Author byline as per print journal: Brian Godman, BSc, PhD; Michael Wilcock, MPharm; Andrew Martin, MPharm; Scott Bryson, MSc, MPH; Christoph Baumgärtel, MD; Tomasz Bochenek, MD, MPH, PhD; Winne de Bruyn, BSc; Ljiljana Sović Brkičić, MPharm; Marco D’Agata, MSc; Antra Fogele, PhD; Anna Coma Fusté, MSc; Jessica Fraeyman, PhD; Jurij Fürst, MD; Kristina Garuoliene, MD, PhD; Harald Herholz, MD, MPH; Mikael Hoff mann, MD, PhD; Sisira Jayathissa, MBBS, MMedSc (Clin Epi), MD, FRCP (Lond, Edin), FRACP, FAFPHM, FNZCPHM, DClinEpi, DOPH, DHSM, MBS; Hye-Young Kwon, BPharm, MPH, PhD; Irene Langner, MA; Marija Kalaba, MD; Eva Andersén Karlsson, MD, PhD; Ott Laius, PhD; Vanda Markovic-Pekovic, PhD; Einar Magnusson, MD; Stuart McTaggart, MSc; Scott Metcalfe, MBChB, DComH, FAFPHM (RACP), FNZCPHM; Hanne Bak Pedersen, MD; Jutta Piessnegger, PhD; Anne Marthe Ringerud, MPharm; Gisbert W Selke, BSc; Catherine Sermet, MD; Krijn Schiffers, BSc; Peter Skiold, MSc; Juraj Slabý, MD; Dominik Tomek, Pharm Dr, PhD, MPH; Anita Viksna, PhD; Agnes Vitry, PhD; Corinne Zara, MSc; Rickard E Malmström, MD, PhD

Submitted: 27 March 2015; Revised: 11 June 2015; Accepted: 24 August 2015; Published online first: 7 September 2015

Introduction

The increased use of generic medicines is essential to sustain healthcare systems given the ever-increasing pressure on resources [1–4]. Prices of generic drugs are as low as 2–10% of pre-patent loss prices in some countries [5–7]. Consequently, increased use of generic drugs can generate substantial savings, which can be redirected into funding new valued high-priced medicines [2, 5–12], which is especially important for countries struggling to fund these medicines. A number of strategies globally have been initiated to encourage prescribing and dispensing of generic drugs rather than the originator (brand-name) drug, as well as patented products in a class in which all medicines are seen as essentially similar at therapeutically equivalent doses [4, 8–12].

Increasing use of generic drugs does not appear to compromise care, and many studies have reported little or no difference in outcomes across a range of products and classes [13–18]. In Europe, only generic drugs produced in accordance with the European Medicines Agency’s strict guidelines and definitions [19] are granted marketing authorization.

Well-known and agreed exceptions to generics prescribing or substitution include lithium, theophyllines, some anti-epileptic drugs, modified release preparations and immunosuppressants. In these cases, brand-name prescribing is endorsed [20–23]. Agreed exceptions to generics prescribing, including medicines to treat epilepsy and prevent organ rejection, also exist in Germany and Sweden [6, 24].

A new emerging problem, however, has come to the fore in recent years, concerning the expiry of patents for medicines that have patents for more than one indication, and the threat of legal action by the manufacturer of the originator drug against physicians. This situation occurred recently in the case of pregabalin for the treatment of epilepsy and generalized anxiety disorder (GAD) when the basic patent for pregabalin expired in July 2014 in a number of European countries. The patent for its second medical use, protecting the originator drug Lyrica’s use in treating neuropathic pain, extends to July 2017 in Europe [25, 26]. In the UK, this resulted in the manufacturer of the originator drug (Lyrica) claiming patent infringement and warning doctors not to prescribe the generic drug pregabalin for neuropathic pain [26, 27]. As far as we are aware, this is the first time this has happened, and has serious implications for health authorities.

Prior to this, the originator manufacturer of Lyrica had been fined heavily for promoting gabapentin (prelude to pregabalin) off label for the treatment of neuropathic pain [28–31], although it is now recommended for this indication [32]. In addition, there have been concerns with the methodological limitation of some of the studies of pregabalin in neuropathic pain [33–35]. Pregabalin, for example, is currently not listed in the ‘Wise List’ of Stockholm Metropolitan Healthcare Region because of efficacy and safety concerns compared with other treatments for these conditions [36]. However, there are increasing concerns with the implications of the activities of second use patents with Lyrica [26, 37].

In this paper, historical developments in Germany and the UK relating to this case are examined. Personnel from regional and national health authorities from principally across Europe, and advisers to health authorities working in universities, were then surveyed to ascertain the current situation with pregabalin in their country and to determine the best strategy for maximizing savings for countries once a product loses its patent for any indication.

United Kingdom

In the UK, the international non-proprietary name (INN) prescribing rate is over 80%, and up to 98–99% of non-contentious generic drugs, such as proton pump inhibitors, renin-angiotensin inhibitors and statins, with pharmacists not permitted to substitute an originator drug with a generic drug when the originator drug is prescribed [7, 20, 21, 38].

The UK medicines agency recently issued advice on which epilepsy drugs to prescribe by brand name (originator) and which by INN [39]. Pregabalin was considered suitable for INN prescribing [39], which was endorsed by the originator company stating ‘there will be no clinical superiority of the originator branded medicine Lyrica over generic pregabalin’ [25].

The extended patent for neuropathic pain resulted in the originator company writing to all Clinical Commissioning Groups (CCGs) in England and Health Boards in Scotland in November 2014 pointing out that generics of pregabalin were expected to be approved only for GAD and epilepsy indications, and that the prescribing of generic pregabalin for neuropathic pain could represent ‘off-label’ use. This would be considered a patent infringement constituting an unlawful act, with the originator company reserving all legal rights in this regard [25–27].

The wish of generics companies to make generic pregabalin available in the UK across all indications resulted in a court case, with the originator company as claimant and the Actavis group as the principal defendant [26, 40]. The judge in his deliberations, posted on 21 January 2015, granted Actavis the possibility to launch generic pregabalin and again stated that the best way forward was to try to ensure physicians prescribe Lyrica for the treatment of neuropathic pain and pregabalin for other conditions, including epilepsy [40, 41].

The actions of the originator company are unsurprising. In 2013, global sales of Lyrica generated US$4.6 billion for the company [40]. In the UK, sales of Lyrica increased by 53% between 2011 and 2013 to about US$310 million. It is estimated that 54% of prescriptions in September 2014 were for treating pain, of which 44% was for neuropathic pain [40]. In 2014, sales of Lyrica were GBP 250 million (US$390 million) [26].The potential loss in revenue, therefore, would hugely impact company sales – estimated to be GBP 220 million per year (US$340 million) across all indications assuming high INN prescribing rates and generic drug prices rapidly falling by 90% of the price of Lyrica [7, 42].

In an attempt to preserve sales of Lyrica, the originator company has been proactive in lobbying groups in the UK who could influence physician prescribing, such as the Medicine Management groups within CCGs, the Pharmaceutical Services Negotiating Committee, the General Practitioners Committee of the British Medical Association, and the National Health Service [26, 32, 37, 43–45]. For instance, National Health Service (NHS) England in March 2015 issued advice to all CCGs that within electronic prescription systems there should be a notice or advice box stating ‘If treating neuropathic pain, prescribe Lyrica (brand) due to patent protection. For all other indications, prescribe generically’ [45]. The Pharmaceutical Services Negotiating Committee stated to its members they should be aware that the originator company still retains the indication for neuropathic pain. Members were also made aware that following a high court decision, ‘it was agreed by all parties that the generic [drug] producers would write to CCGs to ensure they were aware that the generic [drug] could not be supplied for the patented indication. A CCG or other party that promotes the supply of generic pregabalin for the patented indication risks facing legal action’ [43].

This situation in the UK has important future implications for generics and biosimilars companies across countries, as it may impede the ability of health authorities to fully realize potential savings from generics and biosimilars once the first indication loses its patent, especially if pharmaceutical companies look to extend the number of indications for their new medicines once launched in an attempt to extend the patent life.

Germany

Germany has taken a different approach to the UK. Currently, nine pregabalin generics are available and reimbursed in Germany (up to April 2015), all of which have the indications for epilepsy and anxiety disorders. The situation, however, is now less clear cut as the originator manufacturer, has taken Ratiopharm, Hexal, 1A Pharma, Glenmark and Aliud Pharma and some Sickness Funds (German payers) to court in an attempt to conserve Lyrica sales for neuropathic pain (up to 10 April 2015) [46]. The legal battle is still ongoing. The originator company’s previous strategy to promote Lyrica was to communicate directly with physicians or via KVs (regional doctors’ associations) by letter, making it clear that Lyrica was the only pregabalin licensed for neuropathic pain [47]. However, these communications were largely dismissed by KVs because the focus was on legal rather than medical issues, and the KVs continued to advise physicians to reach targets of generics prescribing of at least 85%. In addition, the Social Code Book V (SGB V), which is decisive for Sickness Funds, stated in paragraph 129 that generics substitution is possible wherever at least one indication matches [48–50].

The contrast between the situation in the UK and the situation in Germany, and the implications for potential savings when other pharmaceutical products lose their patents for some but not all indications, has led health authorities, across Europe, to review the current status of pregabalin in other countries in order to refine their own strategies if possible.

Aim of study

A qualitative study was undertaken to ascertain the current situation between generic pregabalin and Lyrica among health authorities principally from across Europe. This included a range of Central, Eastern and Western European countries with different epidemiology and funding of health care, as well as policies to enhance the prescribing of generics. This builds on the situation Germany and the UK, and is in line with current recommendations for conducting cross-national research projects [51]. The aim was to maximize future savings for countries once a product loses its patent for any indication.

Materials and methods

Personnel from 33 regional and national health authorities mainly from across Europe, and personnel from nine universities working closely as advisers to health authorities or with insight into health authority activities, were contacted by email to provide answers to the following four questions (up to April 2015):
1. Are you aware of any similar examples to the situation of pregabalin and Lyrica in the UK from other pharmaceutical companies for small molecules once the patent has been lost (biosimilars are a different issue)? If so, what were these and how were they handled (if at all).
2. Was Lyrica reimbursed in your country? If yes, for what indications?
3. Has generic pregabalin been launched in your country/about to be launched? If yes what date (month) and indications?
4. Has the originator company issued a letter to healthcare professionals in your country similar to the letter issued to CCGs in the UK? If yes, what actions (if any) are being taken?

This was supplemented with knowledge from other high-income countries taking different approaches to the availability of generic pregabalin to potentially provide additional examples.

All health authority personnel are involved with either pricing and reimbursement decisions, decisions concerning funding or monitoring the use of medicines, or both, including generics, in their countries and regions. Consequently, it was felt that they would have the most insight into the current situation concerning pregabalin and Lyrica in their countries and regions. European countries included those from Central, Eastern and Western Europe to ensure legitimacy with the findings. Personnel from regions in The Netherlands, Sweden and the UK were also included, as healthcare budgets in these countries are devolved downwards.

The written information supplied by the co-authors and others for each of the questions for each country was collated and summarized by the corresponding author. The summarized information was subsequently checked via email and face-to-face contact with the relevant co-author(s) to ensure the accuracy of the summarized information. The information supplied was subsequently summarized into five categories to improve the interpretation of the findings and the implications for the future, building on the situation in England and Germany.

The five categories included:

• Countries in which Lyrica was never reimbursed; consequently generic pregabalin is less of an issue for the originator company, see Table 1.
  
• Countries in which the patent life for Lyrica has been extended, negating the threat from generic pregabalin until all three indications have lost their patent, see Appendix 1.
  
• Countries in which generic pregabalin is currently not reimbursed and the future situation regarding generic pregabalin is unknown, see Appendix 2.
  
• Countries in which generic pregabalin is currently not reimbursed; however, the country is likely to follow the example of either the UK and restrict the prescribing of pregabalin for neuropathic pain, alternatively reimburse pregabalin across all indications, see Table 2.
  
• Countries in which pregabalin is available and reimbursed, see Table 3.
  

Potential or actual demand-side measures among the health authorities were not broken down into the ‘four Es’: education, engineering, economics and enforcement, as in our previous paper on generic clopidogrel [52]. This is because pregabalin may not be available and reimbursed across Europe and the other chosen countries.

This information was supplemented with a limited literature search for further information about generics generally, pregabalin and the activities of the originator company, including recent court cases, as well as relevant papers known to the co-authors. A similar methodological approach was used when reviewing health authority activities when generic clopidogrel became available [52].

Results

The results of the survey revealed that respondents were typically unaware of similar examples to pregabalin and Lyrica in their countries. For example, generic clopidogrel was reimbursed and endorsed by health authority personnel from across Europe despite generic clopidogrel not including all licensed indications at launch [52]. The main exception was Lithuania, see Table 2, with Glivec and generic imatinib.

The current situation for Lyrica and generic pregabalin among health authorities and health insurance companies across Europe and other selected countries is included in Tables 1–3 as well as Appendices 1 and 2. This also includes additional activities in Scotland.

Discussion

In this paper, we have described the situation across Europe following the launch or imminent launch and reimbursement of generic pregabalin. We were not surprised by the activities of the originator company in the UK in view of the current high levels of INN prescribing, no clinical issues with patients being switched between generic pregabalin or Lyrica across indications, and the high sales of Lyrica globally and in the UK [7, 21, 25, 39, 40, 65].

The threat of legal action against physicians taught to prescribe generically is a major concern among health authorities already struggling to fund increased volumes and new high-priced medicines within available budgets [66]. It also raises issues about off-label prescribing generally and pharmacists checking the use of medication with every patient [37]. Moreover, it would seem that this is the first time that an originator company has threatened court cases against physicians in an extended patent use situation. Previous examples can be found in some countries such as Lithuania, see Table 2; however, no coordinated approach has been taken across countries. These concerns are exacerbated if such activities make European markets unattractive for generics companies, thereby reducing potential savings once a product loses its patent. It is also unhelpful to influence physicians to remember to prescribe different versions of the same molecule for different indications. This could, however, potentially be addressed through increasing use of electronic prescribing support systems. Actions of this nature also impede constructive working relationships between pharmaceutical companies and health service personnel [26].

As seen in Tables 1–3, and Appendices 1 and 2, very different approaches have been taken across countries to the availability of generic pregabalin. In addition to historic approaches taken in Germany, countries such as Czech Republic, Estonia, Republic of Srpska, Bosnia and Herzegovina, and Serbia, see Table 3, are good examples of approaches taken to enhance the prescribing of pregabalin across all indications. The situation in Austria, Poland, and Slovenia will be closely monitored, see Tables 2 and 3, to see if they could also provide examples of potential ways forward to enhance the prescribing of pregabalin across all indications.

Lithuania, Norway and Sweden will also be closely monitored to see whether the originator company will be successful in limiting the prescribing of generic pregabalin in practice to epilepsy and GAD, with Lyrica prescribed and dispensed for neuropathic pain, see Table 2 and Appendix 2. Whether these countries will follow the examples of Bosnia and Herzegovina, Czech Republic, Estonia, Germany (historic), Republic of Srpska Bosnia and Herzegovina, and Serbia, see Table 3, once pregabalin is available and reimbursed remains to be seen.

It is interesting to note the different approaches taken by the originator company to the KVs in Germany initially compared with regional health authorities in England and Health Boards in Scotland, see Table 3. This acknowledges adherence to current stipulations of Social Code Book V serving as an example to other countries worried about such developments in the future, although this is now being challenged.

The introduction of reference priced systems with reimbursement typically just covering the costs of the lowest priced molecule is another way forward, given the extent of internal reference pricing across Europe once multiple sources of a product become available [1]. This works best if originator companies drop their prices to compete; alternatively, the situation is pre-empted as seen for instance in Spain, see Table 3. Alternatively, the price of the originator (brand name) is reduced over time despite the protestations of the originator manufacturer, as seen in South Korea, see Table 3. Difficulties could, potentially occur if reimbursement or substitution for one indication is not recommended, which could occur in Sweden for treatments for epilepsy, see Table 2. This has not currently been a problem in South Korea with multiple pregabalin packs available from different manufacturers, see Table 3. This situation could potentially reduce the attractiveness of the market to generics companies if originator (brand name) manufacturers are happy to drop their prices to those of generics to compete in the knowledge that patients may prefer to stay with the originator if copayments are the same in the absence of any substitution in pharmacies. This is, however, being resisted by the originator company in South Korea, see Table 3.

The developments surrounding Lyrica and generic pregabalin, including potential health authority activities to enhance the prescribing of generic pregabalin, will be closely monitored over the coming months. This will be combined with research on the resultant effect of prescribing and dispensing of pregabalin or Lyrica in practice. The objective will be to provide further guidance to health authorities with their increasing need to maximize savings from generics or biosimilars once they become available for at least one indication. This is essential to maintain the ideals of comprehensive and equitable healthcare especially in Europe.

Conclusion

We have documented different approaches to the availability of generic pregabalin, with countries such as Germany historically having measures in place to enhance the prescribing of generics once at least one indication is off patent. This contrasts with countries such as the UK where generic pregabalin can only be prescribed for some but not all indications. This appreciably reduces potential savings from the availability of generics, which is an increasing concern given ever growing pressures on available resources.

Note from corresponding author

The situation in the UK will now be closely monitored following a recent court judgement post acceptance of the paper overturning the originator company’s patent for pregabalin for pain control; although, this is currently being challenged by the company [67].

Acknowledgements and financial disclosure

We thank Ms Elina Asola for the current information regarding Finland, Ms Laura McCullagh and Ms Susan Spillane for the current information regarding Ireland, and Ms Marie-Camille Lenormand for information regarding France.

All authors wish to thank the English editing support provided by Ms Maysoon Delahunty, GaBI Journal Editor, for this manuscript.

There are no conflicts of interest from any author. However, the majority of authors are employed by ministries of health, health authorities and health insurance companies or are advisers to them. The content of the paper and the conclusions though are those of each author and may not necessarily reflect those of the organization that employs them.

This work was in part supported by grants from the Karolinska Institutet, Sweden.

Competing interests: None.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Brian Godman^1,2, BSc, PhD; Michael Wilcock³, MPharm; Andrew Martin⁴, MPharm; Scott Bryson^2,5, MSc, MPH; Christoph Baumgärtel⁶, MD; Tomasz Bochenek⁷, MD, MPH, PhD; Winne de Bruyn⁸, BSc; Ljiljana Sović Brkičić⁹, MPharm; Marco D’Agata¹⁰, MSc; Antra Fogele¹¹, PhD; Anna Coma Fusté¹², MSc; Jessica Fraeyman¹³, PhD; Jurij Fürst¹⁴, MD; Kristina Garuoliene^15,16, MD, PhD; Harald Herholz¹⁷, MD, MPH; Mikael Hoffmann¹⁸, MD, PhD; Sisira Jayathissa¹⁹, MBBS, MMedSc (Clin Epi), MD, FRCP (Lond, Edin), FRACP, FAFPHM, FNZCPHM, DClinEpi, DOPH, DHSM, MBS; Hye-Young Kwon^20,21, BPharm, MPH, PhD; Irene Langner²², MA; Marija Kalaba²³, MD; Eva Andersén Karlsson^24,25, MD, PhD; Ott Laius²⁶, PhD; Vanda Markovic-Pekovic^27,28, PhD; Einar Magnusson²⁹, MD; Stuart McTaggart³⁰, MSc; Scott Metcalfe³¹, MBChB, DComH, FAFPHM (RACP), FNZCPHM; Hanne Bak Pedersen³², MD; Jutta Piessnegger³³, PhD; Anne Marthe Ringerud³⁴, MPharm; Gisbert W Selke²², BSc; Catherine Sermet³⁵, MD; Krijn Schiffers³⁶, BSc; Peter Skiold³⁷, MSc; Juraj Slabý³⁸, MD; Dominik Tomek³⁹, Pharm Dr, PhD, MPH; Anita Viksna¹¹, PhD; Agnes Vitry⁴⁰, PhD; Corinne Zara¹², MSc; Rickard E Malmström⁴¹, MD, PhD

¹Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden
²Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
³Head of Prescribing Support Unit, Pharmacy Department, Royal Cornwall Hospitals NHS Trust, Truro, Cornwall TR1 3LJ, UK
⁴North West Commissioning Support Unit (NWCSU), Salford, Manchester M6 5FW, UK
⁵NHS Greater Glasgow & Clyde Prescribing Management Group, Glasgow, UK
⁶AGES Austrian Medicines and Medical Devices Agency and Austrian Federal Office for Safety in Health Care, 5 Traisengasse, AT-1200 Vienna, Austria
⁷Department of Drug Management, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
⁸Utrecht University, Utrecht, The Netherlands
⁹Croatian Health Insurance Fund, 37 Branimirova, Zagreb, Croatia
¹⁰Achmea Zorg and Health, 2 Handelsweg, NL-3707 NH Zeist, The Netherlands
¹¹The National Health Service of Latvia, 31 k-3 Cēsuiela, LV-1012 Riga, Latvia
¹²Barcelona Health Region, Catalan Health Service, Barcelona, Spain
¹³Epidemiology and Social Medicine, Research Group Medical Sociology and Health Policy, University of Antwerp, Antwerp, Belgium
¹⁴Health Insurance Institute, Ljubljana, Slovenia
¹⁵Faculty of Medicine (Department of Pathology, Forensic Medicine and Pharmacology), Vilnius University, Vilnius, Lithuania
¹⁶State Medicines Control Agency, Vilnius, Lithuania
¹⁷Kassenärztliche Vereinigung Hessen, 15 Georg Voigt Strasse, DE-60325 Frankfurt am Main, Germany
¹⁸NEPI – Nätverk för läkemedelsepidemiologi, Sweden
¹⁹Department of Medicine, Hutt Valley DHB, Lower Hutt, Wellington, New Zealand
²⁰Institute of Health and Environment, Seoul National University, Seoul, South Korea
²¹Department of Global Health and Population, Harvard School of Public Health, Boston, MA, USA
²²Wissenschaftliches Institut der AOK (WIdO), 31 Rosenthaler Straße, DE-10178 Berlin, Germany
²³Republic Institute for Health Insurance, Belgrade, Serbia
²⁴,²⁵Drug and Therapeutics Committee, Unit of Medicine Support, Public Healthcare Services, Stockholm County Council and Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden
²⁶State Agency of Medicines, Tartu, Estonia
²⁷,²⁸Faculty of Medicine, University of Banja Luka, Banja Luka, Republic Srpska, Bosnia and Herzegovina; Ministry of Health and Social Welfare, Banja Luka, Republic Srpska, Bosnia and Herzegovina
²⁹Department of Health Services, Ministry of Health, Reykjavík, Iceland
³⁰Public Health and Intelligence, NHS National Services Scotland, Edinburgh EH12 9EB, UK
³¹PHARMAC, 40 Mercer Street, Wellington 6011, New Zealand
³²Health Technologies and Pharmaceuticals, Division of Health Systems and Public Health, WHO Regional Office for Europe, Copenhagen, Denmark
³³Hauptverband der Österreichischen Sozialversicherungsträger, Vienna, Austria
³⁴Section for Reimbursement, Department for Pharmacoeconomics, Norwegian Medicines Agency, 8 Sven Oftedals vei, NO-0950 Oslo, Norway
³⁵IRDES, 10 rue Vauvenargues, FR-75018 Paris, France
³⁶Erasmus University, Rotterdam, The Netherlands
³⁷Dental and Pharmaceuticals Benefits Agency (TLV), PO Box 22520, 7 Flemingatan, SE-10422 Stockholm, Sweden
³⁸State Institute for Drug Control, Czech Republic
³⁹Department of Pharmacology, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia
⁴⁰Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, GPO Box 2471, Adelaide SA 5001, Australia
⁴¹Department of Medicine Solna, Karolinska Institutet, Clinical Pharmacology Karolinska University Hospital Solna, Stockholm, Sweden

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