermore, it has been suggested that RA and AS models are not the most sensitive models for measuring immunogenicity [33, 34]. In addition, difference was observed in the most sensitive of the in vitro FcγRIIIa-dependent assay, raising the question of whether CT-P13 can be considered similar to Remicade [33, 34]. Nevertheless, EMA considered the clinical evidence submitted to be acceptable for approval of all requested indications, whereas Health Canada took a slightly more conservative approach in making its decision due to issues surrounding differential FcγRIIIa activity [28, 29, 31, 32].
Hospira, now a Pfizer company, subsequently received regulatory approval for the adult indications of Crohn’s disease (including fistulizing Crohn’s disease) and ulcerative colitis [35]. However, the evidence basis for the anticipated regulatory approval remains to be determined, i.e. whether paediatric data was submitted for regulatory evaluation.
Health technology assessment and pricing negotiation Both Inflectra and Remsima were submitted to CDR following regulatory approval and represented the first set of SEBs (and first mAb) submitted under the new CDR SEB submission procedure. Remsima was voluntarily withdrawn from the CDR review [36]. In December 2014, the CDEC of the CDR issued the recommendation of ‘List with clinical criteria and/or conditions’ (LWCC) for Inflectra in which the conditions were for the drug to be used ‘in patients for whom infliximab is considered to be the most appropriate treatment option’, and for Inflectra to be listed in the public formularies ‘in a manner similar to Remicade’. The LWCC recommendation applied to all the Health Canada-approved indications for Inflectra (including the two extrapolated indications) [37].
Following the release of the recommendation, Inflectra was submitted for negotiation under the pCPA process and was completed in November 2015 [38]. It is unclear why the process took almost a year but Inflectra represented a first true SEB with multiple indications (approved and subjected to be approved) with substantial budget impact. Therefore, this negotiation may have served as a learning process for the pCPA.
The submitted price of Inflectra represented a ~31% discount [39] relative to Remicade (based on the lowest listed public price in Quebec). However, this level of discount is not seen in other regions. For example, in Norway, the Finnish company Orion Oyi successfully won the tender to supply the country with CT-P13 (also being sold under the name Remsima), with a 69% price discount relative to Remicade, lower than the 51% discount that Hospira was offering [40]. Such discounts are far more aggressive compared to the 15–30% price reduction seen for other biologicals [41]. Although not entirely comparable, the nearly 70% discount is most commonly seen for non-biological generic drugs. This highlights the price pressure that biosimilar companies face. Questions have been raised regarding the sustainability of biosimilar companies under such pricing competition [40].
INESSS’ decision on Inflectra In February 2015, INESSS made a landmark decision regarding the reimbursement of Inflectra [42]. Recognizing that both Inflectra and Remicade ‘have the same generic name, form and content’, INESSS stated that the lowest price would be the price reimbursed for both infliximab products for the four indications (currently Inflectra has the lowest price on Régie de l’assurance maladie du Québec’s [RAMQ] List of Medications). Patients must pay the difference if they wish to receive Remicade. The most significant observation is that the ‘lowest price method’ is applied to Inflectra, perhaps suggesting a form of interchangeability.
In its deliberation, INESSS recognized that the lack of knowledge (regulatory and scientific) impedes acceptance of SEBs in Canada. However, it hopes that its decision will allow prescribers to appreciate the merit of Inflectra. INESSS has also recognized that factors such as accessibility to certain clinics can limit the uptake of Inflectra. Indeed, in the most recent issue of the formulary (List of Medications) [43], RAMQ stated that the only exception to the lowest price method applicable to infliximab is when prescribers indicate to the pharmacist that Remicade is preferably prescribed to Inflectra because the Remicade perfusion centre is closer to the patient’s home or is more readily accessible, given the patient’s health condition, compared to those for Inflectra. RAMQ stated that this exception has an end date of 3 October 2016.
Other public plans’ decision on Inflectra After the successful completion of the pCPA negotiation, public plans began to list Inflectra on their formularies. Compared to Quebec, the publicly available list prices of Inflectra across the plans represented between 33–47% discount relative to those of Remicade, which are much higher than Quebec, see Table 2. Perhaps more significantly, many of the public plans preferentially reimburse Inflectra over Remicade for patients new to infliximab, i.e. new infliximab patients will only be covered for Inflectra, and those who failed one infliximab will not be allowed to switch to another infliximab. Some Atlantic provinces also provide reimbursement for Inflectra for indication (psoriatic arthritis) that is not reimbursed for Remicade. This is a clear signal from the drug plans to bolster the success of SEBs.
Despite such generous reimbursement policy, it appears that public plans are still cautious regarding interchangeability. Furthermore, only Ontario has reduced the barrier to access to Inflectra (Limited Use – no prior authorization required) compared to Remicade (Exceptional Access – prior authorization required) while the remaining provinces still require prior authorization to access Inflectra.
Filgrastim (Apotex), Insulin Glargine (Eli Lilly), Etanercept (Merck) Filgrastim is the recombinant version of the human glycoprotein granulocyte colony-stimulating factor (G-CSF), which is used to treat neutropenia. Amgen currently sells the innovator filgrastim under the trade name Neupogen. Since the patents on Neupogen expired in Europe in 2006, several versions of the filgrastim SEB have become commercially available in the region [44].
Apotex’s filgrastim SEB, Grastofil (co-developed with Intas Pharmaceuticals Ltd), is currently being sold in Europe, and has recently been accepted for filing by the US Food and Drug Administration (FDA) [45]. Grastofil has been approved by Health Canada for all indications approved for Neupogen although the process has not been smooth as indicated by a patent litigation with Amgen [46]. As mentioned above, Grastofil has been assessed by the CDR and has received a LWCC recommendation from CDEC in March 2016 [18].
Recently, Eli Lilly also launched the SEB version of insulin glargine, Basaglar. Similar to Grastofil, CDR has issued a LWCC recommendation and CDEC also included a ‘Of Note’ commentary [19]. Both Grastofil and Basaglar are under pCPA negotiations as of this writing.
Merck Canada has also submitted an SEB version of etanercept (brand name to be determined) and awaiting regulatory approval and CDR recommendation as of this writing [47].
Private payers
In terms of the spending by private payers, a 2012–2013 Canadian report showed that private insurers paid approximately 35% of all drugs but this was increased to 42% for biologicals for inflammatory conditions, whereas public payers covered 43% for both [5].
The above statistics highlighted both the increasing use of biologicals and the significant financial impact on private payers. Amid these changes, private insurers are seeking ways to offset costs, which include but are not limited to increasing premiums and/or utilizing prior authorizations. Indeed, the introduction of SEBs represents a significant opportunity to reduce cost forprivate insurers. For instance, the Canadian private insurer TelusHealth has specified in its Remicade reimbursement special authorization form that patients must have tried and failed Inflectra prior to being authorized to use Remicade [48]. Janssen, in response to the competition, has entered into a preferred pricing agreement with Express Scripts Canada to provide reduced pricing for Remicade for private drug plans offered by providers such as Manulife and Empire Life [49].
Physicians’ and patients’ opinions on SEBs
Physicians and medical associations In a survey of Canadian rheumatologists (81 respondents) [50], 31% were familiar with SEBs. Physicians with greater than 20 years of practice were significantly more likely to be familiar with SEBs compared to respondents with less than 20 years of experience. In addition, approximately two-thirds of the respondents indicated that they were unlikely to offer an SEB as initial therapy if cost was not an issue, mostly due to greater familiarity with brand-name drugs and uncertain long-term safety of SEBs. Even if public and private payers mandate the use of SEBs of an anti-tumour necrosis factor-alpha (anti-TNF-α) biological that physicians would normally not prescribe, e.g. adalimumab is preferred, but an infliximab SEB is mandated, half of the physicians were unlikely to offer them to patients. What is more interesting is that nearly half of the respondents indicated that they would use a non-anti-TNF-α biological to avoid using the SEB. Finally, over half of the respondents disagreed with indication extrapolation to psoriatic arthritis and ankylosing spondylitis, citing clinical and pathophysiological differences versus rheumatoid arthritis.
Based on this survey, although rheumatologists are aware that biologicals are costly for their patients (as shown by three quarters of the respondents indicating that patient assistance programmes have an impact when considering biological therapy), one-third of the respondents demanded at least a 50% price reduction to offset the risk associated with switching to an SEB.
While there are certain limitations to the survey, the results suggest that many physicians still have preference for the originator products, and that significant barriers exist for the wide uptake of SEBs by Canadian rheumatologists [50].
Indeed, considerable discussions have taken place within various medical communities and a number of associations (Canadian Rheumatology Association [CRA]; Ontario Rheumatology Association [ORA]; Canadian Dermatology Association [CDA]; and Canadian Association of Gastroenterology [CAG]) have issued position statements regarding SEBs. The overall consensus of these medical associations appears to be that patients should have access to safe and affordable treatment options. Some do not agree on extrapolation of indication while most also agreed that SEBs should not be considered as interchangeable and no automatic substitution should be allowed. Furthermore, most agreed that distinctive International Nonproprietary Name (INN) should be used for SEBs; and all agreed that post-marketing monitoring/registry should be required [51–54]. The Canadian Association of Medical Oncologists has not yet publicly issued a position statement regarding oncological SEBs.
Patient groups/disease societies Perhaps those who will be the most directly impacted by SEBs are the patients themselves. Input from patient groups was taken into consideration in the deliberations of both CDR and INESSS [37, 42]. In the Inflectra reports, patients conceded that although therapeutic options are required for those with arthritis, and SEBs offer another biological drug therapy that may be effective for patients who are biological-naïve or who have failed on other biological drugs, many are uncertain whether SEBs actually offer additional therapeutic options. Some patients questioned whether SEBs are tested as rigorously or even perform as well as the reference product, and were even concerned that because not all indications were evaluated, this could be seen as being in a clinical trial in a real situation for verifying the efficacy and safety of SEB for these indications. There was also concern regarding the potential for switching of Remicade/Inflectra due to the same non-proprietary name between these two products.
From a patient access perspective, some expressed concerns about whether SEB manufacturers would offer patient support. Patients expected that Inflectra will be less costly than Remicade and the money saved can potentially be used to increase access to treatments, some patients believe that they will be forced to choose the SEB due to their insurance policy [37, 42].
Several patient groups/disease societies (the Canadian Arthritis Patient Alliance [CAPA], The Arthritis Society, Crohn’s and Colitis Canada, Canadian Skin Patient Alliance [CSPA], as well as various academic institutions) issued their views on the subject of SEBs. Similar to the positions expressed above, all agreed that there should be no automatic substitution for SEBs, that distinctive names should be given, and that post-marketing surveillance should be mandated. However, the view regarding the issue of indication extrapolation is less than unanimous [55–60]. A recent meeting involving a cross-disciplinary group of specialist physicians (dermatology, gastroenterololgy, nephrology, oncology and rheumatology), patients, patient group representatives and pharmacists, reached a consensus that indication extrapolation can be considered but should be based on robust and in-depth clinical data [61].
Lessons from European Union to increase uptake
Despite the perceived value of SEBs, the uptake of SEBs has been relatively slow. According to IMS, the historic (2007) estimation for biosimilar market in the EU was expected to be US$16–20 billion per year by 2010–2011, and it was forecasted that the sales of biosimilars would be US$25 billion by 2020. However, by 2012, the actual sales were only US$0.6 billion [62, 63]. The EU has higher biosimilar uptake compared to Canada, partly due to the early introduction of biosimilars. Within the EU, biosimilars for molecules such as G-CSF and epoetin (EPO) have relatively high uptake percentage, and this has been in part contributed by the role of the payers in these countries.
In the UK, biosimilar G-CSF is hospital prescribed. A single preferred agent is selected via a transparent multifactor tender. Hospital protocols are changed to reflect the winning bid with exception criteria for defined patient groups. Success of uptake in achieving real savings is also published. All these processes led to a ~90% uptake for biosimilar G-CSF in the UK.
In Germany, outpatient physicians treating statutory health plan patients are members of the Kassenärztliche Vereinigung (KV), the professional association of outpatient physicians. There are 17 KVs in total, each covering a geographic region in Germany. There are several strategies that are used to facilitate biosimilar uptake. For instance, biosimilar quotas are utilized for EPO in each of the KV regions to increase uptake. In addition, physicians’ budgets are tracked by prescription utilization management tools and physicians are also provided with education sessions to reinforce the concept of biosimilar medicines. Finally, payers also endorse biosimilars as safe and effective via ‘dear doctor’ letters and address potential concerns. As a result, the uptake for biosimilar EPO is ~60% [64].
In Norway, the combination of the tendering system and a substantial discount has resulted in a more than 90% market share for the infliximab biosimilar as of mid-2016 [65].
Clearly, strong regulatory presence and price incentive are needed to assist the uptake of biosimilars, particularly for countries with well-developed regulations. Overall, the current trend in the US, EU, and emerging markets is that payers and policymakers are expected to increasingly become biosimilar advocates. This is partially reflected in the 2015 European Generic medicines Association–European Biosimilars Group meeting in the UK (April 2015) where both EMA and FDA agreed that biosimilars could be licensed for multiple indicationswithout performing clinical studies for each area. The Vice-Chair of the EMA Working Party on Similar Biological Medicinal Products (BMWP) Dr Martina Weise, FDA’s Center for Drug Evaluation and Research’s Associate Director of Therapeutic Biologics Dr Leah Christl, and EMA Head of Quality Dr Peter Richardson, all stressed that analytical methods and functional assays, e.g. pharmacokinetic and pharmacodynamics, are more sensitive to quality attributes and often much more valuable to regulators, and that clinical studies are the most blunt tool we have to confirm the similarity which are sometimes not needed [66]. FDA’s Dr Leah Christl also went on to state that they have seen sponsors who identified analytical differences between the biosimilar and the reference product but concern was not raised from a regulatory perspective. Finally, Dr Leah Christl also stated that FDA is planning outreach programmes to educate industry and prescribers about the importance of structural and functional analysis over patient studies in proving similarity [66].
Indeed, as stated elsewhere in this paper, policies to promote SEB uptake in the form of preferential reimbursement have been adopted by the Canadian provincial reimbursement bodies. However, without reducing barrier to access, e.g. removal of prior authorization, or allowing interchangeability, the full potential of SEBs in providing true cost savings to public plans may be limited.
Summary
The SEB regulatory and reimbursement experience in Canada remain in its infancy. Although substantial economic benefits can be achieved with the use of SEBs, their wider acceptance by payers, prescribers and patients remain to be seen, especially with the first mAb, i.e. Inflectra. More support is needed in order to allow stakeholders to fully comprehend the concept of SEBs so that these therapies can be properly evaluated and utilized.
Acknowledgements
The authors would like to acknowledge Mr Ferg Mills, MSc, Principal Consultant, Wyatt Health Management, for his valuable input into the preparation of this article. A portion of the information contained in this article has previously been presented at ISPOR North America (2015, 2016) and CADTH Symposium (2016).
Competing interests: Dr Eric Siu is employed by Wyatt Health Management (WHM) and Mr George Wyatt is the owner of WHM. WHM has worked with one or more companies that manufacture the biosimilars listed in this publication. However, WHM did not receive funding or use proprietary information from these sources for the preparation of this manuscript.
Provenance and peer review: Not commissioned; externally peer reviewed.
Co-author
George Wyatt, BSc, MBA
Wyatt Health Management, Suite 201, 7025 Tomken Road, Mississauga, Ontario L5S 1R6, Canada
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Author for correspondence: Eric CK Siu, MSc, PhD, Director, Scientifi c Aff airs, Wyatt Health Management, 7025 Tomken Road, Suite 201, Mississauga, Ontario L5S 1R6, Canada
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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:
The development of biological medicinal products is in rapid growth and as patents for reference products expire, new biosimilar products become available. This has a marked impact on several stakeholders; from patients and physicians to decision-makers, and on activities; from treatment of patients to the conduct of pharmacovigilance. The Danish Medicines Agency (Laegemiddelstyrelsen, DKMA) has increased its focus on the pharmacovigilance of biologicals and is implementing an action plan jointly with a working group comprising representatives from the Danish Medical Association, the pharmaceutical industry and the five Danish Regions.
Submitted: 30 June 2016; Revised: 1 July 2016; Accepted: 4 July 2016; Published online first: 7 July 2016
The Danish healthcare system
Denmark is a small Scandinavian country of about 5.5 million people. The country is politically divided into five Regions responsible for the governance of public hospitals across the country. The Danish healthcare system is financed via income taxes and generally, treatment and medication provided by public hospitals are free of charge to Danish citizens. To ensure equal treatment possibilities and rational use of healthcare budgets, a national council for the use of expensive hospital medicines (Rådet For Anvendelse Af Dyr Sygehusmedicin, RADS) makes recommendations on which medicinal products should be used in the hospitals. The supply of medicinal products to Danish hospitals follows a tendering process, which usually covers a 12-month period.
Infliximab as an example
In April 2015, RADS announced that they find biosimilar infliximab equal to the original reference product (Remicade) in efficacy and safety. Based on this, RADS made a recommendation to use the less expensive infliximab product. At that point, Remsima was the less expensive infliximab product available in Denmark and currently still is. Remsima won the national tendering process for infliximab and was consequently supplied to all hospital pharmacies in Denmark in the summer of 2015.
Generally, the hospitals took up the recommendation from RADS that Remsima could be given both to treatment-naïve patients and to patients who were already on Remicade, unless there were scientifically justified reasons not to do so. According to legislation, the treating physician decides which medicinal product should be prescribed and administered.
Consequently, the uptake of Remsima increased rapidly as more and more patients were switched from Remicade to Remsima, and new patients started treatment on Remsima. In the first quarter of 2016, Remsima covered around 97% of infliximab consumption in Denmark.
A dream scenario?
This might seem like a dream scenario, as it would obviously save money for the healthcare system while ensuring the same benefits for the patients, but the reality was a bit more complex. Soon after the switch, patients started expressing their concern regarding the new infliximab product, i.e. Remsima, and approached their physicians for an explanation and to seek assurance. However, the physicians did not seem comfortable about explaining the principle of biosimilarity; hence, the patients remained uncertain about the change that had been introduced in their treatment.
Patient anxiety was further aggravated by the fact that hospitals and Regions in Denmark had put out different information on biosimilars on their websites, and that some Danish scientific societies had issued a slightly different statement compared to the announcement from RADS.
The action plan
Consequently, patients’ organizations approached the Ministry of Health, voicing their concerns, and the Ministry responded by setting up the action plan in partnership with the Danish Medicines Agency (Laegemiddelstyrelsen, DKMA); Action Plan on Biological Medicines, Biosimilars and Vaccines for 2015–2016.
The focus on biologicals is increasing because this type of medicinal products is in rapid development – new biological medicinal products are continuously being developed offering new or improved treatment options within growth hormones, cancer, diabetes and arthritis. At the same time, development of more biosimilar medicines is expected when patents for the reference products expire in the years ahead. The aim of the action plan is to ensure targeted and product-specific monitoring of biologicals. It focuses on four key areas:
• undertaking activities to encourage monitoring of biologicals at product level
• carrying out information activities to improve healthcare professionals’ understanding of product-specific monitoring and ‘peace of mind’ among patients when using the products
• offering digital solutions at hospitals and in medical practices to ease adverse drug reaction reporting from healthcare professionals
• increasing focus within the DKMA on monitoring the safety of using biologicals and biosimilars.
The action plan is being implemented jointly by the DKMA and a working group comprising representatives from the Danish Medical Association, the Danish Association of the Pharmaceutical Industry, the Danish Generic Medicines Industry Association, the Danish Association of Parallel Importers of Medicine, and the five Danish Regions.
First initiatives
The action plan also builds on the EU Pharmacovigilance legislation, which places several obligations on the Member States, including taking appropriate measures to clearly identify any biological medicinal product that is the subject of a suspected adverse drug reaction (ADR) report, with due regard to the brand name and batch number.
This obligation was recently implemented in Denmark through the amendments to two executive orders, which came into effect on 1 January 2016. The aim of the revised executive orders is to increase focus on the monitoring of the use and safety of biological medicinal products, including any adverse reactions that occur when switching between biosimilar and reference medicinal products. One amendment of an executive order implies that healthcare professionals shall make records of the brand name and batch number in patient health records when prescribing any biological medicine. The other amendment of an executive order makes it mandatory that healthcare professionals include, to the extent possible, the brand name and batch number when reporting suspected ADRs. Both executive orders cover certain biologicals listed on the DKMA website. The list focuses on new biologicals and products where a biosimilar is available on the Danish market and so is a dynamic list that will be updated ad hoc.
Furthermore, to encourage ADR reporting on a product level a pop-up message has been implemented in the electronic reporting forms to encourage submission of brand name and batch number.
Dialogue with stakeholders
Another initiative carried out relates to the second focus area; raising awareness on biosimilarity through targeted information. To identify information gaps from a patient perspective, invitations went out to the patient organization for rheumatoid arthritis, colitis, Crohn’s, psoriasis, sclerosis, Danish Cancer Society and Danish Patients, and a meeting was held during the autumn of 2015. Along with providing a clearer picture of what kind of information was requested by Danish patients in relation to treatment with biological medicinal products the meeting also investigated which communication methods would be most suitable to engage with patients and relatives. The dialogue with patients and patient organizations showed that their focus is on having peace of mind and maintaining quality of life and stability in treatment, including continuing to have the drug through the same route of administration and avoiding new kinds of side effects. Furthermore, patients want dialogue with healthcare professionals and to have a say in their own treatment course. It was agreed that information was needed to clarify similarities and differences between biological reference products and biosimilars, specifically in relation to side effects and route of administration. The information should come from neutral authorities and should be available before treatment start and on several platforms.
Information was made available on the DKMA website, and leaflets and short information videos have been produced to inform about similarities and differences between biologicals and biosimilars, including batch variation, and that switching from one to the other should not cause changes in treatment response. In addition, it was highlighted that patients can report suspected ADRs themselves through an electronic reporting form on the DKMA website.
Communication activities targeted at physicians were also carried out to inform about the new legal requirements, the list of selected biologicals and to raise awareness about the uncertainties patients may feel. Information, flyers, including leaflets to patients, were made available to hospitals and physicians via emails to all hospital CEOs, regional drug committees and relevant scientific medical colleges as well as being published on the DKMA website.
In relation to efforts to ease reporting of ADRs from hospitals and general practices, the DKMA has made available a web-service on a national service platform to enable data transmission from local electronic health record (EHR) systems to the DKMA; however, as there are many different electronic systems for health records across the country, the integration to local systems has to be built locally. This part of the action plan falls under the responsibility of the Danish Regions, as they run the hospitals in Denmark.
Work in progress
The ADR reports submitted to the DKMA are continuously evaluated with a particular focus on any pattern possibly related to switching from the reference product to biosimilar infliximab and to review if product names and batch numbers are provided.
The action plan on biologicals and biosimilars will be evaluated by the end of 2016.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
Author: Benedicte Lunddahl, DVM, Danish Medicines Agency, Division of Pharmacovigilance and Medical Devices, 1 Axel Heides Gade, DK-2300 Copenhagen S, Denmark
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.
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.
