This was a joint meeting of the American Society of Transplant Surgeons (ASTS), The Transplant Society (TTS) and the American Society of Transplantation (ATS). The Congress was packed with an impressive number of interesting Symposia, State-of-the-Art Lectures as well as Plenary and Poster Sessions covering all aspects of basic and clinical research and care of transplant patients. Interested readers who were not aware of the World Transplant Congress should visit the meeting website at www.wtc2014.org/
There were however relatively few presentations, sessions and posters dealing with generic or biosimilar medicinal products including talks by Professors Teun Van Gelder (Rotterdam, The Netherlands), Jennifer Harrison (Toronto, Canada), and Rita Alloway (Cincinnati, Ohio, USA), and some relevant posters including one from Montreal with the provocative title ‘Is it ethical to prescribe generic immunosupprssive drugs to our transplanted patients’.
I found the State-of-the Art Address by past Nobel Prize winner Shinya Yamanaka, MD, PhD, particularly thought provoking with respect to biosimilars. Professor Yamanaka described his programme to develop human blood cells, white blood cells, red blood cells and platelet precursors from transformed human fibroblasts. It has been calculated that with ‘only’ fibroblasts from about 140 specific HLA donors it should be possible to generate HLA compatible human blood cells for more than 90% of the Japanese population and apparently human trials using these cells are soon to begin in Japan. Similar programmes might also provide solid organs for use in transplantation. If successful this could solve major problems with human blood product and solid organ availability. However, this would also create the potential for future ‘follow-on’ versions of all of these biological products. Approval and use of such follow-on ‘biosimilars’ would also however create some interesting regulatory and clinical barriers.
GaBI Journal has published papers dealing with transplantation but if the number of attendees present and research topics covered at this meeting is any indication the number of manuscripts and topics covered could increase greatly. I encourage readers who are involved in transplantation to consider GaBI Journal for manuscripts dealing with all aspects of generics, biosimilars and non-biological complex drugs to submit their work for consideration.
Competing interests: None.
Provenance and peer review: Not commissioned; internally peer reviewed.
Professor Philip D Walson, MD
Editor-in-Chief, GaBi Journal
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
The interest in the development, regulatory approval, use, and post-marketing surveillance of generic and biosimilar pharmaceutical products continues to increase; as illustrated by the tremendous number of views (over 1,028,324 since 2012) of articles published in the GaBI Journal.
I expect that this interest will continue to increase after publication of this fourth and final issue of 2014. This issue begins with an Editorial by Dr Brian Godman, a member of our International Editorial Advisory Board, discussing the Original Research paper by Vogler et al. reporting the results of a survey done on the availability and procurement of five selected cardiovascular products in a small number of hospitals in five European countries. These two manuscripts discuss some of the barriers remaining to the more widespread use of well-characterized generic drug products even in European Union countries with access to well-characterized products including the need pointed out by Dr Godman for ambulatory and hospital inpatient sectors ‘to work more closely together to maximize the health gain of patients’.
Additional barriers exist in countries where access to modern regulatory methods and to well-characterized follow-on products are both limited. Professor Cheraghali from Iran proposes in his Letter to the Editor that countries with limited ability to completely evaluate such products should allow ‘limited marketing’ of follow-on biological products under the (undefined) ‘direct surveillance of regulatory authorities’. Regulators in many countries definitely face difficulties in adequately evaluating such products and there are clearly potential (even if poorly documented) benefits to providing patients access to them. However, there are also clear risks. Both process details and actual data on risks and benefits are needed before such a suggestion can be adequately evaluated. We welcome comments on this suggestion from our readers.
In a Review Article Drs TJ Giezen and CK Schneider discuss the importance of product quality and safety assessments of biosimialrs for the extrapolation of indications, as well as the issues of traceability and interchangeability of such products from the perspective of European regulators. The issues raised by this paper illustrate how difficult it is to inadequately evaluate follow-on products even with adequate regulatory resources. The issues raised by these regulators suggest, at least to me, that the process proposed by Professor Cheraghali is unlikely to ensure product quality and patient safety. Of note, in a Regulatory paper Ms Arpah Abas and co-authors suggest that the use of partnerships between countries is an alternative solution to the problems associated with regulating in a resource poor environment such as Malaysia.
In a Commentary, Dr René Anour discusses the use of biosimilars versus ‘biobetters’, i.e. follow-on biological products that without being structurally based on each other; share the same target. He suggests that from a regulator’s perspective the safe use of such products ‘depends on their interchangeability’ and concludes that ‘regulatory guidance will … have to evolve, to keep biosimilars competitive against biobetters and avoid pitfalls in their development’.
In an Opinion paper, Dr David Lim presents why he believes Australia is particularly well positioned to become a leader in the biosimilar field; including its relationships with Asian countries, pricing policies, and laws that limit what can be patented. In a second Opinion paper authors from the European Biopharmaceutical Enterprises (EBE) group (all of whom work for pharmaceutical firms) present their argument for providing more detailed, transparent labelling of both originator and follow-on products to make clear what information came from studies done with follow-on versus originator products.
In a related Pharma News paper one of our GaBI Journal editors, Dr Bea Perks, reviews the ‘toolkit’ developed by the International Alliance of Patients’ Organizations (IAPO) to educate patients and patient organizations about biological and biosimilar medications. The Journal welcomes manuscripts from such patient advocacy groups. It would be especially useful if these groups (or others) presented some actual data demonstrating how labelling or the use of the proposed toolkit improves the efficacy, safety or even the acceptability of such products.
A Pharma News paper by Dr Michelle Derbyshire, another of our editors, abstracts some data on the limited savings produced from the use of generic and biosimilar medicinal products in Europe and in an Abstracted Scientific Content paper our GaBI Journal editor Dr Bea Perks reviews a publication by Leopold et al. from Austria discussing ‘pharmaceutical policy interventions in times of economic recession’ that presents data on the use of generic antipsychotic drugs in Finland and Portugal. Dr Leopold’s publication highlights the potential differences between short- and long-term effects of policy measures and suggests that beneficial short-term effects of cost-sharing might also have unintended negative long-term effects, especially in the most economically challenged populations. I would like to encourage submission of manuscripts providing data comparing the long- versus short-term effects of public policies since they could be of great interest to our readers.
In an Interview with GaBI, Amgen gives an insight on how it intends to gain market share with its biosimilars. The biotech giant believes in encouraging, not forcing, the use of biosimilars and that by emphasizing the quality of its products physicians and patients will choose to use biosimilars. As evidence of how this approach can work the example of a Japanese erythropoietin biosimilar is given.
Finally, I would like to thank all our authors, readers, reviewers, our publisher and our entire editorial staff for all their hard work and to wish all of you a happy, healthy holiday season and coming New Year.
Professor Philip D Walson, MD
Editor-in-Chief, GaBI Journal
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
Dr Brian Godman reviews the paper by Vogler and co-authors on the procurement of generics or originators among European hospitals once multiple sources become available.
Submitted: 28 November 2014; Revised: 3 December 2014; Accepted: 3 December 2014; Published online first: 16 December 2014
Vogler and co-authors have provided valuable insight into the procurement of generic medicines in hospitals among medium-sized European countries [1]. To date, this has been a neglected area with the majority of research and payer focus on ambulatory care because medicine expenditure in hospitals has only been a limited proportion of overall hospital expenditure at 5% to 10% over the years [1]. Pharmaceutical expenditure in ambulatory care is typically the second highest cost component after physician salaries, with expenditure rising by more than 50% in real terms during the past decade [2]. In addition, there are continual pressures on ambulatory care expenditure driven by well-known factors including ageing populations, rising patient expectations and the continued launch of new premium-priced technologies [2–4]. This has resulted in multiple policies and initiatives among authorities across Europe to enhance prescribing efficiency for both new and established medicines [2, 4]. Policies and initiatives for established medicines include encouraging the prescribing of lower cost generics versus originators and patented products in a class where all or nearly all the products in the class or related classes are seen as therapeutically similar [1, 2, 5, 6]. Classes include the proton pump inhibitors, renin-angiotensin inhibitor drugs as well as the statins [2, 5–7]. This takes advantage of an increasing number of products losing their patents in recent years [1, 2, 5, 6].
However, as Vogler and co-authors point out, the focus is changing with new premium-priced medicines, including biological medicines, initiated in hospitals before patients are discharged [1, 8]. This is a concern for the authorities responsible for ambulatory care if physicians are reluctant to change prescriptions to suitable lower cost generics, including generics versus originators, even in countries such as Germany where there is a high rate of generics prescribed [1, 8–10]. This is less of an issue if there is a tradition of International Nonproprietary Name (INN) prescribing across all sectors (UK) for small molecules [1, 6, 11], compulsory generics substitution (Sweden) [1, 6, 12], preference policies for the molecule (The Netherlands) [1, 2, 13], or reference pricing where patients have to cover the additional cost themselves for a more expensive medicine than the quality assured referenced priced medicine [1, 14]. However, this is an issue if patients are discharged on premium priced medicines, including originators, where low cost generics (or branded generics) are equally suitable and there is limited potential for switching in ambulatory care, enhanced by hospitals receiving appreciable discounts and sometimes free medicines [1, 15].
It was with this background, that the current study was conducted. It was encouraging to see a range of countries were studied in this paper with different healthcare systems, different geographies, different approaches to the tendering of medicines in hospital as well as different approaches to the pricing of generics in ambulatory care and measures to enhance their utilization [1]. In addition, concentrating on just one category of medicines, namely cardiovascular medicines, to provide good insights for the reasons stated. The study also built on the considerable contacts of the co-authors through the Pharmaceutical Health Information System (PHIS) network [1].
The study highlighted a number of interesting findings. These included the fact that typically hospitals only carry one product line, mainly the generic, or at the most two, i.e. both a generic and the originator, for a given medicine (only a minority of hospitals in Norway and Slovakia). The only exception was atorvastatin, where apart from Norway the originator was principally supplied. This compares to the ambulatory care sector where there may be multiple presentations available for dispensing from different companies once the patent has been lost [1]. One hospital in Portugal only carried atorvastatin rather than both simvastatin and atorvastatin [1]. This may reflect previously limited demand-side measures in ambulatory care in Portugal preferentially encouraging the prescribing of generic simvastatin rather than patented atorvastatin when it first became available, thereby encouraging the manufacturer of atorvastatin to seek its preferential listing in the hospital formulary [1, 16]. Secondly, just single doses are often supplied in hospitals versus typically full packs in the community with varying tablet sizes and strengths. Thirdly, Norway was the only country in which the surveyed medicines were exclusively centrally tendered leading to appreciable discounts. This provides an example to other countries, backed up by campaigns supporting generics [1]. There was also tendering among hospitals in Portugal, with individual hospitals having the potential to negotiate lower prices if able to do so [1]. Discounts of 100% were seen among the majority of surveyed hospitals in Austria, although discounts and cost-free medicines did not apply to new on-patent medicines. Otherwise, there was limited headroom for appreciable discounts between the hospitals [1]. Dispensing of originators in Austria will increase costs, with Austria having neither INN prescribing, generics substitution nor reference pricing [1, 17]. However, the sickness funds in Austria are looking to address this through information and other campaigns in hospitals [1, 18].
In conclusion, Vogler’s study offers valuable insight into the procurement of generics among hospitals in Europe once products lose their patent. It is hoped this study will be repeated for other product classes and other countries to provide further insight given the extensive networks and experience of the co-authors. This is especially important with growing recognition of the need for both ambulatory care and hospital sectors to work more closely together to maximize the health gain of patients with available resources – ‘Interface Management’ [1, 8].
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
References 1. Vogler S, Zimmermann N, Mazag J. Availability and procurement conditions of originator and generic medicines in hospitals – an exploratory study in five medium-sized European countries. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(4):168-79. doi:10.5639/gabij.2014.0304.040. 2. Godman B, Wettermark B, van Woerkom M, Fraeyman J, Alvarez-Madrazo S, Berg C, et al. Multiple policies to enhance prescribing efficiency for established medicines in Europe with a particular focus on demand-side measures: findings and future implications. Front Pharmacol. 2014;5:106. 3. Garattini S, Bertele V, Godman B, Haycox A, Wettermark B, Gustafsson LL; Piperska Group. Enhancing the rational use of new medicines across European health care systems. Eur J Clin Pharmacol. 2008;64(12):1137-8. 4. Malmström RE, Godman BB, Diogene E, Baumgärtel C, Bennie M, Bishop I, et al. Dabigatran – a case history demonstrating the need for comprehensive approaches to optimize the use of new drugs. Front Pharmacol. 2013;4:39. 5. Godman B, Wettermark B, Bishop I, Burkhardt T, Fürst J, Garuoliene K, et al. European payer initiatives to reduce prescribing costs through use of generics. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):22-7. doi:10.5639/gabij.2012.0101.007 6. Godman B, Abuelkhair M, Vitry A, Abdu S, Bennie M, Bishop I, et al. Payers endorse generics to enhance prescribing efficiency; impact and future implications, a case history approach. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):69-83. doi:10.5639/gabij.2014.0304.017. 7. Moon J, Godman B, Petzold M, Alvarez-Madrazo S, Bennett K, Bishop I, et al. Different initiatives across Europe to enhance losartan utilization post generics: impact and implications. Front Pharmacol. 2014;5:219. doi:10.3389/fphar.2014.00219. eCollection 2014. 8. Björkhem-Bergman L, Andersén-Karlsson E, Laing R, Diogene E, Melien O, Jirlow M, et al. Interface management of pharmacotherapy. Joint hospital and primary care drug recommendations. Eur J Clin Pharmacol. 2013;69 Suppl 1:73-8. 9. Godman B, Sakshaug S, Berg C, Wettermark B, Haycox A. Combination of prescribing restrictions and policies to engineer low prices to reduce reimbursement costs. Expert Rev Pharmacoecon Outcomes Res. 2011;11(1):121-9. 10. Simmenroth-Nayda A, Hummers-Pradier E, Ledig T, Jansen R, Niebling W, Bjerre LM, et al. Prescription of generic drugs in general practice. Results of a survey of general practitioners [Article in German]. Med Klin (Munich). 2006;101(9):705-10. 11. Godman B, Bishop I, Finlayson AE, Campbell S, Kwon HY, Bennie M. Reforms and initiatives in Scotland in recent years to encourage the prescribing of generic drugs, their influence and implications for other countries. Expert Rev Pharmacoecon Outcomes Res. 2013;13(4):469-82. 12. Andersson KA, Petzold MG, Allebeck P, Carlsten A. Influence of mandatory generic substitution on pharmaceutical sales patterns: a national study over five years. BMC Health Serv Res. 2008;8:50. 13. Woerkom Mv, Piepenbrink H, Godman B, Metz Jd, Campbell S, Bennie M, et al. Ongoing measures to enhance the efficiency of prescribing of proton pump inhibitors and statins in The Netherlands: influence and future implications. J Comp Eff Res. 2012;1(6):527-38. 14. Vogler S. The impact of pharmaceutical pricing and reimbursement policies on generics uptake: implementation of policy options on generics in 29 European countries an overview. Generics and Biosimilars Initiative (GaBI Journal). 2012;1(2):93-100. doi:10.5639/gabij.2012.0102.020. 15. Vogler S, Zimmermann N, Habl C, Mazag J. The role of discounts and loss leaders in medicine procurement in Austrian hospitals – a primary survey of official and actual medicine prices. Cost Eff Resour Alloc. 2013;11(1):15. 16. Godman B, Shrank W, Andersen M, Berg C, Bishop I, Burkhardt T, et al. Comparing policies to enhance prescribing efficiency in Europe through increasing generic utilization: changes seen and global implications. Expert Rev Pharmacoecon Outcomes Res. 2010;10(6):707-22. 17. Godman B, Burkhardt T, Bucsics A, Wettermark B, Wieninger P. Impact of recent reforms in Austria on utilization and expenditure of PPIs and lipid-lowering drugs: implications for the future. Expert Rev Pharmacoecon Outcomes Res. 2009;9(5):475-84. 18. Vogler S, Zimmermann N. How do regional sickness funds encourage more rational use of medicines, including the increase of generic uptake? A case study from Austria. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(2):65-75. doi:10.5639/gabij.2013.0202.027.
Author: Brian Godman, BSc, PhD, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
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:
Biotech giant Amgen now has a biosimilars programme that includes nine different molecules. A representative from Amgen has spoken to GaBI about the company’s venture into biosimilars. Topics included how to encourage the use of biosimilars and how a Japanese example of biosimilars uptake can help Europe in increasing use of biosimilars.
Submitted: 25 November 2014; Revised: 4 December 2014; Accepted: 9 December 2014; Published online first: 22 December 2014
Amgen’s views on how to encourage the use of biosimilars in Europe differ from some [1]. In an interview on 10 October 2014, Mr Geoff Eich, Executive Director of External Affairs for Amgen Biosimilars, spoke to GaBI about Amgen’s approach for biosimilars, which is more like a branded biologicals model than a traditional generics approach.
Encourage do not force use of biosimilars
Biosimilars are a good strategic fit for Amgen and it is leveraging its existing biologicals experience and capabilities to build upon a current, successful biologicals development programme. However, it believes that physicians and patients alike should have a choice in prescribing and using biosimilars. This is perhaps in contrast to the European Generic medicines Association (EGA), which believes that governments should introduce pricing and reimbursement policies to force the use of biosimilars [2]. Generics and biosimilars can play a major role in reducing healthcare expenses [3], however, lack of penetration is seen as a lost opportunity and a barrier to future savings [4].
Instead, Amgen believes in ‘a more sustainable method’ of controlling healthcare budgets. This can be achieved by offering physicians and patients the choice of which originator biological or biosimilar they want to use. Amgen considers that physicians and patients can be encouraged to use biosimilars by making the supporting data available in the product information, and that high quality data and the responsibility of manufacturers will support the use of biosimilars. Amgen wants ‘to give assurance and accountability’ with the use of their biosimilars. Therefore, patients will ‘get the value of the lower cost of biosimilars, as well as the accountability’.
Biosimilars use not just based on cost
Use of biosimilars ‘cannot just be a benefit to the government; it has to be a benefit to the patient. In Europe, cost is covered, but in many other countries it is not covered.’ Amgen believes that it is important to maintain high quality standards and manufacturers’ accountability in order to make sure physicians and patients have the confidence needed to prescribe and use these medicines. Such standards should not be a trade-off for cost – Amgen believes you can have both.
The Japanese example
Despite the fact that uptake of biosimilars in Europe is slowly increasing, they still account for a relatively small segment of the European Union (EU) pharmaceutical market [5]. There are currently six classes (ESA – erythropoiesis-stimulating agent, G-CSF – granulocyte colony-stimulating factor, HGH – human growth hormone, FSH – follicle stimulating hormone, insulin, TNF – tumour necrosis factor) with at least one biosimilar, as most biologicals are still patent protected. In fact, even in Germany, which has one of the highest uptakes of biosimilars, they have only reached around 50% by volume [6]. The best biosimilar success story is outside of Europe.
Japan Chemical Research Pharmaceuticals’ (JCR) biosimilar recombinant human erythropoietin kappa (JR-013) was approved for renal anaemia in kidney dialysis patients and premature infants in Japan in 2010 [7], under the Japanese Adopted Name (JAN) of ‘Epoetin kappa (genetical recombination) [epoetin alfa biosimilar 1]’ with the brand name: Epoetin alfa BS Inj 750/1500/3000 ‘JCR’. By the first quarter of 2014, the biosimilar had achieved a market share of 74% compared to the reference product [Kyowa Hakko Kirin’s Espo (epoetin alfa)].
JCR’s biosimilar has achieved this success despite the fact that Japan has a lower generics uptake than in Europe or the US (26% in Japan versus 82% in Germany and 91% in the US [8]), therefore, one would not expect a high uptake of a biosimilar. Biosimilars also have distinguishable international non-proprietary names (INNs) in the country (the JAN system which does not follow INN) which signifies that the medicinal product is a biosimilar in the first place; an issue that has been suggested would affect the uptake of biosimilars [9].
The reason, according to Amgen, that JCR has such a high market share ‘is that the physician and patient are choosing the biosimilar and they do that by choice, not by force’. This example indicates ‘that the whole argument of naming is not as important to uptake as people say’ [10].
The question is what is JCR doing differently and how has it achieved such high uptake for its biosimilar? The answer is that they have worked hard to make sure the clinicians understand how the biological is being developed. They have also emphasized quality. JCR is known as a high quality company, with a good/trustworthy name and their erythropoietin kappa is of high quality. JCR has also carried out a very successful promotional strategy to increase use of the biosimilar and has maintained this over time. Amgen thinks that, in a similar way to JCR, they ‘can make the biosimilar programme more successful in Europe and globally’.
Competitive advantage
The development of biosimilars is nothing short of a challenge and Amgen knows that it is going to take extensive scientific skills to be successful in this market. With more than 30 years of biologicals experience, and a long track record of successfully supplying high quality biologicals to patients around the world, the company is confident in its competitive advantage and ability to deliver on its biosimilars portfolio.
It is scientifically difficult to create biosimilars and Amgen believes that manufacturing nuances will set biosimilars apart and pave the way for the company to become a leader in the field. In short, Amgen believes that manufacturing matters. However, generics giants like Mylan and Sandoz have said that it is risky to play up differences because of physician and patient concerns about the safety of biosimilars.
Amgen agrees that instilling confidence in stakeholders will perhaps be the number one challenge to overcome. Physicians and patients may wonder if there is compromise in the quality of the product in order to achieve cost savings. Amgen is committed to patient safety and it believes that education of these key stakeholders will be important for instilling physician and patient confidence, and ultimately for the success of biosimilars.
The fact is, biosimilars are made in living cells and therefore no two biosimilars will be the same and no biosimilar will be the same as the reference product. Mr Scott Foraker, Amgen’s Vice President and General Manager of biosimilars, points to this when he says ‘biosimilars are not all the same and each will represent a distinct therapeutic choice’. However, he believes that, ‘in each challenge, we have unique and significant competitive advantages’.
Mr Geoffrey Eich, Executive Director of External Affairs for Amgen Biosimilars, believes that it is within those fine nuances that Amgen is planning to break away from the pack. ‘That is where we are going to see the value of experience, the value of quality, and frankly different strategies and philosophies on how to bring them to market,’ Mr Eich said.
Mr Foraker has also praised the US Food and Drug Administration’s ‘thoughtful and deliberate’ approach toward biosimilars. Adding that regulators ‘want to be cautious, because they understand the sensitivity and complexity in developing biologic[al]s, and that makes perfect sense.’
Competing interests: None.
Provenance and peer review: Article prepared based on the interview conducted on 15 October 2014; internally peer reviewed.
Reported by Michelle Derbyshire, PhD, GaBI Online Editor
References 1. GaBI Online – Generics and Biosimilars Initiative. Amgen expands biosimilars programme [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Dec 9]. Available from: www.gabionline.net/Biosimilars/News/Amgen-expands-biosimilars-programme
2. European Generic medicines Association (EGA). Frequently asked questions about biosimilar medicines. July 2011 [homepage on the Internet]. 2012 Jun 7 [cited 2014 Dec 9]. Available from: www.egagenerics.com/index.php/biosimilar-medicines/faq-on-biosimilars
3. Derbyshire M. Reducing the European healthcare budget with generics and biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(4):200-1. doi:10.5639/gabij.2014.0304.046
4. Perks B. Weighing up the cost of switching to biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2014;3(42):100. doi:10.5639/gabij.2014.0302.025
5. GaBI Online – Generics and Biosimilars Initiative. Use of biosimilars in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Dec 9]. Available from: www.gabionline.net/Reports/Use-of-biosimilars-in-Europe
6. GaBI Online – Generics and Biosimilars Initiative. UK biosimilars uptake lower than in some other EU countries [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Dec 9]. Available from: www.gabionline.net/Reports/UK-biosimilars-uptake-lower-than-in-some-other-EU-countries
7. GaBI Online – Generics and Biosimilars Initiative. Biosimilar EPO and infliximab, adalimumab get formal Japanese approval [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Dec 9]. Available from: www.gabionline.net/Biosimilars/News/Biosimilar-EPO-and-infliximab-adalimumab-get-formal-Japanese-approval
8. Sawai. Situation of generics in Japan [homepage on the Internet]. [cited 2014 Dec 9]. Available from: www.sawai.co.jp/en/generics/
9. Blank T, et al. Safety and toxicity of biosimilars—EU versus US regulation. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(3):144-50. doi:10.5639/gabij.2013.0203.039
10. Alexander E. 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
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:
Australia currently has a small generic and biosimilar medicine industry despite having a good track record in biomedical research and a sound reputation in producing high quality but small volume biological pharmaceuticals. In recent times, Australia has made incremental changes to its regulation of biosimilars – in patent registration, in the use of commercial confidential information, and in remuneration. These improvements, together with Australia’s geographical proximity and strong trade relationship with the Asian biocluster, have positioned Australia to take advantage of potential public cost savings from the increased use of biosimilars.
Submitted: 24 October 2014; Revised: 17 November 2014; Accepted: 20 November 2014; Published online first: 3 December 2014
Introduction
The cost of providing health care has increased significantly worldwide [1]. Efficient and effective cost-containment measures are desired [2]. The use of generic pharmaceuticals is of interest to health economists because generics are usually cheaper than originators, hence, they contribute to a sustainable health system [3]. Similarly, cost savings are expected from the increased use of biosimilars [4].
Despite the fact that biosimilars are relatively new – the MeSH term ‘biosimilar pharmaceuticals’ was only introduced in 2012 – the biosimilars market is potentially the single fastest growing pharmaceutical sector, with an estimated US$67 billion in global sales by 2020 [5]. This has stimulated the emergence of non-conventional pharmaceutical investors such as Fujifilm and Samsung, as well as countries such as Brazil, China, India, Mexico, South Korea, Russia and Turkey, who view biosimilars as a key macroeconomic driver of growth [5].
Australia is a relatively small and new pharmaceutical market with a good reputation in producing high quality but small volume biological pharmaceuticals [6, 7]. At a recent national medicines conference, the Australian regulator – Therapeutic Goods Administration (TGA) – indicated that Australia was ready for biosimilars. Specifically, TGA sees its role in ‘posing as few barriers as possible to the registration of biosimilars, while simultaneously assuring the quality, safety and efficacy of those biosimilars both before and after registration’ [8]. The focus of this article is to appraise TGA’s proposed role, with a focus on whether Australia is positioned to take advantage of biosimilars. Specifically, the issues of biosimilars in relation to the Australian patent scheme, the use of commercial confidential information by TGA, and remuneration under the national Pharmaceutical Benefits Scheme (PBS) are discussed.
Preregistration: patent
The critical question concerning the regulation of biosimilars is whether the current Australian patent system impedes the entry of biosimilars into the marketplace.
Prior to registration of biosimilars with regulators and eventual marketing of the product, a key step in the process is the application for patent protection. The Australian administrative agency for intellectual property – IP Australia – recently completed a review of Australia’s pharmaceutical patent system. The panel of experts considered patentability of biosimilars and acknowledged that ‘biosimilars are not considered to be bioequivalent to a reference biological product. This is due to the highly complex nature of biological medicinal products & the clinical performance of biologic[al]s is often highly dependent on the methods of manufacturing and purification. Even minor differences in the environment or manufacturing process can compromise biological activity and safety for some biologic[al] drugs’ [9]. The Panel further stated that there is a need for an integrated approach to the regulation of pharmaceuticals beyond patent issues [9]. The Panel felt that ‘the patent landscape for biologic[al]s is no more complex than that for small-molecule drugs’, and did not warrant specific patent protection, such as increased length of confidential data protection or extended patent terms.
Innovators often file for separate patent protection for their upstream manufacturing process and their downstream end product at the same time. For biosimilars, the upstream–downstream nexus is arguably more relevant than for small molecule generics, especially with respect to safety and efficacy. For example, when the biosimilar epoetin alfa, Eprex was blamed for increased immunogenicity and development of pure red cell aplasia, two hypothetical causes were suggested: (i) leachates from uncoated rubber stoppers, and (ii) the change from human serum albumin to polysorbate-80 as a stabilizer [10, 11]. Any differences in the upstream production of biosimilars can result in significant differences in the biological characteristics of the downstream end product.
It is generally accepted that the aim of the Australian patent system is primarily economic: an exchange of exclusive rights in return for innovation [12]. If indeed the principal objective of the Australian patent system is to incentivize innovation, one must rightly question whether the consequence of the innovator’s attempt to patent and protect various modes of upstream manufacturing as well as the downstream end product does, in fact, stimulate innovation.
Australia recently enacted the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 aiming to address the issue of the ‘patent thicket’. The amendment came into effect in April 2013. Section 7 of the Patent Act 1990 was amended with respect to an element of the legal test that decides whether the subject of a patent application is ‘inventive’, and hence can be afforded patent protection. The amended section relates to the common general knowledge/prior art base, which a skilled addressee may consider when approving the patent application. The prior art base is no longer restricted to information extent in Australia. Furthermore, sections 18 and 7A require that a patent needs to be of particular benefit to the public as disclosed in its current form, as opposed to whether it could prove useful at some future date after further research. Section 40(2)(a) further demands that the disclosure of the invention be clear enough, complete enough and contain the best method known to the patent applicant for the invention to be recreated by a person skilled in the relevant art. The effect of amended section 40(3) imposes on the patent applicant the duty to fairly base the description of each of its claims and mandates that the scope of the claims be not broader than is justified by the extent of the description. Section 199C further provides for certain types of non-commercial experimental activities to be undertaken without infringing on the innovator’s patent rights. These include determining the properties of the invention, the scope of the patent claim, and the validity of the claim; as well as improving or modifying the invention. Collectively, the Raising the Bar amendments aim to restrict the scope of claims upon which the innovator can fairly base its invention thereby narrowing the scope of the patent and making it easier for a biosimilar sponsor to seek a patent for its product. The amendments may also have the effect of preventing ‘evergreening’ one’s pharmaceutical product, once the patent has been granted.
Registration: confidential information
For a pharmaceutical product to be supplied in Australia, a sponsor must apply to TGA for its product to be listed in the Australian Register of Therapeutic Goods. During the assessment process, detailed product information, such as quality, safety and efficacy, and manufacturing information, must be submitted to TGA.
The European Medicines Agency (EMA) has led the regulation of biosimilars since 2003. The regulatory process has been inclusive of both the pharmaceutical industry and the regulators through the development of concept papers, followed by draft guidelines. Clinical, non-clinical and product class guidelines are publicly available. Consequently, several countries have looked to EMA regulations for guidance. Specifically, TGA has opted to adopt the EMA guidelines in the regulation of biosimilars in Australia.
With respect to the naming of pharmaceutical products, TGA dictates that the name of a biosimilar is to be made up of: (i) the reference product’s Australian Biologic Name, and (ii) a biosimilar identifier, consisting of the prefix sim(a)- and a three-letter code issued by the World Health Organization’s (WHO) International Nonproprietary Name (INN) Committee. The three-letter code will eventually be harmonized to the four-letter code. The biosimilar sponsor will need to first apply to the WHO’s INN Committee for a biosimilar four-letter code; then to the Australian Biologic Name Committee for the use of the INN three-letter code in the biosimilar identifier; and finally to request for this identifier to be added to the list of Australian Approved Names. If there are detectable quality differences in the biosimilar as compared with the innovator product, the biosimilar sponsor will also need a different Australian Biologic Name.
To evaluate the quality assurance of the manufacturing of biosimilars, knowledge of analytical methods, in-house standards, specifics of the production process, historical development process, validation and full characterization data are needed. However, these are deemed proprietary information and little is available in the public domain. A systematic review of research outcomes and pharmaceutical sponsorship found that research funded by the pharmaceutical industry was less likely than publicly-funded research to be published; and if published, more likely be in favour of the sponsor (OR 4.05, 2.98−5.51) [13]. There have been allegations that pharmaceutical companies have selectively published favourable findings of self-funded research, which bolster one’s apparent success, and that unfavourable findings were not published. As information about the upstream process and methods of manufacturing are critical to the downstream biosimilar products, the handling of confidential information takes on extra importance.
Unlike the US’s 12-year marketing exclusivity period for the innovator [14], Australia’s data exclusivity is currently five years pursuant to section 25A of the Therapeutic Goods Act 1989. Within this time, TGA cannot without the permission of the innovator use the initial data submitted to assess an application for registration from a biosimilar sponsor. The data exclusivity provision does not, however, prevent a biosimilar manufacturer from conducting its own research and submitting its own dossier for listing by TGA within this data protection period.
Recently, TGA conducted a review of its policy on disclosure of commercially confidential information under section 61 of the Act. The review concluded that it is lawful for TGA to release confidential information to other national regulators (such as for the listing on the PBS) and international agencies [15]. This affirmation is of relevance to biosimilars especially given the global nature of trade and citizen movement, which warrants international collaboration in the regulation of quality, safety and efficacy of pharmaceuticals of all types. Specifically, the Australian Government signed a treaty with New Zealand that established a central agency (Australia New Zealand Therapeutic Products Agency) for the regulation of therapeutic goods in both countries; and, more recently, TGA has agreed to participate in the European Decentralised Procedure for the evaluation of generics [16]. There are similar moves for Europe, Japan and the US for harmonized evaluation [17, 18].
Tracking immunogenicity
It is not possible to predict the immunogenic potential of a biosimilar from its molecular structure or even from the results of preclinical and animal trials. In addition, the antibody response induced by a biosimilar may have a different character and clinical consequence compared with that of the innovator. A large and longer duration cohort study may be required to study safety and efficacy of a biosimilar. Such a pharmacovigilance study is expensive to conduct due to the duration of the study and the number of participants required. With a biosimilar, post-marketing pharmacovigilance may be the only means of conducting such an assessment. Sharing of information among national and international regulators may be a solution.
With biosimilars, such as filgrastim (rbe*) (Tevagrastim sponsored by Aspen Pharmacare Pty Ltd, Nivestim by Hospira Pty Ltd, Zarzio by Sandoz Pty Ltd, and Neupogen by Amgen Australia), batch-to-batch variation is to be expected. When there is only a single brand on the market, any adverse effect such as immunogenicity may be tracked to the innovator product if the Australian healthcare practitioner reports the adverse effect to the Advisory Committee on the Safety of Medicines. However, not all Australian community pharmacies currently provide batch tracking [19]. This poses a logistical issue in post-marketing pharmacovigilance of biosimilars when more than one branded product is available on the market. The ability to share information among national regulators under the Act becomes vital. Australia has a streamline parallel evaluation by TGA and for listing under the PBS.
*This in Australia denotes ‘recombinant bacteria E.coli‘ and indicates production from bacteria genetically modified by recombinant DNA technology [ref: TGA (2013) Australian Public Assessment Report for Filgrastim (rbe), proprietary product name Zarzio, sponsor Sandoz Pty Ltd, Canberra, ACT: Department of Health.
Global information sharing
The quality of ‘follow-on biologics’ manufactured in low-income countries may be sufficiently different to those manufactured in more strictly regulated high-income countries that they do not qualify as biosimilars. Nonetheless, the latter countries can learn from the experience of the former, which may have the large population necessary to study the efforts of biological exposures. With the ease of international movement and ability of any citizen to source cheaper ‘follow-on biologics’ from low-income countries, pharmacoepidemiological adverse effects data and information on management could be gleaned from information sharing with low-income countries. The sharing of information also enables low-income countries to have access to essential information about a particular biological, and in the process strengthen their own capacity. Australia has established trade relationships and is in close geographical proximity to the Asian biocluster – specifically China, India, Japan and South Korea. Australia has a reputation of producing high quality pharmaceuticals (including biologicals) [7], stable regulatory and remuneration frameworks, and a sound national medicines policy that advocates for a viable pharmaceutical industry and affordable access that have all survived successive changes of government. This puts Australia in a unique position to influence the Asia-Pacific regional regulation of biosimilars.
PBS is the monopolistic buyer of pharmaceuticals in Australia. Section 101 of the National Health Act 1953 stipulated that the Pharmaceutical Benefits Advisory Committee can only recommend listing a pharmaceutical on PBS after a positive cost-effectiveness or cost-minimization analysis of the application. If the application is for a product, which is more costly than alternate therapies, significant improvement in the efficacy or reduction of toxicity needs to be demonstrated. This is the legislative basis for reference pricing or benchmarking in Australia. Prices of all pharmaceuticals in the group are tied to that of the lowest, or occasionally the average, price in the group. To further contain costs through increased use of generics, a series of amendments were made to the Act. Of relevance are brand premiums in 1990, brand substitution by pharmacists in 1994 and therapeutic group premiums in 1998 [20, 21]. More recently in 2007, Formula 1 (F1) and Formula 2 (F2) reference pricing was introduced. Pharmaceuticals listed in the F1 schedule are mostly stand-alone branded innovator drug products and not interchangeable. Pharmaceuticals listed on the F2 schedule are ‘generic’. When an equivalent generic drug becomes available, the innovator drug can be moved from F1 to F2, resulting in a significant price reduction. Section 99ACEA of the Act clarified that such a price reduction applies to the ‘same pharmaceutical item’, ‘same drug’ and ‘biosimilar’. The Australian Government can move innovator biological products from F1 to F2 and apply the compulsory price reduction when a biosimilar becomes available on PBS. However, as of October 2014, the biosimilar epoetin lambda was still assigned the higher F1 pricing. Likewise, all somatropins in Australia continued to have F1 pricing as they were approved and registered as new entities.
Other features of the 2007 amendment (F1-F2 pricing) include price disclosure for pharmaceuticals listed in the F2 schedule, termination of reference price link between pharmaceuticals listed in F1 and F2 schedules, and the precondition for pharmaceuticals listed in the F2 schedule to be ‘interchangeable on an individual patient basis’.
The issue of interchangeability and substitution was coined the ‘fifth hurdle’ of regulating biosimilars [22]. In Australia, most – if not all – biosimilars are currently dispensed through hospital pharmacies. Both TGA and PBS do not allow automatic substitution of biosimilars [23] and none of the currently available biosimilars are deemed interchangeable [24]. Australia’s lead evidence-based medicine/quality use of medicine agency – NPS MedicineWise – advises clinicians to view switching and substitution as a change in clinical management [24]. This advice is likely to confuse clinicians, as there are a number of pseudo-biosimilars, e.g. Aczicrit, Grandicrit and Novicrit all marketed by Sandoz Pty Ltd, on the market. An analysis needs to be conducted to ascertain whether such pseudo-biosimilars have the effect of saturating the market and forcing out competition that would infringe the misuse of power provision under section 46 Competition and Consumer Act 2010.
Conclusion
Australia is a relatively small market for multinational pharmaceutical manufacturers; however, its reputation of producing high quality pharmaceuticals, close proximity to, and strong trade relationship with, the Asian biocluster puts Australia in a unique position to influence the regional regulation of biosimilars. Three specific aspects of incremental changes to the Australian regulation of biosimilars in relation to potential public cost savings are described here. The Raising the Bar amendments to the Australian patent system may reduce the scope of what an innovator can claim to be patentable, and encourage early entry by biosimilars. The fact that biosimilars still attract F1 pricing may be an economic incentive provided by the PBS until the necessary volume threshold is reached by the biosimilars sponsors. For the policymakers, the affirmation that it is lawful for TGA to share commercial confidential information with national and international regulators, and the shorter data exclusivity period, may result in more efficient decision-making in granting biosimilar approval and licensing by TGA.
Acknowledgement
I acknowledge and appreciate the guidance and suggestions from the editors and my hepatitis C research collaborators, although I accept all responsibility for this work. This work is supported by the Queensland University of Technology’s Early Career Academic Recruitment and Development Grant.
Editor’s note:
The Australian Government announced on 24 November 2014 that it would cease joint effort with the current New Zealand Government to establish the proposed joint therapeutic products regulator. However, in the joint media release by both countries’ Minister of Health, Australia and New Zealand remain committed to cooperate on the regulation of therapeutic products. Australia’s TGA and New Zealand’s Medicines and Medical Devices Safety Authority (Medsafe) will continue to explore other means of harmonization activities under the terms of the treaty. These include new information sharing agreement and formalizing mutual recognition of good manufacturing practice audits.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
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3. Lofgren H. Generic drugs: international trends and policy development in Australia. Pharmaceutical Industry Project: Equity, Sustainability and Industry Development Working Paper Series. August 2002, Centre for Strategic Economic Studies: Melbourne. 2002 Sep 28 [cited 2014 Nov 20]. Available from: http://vises.org.au/documents/pharma/10-Role_of_generics.PDF
4. Haustein R, et al. Saving money in the European healthcare systems with biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):120-6. doi:10.5639/gabij.2012.0103-4.036
5. IMS Health. Shaping the biosimilars opportunity: a global perspective on the evolving biosimilars landscape. 2011 [homepage on the Internet]. 2012 Jan 5 [cited 2014 Nov 20]. Available from: http://www.imshealth.com/ims/Global/Content/Home%20Page%20Content/IMS%20News/Biosimilars_Whitepaper.pdf
6. Australian Government. Department of Health and Ageing. Strategic review of health and medical research. Final report. February 2013.
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24. National Prescribing Services Ltd. Biosimilars – what you need to know. Health News and Evidence. 7 November 2013 [homepage on the Internet]. 2014 [cited 2014 Nov 11]. Available from: http://www.nps.org.au/publications/health-professional/health-news-evidence/2013/biosimilars#References.
Author: David Lim, DPH, Lecturer, School of Clinical Sciences, Queensland University of Technology; Member, Institute of Health and Biomedical Innovation – Health Determinants and Health Services Theme, Queensland University of Technology, GPO Box 2434, Brisbane, Queensland, AU-4001, Australia
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.
The world market for medicinal products is expected to reach US$1 trillion in 2014. Global spending on medicines is expected to grow to nearly US$1.2 trillion by 2017 [1]. As governments around the world try to rein in healthcare expenses, generics and biosimilars can play a major role in reducing this budgetary burden.
Intellectual property
Intellectual property (IP) rights are of critical value in a knowledge-based society and pharmaceutical companies are particularly dependent on appropriate patent protection and enforcement. Equally, effective competition between originator and generic drugs generates incentives for originator pharmaceutical companies to continue investing in research and development.
Budget constraints
Due to a combined effect of the so-called ‘patent cliff’ (when a large number of key small molecule brand-name drugs become open to competition from generics) and the current economic crisis, in recent years most OECD (Organisation for Economic Co-operation and Development) countries have even experienced a consolidation or decrease in pharmaceutical expenditure as a share of total healthcare expenditure. Most of these savings have been achieved by the replacement of expensive brand-name drugs with low cost generics.
Other changes have also been introduced to reduce spending on medicines. Changes affecting reimbursement lists and procedures, e.g. de-listings, introduction of positive and/or negative lists; and the reference price system, i.e. changes in pricing methodology allowing lower reference prices, broader clusters of similar medicines, and/or the pricing of generics in a cluster (‘generic price link’) are being made.
Measures to increase the uptake of generics, such as making prescribing by international non-proprietary name mandatory and the use of public awareness-raising campaigns, have been frequently used.
Despite these measures, pharmaceutical expenditure still accounts for a considerable percentage of total healthcare spending in Europe. In 2011, spending on drugs as a percentage of total healthcare spending ranged from 6.8% in Denmark to 33.4% in Hungary; followed by Greece (28.5%) and the Slovak Republic (27.4%).
European Union measures
The European Union (EU) has introduced several measures, such as a centralized procedure for the authorization of medicines, rules facilitating the approval of generics, support to small- and medium-sized enterprises (SMEs), and regulatory data protection incentives to promote innovation while assuring timely access of patients to medicines.
Biosimilars
Biosimilars can also play a major role in improving public health since they address the need for the responsible allocation of public funds while opening up promising treatment options for patients by increasing their affordability. However, to realize the potential benefits that biosimilars offer requires not only a robust regulatory framework such as the one in place in the EU, but also effective risk management.
Experience to date suggests that the most important conditions required for market uptake of biosimilars are factors such as:
physician perception
patient acceptance
local pricing and reimbursement regulations
procurement policies and terms.
Fostering the informed uptake and improving early access to high quality biosimilars on the basis of the EU’s regulatory framework, i.e. through access to unbiased information and education of patients, healthcare professionals and payers, while closely monitoring the EU’s market penetration of biosimilars may contribute to the success of the dual objectives of improving overall public health and the sustainability of Member States’ healthcare systems.
According to IMS Health, although biosimilars are a small segment in the total pharmaceutical market (~1%), they have experienced exceptional growth (38% in 2012). Biosimilars’ share of the accessible European market has grown steadily from their launch and is now at 18%. Biosimilars have a 13% share of the growth hormone market, 19% of the erythropoietin market, and 49% of the granulocyte colony-stimulating factor market [2].
The per capita uptake of biosimilars and the size of the accessible market however differ between European markets [3]. For example, in the UK biosimilars make up only 30% of the volume market share of their reference products, despite the fact that the UK has one of the highest market shares of generics in Europe. In 2010, 83% of prescriptions in England were prescribed and 67% were dispensed as generics [4]. The UK biosimilars uptake is significantly lower than in Germany, where biosimilars have around 50% volume uptake [5].
Continued effort
Member States’ governments will need to continue their efforts to limit the future growth in medical expenditures, especially for medicines. The use of generics and biosimilars is therefore expected to be promoted as a lower-cost alternative by public and private payers. However, lack of competition and insufficient or ineffective policies promoting the use of generics and biosimilars can limit the ability of governments to implement budgetary savings.
Competing interests: None.
Provenance and governance: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board, internally peer reviewed.
Michelle Derbyshire, PhD, GaBI Online Editor
References 1. European Commission. Commission staff working document. Pharmaceutical industry: a strategic sector for the European economy. 1 August 2014. SWD(2014) 216 final/2 [homepage on the Internet]. 2014 Aug 1 [cited 2014 Oct 16]. Available from: http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/pharmastrategy_en.pdf
2. Dunn C. Biosimilar accessible market: size and biosimilar penetration. Prepared for EFPIA-EGA-EuropaBio, April 2012.
3. GaBI Online – Generics and Biosimilars Initiative. Use of biosimilars in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Oct 16]. Available from: www.gabionline.net/Reports/Use-of-biosimilars-in-Europe
4. Health and Social Care Information Centre. Prescriptions Dispensed in the Community Statistics for England – 2000-2010 [NS]. 27 July 2011 [homepage on the Internet]. 2014 Oct 16 [cited 2014 Oct 16]. Available from: http://www.hscic.gov.uk/pubs/presdisp2000–10
5. GaBI Online – Generics and Biosimilars Initiative. UK biosimilars uptake lower than in some other EU countries [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Oct 16]. Available from: www.gabionline.net/Reports/UK-biosimilars-uptake-lower-than-in-some-other-EU-countries
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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 attractiveness of the biosimilar regulatory pathway is threatened by so-called biobetters. This paper provides definitions and an overview of recent developments.
Submitted: 27 October 2014; Revised: 7 November 2014; Accepted: 12 November 2014; Published online first: 25 November 2014
Concerning the biosimilar landscape, the European Medicines Agency (EMA) was among the first institutions to offer a legal basis and regulatory guidance for biosimilar development. Since 2004, the available guidance documents have flourished and evolved to ensure high standard biosimilar medicines for patients throughout the European Union (EU). Biosimilar medicines seemed to be the ideal solution for healthcare representatives in fear that a growing number of highly expensive biologicals would sooner or later crash their systems and leave the costs of high-end treatment to the patient. Additionally, biosimilars, like generics, were considered innovation drivers, urging developers to focus on novel targets rather than stick with established top sellers.
After the first guideline was in place, the new concept was taken up with varying speed and varying success. While some markets were quick on uptake of biosimilars, other countries seemed more hesitant to incorporate the novel concept into daily practice [1]. It took time, but in 2013, biosimilar development started to gain momentum, with the positive CHMP (Committee for Medicinal Products for Human Use) opinion to Celltrion’s Remsima (infliximab) – the first biosimilar monoclonal antibody – developed from a South Korean Company. Even more encouragingly, within the EU, Remsima was able to obtain all major indications of originator Remicade by extrapolation. To date, 19 biosimilar medicines have a valid marketing authorization, and many more are waiting in the pipelines. More and more European markets jumped on the biosimilar bandwagon resulting in Italy overtaking Germany as the biggest European biosimilar market [1]. Biosimilars can be considered a success story – yet they are in fierce competition with a different player, which is from a European regulatory perspective, no player at all – the ‘biobetters’.
The term ‘biobetter’ was presumably invented by Mr GV Prasad, CEO of Dr Reddy’s Laboratories, at a bio-investor’s conference in Mumbai, India, in 2007 and has been excessively used ever since, possibly to a degree, where there is no unified definition for this marketing term [2].
While biosimilars, as the term suggests, aim to establish similarity to a known biological, biobetters seek superiority in one or various aspects of their clinical profile. While working against the same target protein, biobetters include structural changes, bi-functional targeting (with or without a biosimilar core) or an improved formulation that may result in an expected improvement in safety and/or efficacy [3].
Sharing the same target and being an improved version of a known biological sets biobetters apart from so-called ‘me-too biologicals’, which, without being structurally based on each other, share the same target, e.g. anti-TNFα monoclonal antibodies.
An interesting example of a biobetter, which could possibly reduce the impact of potential biosimilar candidates is the development of Roche’s obinutuzumab (Gazyvara), an anti-CD20 monoclonal antibody, which has shown superior efficacy in the treatment of chronic lymphocytic leukaemia (CLL) compared to its ‘originator’ rituximab (MabThera, Roche). Gazyvara gained EU marketing authorization for previously untreated CLL in 2014 – before biosimilar candidates of rituximab managed to finish their development programmes. However, it remains to be proven if Gazyvara can demonstrate a more favourable benefit/risk ratio than rituximab in other indications than CLL and to what extent it will replace MabThera, as well as putative biosimilar rituximabs, in the future.
While no special regulatory pathway for biobetters exists, a biobetter will always be treated as a product with new active substance from a regulatory perspective, some ‘short cuts’ might remain for biobetter developers. Knowing your target can reduce R & D costs, prior related drugs may help with choices of biomarkers and safety monitoring will most likely focus on known side effects of the already established target pathway. Furthermore, if a biobetter gains a marketing authorization, this may lead to market exclusivity, even if no patent protection will be issued. Sometimes, biobetter development is even used as a defence strategy of originator companies, to protect their market niche against possible biosimilar candidates via line extensions, as in the case of a subcutaneous formulation of Roche’s trastuzumab, which gained positive marketing authorization in 2013 shortly before Roche’s Herceptin (intravenous trastuzumab) patent expired in 2014.
Apart from the lack of new targets, the rise of biobetters can partly be attributed to certain regulatory pitfalls in the European biosimilar regulatory framework. For instance, the sensitive issue of interchangeability has, to date, not been addressed by EMA because interchangeability is tightly connected to substitution which is a national issue. In the absence of national legislation and guidelines, the decision if and under which circumstances interchangeability could be established remains with to individual doctors, especially in the context of hospital tendering processes [4]. Hence, it remains unclear whether, like generic drugs, biosimilars will be prescribed interchangeably with their originator in the near future.
To keep the biosimilar concept attractive for companies, regulatory guidance needs to evolve to more thoroughly address most urging regulatory questions in order to ease global developments. In line with this, the concept of extrapolation of indication has further been elaborated in a recent article issued by members of EMA’s Biosimilar Medicinal Products Working Party, specifying circumstances under which extrapolation to all originator’s indications can be possible [5]. Furthermore, in 2013 the new draft of EMA’s overarching biosimilar guideline opened the door to waiving clinical studies in biosimilar development under specific circumstances, e.g. for structurally more simple biological medicinal products, which in the future will have to be further specified to help companies in planning their biosimilar development programmes [6].
In conclusion, in a highly regulated market, such as the EU, the biosimilar concept stands a fair chance to continue posing an attractive regulatory pathway for drug developers, compared to developing ‘biobetters’ via a full application, thereby fulfilling the rising need for cheaper biological medicinal products. Regulatory guidance will further have to evolve, to keep biosimilars competitive against biobetters and to avoid pitfalls in their development.
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
References 1. Rickwood S, Biase SD. Searching for terra firma in the biosimilars and non-original biologics market. IMS Health, 2013.
2. DePalma A. Will biobetters beat biologics? October 2011 [homepage on the Internet]. [cited 2014 Nov 10]. Available from: http://social.eyeforpharma.com/forecasting/will-biobetters-beat-biologics
3. Dolinar RO, Reilly MS. The future of biological therapy a pathway forward for biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(1):36-40. doi:10.5639/gabij.2013.0201.014.
4. European Medicines Agency. Questions and answers on biosimilar medicines (similar biological medicinal products). EMA/837805/2011. 27 September 2012 [homepage on the Internet]. [cited 2014 Nov 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf
5. Weise M, Kurki P, Wolff-Holz E , Bielsky MC, Schneider CK . Biosimilars: the science of extrapolation. Blood. 2014 Oct 8. pii: blood-2014-06-583617. [Epub ahead of print]
6. European Medicines Agency. Draft guideline on similar biological medicinal products. CHMP/437/04 Rev 1. 22 May 2013 [homepage on the Internet]. [cited 2014 Nov 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf
Author:René Anour, DVM, Senior Clinical Expert, Department Clinical Assessment Safety & Efficacy, Institute Assessment & Analysis, Austrian Medicines & Medical Devices Agency (AGES), Austrian Federal Offi ce for Safety in Health Care (BASG), 5 Traisengasse, AT-1200 Vienna, Austria
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Abstract:
The regulatory oversight of biologicals in Malaysia is established by the National Pharmaceutical Control Bureau (NPCB), Ministry of Health. At the agency, the Section on Biotechnology Product Registration exercises the marketing authorization function as the National Regulatory Authority (NRA). This paper provides an overview of the organization, regulatory expectations and current practices of the evaluation of biologicals in Malaysia. Recent developments in the regulation of biologicals, focusing on biosimilars, are also presented. Because of the rapid pace of science and evolving regulatory controls, collaboration with local and international stakeholders is key to enhancing the safety and availability of biologicals/biosimilars in a cost-effective manner while meeting important medical needs. As resources for capacity building are not always at our disposal, we actively explore partnerships with our international counterparts who face common regulatory challenges.
Submitted: 19 September 2014; Revised: 23 October 2014; Accepted: 28 October 2014; Published online first: 10 November 2014
Background
In Malaysia, the evaluation of biologicals has been incorporated into a regulatory system established for the purpose of providing marketing authorization for medicinal products. The past decade has witnessed not only a market dominance of biologicals, led by a wave of biologicals discovered in the 80s and 90s to address the treatment of diseases with unmet needs, but also an increase in the market penetration of ‘copy products’ of blockbuster biologicals with expired patent protection. The use of recombinant enzymes as replacement therapy for enzyme deficiency diseases such as Fabry disease and Pompe disease addresses the core physiological deficiency and offers specific disease treatment, a feat not possible to achieve with current, chemically synthesized compounds. However, the rapid development of biological compounds and their follow-on versions have posed considerable challenges to drug regulators worldwide.
As a result, a dedicated regulatory pathway has been created for biologicals and biosimilars, which is really a paradigm shift from evaluating each product on its own merit based on its biological nature – inherently variable, complex, and unique. Even then, regulators constantly face the pressure of keeping up with trends and advances in biotechnological manufacturing and analytical tools.
Introduction to the organization
The National Pharmaceutical Control Bureau (NPCB) is the National Regulatory Authority (NRA) in Malaysia. NPCB was established as a secretariat to the Drug Control Authority (DCA), an executive body chaired by the Director-General of Health, for the approval of all pharmaceutical, health and personal care products, as described in the Control of Drugs and Cosmetics Regulation of 1984 [1].
NPCB is responsible for ensuring the quality, efficacy and safety of medicinal products prior to release in the Malaysian market. In upholding the three tenets of quality, efficacy and safety, NPCB regularly engages with both internal and external partners. Internal partners include public health and health technology assessment agencies within the Ministry of Health Malaysia, while external partners/counterparts include healthcare professionals, academia, industry representatives, the World Health Organization (WHO) and other NRAs. The mission of NPCB is to implement effective regulatory controls that contribute to improving health care for Malaysians.
Among its regulatory control strengthening strategies, NPCB strives to improve the efficiency of work processes via its Quality Management System (QMS). NPCB currently maintains the standards of MS ISO 9001:2008. As not all the agencies within the Ministry of Health are MS ISO 9001:2008-compliant, this makes NPCB one of the few health agencies with a QMS that matches international expectations.
NPCB is a WHO Collaborating Centre for Regulatory Control of Pharmaceuticals. Through the Association of Southeast Asian Nations (ASEAN) Technical Cooperation among Developing Countries (TCDC) programme, NPCB has served as a regional training centre since 1986. Several NPCB officers have travelled overseas as consultants to assist in the development of pharmaceutical regulatory control systems.
Evaluation of biologicals in Malaysia
The classification of a medicinal product as a biological is clearly defined in the Drug Registration Guidance Document (DRGD), together with a list of included and excluded product types [2]. Appendix 3 of this document includes regulatory guidance on the registration of biologicals. For the purpose of product registration, the terms ‘biotechnology’ and ‘biologicals’ can be used interchangeably, as evaluation of both product categories are conducted by the same team of evaluators. In the context of product registration, biologicals encompass both naturally occurring substances extracted from living organisms and biotechnology-derived products. This includes biotechnology products, blood-derived products and vaccines. Currently, the following product types are not evaluated by the Biotechnology Section: (1) metabolites from microorganisms, e.g. antibiotics and some hormones; (2) macromolecules produced by chemical synthesis, e.g. peptides such as lung surfactants and oligonucleotides; and (3) whole blood or cellular blood components.
At NPCB, biological evaluation activities are performed by the Biotechnology Section, a division within its Centre for Product Registration. As biologicals include a wide range of product categories, the sub-divisions of the Section reflect its current product portfolio: vaccines, blood-derived products, and biotechnology products including biosimilars. The product types currently registered at NPCB include: monoclonal antibodies (mAbs), recombinant human insulin and insulin analogues, hormones, cytokines, antibody-drug conjugates, vaccines and plasma fractionation/recombinant analogue products. Figure 1 shows the breakdown and total number of biological products registered in Malaysia in the past five years. For a list of drugs registered in any particular year, readers may refer to the annual reports published on the NPCB website (http://portal.bpfk.gov.my/index.cfm).
The numbers in brackets at the top of each column indicate the total number of registered products in that year. Products containing different strengths of the same drug substance are considered as one product (see keys in Figure 1).
Quality assurance
The general principles of evaluation of biologicals at NPCB are consistent with current international regulatory practices. As a requirement for quality assurance, every biological must comply with the principles of Good Manufacturing Practice (GMP) for biologicals as established in the guidance documents of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S) [2]. NPCB has been a PIC/S member authority since 1 January 2002 and every biological product submitted for evaluation must possess a valid GMP certificate as issued by a PIC/S member authority. For products submitted without prior PIC/S GMP certification, the GMP inspection team from NPCB will inspect and certify the manufacturing facility. This is a prerequisite for product dossier submission. NPCB believes that a PIC/S GMP certification is key to risk reduction and establishment of a quality system that ensures consistent production. In addition to quality assurance by GMP, all steps involved in the gathering of the starting materials, e.g. plasma from screened donors, product manufacturing, and excipient source are scrutinised to the strictest level in line with international standards in order to further ensure non-transmission of adventitious agents to users.
Registration process and requirements
Within the ASEAN economic community, a biological product submission must adhere to the organization and document requirements as outlined in the ASEAN Common Technical Dossier (ACTD) format [3]. Table 1 highlights the differences in format between the ACTD and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use – Common Technical Dossier (ICH-CTD), as formulated by regulators from the ICH (Europe, Japan and the US) regions [4].
The table lists the parts of a biological product submission dossier for the purpose of registration. The dossier requirement according to ACTD is compared with the dossier requirement according to ICH-CTD.
The inherent complexity of biological molecules calls for regular creation of new and product-focused regulatory guidance documents to account for evaluation of new molecules and technologies. Regulatory guidance has always evolved with advances in recombinant technology and bioprocesses. In addition to the ACTD dossier and DRGD for product registration in Malaysia, requirements for registration of biologicals are consistent with the guidances established by WHO and ICH. Other regulatory expectations such as those published by mature and referenced regulatory agencies, for instance, the European Medicines Agency (EMA) and the US Food and Drug Administration (US FDA), can also be referred to. NPCB strives to emulate the examples set by more established regulatory authorities in order to avoid replication, preferring to adopt and adapt the regulatory guidance from these agencies as appropriate for local use. At the same time, NPCB has been represented in the formulation and implementation of regulatory guidance documents at WHO level, via participation in implementation workshops, especially for biosimilars.
Evaluation of every biological product is performed via the established procedure for a pharmaceutical product registration at NPCB. Submission of a biological product registration dossier is conducted through an online and manual system. Since 2011, NPCB has been operating an online product registration system under the acronym QuEST3 (Quality, Efficacy and SafeTy 3; the digit ‘3’ indicates the current system version). The paper-based manual submission system is still retained and complements the online QuEST3 submission system.
The registration process for a biological at NPCB begins when an online submission by an applicant is received. Once the dossier is deemed to fulfill the requirements for registration, a manual submission process takes place, where the applicant submits the printed documents for evaluation. The applicant is also required to submit the analytical methods and validation documents for evaluation at the Centre for Quality Control, NPCB. NPCB regularly consults external experts (academicians, clinical consultants, and public health and blood product experts) throughout its evaluation process. External experts and key opinion leaders (KOLs) are selected for independence, with the highest level of confidentiality in place. Internal product evaluation meetings are held among the various centres at NPCB to formulate an evaluation report that can be presented to DCA for consideration. The possible outcomes at the DCA level are: (1) product is registered; (2) product is rejected, with reasons or; (3) product is withheld pending further information from applicant. An approved biological product will be assigned a unique registration number beginning with the prefix ‘MAL’ and ending with the letter ‘A’ for poison or ‘X’ for non-poison classification in accordance with the Sale of Drugs Act 1952 [5]. Parties objecting to a DCA decision may appeal to the Minister of Health within 14 days of the DCA decision. Figure 2 summarizes the biological product registration process at NPCB.
The flowchart shows the biological product registration process in Malaysia. The evaluation process encompasses internal deliberation on a product’s quality, efficacy, and safety characteristics, and consultation with external subject matter experts. Correspondence (via letter, email or face-to-face meeting) is maintained with the applicant several times during the product evaluation process in order to obtain additional product information as necessary. Information on membership and terms of reference of DCA is available on the NPCB website (http://portal.bpfk.gov.my/index.cfm).
NPCB shares a common challenge with other NRAs, i.e. to ensure satisfactory quality, safety and efficacy in approving a drug product within certain time limits. For a biological product, the timeline has been set at 245 working days. The timeline is shortened to as little as 90 working days if a certain product has been assigned a ‘priority review’ status. In the past, some biological products were assigned such status due to great promise in fulfilling an unmet medical need, e.g. a rare disease/oncology indication, or to address a threat to public health.
Besides new product registration, the Biotechnology Section also handles evaluations for an extension or update to an indication and dosage of an approved product. Generally, the processing of such an application follows the new product registration pathway, see Figure 2. In addition, we evaluate changes to a product’s profile throughout its life cycle (as long as a product remains registered). Changes to product quality, including manufacturing process improvement, updates to a product’s label and prescribing information, and extension of product dosage forms and packaging must also undergo evaluation via the variation pathway.
Recent developments on regulation of biologicals in Malaysia
The Section on Biotechnology Product Registration at NPCB has received applications to register biosimilar products since the establishment of its biosimilar regulatory pathway in 2008. As one of the first countries to define a regulatory process for biosimilars, Malaysia has avoided marketing of any ‘biogenerics’ or ‘me-too biologicals’ with untested quality, safety, and efficacy profiles compared to those of innovator biologicals. The Malaysian guidance document and guidelines for registration of biosimilars (2008) adopted the regulatory expectations at EMA, with incorporation of local expectations. It contains a provision to align requirements with the global similar biotherapeutic product (SBP) guideline published later (in 2009) by WHO. A comprehensive discourse on this topic is discussed elsewhere [6]. To update, a total of five biosimilar products have been registered by DCA as at 31 July 2014. The breakdown on the product types is shown in Table 2. Only biosimilar compounds of relatively smaller size and lesser complexity have been registered. The reference products for these biosimilars have been marketed in Malaysia for several years with an appropriate volume of use. The extrapolation of untested indications for these biosimilars to some or all of the approved indications for the reference products was allowed during product approval. Considerations are specific to each case, based on evidence and justifications provided by the applicant. For example, Binocrit was approved for all indications for the reference product Eprex except subcutaneous use in renal disease. Based on biopharmaceutical market trends and projections, and the availability of many innovator monoclonal antibody products in the Malaysian market, we anticipate applications for biosimilar monoclonal antibodies to follow suit.
For each product, the brand name in the local market and marketing authorization holder in Malaysia is provided. The indication refers to the diseases for which treatment with the biosimilar product has been approved. The name of the original product developer is listed under the column labelled RBP (reference biological product).
International relations
NPCB is working towards increasing its international presence by frequent exchanges with regulatory counterparts worldwide. The International Conference of Drug Regulatory Authorities (ICDRA), which has been held by WHO since 1980, provides both newer NRAs, such as NPCB, as well as more mature NRAs, such as EMA, US FDA, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) with a way to interact and explore strategies for strengthening collaboration. In the recent 16th ICDRA, Rio de Janeiro, Brazil, 24–29 August 2014, NPCB participated in the pre-conference programme on biosimilars.
Besides the activities led by WHO, other regulatory harmonization activities are conducted and frequently participated in by NPCB regulators at the Asia-Pacific and ASEAN regional levels. Within the Asia-Pacific Economic Cooperation (APEC) region, the APEC Harmonization Center (AHC) frequently coordinates regulator-industry participated forums in an effort to streamline regulatory requirements and drug product registration processes among member economies. Our regulators have participated in the AHC Biotherapeutics Workshop series and found the presentation and discussion sessions of immense benefit for application to our daily activities at NPCB.
Within the ASEAN region, Malaysia is the lead country for the ASEAN Consultative Committee for Standards and Quality – Pharmaceutical Product Working Group (ACCSQ-PPWG), with efforts towards harmonization of regulations across member states. Ongoing efforts in the regulation on biologicals focus on collating and harmonizing regulatory guidance in vaccine regulation. The group aims to establish a common set of vaccine-related registration guidelines for use within the ASEAN economic zone. In these documents, a vaccine developer can find specific requirements on the organization of a vaccine submission dossier in addition to specific stability testing requirements in ICH climatic Zone IV, i.e. hot and humid countries.
As our country is a member of the Organization of the Islamic Conference (OIC), NPCB has been represented in meetings concerning harmonization of standards on pharmaceuticals including vaccine regulation. This initiative aims to encourage self-sufficiency on pharmaceutical and vaccine products among member countries through increases in production.
Internal and external relations
In exercising its function as a pre-marketing authorization evaluation section, the Biotechnology Product Registration Section regularly engages in communication with its internal and external counterparts.
Within the organization, the Centre for Inspection and Licensing conducts inspections on biological manufacturers, from drug substance to drug product manufacturing and packaging activities. This is important to uphold the expected quality standards as established and maintained by the PIC/S. In the spirit of harmonization of GMP inspection standards, a mutual recognition system of inspections conducted among PIC/S member authorities allows NPCB to accept GMP inspection results from member PIC/S NRAs. NPCB’s GMP inspection team currently travels to manufacturing facilities across Malaysia and also to countries with non-PIC/S member NRAs to inspect biological manufacturers. These foreign inspections are conducted as a prerequisite for submission of a biological product application.
In our evaluation of quality control methods used for a biological product, our work is complemented by the evaluation activities at the Centre for Quality Control. At the centre, evaluators specializing in various analytical methods assess manufacturer’s quality control reports on analytical procedures and analytical method validation. The long-term goal here is to eventually perform market sampling and testing on registered biological products, a process which is currently lacking. This is currently a tall order, mainly due to the lack of a dedicated biological testing facility and funding constraints, but the centre has identified some products with simpler biological structure, e.g. insulin and erythropoietin, as a midterm strategy to kick start laboratory testing activities. Nevertheless, the evaluation of analytical procedures and analytical method validation still assists decision-making at the pre-marketing authorization level.
As for safety and efficacy evaluation of the products, we engage our local health experts in providing inputs on both aspects. For this purpose, NPCB frequently identifies and maintains a list of KOLs across medical fields, some of whom are actively involved in clinical trials on pre-marketed biologicals conducted in health institutions across Malaysia. DCA considers the health experts’ comments, but the decision to grant a marketing approval or not is strictly that of DCA.
In engaging our stakeholders, regular dialogues serve as a platform for new information sharing and promulgation of regulatory updates. The attendance in these dialogues includes manufacturers, industry associations and consumer representatives. Our experience demonstrates that transparent and open dialogues with all relevant stakeholders are key to putting in place a robust and pragmatic regulatory framework. At other times, advice on product registration and safety/efficacy can be obtained from the NPCB regulators through various communication channels, e.g. telephone, email, or face-to-face meetings. NPCB runs telephone call centres to respond to enquiries on product registration and product safety, including those from the general public. Information on ways to contact NPCB regulators is made available on the organization website (http://portal.bpfk.gov.my/index.cfm).
NPCB is actively seeking bilateral governmental partnerships as a forum for establishing a closer working relationship for the mutual strengthening of regulatory activities. Memorandum of Understandings (MoUs) have been signed between NPCB and the Health Sciences Authority (HSA) Singapore, as well as between NPCB and the Ministry of Health Brunei Darussalam. Following establishment of these MoUs, several regulatory exchange sessions in the form of bilateral meetings have been successfully held and the meetings explore, among other things, collaboration in the form of training programmes for regulators in these agencies. With regards to training of NPCB regulators, an annual training programme has been set up to fund NPCB regulators for overseas attachment at NRAs in Australia, the European Union, Japan, Switzerland, Taiwan and Thailand. The knowledge gained through these attachments has been disseminated at the internal level in our effort to increase our regulatory capacity for evaluation and control of a diverse biological product portfolio.
Challenges ahead
In keeping up with new biologicals and cutting-edge manufacturing methods, the regulators at NPCB participate in meetings held by WHO and other health-focused initiatives. At WHO level, NPCB regularly consults experts and receives advice and guidance on evaluation of new product types, e.g. biosimilars of different product types. NPCB regulators also participate in discussions held by WHO partner initiatives such as the Dengue Vaccine Initiative (DVI) meetings among Early Adopter Countries (EACs) in preparation for receiving the first novel dengue vaccine registration dossier.
In view of the challenges ahead, much needs to be achieved within our organization. As a basis for capacity building, a training programme for evaluators is maintained, with continuous updates based on projection of biological product registration. The focus of current training includes evaluation of a Quality by Design (QbD) product dossier, regulatory considerations on specific biosimilar products, e.g. monoclonal antibodies, and technical knowledge on cellular and gene therapy product (CGTP) manufacturing processes. A positive development is that biological regulation has been assigned as one of the priority-need areas by our management. Scholarships for postgraduate study programmes are offered annually to NPCB staff for specialized training in biologicals evaluation at local and overseas universities. The management at NPCB believes in staff motivation via sufficient appreciation and attractive remuneration. In the pharmacy services programme within the Ministry of Health, an evaluator is enrolled with a clear career pathway towards attaining the highest level of work satisfaction. In all, a conductive working environment for staff is necessary to instill a professional yet caring attitude whilst discharging their duties towards improving the health of the Malaysian population.
In conclusion, recent developments in biotechnology and health care have opened up a new and exciting vista to regulators. There is an urgent need to match appropriate regulatory control with biotechnological innovations to ensure adequate quality, efficacy, and safety of novel biologicals.
As resources for capacity building are not always available within our organization, partnerships in the form of mutual recognition agreements, experience-sharing sessions, and harmonization of regulatory requirements are actively promoted with our external stakeholders to jointly face the challenges ahead.
Additional information
In 2013, NPCB participated in a benchmarking system on vaccine registration by the WHO, i.e. the WHO NRA Assessment System and Institutional Development Plan (IDP). The objectives of this exercise are to strengthen the regulatory oversight of vaccine registration according to the IDP and to increase capacity towards achieving a functional NRA status. The WHO development plan consists of functionality parameters as determined by the identified regulatory functions: (1) marketing authorization and licensing activities; (2) post-marketing adverse events following immunization (AEFI); (3) lot release; (4) laboratory access; (5) regulatory inspections and; (6) oversight of clinical trials. The WHO audit team that visited NPCB has verified the partial functionality based on NRA self-assessment on vaccine registration. The team has provided NPCB with specific recommendations on achieving full functionality. NPCB is currently carrying out steps to implement those recommendations, focusing on functions (3) and (4) while preparing for a functionality assessment audit by WHO in the near future.
Acknowledgements
The authors wish to thank their past and present colleagues and collaborators, for valuable discussion and sharing sessions that have contributed in one way or another to the writing of this article.
Prior presentation: Part of this paper was presented at the 2013 APEC Harmonization Center Biotherapeutics Workshop, Seoul, Korea, on 26 September 2013 by Dr Yvonne Siew Khoon Khoo.
Funders: None.
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
National Pharmaceutical Control Bureau
Ministry of Health Malaysia
Lot 36 Jalan Universiti, 46200 Petaling Jaya, Selangor, Malaysia
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Author for correspondence:Yvonne Siew Khoon Khoo, BPharm (Hons), MMedSc, PhD (Pharmacology); Biotechnology Section, Centre for Product Registration, National Pharmaceutical Control Bureau, Ministry of Health Malaysia, Lot 36 Jalan Universiti, 46200 Petaling Jaya, Selangor, Malaysia
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.
Two countries that were affected by the recent economic recession in different ways, and amended their pharmaceutical policies very differently, have provided researchers with an invaluable data set pointing to the strengths and weaknesses of contrasting pharmaceutical sector policies. The use of antipsychotic medicines across Finland and Portugal following the recession has been analysed in order to gauge the impact of pharmaceutical policy interventions.
Christine Leopold of Gesundheit Österreich, Vienna, Austria, and colleagues looked at monthly sales data for antipsychotic medicines in Portugal and Finland between January 2007 and December 2011 [1]. They estimated changes in overall use and generics market share by comparing pre-policy and post-policy levels and trends. Markedly different alterations to pharmaceutical policy in Finland and Portugal led to increases in generics market shares of major antipsychotic products, but also a slight decrease in the use of antipsychotic medicines overall.
Different European countries have developed different strategies to contain medicines expenditure during tough economic times. Despite these differences, they all aim to cut costs without limiting access to much needed medicines. Antipsychotic medicines are essential for the treatment of severe chronic mental illnesses such as schizophrenia, bipolar disorder and autistic disorders. Leopold et al. studied these relatively expensive medicines because they represent a large component of public spending on medicines, and are frequently a target of cost-containment policies [2, 3].
Although the pharmaceutical sector policies in both Finland and Portugal gave rise to an increased market share for generics, the slight decrease in overall use of antipsychotic medicines was a concern since these drugs might have been needed more, rather than less, during an economic recession.
Finland and Portugal altered their policies in very different ways. Finland introduced a well-prepared mandatory generics substitution policy in April 2003, requiring pharmacists to substitute higher priced branded medicines with less-costly generic versions. Portugal’s approach was less uniform, comprising a mix of cost-containment measures including statutory discounts granted to public payers, changes in reimbursement rates, and a generics campaign that were ongoing before and after October 2010.
The most frequently sold active substance in both countries (clozapine in Finland and risperidone in Portugal) did not increase in generics market share, but this was for very different reasons. Risperidone already had a 90% share of the market in Portugal, so this was unlikely to increase significantly. In Finland, meanwhile, clinicians might have been reluctant to switch patients from clozapine to generic drug alternatives due to reports of worsening clinical status associated with generics substitution [4].
Nevertheless, two of the three leading active substances in the antipsychotic class (quetiapine and risperidone) experienced substantial increases in generics market share in Finland. While in Portugal, the combination of policies resulted in a major increase in generics market share for one molecule, amisulpride.
Several different strategies to contain medicines expenditures have been in place across Europe [5, 6]. Changes in patient co-payments for medicines and increases in value-added taxes on medicines were among the most frequently implemented cost-containment measures in 2010 [7]. These measures tend to shift cost burden to those who need medicines. While pharmaceutical sector cost-containment policies might achieve financial savings for the public health system, it is possible that they also have unintended effects in the form of decreased use of needed medicines when patients cannot afford to pay a higher share of medicines costs.
Initiatives aimed at increasing generics uptake play an important role in reducing pharmaceutical expenditure by using lower-priced medicines, where available, instead of expensive originator medicines. Key policies to encourage generics use have been devised for different stakeholders: prescribers, pharmacists and patients. At the beginning of 2013, 22 out of the 27 European Union Member States had generics substitution in place, and 23 allowed International Nonproprietary Name (INN) prescribing [8]. Lithuania and Slovakia, recently chose to switch from voluntary to obligatory INN prescribing because previous voluntary policies had not been fully enforced and tended to be less successful in achieving planned outcome than mandatory policies [9]. Conversely, high generics uptake has been achieved in the UK with voluntary INN prescribing, and a decision was made against the introduction of generics substitution planned for 2010 following a public consultation.
The findings in this latest study highlight the importance of examining the long-term effects of policy measures. The authors conclude that: ‘Increases in cost-sharing may have beneficial short-term impacts on public spending, but might also entail unintended long-term reductions in utilization, particularly for economically disadvantaged populations.’
Competing interests: None.
Provenance and governance: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board, internally peer reviewed.
Bea Perks, PhD, GaBI Journal Editor
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3. GaBI Online – Generics and Biosimilars Initiative. Implications of the changes in venlafaxine utilization in Sweden following generics [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Sep 16]. Available from: www.gabionline.net/Generics/Research/Implications-of-the-changes-in-venlafaxine-utilization-in-Sweden-following-generics
4. Kluznik JC, Walbek NH, Farnsworth MG, Melstrom K. Clinical effects of a randomized switch of patients from clozaril to generic clozapine. J Clin Psychiatry. 2001;62 Suppl 5:14-7.
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6. GaBI Online – Generics and Biosimilars Initiative. French Government pushing generics [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Sep 16]. Available from: www.gabionline.net/Generics/General/French-Government-pushing-generics
7. GaBI Online – Generics and Biosimilars Initiative. Generics policies in Europe have room for improvement [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Sep 16]. Available from: www.gabionline.net/Generics/Research/Generics-policies-in-Europe-have-room-for-improvement
8. Vogler S, Zimmermann N, Habl C. Understanding the components of pharmaceutical expenditure—overview of pharmaceutical policies influencing expenditure across European countries. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(4):178-87. doi:10.5639/gabij.2013.0204.051
9. WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies. Pharmaceutical policy monitoring exercise with national competent authorities representated in the PPRI (Pharmaceutical Pricing and Reimbursement Information) network. Bi-annually, latest update: February 2013 (unpublished).
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Abstract:
Clinical safety is important during the development of a biosimilar. This paper provides an overview of the main aspects related to the safety assessment of biosimilars. The European Medicines Agency’s ‘Guideline for similar biological medicinal products containing biotechnology-derived proteins as active substances: non-clinical and clinical issues’, which is currently under revision, forms the basis for the topics discussed in this paper. Topics discussed include adverse events related to an exaggerated pharmacology, immunogenicity including assay development, extrapolation of indications in relation to safety assessment and pharmacovigilance.
Submitted: 29 August 2014; Revised: 2 September 2014; Accepted: 3 September 2014; Published online first: 5 September 2014
Introduction
The safety profile of biologicals can often be attributed to: a) adverse events related to an exaggerated pharmacology, and b) immunological reactions, including immunogenicity and infusion-related reactions [1, 2].
Adverse events related to an exaggerated pharmacology can be illustrated by the occurrence of infections during the use of biologicals with a strong immunosuppressive mode of action. Patients treated with tumour necrosis factor alpha (TNF-alpha) inhibitors should, for example, be tested for latent tuberculosis before treatment is initiated due to an increased risk of tuberculosis related to treatment with these agents. TNF-alpha plays an important role in human immune defence against the mycobacterium tuberculosis bacterium. Patients with latent tuberculosis should, therefore, receive anti-tuberculosis treatment before starting treatment with a TNF-alpha inhibitor [1–6].
Immunological reactions are varied, and can include the formation of antibodies, allergic reactions, and administration-site conditions, which are inherent to the biological nature of these agents and the parenteral route of administration. If antibodies are formed they often have no clinically relevant effect, but in some cases they are directed against the administered biological, neutralizing the agent’s effect and in some cases antibodies are not only directed against the administered biological but also against the endogenous available protein. Neutralizing anti-drug antibodies (ADAs) result in a diminished clinical response to the biological, and their presence is reflected in clinical practice by the administration of higher doses and/or more frequent dosing over time. A study by Bartelds et al. found that about one third of patients treated with adalimumab for rheumatoid arthritis developed neutralizing antibodies within three years after the start of treatment [7].
Testing for the presence of neutralizing antibodies is receiving more and more attention in clinical practice, partly as a result of available tests and trained staff able to use them. In addition, ADA has been associated with severe infusion reactions following treatment with monoclonal antibodies [8]. The development of antibodies directed against both the administered biological and the endogenous available protein can be illustrated by the well-known Eprex® case. After a change in the formulation of epoetin-alfa, patients developed antibodies against both the administered epoetin and also against the endogenous available erythropoietin, resulting in a complete depletion of erythropoietin and a serious condition: pure red cell aplasia. As illustrated by the Eprex® case, a change in the production process of a biological might influence the immunogenic potential of that biological, and any change in the production profile should, therefore, be clearly evaluated during the production of all biologicals [9–13]. Several factors are known to influence immunogenicity in clinical practice, including the presence of impurities and/or leachables, and protein aggregation. The subcutaneous route of administration is in general more immunogenic than the intravenous route of administration, and the concomitant use of other immunosuppressive agents is known to reduce the formation of antibodies. Alongside these factors, an individual patient’s genetics and age are known to influence immunogenicity [10, 14]. Adverse events related to the parenteral mode of administration are often reflected in adverse reactions at the site of administration.
Clinical safety is important during the development of a biosimilar. This paper provides an overview of the main aspects related to the safety assessment of biosimilars. The European Medicines Agency’s ‘Guideline for similar biological medicinal products containing biotechnology-derived proteins as active substances: non-clinical and clinical issues’, which is currently under revision, forms the basis for the topics discussed in this paper [15].
Clinical safety during biosimilar development
Data related to the clinical safety of the biosimilar should be collected during the complete clinical development programme and should be captured during initial pharmacokinetics and/or pharmacodynamics studies and also as part of the pivotal clinical efficacy study [15]. A complete overview of all safety data collected should be submitted to the regulatory authorities for assessment.
Safety related to an exaggerated pharmacology
Adverse events related to an exaggerated pharmacology known for the reference product will also occur during use of the biosimilar. Differences in adverse events related to an exaggerated pharmacology, which can be related to the biosimilar and not to a chance finding, may preclude registration as a biosimilar and should be carefully evaluated in relation to the totality of evidence obtained for the biosimilar.
The safety data available for the reference product should specifically be taken into account and should form the basis for the safety evaluation of the biosimilar [15]. For the infliximab biosimilars Inflectra® and Remsima®, safety issues of special interest were identified which are known safety concerns for the reference product, Remicade®. These safety issues included heart failure, serious infections, serious infusion reactions, delayed hypersensitivity reactions (serum sickness), systemic lupus erythematosus/lupus-like syndrome, hepatobiliary events, demyelinating disorders, haematologic reactions and lymphoma [16–18]. Due to a relatively limited number of patients, the pivotal clinical efficacy study is in general not capable of detecting differences in rare adverse events between the biosimilar and the reference product. However, the equivalence design used for the pivotal clinical efficacy trial of the biosimilar is usually much larger than the superiority trails against placebo that formed the basis for the approval of the reference product. This results in a safety database which is usually sufficient for the assessment of the biosimilar. In addition, adverse events should be compared by type, severity and frequency in order to provide as complete as possible a comparison between the safety profile of the biosimilar and the reference product [15]. A thorough evaluation of the particular cases, in light of the totality of evidence as regards biosimilarity, is needed in case differences are observed between the biosimilar and the reference product; in other words, is a more adverse safety profile scientifically plausible? For the biosimilar infliximab, a numerical imbalance was found in serious adverse events in the pivotal clinical efficacy trial, with a higher incidence of serious infections, including tuberculosis. A thorough review of all the available data suggested that the difference was most likely a chance finding and that this should be further evaluated as part of the risk management plan (RMP). The following arguments were considered:
Four cases of tuberculosis in the biosimilar arm did not fulfill adequate diagnostic criteria of tuberculosis and/or had pre-existing suspicious pulmonary lesions.
The total rate of infections was comparable in both treatment arms.
The tuberculosis rate in patients treated with the biosimilar was comparable to those reported in historical studies with the reference product, whereas it was unexpectedly low in patients treated with the reference product.
Seroconversion in the interferon-gamma release assay was equally frequent in both treatment arms.
From a mechanistic point of view there is no plausible explanation for a difference in host defence between the two products.
This example illustrates a challenge in the safety assessment of a biosimilar and the need for a thorough post-marketing follow-up, especially if differences are observed during the assessment of safety data collected throughout clinical development [15, 16].
Immunogenicity assessment
Immunogenicity and other immunological reactions, e.g. infusion and hypersensitivity reactions, are especially important during the development of a biosimilar. As already mentioned in the introduction, a change or a difference in production process might influence the characteristics of the biological and potentially its immunogenic potential – notably, in either an adverse or beneficial way. Since the production process of a biological is proprietary knowledge of a company, biosimilar companies should develop their own production process [9–12]. Assessment of immunogenicity, therefore, already starts during the quality assessment of the biosimilar, where the physicochemical characteristics of the biosimilar and the reference product are extensively assayed, assessed and compared. If differences are found, for example, differences in glycosylation, companies are advised to clearly evaluate these differences in relation to the immunogenic potential of the biosimilar [14].
Immunogenicity assessment is an important part of the clinical development programme and should also be investigated in a comparable way between the biosimilar and the reference product. The amount of immunogenicity data needed will depend on experience gained with the reference product and/or the product class. Immunogenicity data for chronically administered biosimilars should normally be collected pre-licensing for up to one year. However, shorter follow-up might be justified based on the immunogenicity profile of the reference product. If, for example, it is known that immunogenicity for the reference product mostly develops within six months after the start of treatment, collection of immunogenicity data for the biosimilar less than one year pre-licensing may be justified. Immunogenicity data for the additional period, up to one year, could then be submitted post-authorization, if considered necessary by the regulatory authorities [15]. In addition, other aspects related to immunogenicity, e.g. route of administration and/or type of disease; should be included and preferably tested in the most sensitive patient population [10, 14].
Immunogenicity testing of the biosimilar and the reference product should be conducted within the biosimilar comparability exercise by using the same assay format and sampling schedule. The assay used to detect antibodies is an important consideration during the clinical development of a biosimilar and should meet all current standards. Comparison of data obtained for the biosimilar with historical data obtained for the reference product is generally not considered appropriate due to continuing developments in this field.
Assays have over time evolved to be much more sensitive. If one were to directly compare the immunogenicity of a biosimilar measured using a current assay with historical data of the reference product using an outdated assay, then it could appear that the biosimilar exhibits a much higher immunogenicity since the current assay is much more sensitive. This would not result in comprehensive data. Preferably, two assays should be used which are capable of detecting antibodies against both the biosimilar and the reference product. However, if only one assay is used, the assay should be capable of detecting antibodies to the biosimilar. This will provide a conservative comparison between the biosimilar and the reference product, and biosimilar companies should take into consideration that the one assay approach may result in higher antibody levels for the biosimilar as compared to the reference product. Differences found between the biosimilar and the reference product need to be justified in the application dossier. In principle, the incidence of antibodies and antibody titres should be measured and presented [14]. Assessment and interpretation of antibodies in relation to the potential effect on clinical efficacy and safety is important, as illustrated by the development of the infliximab biosimilar. Development of antibodies to infliximab was associated with an increase in the frequency of hypersensitivity/infusion-related reactions in patient groups treated with both the biosimilar and the reference product [16, 17].
In principle, the safety profile of the biosimilar and the reference product should be comparable. This also relates to immunogenicity. However, one exemption might be possible: if a lower immunogenicity is found for the biosimilar, this might not preclude approval as a biosimilar. Reduced development of neutralizing antibodies to the biosimilar could erroneously suggest that the biosimilar is more efficacious than the reference product when analysing the entire study population (since efficacy is less antagonized). The biosimilar company is therefore recommended to perform a subgroup analysis of patients treated with both the biosimilar and the reference product which did not mount an ADA response during the clinical trial. This subgroup analysis could be helpful to establish that the efficacy of the biosimilar and the reference product are in principle similar if not impacted by an immune response. [15].
Extrapolation of indications
Extrapolation of indications is a key aspect in the development and approval of biosimilars in Europe. Safety of the biosimilar should also be taken into account in relation to the mode of action of the biological in different indications. Adverse events related to an exaggerated pharmacology will apparently also occur in different indications of the biological. Immunogenicity is related to different aspects as discussed in the introduction, which might differ between indications, e.g. differences in concomitant medication and/or duration of treatment. Extrapolation of immunogenicity data from one indication to the other should, therefore, be justified based on the knowledge obtained with the reference product and/or product class. In case differences exist, there might be a need for additional immunogenicity studies in one or more specific indications [15].
Pharmacovigilance
The safety profile of the biosimilar should be evaluated on an ongoing basis during use in clinical practice. The same rules and obligations apply for biosimilars as for any other biological medicinal product, which means that a RMP must be submitted as part of the application procedure as well as Periodic Safety Update Reports (PSURs) and the collection of adverse events identified and reported after approval.
The RMP of the biosimilar should, as a starting point, be based on the RMP and knowledge obtained with the reference product and should take into account identified and potential risks associated with the use of the reference product. Immunogenicity and infusion-related reactions should specifically be addressed in the RMP and, if needed, additional pharmacovigilance activities to identify these reactions should be described. It is expected that spontaneous reporting of adverse events will generally not be able to detect effects of neutralizing antibodies and therefore other activities should be considered, e.g. measuring neutralizing antibodies in a subset of the population as part of a post-marketing obligation, where deemed necessary. Any specific safety monitoring for the reference product should, in principle, also apply to the biosimilar. In some instances there will be a need to compare certain adverse events of interest between the biosimilar and the reference product. With very rare events, e.g. progressive multifocal leukoencephalopathy during use with rituximab, any case will contribute to the general knowledge about this very rare condition and a comparison will not be possible due to the limited number of cases. Biosimilars are, therefore, encouraged to participate in already existing registries of the reference product.
Several registries are in place in Europe, particularly with biologicals used for rheumatoid arthritis, which have contributed greatly to the general knowledge on the safety and efficacy of the agents during use in clinical practice [1, 15]. The biosimilar infliximab will, for example, perform several post-marketing studies in already existing registries used for RA [16, 17].
Risk minimization measures in place for the reference product should generally also apply to the biosimilar, e.g. a patient alert card for serious infections related to the use of Remicade® is also included in the risk minimization programme of the biosimilar infliximab [16–18]. One exemption to this approach is risk minimization activities in place for the reference product which are specific for the device by which the reference product is administered [15]. The device by which the biological is administered might differ between biosimilar and reference product and might consequently need different educational measures to realize correct use in clinical practice [15].
An important issue related to pharmacovigilance is traceability of the administered biological, which applies to all biologicals and is not specific to biosimilars. Therefore, all appropriate measures should be taken to identify clearly any biological medicinal product which is the subject of a suspected adverse reaction report, with due regard to its brand name and batch number. This not only applies to the collection of spontaneously reported adverse events, but also during pharmacoepidemiological studies, including registries [15].
Conclusion
Safety assessment is an important part of the development of a biosimilar. Safety data should be collected throughout the complete clinical development programme and should be compared between the biosimilar and the reference product. Assessment of immunogenicity is especially important in this context due to the potential impact of changes in the production process and consequently on clinical safety. Differences in the safety profile will question biosimilarity and will require appropriate in-depth assessment and evaluation. A lower immunogenicity of the biosimilar might, however, be acceptable. Extrapolation of safety data from one indication to the other is possible and should be justified, especially with regard to immunogenicity and potential differences in the characteristics of the patient population and the disease in which the biological is used.
The same pharmacovigilance rules apply for biosimilars as for any other biological. Within the RMP the knowledge obtained with the reference product should be the basis for the content of the RMP and the obligatory post-marketing requirements, including risk minimization measures. Traceability is important and measures should be implemented to improve traceability.
Acknowledgement
All members and experts of the Biosimilar Medicinal Products Working Party (BMWP) of the Committee for Medicinal Products for Human Use (CHMP) are acknowledged for the discussions during the revision of the aforementioned guideline.
Disclaimer
The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
Authors
Thijs J Giezen, PharmD, PhD
Foundation Pharmacy for Hospitals in Haarlem, 24 Boerhaavelaan, NL-2035 RC, Haarlem, The Netherlands
Christian K Schneider, MD
Danish Health and Medicines Authority, Division of Medicines Licensing and Availability, 1 Axel Heides Gade, DK-2300 Copenhagen S, Denmark, and Twincore Centre for Experimental and Clinical Infection Research, 7 Feodor-Lynen-Strasse, DE-30625 Hannover, Germany
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6. Martin-Mola E, Balsa A. Infectious complications of biologic agents. Rheum Dis Clin North Am. 2009;35(1):183-99.
7. Bartelds GM, Krieckaert CLM, Nurmohamed MT, et al. JAMA. 2011;305(14):1460-8.
8. Steenholdt C, Svenson M, Bendtzen K, et al. Severe infusion reaction to infliximab: aetology, immunogenicity, and risk factors in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2011;34(1):51-8.
9. Shankar G, Shores E, Wagner C, Mire-Sluis A. Scientific and regulatory considerations on the immunogenicity of biologics. Trends Biotechnol. 2006;24(6):272-80.
10. Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther. 2002;24(11):1720-40; discussion 1719.
11. Schellekens H. Immunological mechanism of EPO-associated pure red cell aplasia. Best Pract Res Clin Haematol. 2005;18(3):473-80.
12. Schellekens H. Follow-on biologics: challenges of the next generation. Nephrol Dial Transplant. 2005;20 Suppl 4: iv31-6.
13. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Eng J Med. 2002;346(7):469-75.
14. European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. EMEA/CHMP/BMWP/14327/2006. 13 December 2007 [homepage on the Internet]. 2008 Jan 10 [cited 2014 Jul 22]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdf
15. European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005 Rev. 1. 3 June 2013 [homepage on the Internet]. 2013 Jun 19 [cited 2014 Jul 19]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/06/WC500144124.pdf
16. European Medicines Agency. Committee for Medicinal Products for Human Use. European Public Assessment Report Inflectra. 27 June 2013 [homepage on the Internet]. 2013 Sep 30 [cited 2014 Jul 19]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002778/WC500151490.pdf
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Author for correspondence: Thijs J Giezen, PharmD, PhD, Foundation Pharmacy for Hospitals in Haarlem, 24 Boerhaavelaan, NL-2035 RC, Haarlem, The Netherlands
Disclosure of Conflict of Interest Statement is available upon request.
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 European Medicines Agency (EMA) has led the development of biosimilar regulatory pathways globally, tailoring their approach to meet the specific and scientifically determined needs of biosimilar development. However, the information-driven stepwise approach encouraged by this pathway leading to approval of biosimilar products is only reflected in a single section of the product labelling for healthcare professionals and patients, which so far has followed a generic drug approach in Europe.This paper reviews the need for sufficiently detailed and transparent labelling and product information (PI) regarding biosimilars to enable informed decision-making by physicians and patients and therefore ensure appropriate safe and effective use of the medicine. The authors, representing the European Biopharmaceutical Enterprises (EBE), argue that it is necessary to ensure that the evidentiary basis and terms of approval for each biosimilar and its reference product are clear, and so they set out a proposal for transparency concerning evidence generated for these respective products. Approaches to labelling of biosimilars will be examined to highlight potential ways forward in ensuring more informed clinical use and to generate trust in these important medicines. A consideration of these various aspects will illustrate the value to have detailed specific guidance on biosimilar labelling, which could be developed based on open dialogue with key stakeholders.
Submitted: 1 September 2014; Revised: 23 September 2014; Accepted: 9 October 2014; Published online first: 22 October 2014
Introduction
Europe has been instrumental in the global development of biosimilars, with 12 biosimilar molecules approved, marketed as 18 brands in six classes: somatropin, epoetins, filgrastim, follitropin alfa, insulin glargine, as well as the first biosimilar monoclonal antibody (mAb), infliximab (marketed as Inflectra, Remsima), approved in September 2013 [1, 2].
The requirements and procedures for the marketing authorization for medicinal products for human use in Europe Union (EU) are primarily laid down in Directive 2001/83/EC, as amended. This Directive provides distinct legal frameworks for innovator products, small molecule generic products and biosimilar products, dictating the amount of quality, preclinical and clinical data required to support approval and marketing. To the latter point, small molecule generic products whose formulation or manufacturing method have not been modified in any way that may impact the bioavailability [3] do not require any preclinical or clinical trial data of their own as bioequivalence with a reference product (innovator) can be established through in vitro testing alone. For biosimilar products, in contrast, such a formulaic approach cannot be used. The amount of data to be generated is determined in a stepwise approach, directly comparing the biosimilar with the reference product and the outcome informing the next step. This may result in the need for more or less extensive comparative clinical data. Indeed, the European Medicines Agency (EMA) draft revised guideline, ‘Guideline on Similar Biological Medicinal Products’ states that ‘standard generic approach (demonstration of bioequivalence with a reference medicinal product by appropriate bioavailability studies) which is applicable to most chemically-derived medicinal products is in principle not appropriate to biological/biotechnology-derived products due to their complexity’ [4].
The legal framework for biosimilars enabled EMA to pioneer the regulatory review of biosimilars according to a new scientific approach [5]. However, legal and scientific distinction has not been consistently reflected in the product labelling, with there being differences in the level of detail provided.
The Committee for Medicinal Products for Human Use (CHMP) appears to have adopted a labelling approach used for small molecule generic products, with only a small distinction made between the product labelling of the reference and generic products for biosimilar products. This is also illustrated with the recent EU approval(s) of Remsima and Inflectra [1, 2], where such an approach was applied.
Product labelling: what every physician needs to know
As defined by EMA [6] the product labelling, in particular the Summary of Product Characteristics (SmPC) is a key component of the marketing authorization of all medicines in the EU and the basis of information for healthcare professionals on how to use a medicine safely and effectively. Updates to the SmPC are made throughout the lifecycle of a medicine as new efficacy and/or safety data emerge or change in the safety profile become apparent. The SmPC also forms the basis for the preparation of the Patient Information Leaflet (PIL), which is an important document for relaying information on medicines to patients.
Instructions on what needs to be detailed in the SmPC are provided in the ‘Guideline on Summary of Product Characteristics’ and when read in conjunction with other guidelines clearly defines the level and type of information that should be reflected in SmPC for all products, including biosimilar medicines. Despite there being general guidance pertaining to the content required for the SmPC as discussed, it is acknowledged there is a requirement for further dialogue regarding detailed specific guidance for biosimilars to be developed.
The structure of the SmPC in relation to biosimilars was addressed by the chair and members of the Biosimilar Medicinal Products Working Party (BMWP), Schneider et al. [7] using mAb as the example. The BMWP authors outlined three potential labelling scenarios, see Table 1, to be considered for labelling of biosimilars, ranging from an identical product label to the reference mAb through to a completely distinct label only reflecting data generated for the biosimilar [7]. As each of the labelling scenarios presented had their pros and cons, the BMWP authors were of the opinion that it was not yet clear how best to conclude the matter.
Other groups have also sought to address the issue, including the European Biopharmaceutical Enterprises (EBE) [8], EuropaBio [9] and the Association of the British Pharmaceutical Industry (ABPI) [10].
The EBE welcomes the BMWP’s acknowledgement that adequate scientific information for biosimilars should be provided and in this regard the product label is the essential component for prescribers [7]. This also corresponds with the key learnings from the Process on Corporate Responsibility in the field of Pharmaceuticals, initiated by DG Enterprise that physician perception and patient acceptance impacts biosimilar uptake [11]. It was concluded that a robust regulatory framework, effective risk management, transparency, and continued education would help engender confidence in the appropriate use of innovator biological medicines and biosimilars. To explain their rationale for not distinguishing the reference from the biosimilar label, the BMWP of EMA has emphasized concern that differential product labelling could implicitly suggest a difference between the biosimilar and the reference product. The latter could be prone to misperception by prescribers who could falsely conclude that the level of evidence created to lead to approval of a biosimilar is less than the usually expected standards for a novel product, if the concept of biosimilars is not understood [1].
While the EBE [12] acknowledges the reasons and concerns highlighted by BMWP, the EBE position is that the SmPC would be better served if it were represented by a combination of information from both the biosimilar and the reference product, see Table 1, if the label is different. Such an approach is of crucial importance in developing an understanding and acceptance of biosimilars.
Labelling standard of biosimilars: why a combined approach fits the purpose
Three possible scenarios for the labelling (including SmPC and PIL) of biosimilars have been described by Schneider et al. [7]. Adaptations of the proposed labelling options of biosimilars are briefly described in Table 1, which gives an overview of the approaches and relevant key considerations:
EBE believes that Approach C is best suited. First of all, the unique considerations that apply to biosimilars (as compared to generics) exclude Approach A as a suitable option because it does not include relevant data the biosimilar manufacturer has compiled for its clinical comparison. Yet prescribers may want to see such biosimilar data alongside that for the originator, as this will explain the basis for which indications have been approved. Furthermore, by using biosimilar data only (Approach B) characterization data is not included, thus neglecting the proof of biosimilarity. This characterization assumes that the long-term safety profile for the reference product should be applied to the biosimilar and that therefore class warnings, etc.; are appropriate for both products. In addition, because Approach B only provides biosimilar data, this also means that the prescriber needs to refer back to the reference product’s label to complete their understanding of the product, and this is not practical. Approach C is the more balanced approach that can enable transparent disclosure of all relevant information related to the biosimilar and the reference product. Furthermore, Approach C is an approach that also allows transparency on where the data generated comes from, either from the originator or from the biosimilar developer and, additionally, which indications are granted by extrapolation.
Five points that show the need for detailed specific guidance on what a transparent label for biosimilars would look like
EBE identifies that there are five important points for consideration, which arise when prescribers refer to the SmPC of a biosimilar, and these should be considered in any policy guidance related to the matter. They are:
Quantity of data. There is the concern that physicians would directly relate similarity to the amount of clinical data provided in the SmPC. However, in accordance with the biosimilar concept the more similar the product is to its reference product, the less clinical data will need to be generated during its own development. Therefore, only by the SmPC containing a combination of information/data relevant to the originator and biosimilar could the CHMP conclusions be provided to the prescriber. Some stakeholders also argue that the inclusion of preclinical and clinical data on the biosimilar is misleading because the assessment of biosimilarity is primarily based on extensive analytical comparisons which may not be included in the SmPC. EBE is of the opinion that biosimilars must be labelled according to agreed guidelines that apply to all medicinal products. However, since the SmPC does not usually contain analytical data, it would also be important to explain the inclusion of relevant analytical data to prescribers.
Extrapolation of indication. In terms of labelling, taking a generics approach (the identical product label) could lead to misperceptions by physicians that these are identical products, which biosimilars cannot be. As Weise et al. [13] state in their article titled Biosimilars: what clinicians should know: ‘It must be clearly understood that a biosimilar, as opposed to a small chemical generic, cannot automatically claim all indications of the reference product and that any extrapolation of data requires sound scientific justification’. Applying a generics style of labelling to biosimilars may lead physicians to the (wrong) assumption that the generics approach would also apply to extrapolation of indications. In contrast, transparent information about the decision-making would not only facilitate the understanding of the nature of biosimilars (and their assessment by CHMP) but also increase confidence in their use.
Switching. Decisions around switching require transparent product information so that prescribers can make their choices confidently. As the EMA Q&A document on biosimilar medicines [14] states the following about switching: ‘For questions related to switching from one biological medicine to another, patients should speak to their doctor and pharmacist’, it is therefore of upmost importance that there is full transparency that the product in question has been licensed as a biosimilar and its terms of approval are explained in the SmPC and PIL to enable an informed decision by all end-users. There should be a debate about to what extent switching data, where available, should be included on the product label.
Pharmacovigilance. In supporting the aims of the Pharmacovigilance Directive reporting requirements for biologicals (including brand name and batch number) should be included on the prescription in order to improve traceability and enhance pharmacovigilance. Some biological products already include guidance of this sort in Section 4.4 (Special warnings and precaution for use) of their SmPC, see for example the SmPC for adalimumab – in order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded [15].
Drift. Once a biosimilar has been approved, there is currently no legal or regulatory requirement for biosimilarilarity to be re-established at any time. It is well acknowledged that the reference product and its biosimilar will have separate life-cycles which could affect the safety and efficacy profile, while having no change to the other, and which could undergo patterns of drift and evolution that ultimately result in two products that are no longer biosimilar (divergence) [16].
In light of the above considerations, EBE maintains that a single sentence added in section 5.1: Pharmacodynamic properties of the SmPC and a reference to the EMA homepage informing the prescriber that the product is a biosimilar and providing reference for further information does not seem to be sufficient. The information refers the reader to the EMA homepage [17], offering no guidance to physicians and patients to help them navigate to the relevant information and documentation.
Besides this, EBE considers that section 5.1 is not the most relevant section for such a statement, as the information applies to the whole product label and not only to pharmacodynamic properties. More importantly, details of pharmacodynamic properties are not reflected in the PIL and there is a lack of transparency informing patients to the fact a product is a biosimilar medicine.
The SmPC and other supporting documents
It is acknowledged that the SmPC is the most widely used reference document for physicians, however, there are other important documents published in the EU which provide information about the product and its basis for approval: the European Public Assessment Report (EPAR) which is a summary of the review and conclusions of the scientific assessment by CHMP; and in a patient friendly format: the Patient Information Leaflet. Table 2 below provides a short description of each of these documents.
For recent biosimilar approvals the ‘generic’ approach to labelling has been agreed by EMA and therefore alludes that it has been considered as representing the most appropriate method for communicating information to physicians. While it is acknowledged that the ‘generic’ labelling approach, taken for the recently approved biosimilars, infers that physicians who would like to have an in-depth understanding of the scientific discussion can refer to the published EPAR on their website, it should be noted that these documents have important limitations in their use as vehicles for educating physicians and patients across the EU, see Table 2.
As the full EPAR information is only available in English, this effectively restricts the number of physicians across the EU who can rely on it as a source of information. In practice, the prescriber would need to refer to separate EPARs, the biosimilar(s) and reference product, in order to scrutinise the data generated when deciding whether to switch their existing medication to the biosimilar. If more than one biosimilar product were available, this would further increase the time needed by a physician to evaluate the therapeutic information. Physicians are already dissatisfied with the increasing time they must spend on administrative tasks and paperwork, as this limits their time for face-to-face patient care [18].
EPARs are primarily designed to provide information on how a medicine was assessed by CHMP and to describe scientific conclusions of the relevant Agency committee. Physicians are likely to be unaware that the EPAR document itself is not updated, but rather is complemented by additional documents such as summaries called ‘Procedural steps taken and scientific information after authorisation’ [19].
Recently, the Alliance for Safe Biologic Medicines (ASBM) [20] surveyed 470 prescribers located in France, Germany, Italy, Spain and the UK regarding information sources used for learning about medicines. The respondents were specialists who prescribed biologicals, including nephrologists, rheumatologists, dermatologists, neurologists, endocrinologists and oncologists and so their perspectives reflected hands-on clinical experience with biologicals in a therapeutic setting. The results indicate that among available information sources, EPAR was the least preferred method (19%), while the SmPC was the next most important source document physicians refer to when they need specific details about a product (43%) after published literature.
Detailed biosimilar labelling guidance in other jurisdictions
Whilst EMA, pioneered the biosimilar approval pathway, specific biosimilar product labelling guidelines have as yet to be developed, whereas other countries have already made provisions on how biosimilar product labels should be presented.
When reviewing the situation in the US, Switzerland and Canada, not unexpectedly, it becomes evident that guidance on the content of biosimilar product labels varies from country to country.
United States
In the US, although biosimilars are still to be registered, FDA has recognized the importance of labelling for biosimilars and is working to reduce potential ambiguities by ensuring clear statements within appropriate sections of the Prescribing Information [21]. Section VIII of the FDA draft guidance on scientific consideration in demonstrating biosimilarity states that labelling of a proposed product should include all the information necessary for a healthcare professional to make prescribing decisions, including a clear statement advising that the product approved is a biosimilar and that it has or has not been determined interchangeable with the reference products [22].
Switzerland
In Switzerland, Swissmedic has also been clear in differentiating between the terms ‘reference product’ and ‘comparator product’ in order to emphasise the fact that candidate biosimilars are characterized by documentary reference to the Swiss reference product [23]. The guideline also lays out the responsibilities to keep the PI of the biosimilar up to date is that of the authorization holder. In particular, the authorization holder must actively monitor changes to the safety text of the reference product and must submit either an appropriate application for a variation or provide clear scientific justification if the texts are not to be adapted.
Canada
Health Canada’s approach for their first approved biosimilar mAb (Remsima/Inflectra) approved in January 2014 shows the clearest distinction to the approach that EMA followed, see Table 1. As the guideline states, the sponsor of a biosimilar is not able to utilize the product monograph of the reference biological drug in its entirety as that of its own product [24]. Furthermore, the monograph details additional requirements clarifying that the product is a biosimilar. These include key data on which the decision for market authorization was made, tables showing the results of the comparisons between the biosimilar and reference biological drug, and information on the indications approved for use.
The way forward
On the basis of the arguments provided, EBE recommends that an approach of greater transparency within the product labelling of the biosimilar be provided. A combination of information on both the biosimilar and the reference product (Approach C) is recommended and to define what this entails, greater dialogue is required between EMA, BMWP, industry, opinion leaders and patients. As EPAR is not a preferred information source, in its current setting, it should not replace the important role of SmPC as the primary point of reference.
EBE is of the position that the generation of detailed specific guidance on the product labelling of biosimilars is of crucial importance to realize consistency and transparency of biosimilar labels, which will lead to a better understanding and acceptance of these products with all stakeholders. Most importantly, consideration should be given to ensuring the SmPC for biosimilars details information most relevant to the prescriber.
Although it will be challenging to achieve an ideal solution which encompasses the needs of all stakeholders, it is preferable that clinicians have ready access to the relevant information regarding biosimilars to enable informed decision-making by physicians and patients and therefore ensures safe and effective use of the medicine. Clearly, further education and dialogue on biosimilar concepts is needed and this is a widely shared agenda. Equally important is the need to build trust together with understanding, and the foundation for this is transparency and open dialogue. To meet these aims, EBE recommends a thorough consultation with all stakeholders to explore the needs and the best approaches for providing appropriate product labelling guidance for biosimilars in the EU.
Competing interests: This paper is authored and funded by the European Biopharmaceutical Enterprises (EBE) and represents the policies of the organization.
EBE is the European trade association that represents biopharmaceutical companies of all sizes operating in Europe. Membership is open to all companies using biotechnology to discover, develop and bring new medicinal products to market.
Provenance and peer review: Not commissioned; externally peer reviewed.
Contributing authors from EBE
Keith Watson, AbbVie
Virginia Acha, Catherine Akers, Amgen
Alexander Roediger, MSD
Åsa Rembratt, Novo Nordisk
Edward Hume, Pfizer
Fabio Bisordi, Marloes van Bruggen, Roche
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Author for correspondence:Edward Hume, Pfi zer Ltd, Walton Oaks, Dorking Road, Tadworth, Surrey, KT20 7NS, UK
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