- Email: [email protected]
Post-innovation innovation of medicinal products
Drug Discovery Today: Technologies
Vol. 8, No. 1 2011
Editors-in-Chief Kelvin Lam – Harvard University, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Innovative methods in drug regulatory sciences
Post-innovation innovation of medicinal products Hubert (Bert) G. Leufkens1,2,*, Huub Schellekens1, Bo Aronsson3 1
Utrecht Insitute for Pharmaceutical Sciences (UIPS), Utrecht, The Netherlands Medicines Evaluation Board (MEB), The Hague, The Netherlands 3 European Medicines Agency (EMA), London, UK 2
Pharmaceutical innovation is a continuous process and does not stop after a medicinal product has been approved for marketing. Post-innovation innovation fuels research into new applications, better profiling
Section Editors: Bert Leufkens – Universiteit Utrecht, Utrecht, The Netherlands; Hans-Georg Eichler – European Medicines Agency, London, UK.
of the target population of a product and other methods to ensure a sustained benefit-risk balance over time. Over the last couple of years several new legislative frameworks with relevant innovation spin-offs (i.e. applications for new indications, risk management plans, biosimilars, active control comparisons) have been introduced into the European regulatory system with challenging opportunities for continuous learning and post-innovation innovation. Regulators have the task to reflect on these frameworks in terms of how these contribute to patient safety, public health and innovation.
Introduction Current drug development encompasses a wide range of activities from designing complete new molecules for unmet medical needs, incremental change and improvement of existing products, up to serendipity inspired radical changes of the target of a medical product during clinical development or after approval for marketing of an initial application. For all these pathways of what Gelijns in 1998 coined as ‘postinnovation innovation’, numerous appealing examples are *Corresponding author.: H.B.G. Leufkens ([email protected]) 1740-6749/$ ß 2011 Published by Elsevier Ltd.
DOI: 10.1016/j.ddtec.2011.06.001
available [1]. She considered three different scenarios of innovation pathways after medical technologies have been initially authorized and used in clinical practice: (1) new basic-science investigations elucidate the mechanisms of action of a certain technology fuelling inspiration for new applications; (2) translational research identifies new uses of the technology either in the laboratory or at the bedside facilitating to look for applications to other conditions with similar biological mechanisms; (3) postmarketing clinical observations about previously unrecognized uses of the technology. Among medical devices, the laser has been recognized as one of the most powerful and versatile advances over the last few decades, including applications in the laboratory, computer printers, bar-code scanners, telecommunications and eye disease [1]. These three pathways are actually not independent and may occur simultaneously. Prevalent features of ‘post-innovation innovation’ include an open mind of both industry developers and regulators and medical practitioners for the fact that certain technology-indication for a disease combinations are not static, the presence of clinical and patient champions to drive such dossiers to a successful end and whether pertinent economic incentives for developers are in place. Also the indications for use of many medicinal products have evolved over time. A classic case is aspirin, for decades an inflammatory painkiller, but over the years also indicated for e37
Drug Discovery Today: Technologies | Innovative methods in drug regulatory sciences
many other indications in the cardiovascular and neurological field [2]. The same holds for thalidomide, originally developed as a sleeping pill in the late 50s that turned out to cause dramatic birth defects, nowadays licensed for multiple myeloma, but tested and off-label use for many other indications as well [3]. On 24 January 2008, the EMA Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for a marketing authorisation of thalidomide to be used to treat multiple myeloma in combination with other medicines (melphalan and prednisone). Because thalidomide was well known to cause birth defects, several measures were put in place to minimise the risk of exposure of unborn children to the medicine. The CHMP concluded that thalidomide’s benefits outweighed its risks for the treatment of multiple myeloma, provided that robust measures were put in place to avoid exposure of unborn children [4]. In the advent of this opinion, various patient groups had advocated in favour of a marketing authorization for the indication of multiple myeloma, while other groups, particularly thalidomide victims, protested against such an authorization pointing to the devastating teratogenic risks and the alleged inability of authorities to control off-label use [3,5]. Despite the fact that most investments in pharmaceutical innovation are made by industry during the period of patent protection (i.e. around the first 15 years) drug usage itself has had always a long time horizon. More than two out of three prescriptions doctors write out today are for products initially developed more than 15–20 years ago. In terms of volume, most patients use ‘old’ medicinal products. These products have shown robust evidence for efficacy over the years and their safety profile has been well developed and understood (e.g. metformin, methotrexate, and simvastatin) [6]. Moreover, because of their off-patent nature their cost-effectiveness is attractive for payers and governments. Although quality concerns have been expressed and are putting ample emphasis on regulatory systems to assure that standards of generic products are met albeit increasing globalisation, complex and long production and logistics chains and increasing cost pressures on the industry, generic pharmaceutical products constitute an important part of our therapeutic arsenal [7,8]. In this review we will evaluate the concept of ‘post-innovation innovation’ from different perspectives, including the existing European regulatory framework and how different parts of this framework have important innovative spin-offs, sometimes intended, not always. We will underpin the importance of sustainable drug development over time as pharmaceutical products are never ‘finished’. There is always good reason to improve the targeting of the therapeutic molecule to the best responders, improve the dose and duration and to increase the benefit–risk by changing the pharmaceutical dosage form. Four current European regulatory features will be highlighted, including increased applications e38
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Vol. 8, No. 1 2011
for new indications, Risk Management Plans obligatory in Europe since 2005, the regulation of biosimilars also in place since 2005, and the mounting regulatory plea for active control comparisons to support robust benefit–risk weighing, but also resulting in stimulating knowledge development for ‘old’ medicinal products, very often off-patent with a lack of incentives for the innovator industry to invest in.
Regulatory features with innovation spin-offs Application for new indications When we look at the flow of applications industry submits to the EMA, numbers for claims of a new indication (variation of Section 4.1 of the SmPC) are virtually the same as for applications with a new active substance, 24 versus 22, respectively in 2010 [9]. The development of the indication profile of TNFa blockers over the years (i.e. rheumatoid arthritis, Crohn’s disease) [10] or products for oncology indications [11] is a clear example. An application for a new indication is not always for a new distinct disease but very often also for a shift from second line to first line therapy, from adults to children and so on. From an innovation perspective, applications for new indications have become one of the mainstays of clinical development of medical products, a feature that is also related to the multi-target nature of today’s therapeutic molecules. Monoclonal antibodies or tyrosine kinase inhibitors affect multiple mechanistic pathways making them possibly suitable for a diversity of clinical indications. While critics of the pharmaceutical industry argue against this ‘drugs looking for a disease’ or ‘salami slicing of indications’, it has become obvious that a significant share of today’s pharmaceutical development lies in the surge of applications for new indication offering ample opportunity for knowledge building and learning about the various properties of a medicinal product. The fact that the regulatory system requires that companies justify every therapeutic claim with data and evidence is a strong driver for further clinical deepening of the potential of an existing product.
Risk management plans Since November 2005, an EU Risk Management Plan (EURMP) has become an integral part of a marketing application for all new chemical entities in the EU. Moreover, risk management plans can be required as part of an application for a new indication [12]. In the EU-RMP, the safety profile of the medicine has to be summarized and crucial safety issues have to be specified to plan proactively for pharmacovigilance activities, including post-authorization safety studies (PASS) and if appropriated adequate risk minimisation measures, once the product is approved and used in clinical practice. This pharmacovigilance model intends to produce a shift from a reactive, passive mode of risk management to a more pro-active, planned and science based [12]. A recent analysis
Vol. 8, No. 1 2011
of the quality of the first cohort of EU-RMPs showed several important opportunities for improvement, including comprehensiveness of the PASS study protocols, level of inclusion of EU populations in the planned studies and feasibility of the proposed risk-minimisation plans [13]. Moreover, several crucial points regarding implementation of EU-RMPs in clinical practice and the transparency of its contents have been identified [14]. However, the model of EU-RMP, also strengthened in the new EU Legislation on Pharmacovigilance and addressed elsewhere in this series by Arlett et al., can be seen as a structured vehicle for ‘post-innovation innovation’. Obviously with a strong focus on possible harms of a medicinal product, but with a great opportunity to learn more about the full profile of the medicinal product, for example, practice experience, answers to pre-approval uncertainties, and unexpected benefits. RMPs seem to have a broader scope of spin-offs than the initial safety objective for which they were developed [13].
Biosimilar regulation Also since 2005, the EMA ‘Guideline on similar biological medicinal products containing biotechnology-derived proteins as an active substance: non-clinical and clinical issues’ (EMEA/CPMP/42832/05/) lays down the general requirements for the demonstration of the similar nature of two biological products in terms of safety and efficacy. These so-called biosimilars are new biological medicinal products claimed to be ‘similar’ to a reference medicinal product, which has already been granted a marketing authorisation in the past [15,16]. Since the development and the introduction of the biosimilar regulatory framework, there have been discussions about the clinical comparability and interchangeability of such products, resulting also in strengthening the regulatory requirements to pharmaceutical companies regarding showing essential similarity between the biosimilar and the innovator product. Moreover, several crucial points have been indentified regarding safety management of such products particularly because of the fact that confounding by disease (severity) and traceability of which product batch an individual patient has used remain crucial issues when evaluating possible drug induced harm [17]. However, albeit all these challenges the way these companies active in biosimilar development have anticipated the regulatory requirements has driven substantial innovation in protein characterisation, further research on immunogenicity, production technologies and patient registries building [16]. Stricter pharmaceutical regulation to enable biosimilar development has resulted not only in biotech products with an ensured benefit–risk, but also in broader offshoots in knowledge and technology creation.
Active control comparisons Randomized and controlled comparisons (RCT) of drug effects against placebo are the key to clinical development
Drug Discovery Today: Technologies | Innovative methods in drug regulatory sciences
and since the streptomycin trials for tuberculosis in the late 1940s, the accepted paradigm to show evidence of efficacy. Over the years, various modifications both in design and analysis of placebo comparisons have been developed. However, placebo controls are not always possible and wanted and comparisons with active controls are increasingly required by regulators in order provide insight in how the product behaves against the most commonly used standard treatment. This insight is particularly crucial when modest efficacy is shown in a placebo comparison, giving discussions about the added clinical benefit over existing products, or when certain safety issues have to be weighted against possible additional benefits a new product may provide. A recent example is dronedarone (Multaq), an anti-arrhythmic medicine. This medicine was studied in five placebo-controlled trials but also in a study comparing Multaq with amiodarone (another medicine used to prevent atrial fibrillation) [18]. However, active control comparisons have their own challenges with respect to issues like essay sensitivity and choice of control, and are currently not always parts of a marketing application dossier [19]. Stimulated by the way third-party payers look at clinical relevance and the appealing regulatory question: – What is the benefit–risk of the new product given what we know of the product currently used in clinical practice? – We may anticipate increasing demand for comparisons of new products against standard care treatments [20]. CHMP also increasingly asks for data from head-to-head comparisons and has stimulated recently the debate about when such studies are justified, needed and feasible to do [21]. But apart from addressing the question of relative efficacy and effectiveness, active control comparisons have provided a wealth of spin-off learning on ‘old drugs’ like methotrexate in rheumatoid arthritis, beta-blockers in the treatment of hypertension or metformine for diabetes type II.
Discussion The framework of regulating pharmaceutical products has many legal, scientific and public health dimensions, and is increasingly exposed to ample criticism from various societal stakeholders [22–24]. Society expects, for good reasons, that regulators protect patients and public in general from drug induced harm in a independent and transparent way. At the same time, pharmaceutical innovation, that is, bringing new products for unmet medical needs to the clinic, is a function of regulation as well. Looking at regulators only in their role as watch-dog or alleged hurdle to innovation impairs to have a broader look at how regulation may also have important additional positive spin-offs, may not be always intended but important to identify and to appreciate. The four regulatory features described here started initially as set of (extra) regulatory requirements but turned out also to stimulate new ways of thinking, new insight and a continuous cycle of postinnovation innovation. The lifecycle of medicinal products www.drugdiscoverytoday.com
e39
Drug Discovery Today: Technologies | Innovative methods in drug regulatory sciences
needs a long view with an open eye for incremental changes and improvements over time in terms of new applications and pharmaceutical dosage forms. This may also be true for Boeing 747s, designed and developed in the late 60s and first flown commercially in 1970, but not for most commodity technologies like iPhones or photograph equipments [25]. The market cycles of the latter are short and virtually every decision to purchase such a technology results in buying an ‘old’ product, as probably there will be most launches of new models the next day following the purchase. By contrast, medicinal products have long lifecycles also enhanced by business models of generic introductions of innovator products and development of biosimilars in case of biologicals. Innovation in medical devices has learned us how users can modify medical technologies. Shih et al. have stated that traditional systems of regulatory approval and reimbursement of medicinal products do not or hardly account for the dynamic process of this type of ‘reinvention’ and that there have been only little incentives for systematic collection of data to determine which modifications are most beneficial [26]. A potential role of users’ alignment in pharmaceutical innovation has also stressed by other analysts, particularly also after products have been introduced and widely used in clinical practice [27]. A crucial factor remains funding of research with only limited economic incentives, but with important public health relevance. Italian regulators have found a possible and an interesting way out to create incentives for such ‘independent research’ [28]. An additional most crucial question is whether regulatory systems at the moment are prepared to address important challenges in drug development and innovation [29]. Stimulating regulatory science is proposed as one of the steps to be taken to bring effective and sustained regulation forwards [30]. This review shows that incremental spin-offs of the regulatory framework also can work out in a beneficial way, both for patients and for pharmaceutical innovation. Looking at these incremental spin-offs of regulation also poses the question whether current incentives for developing new pharmaceutical products are efficient enough to deliver. The innovation gap in the case of antibiotics clearly shows that drug discovery, development and regulation go hand in hand with synergy in the various incentives systems, also beyond bringing the product to the market as such (i.e. reimbursement systems, hospital policies) [31]. It is a complex chain of interrelated mechanisms and when one element is not in place or works not in the wanted direction, a system failure is very much probable. But in conclusion, regulatory interventions, and we have discussed briefly in this review four of them in the context of the European system, may have multiple effects, some in favour of innovation, some not. Some are in favour of protecting public health, some not. Regulators have a task in constantly evaluating, and adjusting when needed their contributions to e40
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bring new therapeutic scenarios to the patient. Enhancing post-innovation innovation is only one piece of that.
References 1 Gelijns, A.C. et al. (1998) Capturing the unexpected benefits of medical research. N. Engl. J. Med. 339, 693–698 2 Patrono, C. and Rocca, B. (2009) Aspirin, 110 years later. J. Thromb. Haemost. (Suppl. 1), 258–261 3 Annas, G.J. and Elias, S. (1999) Thalidomide and the Titanic: reconstructing the technology tragedies of the twentieth century. Am. J. Public Health 89, 98–101 4 European Public Assessment Report (EPAR). Thalidomide Celgene. EPAR Summary for the public. EMEA/H/C/823, 2008 5 EURORDIS Paris, June 8th 2004 Press Release. Thalidomide: patients denounce the withdrawal of the marketing authorisation application for multiple myeloma treatment 6 Moore, N. et al. (2010) Are generic drugs really inferior medicines? Clin. Pharmacol. Ther. 88, 302–304 7 Choudhry, N.K. and Shrank, W.H. (2010) Four-dollar generics-increased accessibility, impaired quality assurance. N. Engl. J. Med. 363, 1885–1887 8 Walsh, G. (2010) Biopharmaceutical benchmarks 2010. Nat. Biotechnol. 28, 917–924 9 European Medicines Agency, Annual Report 2010 10 Luijn, J. van et al. (2010) Post-approval trials of new medicines: widening use or deepening knowledge? Analysis of 10 years of etanercept Scand. J. Rheumatol. Sep 21 [Epub ahead of print] 11 Tafuri, G. et al. (2010) Therapeutic indications in oncology: emerging features and regulatory dynamics. Eur. J. Cancer 46, 471–475 12 Borg, J.J. et al. (2011) Strengthening and rationalizing pharmacovigilance in the EU: where is Europe heading to? A review of the new EU legislation on pharmacovigilance Drug Saf. 34, 187–197 13 Giezen, T.J. et al. (2009) Evaluation of post-authorization safety studies in the first cohort of EU Risk Management Plans at time of regulatory approval. Drug Saf. 32, 1175–1187 14 Frau, S. et al. (2010) Risk management plans: are they a tool for improving drug safety? Eur. J. Clin. Pharmacol. 66, 785–790 15 Schneider, C.K. and Kalinke, U. (2008) Toward biosimilar monoclonal antibodies. Nat. Biotechnol. 26, 985–990 16 Schellekens, H. and Moors, E. (2010) Clinical comparability and European biosimilar regulations. Nat. Biotechnol. 28, 28–31 17 Giezen, T.J. et al. (2009) Pharmacovigilance of biopharmaceuticals: challenges remain. Drug Saf. 32, 811–817 18 European Public Assessment Report (EPAR) for Multaq, http:// www.ema.europa.eu/docs/en_GB/document_library/EPARSummary_for_the_public/human/001043/WC500044536.pdf2010 19 van Luijn, J.C. et al. (2007) Availability of comparative trials for the assessment of new medicines in the European Union at the moment of market authorization. Br. J. Clin. Pharmacol. 63, 159–162 20 Eichler, H.G. et al. (2010) Relative efficacy of drugs: an emerging issue between regulatory agencies and third-party payers. Nat. Rev. Drug Discov. 9, 277–291 21 CHMP Reflection Paper on the need for active control in therapeutic areas where use of placebo is deemed ethical and one or more established medicines are available. EMA, 2010, http://www.ema.europa.eu/docs/ en_GB/document/01/WC500100710.pdf 22 Breckenridge, A. et al. (2011) Evolution of regulatory frameworks. Nat. Rev. Drug Discov. 10, 3–4 23 Mullard, A. (2011) Mediator scandal rocks French medical community. Lancet 377, 890–892 24 Gøtzsche, P.C. and Jørgensen, A.W. (2011) Opening up data at the European Medicines Agency. BMJ 342, d268610.1136/bmj.d2686 25 Ettlie, J.E. (2006) Managing Innovation: New Technology, New Products and New Services in a Global Economy (2nd edition), Elsevier 26 Shih, C. and Berliner, E. (2008) Diffusion of new technology and payment policies: coronary stents. Health Aff. (Millwood) 27, 1566–1576 27 Smits, R.E. and Boon, W.P. (2008) The role of users in innovation in the pharmaceutical industry. Drug Discov. Today 13, 353–359
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28 Italian Medicines Agency (AIFA) Research & Development Working Group, (2010) Feasibility and challenges of independent research on drugs: the Italian medicines agency (AIFA) experience. Eur. J. Clin. Invest. 40, 69–86 29 Eichler, H.G. et al. (2008) Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma. Nat. Rev. Drug Discov. 7, 818–826
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Schellekens, H. et al. (2011) Drug regulatory systems must foster innovation. Science 332, 174–175 Freire-Moran, L. et al. (2011) the ECDC-EMA Working Group Critical shortage of new antibiotics in development against multidrug-resistant bacteria-time to react is now. Drug Resist Updat. 14, 118–124
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Vol. 8, No. 1 2011
Editors-in-Chief Kelvin Lam – Harvard University, USA Henk Timmerman – Vrije Universiteit, The Netherlands DRUG DISCOVERY
TODAY
TECHNOLOGIES
Innovative methods in drug regulatory sciences
Post-innovation innovation of medicinal products Hubert (Bert) G. Leufkens1,2,*, Huub Schellekens1, Bo Aronsson3 1
Utrecht Insitute for Pharmaceutical Sciences (UIPS), Utrecht, The Netherlands Medicines Evaluation Board (MEB), The Hague, The Netherlands 3 European Medicines Agency (EMA), London, UK 2
Pharmaceutical innovation is a continuous process and does not stop after a medicinal product has been approved for marketing. Post-innovation innovation fuels research into new applications, better profiling
Section Editors: Bert Leufkens – Universiteit Utrecht, Utrecht, The Netherlands; Hans-Georg Eichler – European Medicines Agency, London, UK.
of the target population of a product and other methods to ensure a sustained benefit-risk balance over time. Over the last couple of years several new legislative frameworks with relevant innovation spin-offs (i.e. applications for new indications, risk management plans, biosimilars, active control comparisons) have been introduced into the European regulatory system with challenging opportunities for continuous learning and post-innovation innovation. Regulators have the task to reflect on these frameworks in terms of how these contribute to patient safety, public health and innovation.
Introduction Current drug development encompasses a wide range of activities from designing complete new molecules for unmet medical needs, incremental change and improvement of existing products, up to serendipity inspired radical changes of the target of a medical product during clinical development or after approval for marketing of an initial application. For all these pathways of what Gelijns in 1998 coined as ‘postinnovation innovation’, numerous appealing examples are *Corresponding author.: H.B.G. Leufkens ([email protected]) 1740-6749/$ ß 2011 Published by Elsevier Ltd.
DOI: 10.1016/j.ddtec.2011.06.001
available [1]. She considered three different scenarios of innovation pathways after medical technologies have been initially authorized and used in clinical practice: (1) new basic-science investigations elucidate the mechanisms of action of a certain technology fuelling inspiration for new applications; (2) translational research identifies new uses of the technology either in the laboratory or at the bedside facilitating to look for applications to other conditions with similar biological mechanisms; (3) postmarketing clinical observations about previously unrecognized uses of the technology. Among medical devices, the laser has been recognized as one of the most powerful and versatile advances over the last few decades, including applications in the laboratory, computer printers, bar-code scanners, telecommunications and eye disease [1]. These three pathways are actually not independent and may occur simultaneously. Prevalent features of ‘post-innovation innovation’ include an open mind of both industry developers and regulators and medical practitioners for the fact that certain technology-indication for a disease combinations are not static, the presence of clinical and patient champions to drive such dossiers to a successful end and whether pertinent economic incentives for developers are in place. Also the indications for use of many medicinal products have evolved over time. A classic case is aspirin, for decades an inflammatory painkiller, but over the years also indicated for e37
Drug Discovery Today: Technologies | Innovative methods in drug regulatory sciences
many other indications in the cardiovascular and neurological field [2]. The same holds for thalidomide, originally developed as a sleeping pill in the late 50s that turned out to cause dramatic birth defects, nowadays licensed for multiple myeloma, but tested and off-label use for many other indications as well [3]. On 24 January 2008, the EMA Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for a marketing authorisation of thalidomide to be used to treat multiple myeloma in combination with other medicines (melphalan and prednisone). Because thalidomide was well known to cause birth defects, several measures were put in place to minimise the risk of exposure of unborn children to the medicine. The CHMP concluded that thalidomide’s benefits outweighed its risks for the treatment of multiple myeloma, provided that robust measures were put in place to avoid exposure of unborn children [4]. In the advent of this opinion, various patient groups had advocated in favour of a marketing authorization for the indication of multiple myeloma, while other groups, particularly thalidomide victims, protested against such an authorization pointing to the devastating teratogenic risks and the alleged inability of authorities to control off-label use [3,5]. Despite the fact that most investments in pharmaceutical innovation are made by industry during the period of patent protection (i.e. around the first 15 years) drug usage itself has had always a long time horizon. More than two out of three prescriptions doctors write out today are for products initially developed more than 15–20 years ago. In terms of volume, most patients use ‘old’ medicinal products. These products have shown robust evidence for efficacy over the years and their safety profile has been well developed and understood (e.g. metformin, methotrexate, and simvastatin) [6]. Moreover, because of their off-patent nature their cost-effectiveness is attractive for payers and governments. Although quality concerns have been expressed and are putting ample emphasis on regulatory systems to assure that standards of generic products are met albeit increasing globalisation, complex and long production and logistics chains and increasing cost pressures on the industry, generic pharmaceutical products constitute an important part of our therapeutic arsenal [7,8]. In this review we will evaluate the concept of ‘post-innovation innovation’ from different perspectives, including the existing European regulatory framework and how different parts of this framework have important innovative spin-offs, sometimes intended, not always. We will underpin the importance of sustainable drug development over time as pharmaceutical products are never ‘finished’. There is always good reason to improve the targeting of the therapeutic molecule to the best responders, improve the dose and duration and to increase the benefit–risk by changing the pharmaceutical dosage form. Four current European regulatory features will be highlighted, including increased applications e38
www.drugdiscoverytoday.com
Vol. 8, No. 1 2011
for new indications, Risk Management Plans obligatory in Europe since 2005, the regulation of biosimilars also in place since 2005, and the mounting regulatory plea for active control comparisons to support robust benefit–risk weighing, but also resulting in stimulating knowledge development for ‘old’ medicinal products, very often off-patent with a lack of incentives for the innovator industry to invest in.
Regulatory features with innovation spin-offs Application for new indications When we look at the flow of applications industry submits to the EMA, numbers for claims of a new indication (variation of Section 4.1 of the SmPC) are virtually the same as for applications with a new active substance, 24 versus 22, respectively in 2010 [9]. The development of the indication profile of TNFa blockers over the years (i.e. rheumatoid arthritis, Crohn’s disease) [10] or products for oncology indications [11] is a clear example. An application for a new indication is not always for a new distinct disease but very often also for a shift from second line to first line therapy, from adults to children and so on. From an innovation perspective, applications for new indications have become one of the mainstays of clinical development of medical products, a feature that is also related to the multi-target nature of today’s therapeutic molecules. Monoclonal antibodies or tyrosine kinase inhibitors affect multiple mechanistic pathways making them possibly suitable for a diversity of clinical indications. While critics of the pharmaceutical industry argue against this ‘drugs looking for a disease’ or ‘salami slicing of indications’, it has become obvious that a significant share of today’s pharmaceutical development lies in the surge of applications for new indication offering ample opportunity for knowledge building and learning about the various properties of a medicinal product. The fact that the regulatory system requires that companies justify every therapeutic claim with data and evidence is a strong driver for further clinical deepening of the potential of an existing product.
Risk management plans Since November 2005, an EU Risk Management Plan (EURMP) has become an integral part of a marketing application for all new chemical entities in the EU. Moreover, risk management plans can be required as part of an application for a new indication [12]. In the EU-RMP, the safety profile of the medicine has to be summarized and crucial safety issues have to be specified to plan proactively for pharmacovigilance activities, including post-authorization safety studies (PASS) and if appropriated adequate risk minimisation measures, once the product is approved and used in clinical practice. This pharmacovigilance model intends to produce a shift from a reactive, passive mode of risk management to a more pro-active, planned and science based [12]. A recent analysis
Vol. 8, No. 1 2011
of the quality of the first cohort of EU-RMPs showed several important opportunities for improvement, including comprehensiveness of the PASS study protocols, level of inclusion of EU populations in the planned studies and feasibility of the proposed risk-minimisation plans [13]. Moreover, several crucial points regarding implementation of EU-RMPs in clinical practice and the transparency of its contents have been identified [14]. However, the model of EU-RMP, also strengthened in the new EU Legislation on Pharmacovigilance and addressed elsewhere in this series by Arlett et al., can be seen as a structured vehicle for ‘post-innovation innovation’. Obviously with a strong focus on possible harms of a medicinal product, but with a great opportunity to learn more about the full profile of the medicinal product, for example, practice experience, answers to pre-approval uncertainties, and unexpected benefits. RMPs seem to have a broader scope of spin-offs than the initial safety objective for which they were developed [13].
Biosimilar regulation Also since 2005, the EMA ‘Guideline on similar biological medicinal products containing biotechnology-derived proteins as an active substance: non-clinical and clinical issues’ (EMEA/CPMP/42832/05/) lays down the general requirements for the demonstration of the similar nature of two biological products in terms of safety and efficacy. These so-called biosimilars are new biological medicinal products claimed to be ‘similar’ to a reference medicinal product, which has already been granted a marketing authorisation in the past [15,16]. Since the development and the introduction of the biosimilar regulatory framework, there have been discussions about the clinical comparability and interchangeability of such products, resulting also in strengthening the regulatory requirements to pharmaceutical companies regarding showing essential similarity between the biosimilar and the innovator product. Moreover, several crucial points have been indentified regarding safety management of such products particularly because of the fact that confounding by disease (severity) and traceability of which product batch an individual patient has used remain crucial issues when evaluating possible drug induced harm [17]. However, albeit all these challenges the way these companies active in biosimilar development have anticipated the regulatory requirements has driven substantial innovation in protein characterisation, further research on immunogenicity, production technologies and patient registries building [16]. Stricter pharmaceutical regulation to enable biosimilar development has resulted not only in biotech products with an ensured benefit–risk, but also in broader offshoots in knowledge and technology creation.
Active control comparisons Randomized and controlled comparisons (RCT) of drug effects against placebo are the key to clinical development
Drug Discovery Today: Technologies | Innovative methods in drug regulatory sciences
and since the streptomycin trials for tuberculosis in the late 1940s, the accepted paradigm to show evidence of efficacy. Over the years, various modifications both in design and analysis of placebo comparisons have been developed. However, placebo controls are not always possible and wanted and comparisons with active controls are increasingly required by regulators in order provide insight in how the product behaves against the most commonly used standard treatment. This insight is particularly crucial when modest efficacy is shown in a placebo comparison, giving discussions about the added clinical benefit over existing products, or when certain safety issues have to be weighted against possible additional benefits a new product may provide. A recent example is dronedarone (Multaq), an anti-arrhythmic medicine. This medicine was studied in five placebo-controlled trials but also in a study comparing Multaq with amiodarone (another medicine used to prevent atrial fibrillation) [18]. However, active control comparisons have their own challenges with respect to issues like essay sensitivity and choice of control, and are currently not always parts of a marketing application dossier [19]. Stimulated by the way third-party payers look at clinical relevance and the appealing regulatory question: – What is the benefit–risk of the new product given what we know of the product currently used in clinical practice? – We may anticipate increasing demand for comparisons of new products against standard care treatments [20]. CHMP also increasingly asks for data from head-to-head comparisons and has stimulated recently the debate about when such studies are justified, needed and feasible to do [21]. But apart from addressing the question of relative efficacy and effectiveness, active control comparisons have provided a wealth of spin-off learning on ‘old drugs’ like methotrexate in rheumatoid arthritis, beta-blockers in the treatment of hypertension or metformine for diabetes type II.
Discussion The framework of regulating pharmaceutical products has many legal, scientific and public health dimensions, and is increasingly exposed to ample criticism from various societal stakeholders [22–24]. Society expects, for good reasons, that regulators protect patients and public in general from drug induced harm in a independent and transparent way. At the same time, pharmaceutical innovation, that is, bringing new products for unmet medical needs to the clinic, is a function of regulation as well. Looking at regulators only in their role as watch-dog or alleged hurdle to innovation impairs to have a broader look at how regulation may also have important additional positive spin-offs, may not be always intended but important to identify and to appreciate. The four regulatory features described here started initially as set of (extra) regulatory requirements but turned out also to stimulate new ways of thinking, new insight and a continuous cycle of postinnovation innovation. The lifecycle of medicinal products www.drugdiscoverytoday.com
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Drug Discovery Today: Technologies | Innovative methods in drug regulatory sciences
needs a long view with an open eye for incremental changes and improvements over time in terms of new applications and pharmaceutical dosage forms. This may also be true for Boeing 747s, designed and developed in the late 60s and first flown commercially in 1970, but not for most commodity technologies like iPhones or photograph equipments [25]. The market cycles of the latter are short and virtually every decision to purchase such a technology results in buying an ‘old’ product, as probably there will be most launches of new models the next day following the purchase. By contrast, medicinal products have long lifecycles also enhanced by business models of generic introductions of innovator products and development of biosimilars in case of biologicals. Innovation in medical devices has learned us how users can modify medical technologies. Shih et al. have stated that traditional systems of regulatory approval and reimbursement of medicinal products do not or hardly account for the dynamic process of this type of ‘reinvention’ and that there have been only little incentives for systematic collection of data to determine which modifications are most beneficial [26]. A potential role of users’ alignment in pharmaceutical innovation has also stressed by other analysts, particularly also after products have been introduced and widely used in clinical practice [27]. A crucial factor remains funding of research with only limited economic incentives, but with important public health relevance. Italian regulators have found a possible and an interesting way out to create incentives for such ‘independent research’ [28]. An additional most crucial question is whether regulatory systems at the moment are prepared to address important challenges in drug development and innovation [29]. Stimulating regulatory science is proposed as one of the steps to be taken to bring effective and sustained regulation forwards [30]. This review shows that incremental spin-offs of the regulatory framework also can work out in a beneficial way, both for patients and for pharmaceutical innovation. Looking at these incremental spin-offs of regulation also poses the question whether current incentives for developing new pharmaceutical products are efficient enough to deliver. The innovation gap in the case of antibiotics clearly shows that drug discovery, development and regulation go hand in hand with synergy in the various incentives systems, also beyond bringing the product to the market as such (i.e. reimbursement systems, hospital policies) [31]. It is a complex chain of interrelated mechanisms and when one element is not in place or works not in the wanted direction, a system failure is very much probable. But in conclusion, regulatory interventions, and we have discussed briefly in this review four of them in the context of the European system, may have multiple effects, some in favour of innovation, some not. Some are in favour of protecting public health, some not. Regulators have a task in constantly evaluating, and adjusting when needed their contributions to e40
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bring new therapeutic scenarios to the patient. Enhancing post-innovation innovation is only one piece of that.
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