Generic pregabalin; current situation and implications for health authorities, generics and biosimilars manufacturers in the future

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

Introduction: The manufacturer of pregabalin has a second use patent covering prescribing for neuropathic pain – its principal indication. The manufacturer has threatened legal action in the UK if generic pregabalin rather than Lyrica is prescribed for this indication. No problems exist for practitioners who prescribe pregabalin for epilepsy or generalized anxiety disorder. This has serious implications for health authorities. In Germany, however, historically generics can be legally prescribed for any approved indication once one indication loses its patent.
Aim: To establish the current situation with pregabalin among health authorities principally from European countries.
Methods: Personnel from 33 regional and national health authorities mainly from Europe, and nine from universities across Europe working as advisers to health authorities or with insight into their activities, were surveyed regarding four specific questions via email to shed light on the current situation with Lyrica and pregabalin in their country. The information collated from each country was subsequently checked for accuracy with each co-author by email and face-to-face contact, and collated into five tables.
Results: The scenarios ranged from extending the patent life of Lyrica, e.g. France, endorsing the prescribing of Lyrica for neuropathic pain at the same price as the generic drug, e.g. Catalonia and South Korea, and current prescribing of pregabalin for all indications, e.g. Germany and Serbia. Little activity has taken place in European countries in which generic pregabalin is not yet reimbursed.
Conclusion: The availability of generic pregabalin has prompted a number of different activities to be undertaken among the 33 countries and regions surveyed. The situation in Serbia and the historic situation in Germany provide examples of ways to maximize savings once a product loses its patent for at least one indication.

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 [14]. Prices of generic drugs are as low as 2–10% of pre-patent loss prices in some countries [57]. Consequently, increased use of generic drugs can generate substantial savings, which can be redirected into funding new valued high-priced medicines [2, 512], 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, 812].

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 [1318]. 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 [2023]. 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 [2831], 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 [3335]. 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 [2527].

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, 4345]. 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 [4850].

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:

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 13 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 13, 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 Godman1,2, BSc, PhD; Michael Wilcock3, MPharm; Andrew Martin4, MPharm; Scott Bryson2,5, 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 Garuoliene15,16, 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 Kwon20,21, BPharm, MPH, PhD; Irene Langner22, MA; Marija Kalaba23, MD; Eva Andersén Karlsson24,25, MD, PhD; Ott Laius26, PhD; Vanda Markovic-Pekovic27,28, 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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Author for correspondence: Brian Godman, BSc, PhD, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186 Stockholm, Sweden

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Steps to ensure adequate supply of biological medicines: considerations for the healthcare provider

Author byline as per print journal: Andrew Mica, MBA, Martha Mutomba, PhD, Larry Green, PharmD

Introduction: When drug shortages occur, healthcare providers (HCPs) often must ration drugs, cancel or delay treatments, or utilize alternative drugs that may be less efficacious and/or are associated with increased risk of adverse outcomes, potentially impacting patient care. The likelihood of drug shortages may be increased for biological medicines, which are produced in living cells, require complex manufacturing processes and rigorous regulatory compliance, and are sensitive to storage and handling conditions. Most of the drugs currently in short supply are relatively inexpensive generic sterile injectables. As many suppliers of generic drugs may begin to produce biosimilars in the future, the issue of biological drug shortages may become an important consideration.
Discussion: This manuscript highlights critical supply chain parameters that HCPs should consider when evaluating a manufacturer’s ability to maintain and deliver a continuous supply of biological medicines. Parameters to consider include: 1) effective management of drug inventory; 2) active management of raw material suppliers and supplies; 3) maintenance of multiple facilities to manufacture products; 4) establishment and effective management of robust and secure distribution networks; and 5) continuous improvement in processes and practices to anticipate events that may lead to disruptions in the drug supply chain.
Conclusion: Ensuring that approved biological medicines are available for adequate patient care through normal operations and during periods of supply shortages requires leveraging financial, technological and human resources. Proactive biological manufacturers invest in inventory and supply chain infrastructure to reduce the risk of drug shortages and shorten recovery times during a drug shortage, which should be a consideration by HCPs when making formulary decisions.

Submitted: 7 June 2013; Revised: 5 August 2013; Accepted: 7 August 2013; Published online first: 20 August 2013

Background

Shortages of essential drugs used in treatment, cure, or prevention of diseases have been reported globally in recent years [14]. In the US, drug shortages are routinely tracked by the US Food and Drug Administration (FDA) and the American Society of Health-System Pharmacists (ASHP) [36]. FDA tracks shortages of drugs that the agency considers medically necessary, i.e. drugs used to treat or prevent serious diseases or medical conditions for which there are no suitable drug substitutes to treat these conditions [4]. On the other hand, ASHP tracks shortages of all drugs [7]. Both FDA and ASHP have reported increasing trends in drug shortages. In 2010, FDA reported 178 drug shortages, and this number increased to 251 in 2011 [6, 8]. ASHP reported a total of 166 drug shortages in 2009, and this increased to 211 in 2010 [4, 8]. Health Canada maintains a list of drugs in short supply through the Canadian Drug Shortage Database [9], and the shortage issue is growing as confirmed by a short survey conducted by the Canadian Medical Association in January 2011 [10]. Drug shortages have also been reported in a number of European countries including Germany, Hungary, Italy, The Netherlands, Spain and the UK [1, 11].

Most of the drugs in short supply are relatively inexpensive generic sterile injectables, including chemotherapy drugs, antibiotics, anaesthetics, blood-pressure lowering medications, and common electrolyte solutions and vitamins for patients receiving intravenous nutrition [6, 1215]. A recent article by Woodcock and Wosinska [15] identified failure in quality management of manufacturing facilities as the major driver behind most drug shortages, noting that 56% of sterile injectable drug shortages that occurred in 2011 are directly linked to quality manufacturing issues. Quality issues are also linked to downstream causal events such as plant shutdowns or manufacturing delays due to regulatory actions against a manufacturer for non-compliance to current Good Manufacturing Practice (cGMP) [4, 7, 15]. Also, product quality issues may lead to voluntary or regulatory-mandated product recalls [7, 16], that may potentially lead to drug shortages.

Manufacturing quality issues have also been linked to shortages of a number of biological medicines, which are complex drugs made from living organisms or their products. In 2009, one biological manufacturer announced the shutdown of a plant that produced three of its biological medicines due to the discovery of viral contamination in bioreactors at that plant [17]. As widely reported in the media and other outlets [1720], that plant’s shutdown led to shortages of two of the three affected drugs, impacting patient care. In another example, a general shortage of a biosimilar granulocyte colony-stimulating factor was reported in the UK in 2011, and this shortage continued in 2012 [1]. Additionally, shortages of a pegylated erythropoiesis-stimulating agent were reported in Germany, Spain and the UK, starting in January 2012 [2123].

Impact of drug shortages

In the context of drug shortages, healthcare providers (HCPs) face challenges in ensuring adequate supplies of essential drugs at all times. During a drug shortage, HCPs may need to consider rationing drugs, delaying or cancelling treatments, or utilizing alternative drugs that may be less efficacious and/or are associated with an increased risk of adverse outcomes [13, 13], potentially impacting adequate patient care. Additionally, the healthcare team will need to find alternative drug suppliers, which could result in administration of a more expensive product [24, 7, 8, 24]. As a result, drug shortages can be time consuming and expensive to manage. According to a 2012 industry estimate [25], pharmacists spend an average of eight to nine hours a week addressing drug shortages, compared with only three hours a week in 2004. With respect to increased costs, a survey of US pharmacy directors indicated annual labour costs associated with managing drug shortages to be as high as US$216 million [3, 25], with the increased burden falling mainly on pharmacists, but also impacting physicians, nurses, and pharmacy technicians.

In Europe, manufacturers are required to give two months notification to the European Medicines Agency (EMA) if supply of a product is temporarily or permanently interrupted [26]. In the US, the recently passed Prescription Drug User Fee Act (PDUFA) [27] includes a provision intended to address the drug shortage issue. Reforms in PDUFA require FDA to communicate drug shortages to the public through a drug shortages list, and also to expedite the approval of drugs in need. In addition, FDA released draft guidance [28] explaining the requirements for notifying the agency in the case of a planned discontinuation of certain drug products by manufacturers. FDA is also developing processes to assist with identification of alternative suppliers for drugs on the shortage list, including facilitation of temporary drug importation from manufacturers outside the US [6]. Although these measures may aid HCPs in managing shortages, they do not address many of the issues that may be associated with a manufacturer’s inability to continuously supply essential biological drugs for adequate patient care. It is therefore important for HCPs to understand the complex processes involved in producing biologicals, and factors that are likely to lead to drug shortages.

Drug supply considerations for biological medicines

Currently more than 250 biological medicines have been approved to treat many serious illnesses, including cancer and inflammatory diseases [29]. Approximately 40% of pharmaceuticals in development are biologicals [30], therefore, the number of biological medicines approved to treat patients is expected to increase over the years. The number of biological medicines currently in short supply is much lower compared with that for generic drugs, however, the issue of biological drug shortages may become an important consideration in the future. Most of the drugs currently in short supply are relatively inexpensive generic sterile injectables, and as discussed earlier, the main driver behind these shortages is failure in quality management of manufacturing facilities by the suppliers. As many of the manufacturers supplying generic drugs begin to produce biosimilars, which are similar to but not identical to innovator biologicals, the issue of biological drug shortages may become an important consideration, given the complexity of the biological manufacturing process.

Unlike small molecule drugs that are produced using predictable chemical processes, that can be fully characterized, and are relatively stable [31, 32], biological drugs are produced and isolated from living cells, cannot be fully characterized, and are relatively sensitive to storage and handling conditions [31]. Production of biologicals requires specialized manufacturing facilities with precisely designed equipment for producing the desired product critical quality attributes under aseptic conditions to prevent microbial contamination. This requires highly trained and qualified staff as well as development of robust processes and quality control systems to ensure reproducible production of the same high quality product over the life cycle of the drug. Additionally, regulatory agencies like FDA conduct periodic inspections of both drug substance and final product manufacturing sites to evaluate compliance with cGMP. Manufacturers also have to distribute and store their products under controlled conditions to prevent loss of quality. Furthermore, as with generic injectables, almost all biologicals are administered parenterally from a sterile dosage form, and are thus susceptible to the same manufacturing quality issues that have impacted generic sterile injectables. Thus, manufacturing high quality biological drugs requires robust processes and facility design, rigorous regulatory compliance, and intricate supply chain distribution networks.

Of note, a single source manufacturer may be licensed to market a biological medicine for a particular indication with no alternative therapeutics. However, in some therapeutic areas, a number of biological medicines may be approved to treat the same indication, providing HCPs with alternative therapeutic options for their patients. An example is in inflammatory conditions such as rheumatoid arthritis where a number of biological modulators of the tumour necrosis factor pathway have been approved to treat this condition [33]. Additionally, with expiration of patents and exclusivity rights for some biologicals, biosimilars, are entering regulatory evaluation, approval, and marketing in different regions [34]. This presents HCPs with a choice between the approved innovator biological and one or more of the approved biosimilars. In these instances, HCPs may need to consider a variety of data and information beyond safety and efficacy in making formulary decisions. One such consideration is manufacturer attributes; more specifically, the manufacturer’s ability to reliably maintain a continuous supply of a high quality biological medicine to ensure adequate patient care.

In the following sections, we highlight critical supply chain parameters that HCPs should consider when evaluating a manufacturer’s ability to maintain and deliver a continuous supply of biological medicines. Key considerations for ensuring drug availability in the complex environment of manufacturing, regulatory compliance, and distribution challenges are outlined.

Best practices for mitigating supply shortages of biological medicines

Drug manufacturers may use various modalities to reduce the likelihood of a drug shortage or to shorten recovery time in the event of a drug shortage. These include: 1) effective management of drug inventory systems to minimize interruptions in drug supply; 2) effective management of raw material supplies and inventory to reduce interruptions to manufacturing operations due to shortages or poor quality raw materials; 3) maintenance of multiple facilities licensed to manufacture products to address extended interruptions at a primary manufacturing facility; 4) establishment and effective management of robust and secure distribution networks to ensure that products reach patients without interruption; and 5) continuous improvement in processes and practices to allow for a rapid response to events that may lead to potential disruptions in the drug supply chain.

Effective management of drug inventory can be utilized to minimize interruptions in drug supply
Inventory management is the process of overseeing the constant flow of inventory or units into and out of an existing inventory [35], and is a critical component of any drug supply chain risk mitigation strategy, especially during periods of high demand and/or production interruption. Inventory management is often measured using the inventory turnover ratio (inventory turn) [36]. Inventory turn is defined as the number of times inventory is sold and replaced over a period of time (such as a year) and is generally calculated as cost of goods sold divided by average inventory cost [36].

Typically, for non-pharmaceutical industries, a high inventory turn indicates greater sales efficiency and thus a low risk of monetary loss through stockpiling of unsold inventory [36]. However, for much of the pharmaceutical industry, a relatively low inventory turn is generally preferred, since it implies a large amount of stock on hand at any given time and therefore a decreased risk of drug shortages. Because of increasing economic pressures, some drug manufacturers may try to achieve operational efficiency by reducing drug manufacturing capacity and maintaining low drug inventories to reduce holding costs, as recently seen with sterile generic injectables [15]. If taken to excess, these efficiency measures could lead to additional constraints on the supply chain and increase the likelihood that a supply disruption will result in a drug shortage [12, 15], thus placing the maintenance of stable drug supplies for patient care at risk.

To assess the impact of inventory management on drug shortages in the US, we evaluated reported drug shortages and average inventory turns for seven major manufacturers, see Figure 1. Drug shortage data were as reported by ASHP over a one-year period, from January 2011 to January 2012 [5]. Average inventory turns over a five-year period (2006 to 2012) for the selected manufacturers were derived from financial information published in 10-K reports for each of the companies. For each manufacturer, annual inventory turn was calculated as cost of sales divided by inventory for that year, and these data were used to calculate the five-year average (minimum, maximum) inventory turn. Of note, all manufacturers assessed in this evaluation produce and market both biological medicines and small molecule drugs. No shortages of biological medicines were reported in the US during the assessed time period, and therefore the shortages shown are for small molecule drugs. The two biotechnology manufacturers reported no shortages, the two large pharmaceutical manufacturers reported shortages of one and two drugs, respectively, and the three generics companies reported shortages of 5, 25, and 46 drugs, respectively, see Figure 1A. Of the seven major manufacturers, biotechnology manufacturers had low average inventory turns (1–1.5) and the large pharmaceutical manufacturers had slightly higher turns (1.5–2.0), see Figure 1B. Possibly related to the high number of drug shortages, see Figure 1A, the three generics manufacturers showed higher inventory turns, averaging 2 to 4 turns a year, see Figure 1B.

The average inventory turn for each manufacturer is a surrogate measure of a manufacturer’s inventory practices based on the manufacturer’s product portfolio, and may not necessarily reflect the inventory management practices for a particular product of interest. A more detailed look at inventory practices for the product of interest may be more informative to HCPs. In the example provided earlier, where the discovery of viral contamination in bioreactors led to a plant closure [17], that manufacturer had existing inventory for two of the three impacted drugs; however, the company’s stockpiles were not adequate to mitigate against the extended production loss that occurred, leading to the reported shortages of these two drugs. On the other hand, the manufacturer had an additional production facility for the third impacted product in this case, and therefore did not experience shortages of that particular product [17].

A closer review of practices by leading biological manufacturers indicates a multi-tiered approach to inventory management of individual products through control of cycle stock and safety stock, see Figure 2. In the context of product manufacturing, cycle stock is the portion of inventory that is depleted as orders are shipped and then replenished from the manufacturing floor or from suppliers during normal cycle times [37]. Operational safety stock is inventory carried to mitigate against shortage during periods of increased product demand (to cover variability in supply and demand) [37]. Appropriate inventory levels to maintain for both cycle and operational safety stock are determined through industry standard calculations, which consider manufacturing cycle times, forecasted patient demand, and a customer service multiplier [37]. An additional layer of strategic safety stock can be maintained to cover significant supply disruptions, such as shutdowns due to regulatory actions or natural disasters, quality defect-related quarantine of products, or product recalls. Strategic safety stock levels are applied after consideration of factors such as availability of multiple sources of raw materials and location of manufacturing facilities as well as historical experience with supply disruptions. Management of operational and strategic safety stock levels is applied at all stages of manufacturing in an effort to mitigate the risk of any single disruption in the supply chain. A related practice, in certain instances, is to hold such stock at separate geographic locations to mitigate interruptions in supply.

Active management of raw materials is an important consideration for maintaining a stable drug supply
Ensuring a continuous supply of high quality raw materials is another critical element in maintaining a stable drug supply. Raw materials used in manufacturing biologicals include biological and chemical source materials that are critical to the biosynthesis of the active pharmaceutical such as media ingredients required for cell growth, serum, growth factors, trypsin, and antibiotics, and also physical materials that are part of the finished products such as stoppers and vials [38, 39]. Raw material contamination or compromise is a major safety concern in biological manufacturing and can adversely impact product quality. As such, raw material sourcing is rigorously regulated by agencies, including the FDA.

A high proportion (> 80%) of pharmaceutical raw materials used by US manufacturers is sourced internationally, which can leave drug supply chains susceptible to issues with quality control, distribution, and national and local governmental interventions [40]. To mitigate against these risks, drug manufacturers need to actively manage their raw material supply and suppliers, see Figure 3. One aspect of raw material management is risk assessment based on characteristics of the supplier and the raw material itself as well as the impact of the raw material on the finished product, see Figure 3A. With regards to supplier risk, parameters assessed include the quality of the material produced by the supplier; the technical capabilities of the supplier; and the likelihood of the supplier to stay in business and continue to supply the required high quality raw material [38]. Material risk assessment includes intrinsic safety of the raw material, complexity of the raw material, and ease of handling. Intrinsic safety risk refers to the likelihood of the raw material being contaminated by the nature of its source [39]. As an example, raw materials that are sterilized may be considered safer and therefore less risky compared with raw materials that are not sterilized [39]. Finally, assessment of how the raw material impacts the production process itself is important in ensuring lot-to-lot consistency and therefore product quality. This includes an understanding of raw material attributes and knowing which attributes cause product variability, as well as how to manage those attributes to maintain required specifications in the final product [38].

Another aspect of raw material management is proactive preventative measures that a manufacturer can employ, see Figure 3B, including inventory management, supplier diversification, and application of enabling technologies. Similar to product management practices, raw material inventory management practices such as maintenance of appropriate levels of operational and strategic safety stock can be used to mitigate against drug shortages. With regards to diversification, where possible, raw materials are sourced from multiple suppliers and high-risk materials are stored in multiple geographic locations. Another consideration is the development of active business relationships with suppliers, a practice that drug manufacturers are learning from the commodities industries. Thus, in addition to initial supplier qualification, monitoring of supply quality, and continuous supplier auditing, drug manufacturers also establish active communication channels with suppliers to ensure that information regarding quality and supply of critical raw materials is transparently shared between parties. Some manufacturers also invest in technology for characterizing raw materials. Technologies that may be useful in raw material characterization include the use of nuclear magnetic resonance testing to detect raw material adulteration and application of media treatment technology to prevent drug substance contamination [4143]. These considerations require substantial investment and commitment of time and resources as well as an appropriate organizational infrastructure.

Maintenance of multi-site manufacturing capabilities can address extended supply chain interruptions
Similar to multiple sourcing strategies for raw materials, manufacturers can establish multiple facilities that are licensed to manufacture products [17]. This minimizes the risk of drug shortages due to interruption at the primary manufacturing facility, for example, related to interruptions caused by equipment failure, a regulatory action, or a natural disaster. Critical factors considered in making decisions to invest in multi-site manufacturing include geographic location of the primary site, complexity of the manufacturing process to produce the product, projected lead times to resolve typical manufacturing issues, and the potential effect on patient supply of an unexpected event. These assessments inform decisions regarding capital investment in additional internal manufacturing capabilities, submission of regulatory filings to allow manufacturing in new locations, reservation of back-up capacity with contract manufacturers, or rebalancing demand across existing sites to eliminate large concentrations of risk. Establishing and maintaining multi-site manufacturing capabilities ensures that, in the event of a shortage related to manufacturing site issues, production can resume elsewhere before existing inventory is depleted, providing a high level of protection from unexpected interruptions to drug supply. However, maintaining multiple manufacturing sites for a single product is expensive, and in the current cost-constrained environment, only a few manufacturers are likely to adopt this strategy.

Establishment of robust and secure distribution networks can ensure that manufactured products reach patients
Drug manufacturers rely on extensive and complex distribution networks through distribution centres and wholesalers to deliver drugs from their manufacturing facilities to HCPs and patients, see Figure 4. Delay, diversion, or theft increases the risk of supply shortages. Most biological manufacturers are faced with an additional challenge of the need for temperature-controlled environments throughout the storage and transportation of their products to maintain product quality and integrity.

Biologicals manufacturers use different methods to mitigate distribution-related risks to supply. Products are mostly shipped directly from the manufacturer to hospitals, wholesalers, pharmacies, or physicians’ clinics using controlled distribution channels and validated containers to ensure product quality, see Figure 4A. Where direct distribution is not logistically feasible or cost-effective, manufacturers use audited logistics service providers (LSPs) to extend their distribution networks. Logistics service providers are third party companies contracted to provide logistical support for distributing drug products from the manufacturer to the intended destinations. The support can include transportation, customs clearance, and storage of the drugs. To ensure adherence to internal standards, industry-leading companies train the LSP staff in appropriate product handling and security procedures.

As another protective layer, anti-theft and anti-counterfeiting measures are employed to prevent or mitigate the risk of product diversion or adulteration, see Figure 4B. These measures can include active tracking and monitoring of shipments through satellite networks, use of distribution channels that circumvent local and regional theft hotspots, and utilization of custom packaging materials that enable rapid identification of counterfeit or adulterated product. The use of unique identifiers such as bar codes and lot numbers on packaging may mitigate issues with counterfeit drugs, as this may assist with identification of the product at the site of patient administration. These measures are aimed at reducing the scope of an investigation or subsequent market recall, which can be critical in ensuring uninterrupted supply to patients.

Rapid response to supply interruption signals may limit drug shortage risk
Even the most robust supply management programmes do not eliminate the risk of a drug supply shortage. When these instances do arise – for example, in the case of a natural disaster such as a hurricane or an earthquake – it is critical that a manufacturer will have anticipated such events and is able to communicate supply and demand information quickly and seamlessly across global manufacturing and distribution networks and to rapidly initiate processes to compensate for the reduction in drug supply that may occur, see Figure 5.

Typically, manufacturers rely on automated systems that couple customer ordering information with upstream supply plans and capabilities to ensure that production and shipping activities match customer needs. Some biological manufacturers have integrated these systems into their shop-floor manufacturing and quality assurance systems to synchronize plant and human resources across global networks. Enterprise integration can automatically and effectively manage most variability in supply and demand, even during a supply disruption. It should be recognized, however, that automated systems rely on a set of standard data for planning and managing supply. When information outside the standard data set is introduced into the system, the effectiveness of an automated system can be limited; this might occur when an unexpected and sudden event such as a natural disaster interrupts the process. Accordingly, some biological manufacturers have implemented manual, procedural-based, supply continuity plans that facilitate the flow of information in the event of an unexpected incident. These manual procedures define, in detail, the flow of communication and management decision-making to ensure that market conditions and supply information are well understood across the supply chain and that recovery plans appropriately prioritize the most critical supply requirements. As events unfold, management and teams can rely on these fail-safe processes to facilitate critical decisions quickly and effectively, mitigating the overall impact to patient care.

Considerations for healthcare providers

The anticipated increase in the number of biological medicines in the future will offer HCPs additional therapeutic options for treating patients. In cases where HCPs are faced with choices between biological medicines approved for the same indication, they may need to consider the manufacturer’s ability to reliably maintain a continuous supply of high quality products for adequate patient care.

Safety and efficacy data have traditionally been the considered factors for making formulary decisions, and information on these parameters is usually available through a broad range of well-established sources, including the scientific literature. The information on drug supply parameters presented here has been historically difficult for HCPs to obtain and assess. However, increased attention to drug shortages is leading to a need for more transparency throughout the drug supply chain, potentially providing a competitive advantage to manufacturers that are transparent with respect to internal processes they employ to mitigate drug shortages.

HCPs should seek to understand a manufacturer’s practices to mitigate against drug shortages. This may include understanding information regarding inventory management practices for individual products of interest, e.g. the amount of operational safety stock held to mitigate against periods of increased product demand and the amount of strategic safety stock held to mitigate against significant disruptions in drug supply. Equally important are the risk mitigation measures that a manufacturer employs to ensure adequate and high quality supply of raw materials, especially in the cases of single source raw material suppliers.

HCPs may also seek to assess and understand measures that manufactures take to ensure production of high quality drugs. These measures include investments in maintaining production facilities and equipment, conducting quality control testing and oversight, and developing processes for timely response to indicators of quality issues [15]. Quality-related information can be obtained from various sources. Companies sometimes issue press releases regarding drug recalls, anticipated drug shortages, or delays in product launches due to manufacturing quality issues. Also, FDA inspects manufacturing facilities to assess adherence to cGMP standards and publishes findings of noncompliance on its website [15, 44]. An example of a regulatory publication found at the FDA’s website is an FDA Form 483. This is a notification to the manufacturer of objectionable conditions identified during routine periodic compliance inspections of manufacturing facilities. For more significant violations or in cases where the manufacturer does not take corrective actions following a Form 483 notification, FDA may issue a ‘Warning Letter’ or take other enforcement actions, including revocation or suspension of the biologicals license [44]. The scope and severity of these regulatory actions may be important for HCPs to consider when assessing a manufacturer’s reliability history. As indicated by Woodcock and Wosinska in reference to sterile injectable drugs [15], FDA could consider providing meaningful manufacturing metrics regarding product quality to assist HCPs when making formulary decisions.

Additionally, manufacturer customer service representatives can assist HCPs in understanding product security features and policies and practices regarding distribution management. Manufacturers may also consider preparing overviews of continuity plans to be followed in case of an interruption in production of its drugs, and share these plans with HCPs. This might promote increased transparency amongst stakeholders who are likely to be impacted by an interruption in the drug supply chain.

Another consideration is for HCPs to include assessment of the manufacturer attributes discussed here as part of a formulary checklist. Table 1 provides a checklist of manufacturer attributes to consider.

Conclusion

The recent increase in drug shortages highlights the importance of ensuring that patients receive the medicines they require at all times. Maintaining a continuous supply of approved biological medicines through normal operations and during periods of supply shortages requires leveraging financial, technological and human resources. Proactive drug manufacturers heavily invest in inventory and supply chain infrastructure to reduce the risk of drug shortages and to shorten recovery times in the event of a drug shortage. Therefore, when making formulary decisions, HCPs need to understand and consider critical supply chain parameters that can impact a manufacturer’s ability to maintain a reliable supply of drugs for their patients. To aid in formulary decision making, manufacturers and regulators should consider the value of making such information available. This will become increasingly important as the number of marketed biologicals and the number of suppliers increase.

Funding sources

This work was funded by Amgen Inc.

Competing interests: Mr Andrew Mica, Dr Martha Mutomba, and Dr Larry Green are employees of Amgen Inc and own stock in Amgen Inc.

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

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Author for correspondence: Andrew Mica, MBA, Executive Director, Global Supply Chain, Amgen Inc, One Amgen Center Drive, MS 28–4-B, Thousand Oaks, CA 91320, USA

Disclosure of Conflict of Interest Statement is available upon request.

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Efficient production of recombinant parathyroid hormone (rPTH) fragment 1-34 in the methylotrophic yeast Hansenula polymorpha

Author byline as per print journal: Frank Mueller, MSc, Manal Moussa, MSc, Maria El Ghazaly, MSc, Jan Rohde, PhD, Nicole Bartsch, MSc, Antje Parthier, PhD, Frank Kensy, Dr Ing

Background: Osteoporosis is a bone disease of the elderly that leads to increased risk of fracture. Currently, it affects more than 200 million adults worldwide, placing an enormous economic burden on healthcare providers. Present approved drug treatments of osteoporosis, for example, using bisphosphonates, only reduce bone mineral loss, are variable in prevention of future fractures and can induce serious complications long term. From 2002, availability of the recombinant active, N-terminal 1-34 fragment of human parathyroid hormone 1-34, which directly stimulates bone formation, has provided an alternative, potentially more effective therapeutic agent for treating osteoporosis, especially in its most severe form. We have adopted the methylotrophic yeast strain Hansenula polymorpha (H. polymorpha) for production of recombinant parathyroid hormone (rPTH) 1-34 since its expression system is highly inducible and target proteins are secreted intact into the fermentation broth without the need for enzymatic cleavage of a fusion protein.
Methods: Culture conditions for the growth of selected clones of H. polymorpha super-transformants and their rPTH production capacity were sequentially optimized through the microtitre plate, shake flask, small tank bioreactor scales to the large bioreactor scale.
Results: The production of rPTH 1-34 by transformed H. polymorpha was greatly enhanced by adding the calnexin chaperone gene to the expression plasmid. Implementation of final optimized culture medium constituents and operational fermentation conditions, of which maintenance of constant oxygen tension (pO2) was found to be a critical factor at the 80 litre scale, resulted in yields up to 150 mg active rPTH 1-34 per liter of culture supernatant.
Conclusion: A robust fermentation process for the efficient production of active rPTH 1-34 based on a calnexin super-transformed H. polymorpha clone was developed. Potentially, this has cost-saving benefits for the production and marketing of clinical-grade rPTH 1-34.

Submitted: 3 June 2013; Revised: 31 July 2013; Accepted: 2 August 2013; Published online first: 16 August 2013

Introduction

Currently, worldwide there are over 200 million people affected by osteoporosis, a bone disease mainly of the elderly, particularly postmenopausal women, in which increasing porosity of bone structure through mineral loss significantly heightens risk of skeletal fractures [1]. It has proven difficult to prevent or treat effectively and is a major cause of morbidity and hospital admissions, with severe medical and financial burdens on healthcare systems and society as a whole. Osteoporosis-related bone loss occurs when osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation. Drugs that are approved, such as the widely prescribed bisphosphonates, work by reducing bone resorption.

However, these are mainly administered to patients who have already had fractures, as a preventative measure against further fractures, and are not without risks of complications with long-term usage [2]. Beneficial effects have also been achieved with salmon calcitonin, a hormone that inhibits osteoclast function and increases bone deposition, but it is now less recommended due to its questionable effect on fracture risk and the associated risk of cancer with its prolonged use [3]. In contrast, human parathyroid hormone (hPTH), a polypeptide of 84 amino acids secreted by the parathyroid gland, normalizes serum Ca2+ levels by increasing Ca2+ re-absorption in the kidney and stimulating the osteoclast- and osteocyte-mediated Ca2+ release from bone [4]. This hormone plays a major role in normal bone homeostasis and remodelling, on the one hand by boosting osteoblastogenesis leading to bone formation and on the other hand by indirectly boosting osteoclastogenesis and bone resorption [4]. However, in vivo studies have shown that intermittent short exposure to recombinant human PTH (rhPTH) favoured anabolic bone formation responses over catabolic bone resorption. These led to the development and marketing of rhPTH as an anabolic drug for the treatment of osteoporosis [57]. Both rhPTH (Preotact® ) and a recombinant PTH fragment comprising the biologically active N-terminal amino acids 1-34 (rPTH 1-34; teriparatide, Forsteo® /Forteo® ) have proven to be safe and clinically efficacious in osteoporosis patients, especially postmenopausal women [8], though the ‘side effect profile’ favours rPTH 1-34 [9]. These rPTH products are presently expressed in and manufactured from bacterial (E. coli) and marketed at relatively high costs, approximately Euros 11,000/US$14,000 per 24 months of treatment/therapy in Europe and the US. Thus, there is a clear need for developing more efficient expression and production processes for rhPTH or rPTH 1-34 in order that they may be manufactured more cheaply.

The methylotrophic yeast Hansenula polymorpha (H. polymorpha; Pichia angusta) has been successfully developed as an alternative expression system to bacterial ones for heterologous protein production. H. polymorpha is able to utilize methanol as sole carbon source, resulting in over-expression of methanol utilization enzymes, namely methanol oxidase (MOX) and formate dehydrogenase (FMD), the expression of which reach up to 70% of total protein content of cells [10]. Heterologous DNA can readily be integrated via established techniques into the H. polymorpha genome. Such transformations result in high copy, gene numbers stably integrated in the yeast genome, thereby leading on induction to high gene expression and correspondingly high target protein concentrations. The strongly inducible promoters of MOX and FMD genes can be used as regulatory components of heterologous DNA that are inducible via culture medium constituents for target protein gene expression [14, 15].

Furthermore, insertion of the Saccharomyces cerevisiae (S. cerevisiae) derived MF1 leader sequence into the expression cassette enables secretion of the target protein from H. polymorpha cells, allowing for an easy recovery of target protein from the fermentation broth [1113, 1621]. H. polymorpha transformants have already been utilized in several commercial production processes for the manufacture of recombinant proteins, including interferon-α2a (Reiferon 3 & 6 MIU and Reiferon Retard, Minapharm Pharmaceuticals), Hirudin (Thrombexx and Extrauma, Minapharm Pharmaceucticals), Insulin (Wosulin, Wockardt), hepatitis B vaccine (Hepavax-Gene, Crucell) and other products in clinical development. Thus, the characteristics of the H. polymorpha expression and production system, in which stable heterologous gene expression and synthesis and secretion of recombinant proteins in high quantities are combined, make it suitable for developing a production process for rPTH 1-34 manufacture. In this study, we describe the development of a recombinant super-transformant H. polymorpha strain containing the DNA-sequence coding for rPTH 1-34 and extra copies of the H. polymorpha calnexin (HpCNE1) gene to enhance the secretion of expressed rPTH 1-34. Optimization of rPTH 1-34 expression by manipulation of medium constituents and cultivation conditions in microtiter plates (1 mL scale) and shake flasks (300 mL scale), as well as using an automated DASGIP parallel fermenter system, is described. Further details of the transfer of defined/optimized cultivation conditions and scale-up in successive 2, 8 L and 80 L fermenter systems, in which an intermittent feeding strategy was additionally implemented leading to productivity levels of up to 150 mg/L of intact and active rPTH 1-34 into the culture broth, are provided.

Material and methods

Gene constructs, expression plasmids and generation of H. polymorpha strains secreting rPTH 1-34
H. polymorpha strains secreting rPTH 1-34 were initially generated in wild-type and protease knockout mutants of H. polymorpha KLA8-1. The highest amount of rPTH 1-34 was secreted by strains deficient in protease HpYPS7 (KLA8-1/ΔYPS7). The best of these strains, KLA8-1/ΔYPS7-MFa-PTH 14-11, secreted up to 700 μg rPTH 1-34/L of culture supernatant at the shake-flask scale, as determined with a commercially available ELISA kit (Immutopics International, San Clemente, CA, USA).

It was previously reported that over-expression of the endo-plasmic reticulum chaperone calnexin enhances the export and secretion of recombinant proteins in H. polymorpha [13]. Subsequently, this finding has been confirmed by Artes Biotechnology GmbH (Langenfeld, Germany) with numerous other products. With the aim of improving secretion and enhancing yields of hPTH, extra copies of the HpCNE1 gene were introduced into the strain KLA8-1/ΔYPS7-MFa-PTH 14-11 (henceforth termed PTH 14-11), by super-transformation with an HpCNE1 expression cassette. The latter was incorporated in a plasmid that contains a phleomycin resistance gene as a selectable transformation marker. Phleomycin sensitivity of PTH 14-11 was tested prior to super-transformation, and lethality found to lie between 60 μg/mL and 70 μg/mL.

Electro-competent PTH 14-11 cells were super-transformed with plasmid HCNE-Phleo(d) which contains the HpCNE1 expression cassette, see Figure 1 for maps of the two plasmids used.

After electroporation, phleomycin-resistant transformant colonies were selected on YPD (yeast extract peptone dextrose) plates containing 70 μg/mL phleomycin. Growing colonies were picked for passaging, a procedure that promotes plasmid proliferation and integration. Three passages in selective and two passages in non-selective medium (YPD) were followed by another cultivation in selective medium. Finally, the cultures were streaked on minimal medium without uracil (YNB-glucose) to select for the cells that retained the originally transformed rPTH 1-34 expression plasmids.

The super-transformants were designated KLA8-1/ΔYPS7-MFa-PTH-HCNE or KLA8-1/ΔYPS7-MFa-PTH-Phleo, abbreviated to PTH-HCNE and PTH-Phleo, respectively, and suffixed with the culture number.

Suitable culture conditions had been established in the preceding rPTH 1-34 expression study. These involved growth in complex medium with 2% glycerol as the carbon source (YPG – yeast extract peptone glycerol). Fifty μL of concentrated ‘overnight’ pre-cultures were inoculated in 3 mL YPG medium in culture tubes and incubated in an orbital shaker at 180 rpm and 37°C for 40 h. Cell density was determined by measuring the OD600 of diluted cultures in an Amersham Ultrospec 6300 pro spectrophotometer (GE Healthcare). Cells were removed by centrifugation and cell-free culture supernatants screened for rPTH 1-34 in an ‘in-house&#8217, sandwich ELISA that utilized two commercial antibodies specific for rPTH 1-34 (Bachem; Torrance, CA, USA, and Biotrend GmbH; Germany) and hPTH 1-34 (Bachem; Torrance, CA, USA) for calibration purposes.

Micro-scale fermentation and rPTH 1-34 production scale-up studies

Microtiter plate and shake flask studies
Initially, investigations were performed with a BioLector (m2p-Labs GmbH; Baesweiler, Germany) micro-fermentation flower-plate system, a flower shaped 48-well microtiter plate with improved oxygen transfer capacity, at 0.5–1.5 mL scale. The microtiter plates were sealed by a gas permeable membrane (Abgene: AB-0718).

Based on the findings from medium screening in microtiter plates, process parameters and possible feeding strategies were further optimized. This led to the formulation of Syn6-cp medium, which is the standard Syn6 medium with additional citrate and peptone supplements [12]. Fermentations at the ‘100 mL scale舗 used baffled 500 mL shake flasks and were performed at 180 rpm for 60 h at 30°C in a shake incubator (New Brunswick Innova 44; Enfield, CT, USA). Wheat peptone (Organotechnie; La Courneuve, France) was compared to soy peptone (Merck; Darmstadt, Germany) and the optimum pH range for maximum rPTH 1-34 yield determined.

In a fed-batch mode, further optimization of the culture medium with addition of yeast extract (Organotechnie) was carried out in shake flasks. In 250 mL baffled flasks with a working volume of 50 ml, an induction solution containing 10% methanol, 10% glycerol and 20% wheat peptone was added to the culture batch-wise at a rate of 5 mL feed per 50 mL culture medium after 20 h, 24 h, 42 h, 46 h, 50 h and 67 h of fermentation. Flasks were shaken at 30°C and 180 rpm for 72 hours. Samples were taken 2–3 times daily for OD600, rPTH 1-34 and pH measurement. rPTH 1-34 concentration was quantified using RP-HPLC.

Fed-batch studies in bioreactors
DASGIP parallel stirred 400 mL tank bioreactors (DASGIP AG; Juelich, Germany) with a maximum working volume of 300 mL were used for fed-batch process optimization. A 3 L Biostat B-Plus, a 15 L Biostat C and a 150 L Biostat D (Sartorius Stedim Biotech; Goettingen, Germany) system with working volumes of 2 L, 8 L and 80 L, respectively, were used for scaling up studies and protocol consistency trials.

The culture medium used throughout was synthetic Syn6 medium containing 30 g/L glycerol and supplemented with 100 mM citrate, 50 g/L wheat peptone and 20 g/L yeast extract (Syn6-cp + YE). Its pH was adjusted with phosphoric acid to 5.7 before steam sterilization for 20 minutes at 121°C. The inoculate was prepared from a 100 mL overnight seed culture, which had been cultivated in YPG complex medium in a baffled 500 mL shake flask at 30°C. After inoculation, a 24 h growth phase was followed by an induction phase. During the induction phase a methanol/glycerol/wheat peptone mixture was added in pulses. Different numbers of feed pulses and time intervals between the pulses were evaluated for process optimization. After optimization, pulses were fixed at 4 time points: after 24 h, 30 h, 36 h and 42 h of fermentation. The culture conditions were maintained as follows: unregulated pH starting 5.7—ending 6.1, aeration rate 3 L/min decreased after 24 h to 2 L/min, stirrer speed 700 rpm and temperature 30°C.

During the following scale up of fermentation runs to 8 L and 80 L scale, certain parameters were optimized to achieve a scalable and reproducible process. The pO2 was regulated at a set point of 30% saturation by airflow and stirrer speed. The pulse-wise feeding was changed into a feeding schedule with constant feed rates; different feeding schedules were tested. Based on the results obtained, an optimal feeding schedule was achieved and implemented. The feed rate was controlled by using the following program 0 h–24 h batch phase; 24 h–27 h constant feeding with 20 g/L/h; 27 h–31 h linear increase up to 60 g/L/h; 31 h–39 h constant feeding with 60 g/L/h; 39 h–39.5 h constant feeding with 300 g/L/h; 39.5 h–52 h constant feeding with 60 g/L/h.

The pH was also controlled such that during the growth phase a constant pH of 5.5 was maintained to preserve a reasonable growth rate that would result in a cell density OD600 of around 40 at the end of the growth phase. After 24 h of fermentation, with the beginning of the induction phase, the pH was increased linearly during 6 h to a pH value of 6.1 to promote increased rPTH 1-34 expression, secretion and stability. The temperature was maintained at 30°C during the whole fermentation. The total fermentation time was around 52 h, including 24 h growth phase and subsequent 18 h induction phase.

The rPTH 1-34 concentration in samples taken during a fermentation run was measured by RP-HPLC analysis. Cell growth was monitored by optical density measurement and potential contamination was monitored via microscopic examination using a MEIJI light microscope with a 1,000-fold magnifying oil lens. The rPTH 1-34 activity was also measured using a bioassay based on a transformed HEK293 cell line expressing the parathyroid hormone receptor 1 (PTHR1).

Analysis

Protein analysis by RP-HPLC
Centrifuged and sterile-filtered aliquots (100 μL) of 2 L fermentation samples and 8 L and 80 L fermentation samples were analysed on a Shimadzu LC-2010CHT RP-HPLC- and a Dionex UltiMate 3000 RS RP-HPLC apparatus, respectively, at a wave-length of 214 nm. Samples were separated on a 5 μm Vydac 218TP54 column (250 x 4.6 mm; guard column Vydac 218GD54) at a column oven temperature of 25°C. Elution was performed with a gradient of buffer A [0.1% (v/v) TFA] and buffer B [0.1% (v/v) TFA in acetonitrile], over 26 minutes. The flow rate was adjusted to 1 mL/min. rhPTH 1-34 content was determined by profile comparison with the World Health Organization—International Standard (WHO IS) of rPTH 1-34 standard of known concentration (04/200—NIBSC; South Mimms, Herts, UK).

Protein analysis by western blot
Samples were prepared in the same way as for RP-HPLC. Gel electrophoresis was performed using NuPAGE Novex Mini Gels (Life Technologies/Invitrogen) to separate proteins according to their molecular weight. Subsequent blotting was carried out by transferring the proteins onto nitrocellulose membrane where immune-detection was performed using PTH 1-34 specific antibody (BT71-6072; Biotrend, 1:466 diluted in 1% BSA in tris buffered saline).

ELISA
Initial screen of parental strain before Calnexin insertion was performed using commercially available ELISA kit by a bio-active PTH 1-34-specific ELISA from Immutopics (Immutopics International, San Clemente, CA, USA; Cat. # 60-3900). The principle of this ELISA is that biotinylated anti-PTH 1-34 antibody bound to rhPTH 1-34 is captured on streptavidin-coated wells, and rPTH is detected by a horse-radish peroxidase (HRP)-conjugated anti-human PTH 1-34 antibody and quantified by HRP substrate colouration. This ELISA, used for analysing clinical samples, is able to detect hPTH concentrations at the pg/mL level. The reference used herein was a synthetic rPTH 1-34 (Bachem, Cat.No. H-4835).

Due to the substantial costs of using the commercial kit, an in-house sandwich ELISA was developed afterwards and used for screening Calnexin super-transformant strain. It was established by coating microtiter plate (NUNC Maxisorb) with Rabbit anti-Parathyroid Hormone 1-34 (human) IgG (Bachem, Torrance, CA, USA) as a capture antibody, followed by blocking using Rotiblock (Roth). Standard hPTH 1-34 (Bachem, Torrance, CA, USA) was serially diluted with phosphate buffered saline (PBS) for calibration curve construction as follows: 500 ng/mL; 250 ng/mL; 125 ng/mL; 62.5 ng/mL; 31.25 ng/mL; 0 ng/mL. Samples were diluted in PBS to lie within the calibration curve range. Standard and samples were adsorbed to the plate. Primary antibody (Mouse anti-human Parathyroid Hormone IgG, Biotrend GmbH) and secondary antibody (Goat-anti Mouse HRP Conjugate, BioRad) were applied successively each followed by a washing step using 0.05% Tween 20 in PBS. Finally, development was done using TMB peroxidase substrate (Kirkegaard & Perry Laboratories, Washington, DC, USA) where reaction is stopped using 1 M phosphoric acid optimally after 2–15 minutes, and developed colour was measured at 450 nm in Microplate reader (Tecan GENios). Samples were measured in duplicates.

Potency
Potency of rPTH 1-34 was determined using a cell-based assay (bioassay) developed in cooperation with, and performed at, Bioassay Online, Germany. This bioassay is based on a transformed HEK293 cell line expressing the parathyroid hormone receptor-1 (PTHR1). Stimulation with PTH or rPTH 1-34 at different concentrations leads to concentration-dependent intracellular cyclic adenosine monophosphate (cAMP) formation. Following lysis of cells, the concentration of cAMP is measured with a commercial cAMP kit from Perkin Elmer (Lance Ultra cAMP Kit). WHO IS of rPTH 1-34 (E. coli derived) was used as reference and control, and samples were tested in triplicates. Measurements were made in a time resolved-fluorescence resonance energy transfer (TR-FRET) capable plate reader. Readings and data were analysed by Parallel-Line Assay (PLA) 2.0 Software.

Results

Strain selection
Super-transformation with the HpCNE1 gene expression cassette introduced into the parental, rPTH 1-34 producing, strain PTH 14-11 increased secreted yields of rPTH 1-34 by up to 10-fold, with most integrant colonies up by 2- to 4-fold (data not shown). Of 60 integrants, two, PTH-HCNE numbers #23 and #57, were found to produce the highest rPTH concentrations and were therefore selected for sub-cloning. At minimum 10 randomly selected single colonies per integrant PTH-HCNE pool, the parent pools, and 12 PTH-Phleo control transformants were screened for rPTH 1-34 expression. Final cell densities of all clones, see Figure 2A, were similar to one another, but the rPTH 1-34 ELISA absorbance values were substantially higher than that of the parental PTH 14-11 strain for all PTH HCNE clones and significantly higher, though less so than PTH HCNE clones, for all PTH-Phleo control transformants, see Figure 2B. Averaged absorbance values across #23 and #57 clones were 3–4 times higher (~2000-2500 ng/mL) than the PTH–Phleo control clone and an average improvement factor of 13-fold when compared to that of the parental strain PTH 14–11, see Figure 2C. We finally chose strain #23-1 from among the top rPTH 1-34 producers to be taken forward for fermentation development.

Fermentation strategy optimization in a Biolector system
In this media optimization study, cell growth and protein expression of rPTH 1-34 in all standard media (YPD, YPG, YNB, Syn 6 N) and Syn 6-cp media (standard Syn 6 N media with addition of citrate and peptone), with pH variations between pH 4.0–8.0, were assessed. Table 1 summarizes the compositions of the various Syn 6 media evaluated. Since Syn 6 media tend to precipitation at pH values higher than 5.0, the Syn 6-cp media contained 100 mM citrate (trisodium citrate) to solubilize all media components at pH > 5.0.

Strain #23-1 expression levels were generally elevated between pH 5.0–6.0 in all media. The optimal pH for stable expression of rPTH 1-34 at 25°C or 30°C in Syn 6-cp medium was established as 5.3 (starting pH). Similar high expression levels were found at both 25°C and 30°C, but fermentation at 30°C resulted in much faster cell growth. The latter would lead to a shorter, time saving, process and thus 30°C was chosen as the standard fermentation temperature for all subsequent process development experiments. Twenty-one plant peptones (Sigma, Art. No. 11577) and a standard meat gelatone (Merck) as media supplements were screened. In general, cell growth was not much influenced by the peptones, but protein expression varied widely. Three peptones, potato, wheat and soy AX, were found to increase the rPTH 1-34 expression the most (rPTH 1-34 concentration reached was 4.5 mg/L) and thus were included in further evaluations. Methanol induction and additional supplementation with 10 g/L glycerol and 10 g/L peptone (potato, wheat or soy) improved the rPTH 1-34 expression dramatically with increases 8- to 9-fold, i.e. to ~40 mg/L, over the previous levels.

Batch and fed-batch shake flasks
In 100 mL scale batch cultures in shake flasks, experiments were performed to compare the three peptones (soy, wheat and potato) at two different concentrations, 30 g/L and 50 g/L, and at starting pH of 5.0 or 6.0. The highest productivity of 9.6 mg/L was observed when using the Syn6-cp medium containing 50 g/L wheat peptone and 30 g/L glycerol at a starting pH of 6.0.

In fed-batch 100 mL cultures in shake flasks, protein expression was induced with a mixture of methanol, glycerol and wheat peptone applied after 20 h, 24 h, 42 h, 46 h and 50 h and led to a yield of 25.4 mg rPTH 1-34/L. An additional induction pulse at 67 h had no effect. However, the addition of 20 g/L yeast extract to Syn6-cp media (Syn6-cp+YE) almost doubled yield rPTH 1-34 to 48.2 mg/L, see Table 2.

Scale-up and fermentation consistency – 300 mL scale in the DASGIP system
Further steps to optimize productivity were tested in a small-scale 300 mL parallel bioreactor system under automated and well-controlled fermentation conditions. It was found that four induction pulses were sufficient, starting after 24 h of cultivation with a time interval of 6 h, to achieve high rPTH 1-34 concentrations. Fermentation was begun at pH 5.7, instead of 6.0, since the lower pH proved more supportive for initial cell growth. Nevertheless, the pH increased to 6.1 over the fermentation run. These optimized conditions led to a rPTH 1-34 yield of 68.3 mg/L, around 20 mg/L greater than achieved with the 100 mL scale of shake flasks, see Table 2.

2 L scale in the Sartorius system
Conditions that were found best in the 300 mL production scale were tested and adjusted for maximal rPTH 1-34 yields at the 2 L scale using a Sartorius bioreactor system. With same medium and induction conditions, only the agitation and aeration rates had to be fine-tuned in accordance with the different geometry and stirring and sparging operations of the larger bioreactor. The total fermentation time was around 50 h, including 24 h growth phase then 18 h induction phase. The initial 3% glycerol in the fermentation medium were consumed by growing cells in the first 24 h, after which a methanol/glycerol/peptone mixture was fed into the medium in four consecutive pulses every 6 h. Culture samples were taken during fermentation and analysed for rPTH 1-34 content and cell density. After fermentation for around 50 h, the entire culture broth was harvested and, following cell removal by centrifugation, the supernatant stored at -80°C. The optimized conditions led to consistent and reproducible productivity levels of around 67 mg/L, equivalent to those achieved with the 300 mL scale, see Table 2.

Fermentation at 8 L and 80 L scale
The optimized conditions defined for the 2 L scale, as above, were applied to the 8 L and 80 L scales. Two fermentations were performed at 8 L scale and one at 80 L scale. During these scaled up runs, substrate limitations between feed pulses were observed, which resulted in a sharp increase of the partial oxygen pressure (pO2), probably due to higher oxygen transfer at equal stirrer speed compared to the 2 L scale. To augment production stability for larger scales, certain changes in conditions were successively introduced. Firstly, the pO2 control was set to 30% saturation. This resulted in higher metabolic activity, which led to higher substrate consumption. Accordingly, it was necessary to modify the feed strategy. However, the higher and constant feed rate negatively impacted on the pH, which fell to 5.2, a value at which rPTH 1-34 stability is reduced. Therefore, a pH control was introduced as well, see Material and methods.

By implementing these last optimizations of the fermentation conditions, an improvement in rPTH 1-34 concentration from about 60 mg/L at the 2 L scale to 120 mg/L and 150 mg/L at 8 L and 80 L scale, respectively, was attained, see Table 2. Potency determinations of rPTH 1-34 in samples from an 80 L scale batch (batch number SPM-158-13-D1) in bioassays calibrated with the WHO IS of rPTH 1-34 (specific activity of 10,000 IU/mg) ranged from 9,580–10,920 IU/mg. E.coli derived rPTH 1-34 (Forteo, Eli Lilly) was also tested by this assay as a control and determined potencies ranged from 9,524-10,312 IU/mg. High reproducibility of the optimized fermentation protocol was shown for cell density (OD600), see Figure 3a; and rPTH 1-34 concentrations, see Figure 3b; in three consecutive runs at 8 L and 80 L scales.

Retrospectively, the final optimized fermentation protocol applied at the 8 L and 80 L scale was transferred to the 2 L scale and a comparison was performed between the parental strain PTH 14-11 (without insertion of the calnexin gene) and the PTH-HCNE 23-1 clone (with inserted calnexin gene). The results showed that the parental strain PTH 14-11 produced a yield of rPTH of only 32.9 mg/L, while the super-transformant strain PTH-HCNE 23-1 produced 150 mg/L, i.e. a 4–5-fold higher yield with the calnexin gene insertion. This rPTH 1&34 yield of 150 mg/L was successfully reproduced in six consistency runs, see Table 2.

Graphical representation of the cell density (OD600) values at increasing times during fermentation runs at different bioreactor scales shows a high degree of comparability among runs. Maximum OD600 values were about 270 at the end of fermentation runs (Δ first batch after development at 8 L, second batch after development at 8 L,  third batch after development at 80 L).

Graphical representation of rPTH 1-34 concentrations at increasing times during fermentation runs at different bioreactor scales. Maximum rPTH 1-34 concentrations were about 150 mg/L at the end of fermentation runs (Δ first batch after development at 8 L, second batch after development at 8 L,  third batch after development at 80 L).

A typical RP-HPLC profile of a PTH 1-34 fermentation supernatant sample is presented in Figure 4.

Discussion/Conclusion

In developing high secreting rPTH 1-34 H. polymorpha strains, we made advantage of the known protein stabilizing activity of the chaperone calnexin. This molecular chaperone appears to aid folding mechanisms for proteins when entering the endoplasmatic reticulum [19]. Co-expression of calnexin in a rPTH 1-34 producing H. polymorpha strain enhanced rPTH 1-34 secretion by about 4- to 5-fold over that of the parental strain. Our results support findings published for other proteins such as manganese peroxidase [20], alginate epimerase, fungal consensus phytase, human IFN-γ and human serum albumin [13].

Successful expression of full-length PTH 1-84 or PTH fragments in bacteria or yeasts have been reported elsewhere in the literature [2135], see Table 3. Many of these have utilized fusion protein’ approaches that typically need an enzymatic cleavage or acidification step to release the PTH product. Such processing steps not only requires the subsequent complete removal of the fusion protein partner and of the enzyme, if used, but also unfavorably adds to manufacturing costs. A clear advantage of our H. polymorpha expression system is that rPTH 1-34 is translated intact and exported as the correctly-folded active peptide without having first to ligate it to a secondary protein. Since rPTH 1-34 is also stably active following secretion into the fermentation medium, other processing steps such as unfolding or refolding of fusion proteins extracted from bacteria/E. coli, are avoided, see Table 3. By optimization of culture conditions in a stepwise fashion through scaling up of fermentation volumes, by almost five orders of magnitude to 80 L, we were able to develop and implement a robust rPTH 1-34 production protocol that led to high level secretion and yields of rPTH 1-34, comparable with those achieved by other systems, see Table 3. Moreover, this secretion and accumulation of rPTH 1-34 in high concentration makes subsequent purification process steps relatively more straightforward than with fusion proteins, and which should lead to its more economical manufacture.

In summary, our study has provided strong proof that the methylotrophic yeast H. polymorpha can form the basis of an appropriately efficient expression and production system for the production and potential manufacture of active rPTH 1-34. Advantageously, and without the intervention of enzymatic cleaving of a fusion protein, active rPTH 1-34 is stably secreted into the fermentation supernatant. High yields, as much as 150 mg rPTH 1-34/L, were attained by the development of high expressing, transformed H. polymorpha strains, the optimization of fermentation conditions and operations and the effective scaling up of the production process to high volume bioreactors. In comparison with other manufacturing approaches, our development of a simple, robust and reproducible fermentation protocol for large scale production of rPTH 1-34 potentially offers a more effective, cost saving, possibly superior method for its commercial manufacture.

Acknowledgement

We wish to deeply thank Dr Anthony Meager for his skillful and excellent assistance in language editing and valuable expert comments.

Authors’ contributions

Ms Manal Moussa carried out the fermentation runs in small scale and medium scale. Ms Maria El Ghazaly carried out all analytical experiments except the potency test. Dr Jan Rohde participated and carried out a critical manuscript revision for important intellectual content. Ms Nicole Bartsch and Dr Antje Parthier contributed all fermentation runs at large scale and helped to draft the manuscript. Dr Frank Kensy carried out all experiments in the microliter scale in the BioLector system. Mr Frank Mueller has drafted and revised the manuscript. All authors read and approved the final manuscript.

Competing interests: Ms Nicole Bartsch and Dr Antje Parthier are employees at Scil Proteins in Halle, Dr Ing Frank Kensy is Managing Director at m2p-Labs in Baesweiler and Dr Jan Rohde, Ms Manal Moussa, Ms Maria El Ghazaly and Mr Frank Mueller are employees at Minapharm Pharmaceuticals. The authors have no conflicts of interests that are directly relevant to the content of this manuscript. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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

Co-authors

Manal Moussa, MSc, Minapharm Pharmaceuticals, Cairo, Egypt
Maria El Ghazaly, MSc, Minapharm Pharmaceuticals, Cairo, Egypt
Jan Rohde, PhD, Minapharm Pharmaceuticals, Cairo, Egypt
Nicole Bartsch, MSc, Scil Proteins, Halle, Germany
Antje Parthier, PhD, Scil Proteins, Halle, Germany
Frank Kensy, Dr Ing, m2p-Labs, Baesweiler, Germany

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Author for correspondence: Frank Mueller, MSc, Minapharm Pharmaceuticals, Mina Street, 3rd Industrial Zone A2, 10th of Ramadan City, Cairo, Egypt

Disclosure of Conflict of Interest Statement is available upon request.

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Pharmacokinetics of antimicrobials in obese children

Author byline as per print journal: Mario R Sampson, PharmD; Michael Cohen-Wolkowiez, MD, PhD; Professor Daniel Kelly Benjamin Jr, MD, MPH, PhD; Edmund V Capparelli, PharmD; Kevin M Watt, MD

Introduction: Childhood obesity is common and results in substantial morbidity. The most commonly prescribed drugs in obese children are antibiotics. However, physiological changes associated with childhood obesity can alter antibiotic pharmacokinetics and optimal body size measures to guide dosing in this population are ill defined. This combination can result in therapeutic failures or drug-related toxicities. This review summarizes pharmacokinetic information for antibiotics in obese children and implications for dosing.
Methods: We conducted a comprehensive literature search of PubMed, EMBASE, and International Pharmaceutical Abstracts to identify pharmacokinetic studies of antimicrobial agents in obese children. We included the following search terms: obesity, pharmacokinetics, pharmacodynamics, drug toxicity, dosing, anti-infective agents, antiviral agents, and antifungal agents.
Results: We identified four pharmacokinetic studies of antibiotics in obese children: one for cefazolin and tobramycin, one for gentamicin, and two for vancomycin. Only the cefazolin/tobramycin trial was prospective. The drugs studied differ in their tissue and body water distribution characteristics. Two of the studies (tobramycin and gentamicin) reported pharmacokinetic differences and required dosing modifications in obese children.
Discussion: The lack of pharmacokinetic studies in obese children is pronounced. The scarcity of pharmacokinetic data limits the ability to predict drug disposition using drug physicochemical properties and impedes a rational approach to selection of appropriate body size measures for dosing. Given this knowledge gap, additional trials in obese children are urgently needed and is a public health concern.
Conclusion: Pharmacokinetic studies of antimicrobials in obese children are desperately needed to guide dosing and avoid therapeutic failures or unwanted toxicities.

Submitted: 23 April 2013; Revised: 24 May 2013; Accepted: 27 May 2013; Published online first: 10 June 2013

Introduction

The World Health Organization (WHO) defines obesity as body mass index (BMI)-for-age measurement > 3 standard deviations above the reference median [1, 2]. The United States Centers for Disease Control defines obesity as BMI-for-age-and-sex > 95th percentile [3]. In the US and Europe, the prevalence of childhood obesity is 16.9% and 4–6% [4, 5]. Childhood obesity is common and associated with significant morbidity and mortality. Obese children are more likely to die prematurely or develop weight-related illnesses compared with their normal-weight peers [6, 7].

Obesity results in numerous changes to physiology and body composition that may affect drug disposition, see Table 1 [821]. Pharmacokinetics (PK) can be altered in obesity through changes to volume of distribution (V) and clearance (CL), the primary determinants of drug dosing. Changes in body composition (increased fat mass per kg or per m2) in obese children may result in the need for dose adjustments using different measures of body size such as total/actual body weight (TBW), ideal body weight (IBW), adjusted body weight (ABW), or lean body weight (LBW). Poor outcomes for obese patients with certain life-threatening conditions may result from suboptimal dosing strategies; for example, suboptimal dosing of obese adult oncology patients and obese children following cardiopulmonary resuscitation may be responsible for underdosing and reduced survival, respectively [22, 23].

Antibiotics comprise the class of medications most commonly prescribed in children [24]. Optimal dosing of these drugs in obese children is critical because such patients may be more susceptible to infection [25], and inappropriate dosing can lead to therapeutic failure, antibiotic resistance, and drug-related toxicity. This article will review the current PK information available for antibiotics in obese children and implications for dosing.

Methods

We searched PubMed, EMBASE, and International Pharmaceutical Abstracts databases for PK studies of antimicrobial agents in obese children (all years). We used combined search terms including obesity, pharmacokinetics, pharmacodynamics, drug toxicity, dosing, anti-infective agents, antiviral agents, and antifungal agents. We limited the search to children < 18 years of age. We included studies if they provided PK data in obese children receiving an antimicrobial agent.

This review discusses the following body size descriptors: TBW (kg) = measured body weight; IBW (kg) = 2.3 kg × (height (in)-60) + a, where a = 45.5 kg for women and 50 kg for men; BMI (kg/m2) = TBW/height2; LBW (kg) = b × TBW–(c × BMI × TBW), where b = 1.1 for males and 1.07 for females, and c = 0.0128 for males and 0.0148 for females; ABW (kg) = IBW +0.4 × (TBW–IBW) [2629]; and dosing weight = the weight used by the pharmacy to dispense the drug.

Results

The PubMed search strategy identified 90 articles, among which four studies of antimicrobial PK in obese children met the inclusion criteria. Searches of EMBASE and International Pharmaceutical Abstracts did not yield additional peer-reviewed articles beyond those found in PubMed. One conference abstract describing vancomycin PK in obese children was not included because insufficient study detail was provided. Drugs studied in obese children included cefazolin, tobramycin, gentamicin, and vancomycin, see Table 2.

Cefazolin and tobramycin were studied prospectively in a study of five obese children 2–9 years-of-age (BMI > 95 percentile), and serum PK results were compared with previous results from a study of six non-obese children of similar ages [30]. The dosing weight for obese participants in this study was obtained by calculating the mean of TBW and IBW, whereas non-obese participants were dosed based on TBW. Participants in both cohorts received a single 25 mg/kg dose of cefazolin by 30-minute intravenous (IV) infusion. Ten minutes after completion of the cefazolin infusion, tobramycin was infused over 30 minutes as a single 2 mg/kg dose. Cefazolin steady-state volume of distribution (Vss) and CL normalized by TBW and protein binding were not significantly different between obese and non-obese children. Tobramycin CL normalized by TBW was not significantly different between obese and non-obese children, but Vss normalized by TBW was significantly lower in obese children compared with non-obese children (p < 0.05).

Gentamicin was studied in a retrospective cohort study in 25 obese and 25 non-obese children with a mean ± standard deviation age of 9.9 ± 3.9 years and obese children’s BMI percentile of 98 ± 1.3 [31]. Obese children received significantly lower TBW-normalized doses relative to their non-obese peers (mean 1.86 vs 2.25 mg/kg TBW, p < 0.01), had significantly higher peak concentrations (8.17 ± 2.02 vs 7.06 ± 1.52 µg/mL, p < 0.05), similar trough concentrations (0.95 ± 0.58 vs 0.74 ± 0.24 µg/mL, p = 0.11), and decreased weight-normalized V (0.20 ± 0.05 vs 0.28 ± 0.07 L/kg TBW, p < 0.01).

Two retrospective studies evaluated the PK of vancomycin in obese children. The first study included 70 obese and overweight children aged 2 to < 18 years of age and mean ± standard deviation TBW 43.4 ± 30.4 kg receiving vancomycin [32]. Dose (16.6 vs 17.2 mg/kg TBW, p = 0.295) and dosing frequency were not significantly different between the obese/overweight cohort and their non-obese peers. In spite of similar TBW-normalized doses, mean steady-state trough concentrations were higher in overweight or obese children compared with normal-weight children (9.6 vs 7.4 µg/mL, p = 0.03), but this difference was not clinically significant as both mean troughs were within the target range defined by the study (5–15 µg/mL). Neither the proportion of therapeutic troughs (63.0% vs 61.4%, p = 0.825) nor the frequency of nephrotoxicity (8.5% vs 3.0%, p = 0.093) or red-man syndrome (45.7% vs 50.6%, p = 0.493) differed between obese/overweight and non-obese children, respectively. The other retrospective study of IV vancomycin in 24 obese and 24 non-obese children (mean ± standard deviation 6.8 ± 4.31 years of age and obese BMI percentile 97.3 ± 1.49) showed that obese children received lower TBW-normalized doses (not clinically significant, 14.1 vs 14.9 mg/kg TBW/dose, p = 0.03) and higher, albeit not statistically significant, steady-state serum trough vancomycin concentrations (6.9 vs 4.8 ug/mL, p = 0.052) [33].

Discussion

This review highlights the lack of PK and dosing information for the most commonly used drugs (antibiotics) in obese children. The lack of PK data is not only substantial overall but even more pronounced for orally administered drugs and those undergoing extensive liver biotransformation. For the four antibiotics studied thus far, no clinically relevant differences in drug distribution justify dosing modifications, suggesting that 1) there are truly no differences; 2) larger studies need to be conducted to observe a difference; or 3) children at the extreme of the obesity spectrum need to be included in clinical trials.

Obesity results in numerous changes to physiology and body composition that may affect drug disposition and dosing, see Table 1. Volume of distribution (V) and clearance (CL), the primary determinants of drug dosing, may be affected differently depending on the drug’s physicochemical properties and routes of metabolism and elimination [34, 35]. V may be affected by distribution of drug into tissues, which is determined by drug properties such as lipophilicity, as well as physiologic characteristics such as body composition, organ blood flows, and drug protein- and tissue-binding. Changes in body composition and organ blood flows have been documented in obese adults and children, see Table 1. CL in obese individuals can be affected by weight-related changes in renal function (glomerular filtration rate and renal blood flow) [19, 36] or changes in the activity of drug-metabolizing enzymes [17]. For example, xanthine oxidase and N-acetyltransferase 2-mediated metabolism of caffeine was elevated in obese children compared with non-obese children (p <0.05) [17].

In the absence of data supporting dosing, body size measures are often chosen to dose drugs in obese children on the basis of drug physicochemical characteristics, e.g. lipophilicity, protein-binding, drug distribution profiles, and drug elimination pathways. Traditionally, non-obese children are dosed per kg of TBW, but other body size measures, e.g. IBW, LBW, body surface area; may better correlate with V and CL in obese children and achieve more appropriate exposure.

Due to the expected affinity of lipophilic drugs to adipose tissue, it is hypothesized that lipophilic drugs will have increased V in obese patients, resulting in the need for a higher initial dose. Conversely, hydrophilic drugs are expected to remain in the intra-vascular space, bind less to adipose tissue, and thus lower V, placing children at risk for overdose. Unfortunately, the relationship between a drug’s lipophilicity and its distribution to adipose tissue is not always consistent and predictable, especially for highly lipophilic drugs. A study of five lipophilic ß-blockers found greater binding to lean tissue than adipose tissue [37]. Tobramycin and gentamicin are highly and moderately lipophilic (-LogP = 5.8 and 3.1, respectively), but both distribute primarily in extracellular fluid, not adipose, see Table 3. The distribution is consistent with the finding of decreased Vss/kg TBW in obese children observed for both tobramycin and gentamicin. Vss/kg TBW was also decreased (0.29 ± 0.13 vs 0.33 ± 0.11 L/kg, p = 0.05) in a large prospective study of obese and non-obese adults who received tobramycin or gentamicin [38]. Conversely, cefazolin, a drug with low lipophilicity (-LogP = 0.6), widely distributed to tissues, see Table 3. Based on lipophilicity alone, it would be reasonable to hypothesize that V/kg TBW would be decreased in obese individuals, requiring a lower initial dose per kg of TBW. Lower cefazolin V/kg TBW was seen in obese adults [39] compared with non-obese adults [40]. However, in the five obese children in the study described above, cefazolin V/kg TBW was unchanged compared with their non-obese peers. It is unclear why obesity affects V in adults but not children, but it could be related to a small sample size in the paediatric study that prevented identification of differences. Vancomycin has moderate lipophilicity (-LogP = 3.1) and is distributed to total body water and tissues, see Table 3. Similar to cefazolin, unchanged vancomycin V/kg TBW in children is inconsistent with reports of decreased V/kg TBW in obese adults [41, 42]. Clearly, for the drugs included in this report which were evaluated in small cohorts of children, drug lipophilicity is not predictive of drug distribution. The combination of degree of solubility and extent of metabolism (Biopharmaceutics Drug Disposition Classification System class) also did not distinguish the different distribution profiles of the drugs included in this report, as all four are highly soluble and poorly metabolized.

Studies have investigated the effect of obesity on drug binding to blood proteins or lipids. Serum albumin and total protein levels are unchanged in obesity, while the effect of obesity on alpha-1-acid glycoprotein levels is inconclusive [4345]. However, drug binding is influenced by more than absolute concentrations of serum proteins. Free fatty acid and triglyceride levels may affect a drug’s affinity for serum proteins, and free fatty acids and triglycerides are often increased in obesity. In vitro studies on the effects of free fatty acid levels on protein-binding found increased albumin binding of three out of six acidic antibiotics when the ratio of free fatty acid concentration to protein concentration was > 2; binding of three basic and neutral antibiotics was unchanged regardless of free fatty acid concentration [46].

Drug CL depends on clearance organ size and function. The liver and kidney are lean organs, and LBW is increased in obesity (though less than adipose as a fraction of excess weight). A study of 21 participants with normal liver and renal function found that liver volume was not a significant predictor of antipyrine clearance, while kidney volume appeared to mediate the association between LBW and creatinine clearance [47]. CL can also be affected by obesity-related changes in drug-metabolizing enzyme activity or renal function. Drugs eliminated via glomerular filtration or renal tubular-mediated processes, or that are metabolized by uridine diphosphate glucuronosyltransferase, xanthine oxidase, N-acetyltransferase, and cytochrome P450 (CYP) 2E1, have increased CL reported in obese adults; drugs metabolized by CYP3A4 have decreased CL [48]. Animal studies in obese mice suggest that increased kidney size and glomerular hypertrophy may result in increased glomerular filtration rate [49], and that lipid accumulation in the liver and induction of pro-inflammatory cytokines are possible mechanisms for alteration of drug-metabolizing enzyme expression [50, 51]. Non-alcoholic fatty liver disease is associated with obesity, and clinical studies indicate that CYP2E1 activity is increased with this condition [52, 53]. Other CYPs have not been evaluated in clinical studies of patients with non-alcoholic fatty liver disease; however, an in vitro human liver microsome study of drug-metabolizing enzyme activity found that progression of non-alcoholic fatty liver disease was associated with decreasing activity of CYP1A2 and CYP2C19 and increasing activity of CYP2A6 and CYP2C9 [16].

No CL changes were observed in obese children in the studies included in this review. For cefazolin, this is inconsistent with data in obese adults. Cefazolin CL (4.2 vs 3.9 L/h) and V (13.0 vs 12.3 L) estimates in obese adults [39] were similar to non-obese adults [40]; thus CL/kg TBW and V/kg TBW would be likely reduced in obese adults. As was the case in the studies of obese children, aminoglycoside and vancomycin CL/kg TBW was found to be unchanged in obese adults [38, 41, 42]. One limitation to the evaluation of vancomycin PK in obese children was the large fraction of children in both groups with undetectable trough concentrations [33].

In spite of limited PK data in obese children, dosing recommendations have been suggested. The cefazolin study recommended the use of TBW for initial dosing. The tobramycin study recommended dosing by ABW in obese children, consistent with adult obesity dosing [54]. Unlike the tobramycin study, the gentamicin study recommended dose reduction as opposed to using ABW. Both methods would result in a lower absolute dose administered. Due to the lack of observed obesity effect on vancomycin PK, the two studies recommended the use of TBW for dosing of obese children, consistent with dosing recommendations in obese adults [55].

Prospective studies of antimicrobial PK in obese children are needed to provide information on optimal dosing to clinicians. Future studies should consider drug physicochemical properties in addition to elimination pathways when developing dosing regimens. As stated above, V/kg TBW of moderate to highly lipophilic drugs are more likely to be affected by obesity [56]; effects on CL/kg TBW may be dependent on pathway(s) of elimination. The use of probe drugs for specific elimination pathways would enable extrapolation of results for other substrates of that pathway. The use of modelling and simulation approaches such as physiologically based PK, which incorporates both drug and physiological information, may help to provide mechanistic insights and inform study designs in this special population [57]. As there are no reliable predictors of obesity effects on PK in children, future studies of antibiotics in obese children should be prioritized based on clinical importance and frequency of use.

Conclusion

Optimization of antimicrobial dosing in obese children is at an early stage. Most classes of antimicrobial agents have yet to be studied in this population. Physicochemical properties alone do not reliably predict drug disposition, and traditional body size measures (actual body weight) used for dosing of drugs in obese children do not account for potential changes in CL mechanisms such as drug-metabolizing enzyme activity and renal function. The few studies done to date have not shown clinically relevant differences in PK or dosing in obese children relative to their non-obese peers. Future studies should consider drug physicochemical properties, known physiologic changes in obesity, as well as drug elimination pathways.

Key message
Antibiotics are commonly prescribed to obese children. Obesity-induced changes in antibiotic disposition can lead to toxicity or therapeutic failure. Antimicrobial studies to optimize dosing in obese children are desperately needed.

Acknowledgements

This review was conducted on behalf of the Best Pharmaceuticals for Children Act – Pediatric Trials Network.

Sources of support

This work was funded under NICHD contract HHSN 2752010000031 for the Pediatric Trials Network. MR Sampson is supported by US National Institute of General Medical Sciences 1T32GM86330–1A1. M Cohen-Wolkowiez is supported by US National Institute for Child Health and Human Development 1K23HD064814–01 for his work in paediatric clinical pharmacology and from industry for neonatal and paediatric drug development (www.dcri.duke.edu/research/coi.jsp). DK Benjamin Jr is supported by the US government (1R01HD057956–02, 1R01FD003519–01, 1U10-HD45962–06, 1K24HD058735–01, contract HHSN267200700051C), Thrasher Research Foundation, and industry (www.dcri.duke.edu/research/coi.jsp). E Capparelli is supported by US National Institute of Allergy and Infectious Disease U01AI68632 and 1U54HD071600–01. KM Watt is supported by US National Institute for Child Health and Human Development 5T32HD043029–09 and the Thrasher Foundation (www.dcri.duke.edu/research/coi.jsp).

Competing interests: None.

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

Authors

Mario R Sampson1,2, PharmD
Michael Cohen-Wolkowiez1,3, MD, PhD
Professor Daniel Kelly Benjamin Jr1,3, MD, MPH, PhD
Edmund V Capparelli4, PharmD
Kevin M Watt1,3, MD
1Duke Clinical Research Institute, Durham, NC, USA
2UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
3Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
4Department of Pediatrics, School of Medicine and Department of Clinical Pharmacy, Skaggs School of Pharmacy, University of California–San Diego, La Jolla, CA, USA

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Author for correspondence: Michael Cohen-Wolkowiez, MD, PhD, Duke Clinical Research Institute, PO Box 3499, Durham, NC 27710, USA

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Safety and toxicity of biosimilars—EU versus US regulation

Author byline as per print journal: Tobias Blank, PhD, Tilo Netzer, PhD, Wolfram Hildebrandt, MSc, MA, Angela Vogt-Eisele, PhD, Professor Marietta Kaszkin-Bettag, PhD

Background: As patents for biological drugs begin to expire, the need for scientific guidance on biosimilar drugs grows increasingly important. The European Medicines Agency provided the first guidelines to cover the approval of biosimilars in 2005. On 10 February 2012, the US Food and Drug Administration drafted three guidance documents relevant to approval of biosimilars in the US.
Objectives: The EU and US regulatory approaches to biosimilar approval were compared evaluating the potential impact on characterizing the safety profile of a proposed biosimilar product.
Methods: Applicable legal documents and guidelines from the EU and US were compared. Three main categories were identified as potentially safety-relevant, namely general regulatory requirements, non-clinical and clinical testing strategies.
Results: No fundamental differences were identified between EU and US guidelines concerning the non-clinical and clinical testing strategies. However, extrapolating immunogenicity data from one indication to another is allowed in the US but not in the EU. Further differences were identified in the general regulatory requirements including the reference product, definitions of biological drugs and historic regulatory conditions for distinct product classes. Furthermore, inconsistencies regarding naming and labelling conventions may hamper distinct post-authorization pharmacovigilance measures.
Conclusion: Although the regulatory approaches to biosimilar approval in the US and EU are similar in general scientific content, the identified differences might affect the extent of the testing strategy and post-approval pharmacovigilance measures for biosimilars, in particular depending on the type of approval process (generic versus new drug application). In order to ensure globally comparable safety profiles, harmonization of these topics is highly desirable.

Submitted: 22 February 2013; Revised: 16 July 2013; Accepted: 16 July 2013; Published online first: 29 July 2013

Introduction

As the patent protection for many biological medicinal products begins to expire [1], the need for specific guidance regarding the development and approval of biosimilars grows increasingly important. The European Medicines Agency (EMA) was the first competent authority that issued guidelines for biosimilars in 2005 [2]. Other countries including Canada, Japan, and Korea followed with guidance documents for the approval of biosimilars, which mainly follow the approach of EMA. The World Health Organization (WHO) has also issued a guideline as a general framework, establishing regulatory requirements for the approval of biosimilars [3]. In February 2012, US Food and Drug Administration (FDA) released draft guidance documents for biosimilars; however, no biosimilar drug has yet been approved in the US.

The purpose of this review article is to compare the EU with the US regulatory approaches and to evaluate the potential differences with respect to their implications for characterization of the safety profile of a proposed biosimilar product. In this context, three main areas were identified as potentially relevant, namely non-clinical and clinical testing strategies as well as general regulatory requirements. For the comparison of the regulatory approaches, legal documents and guidelines from both regions were compared and the results are discussed on the background of publicly available literature.

Definition of biosimilars

Since the active substance of a biosimilar is not identical to the active substance of the reference product, the regulatory requirements for approval of generics are inadequate to demonstrate the quality, efficacy, and safety of biosimilars [4, 5].

Importantly, manufacturers of biosimilars do only have access to the finished reference product and have to conduct and establish their own strategies to develop the respective similar drug. Even minor changes to the original manufacturing process may result in alterations to the secondary, tertiary, and quaternary structure of the molecule, which may have an impact on the efficacy and safety of the drug. Thus, the demonstration of high similarity to the reference product regarding quality, safety and efficacy is necessary and has to be demonstrated using a set of comprehensive comparability exercises. Follow-on biologic products not authorized according to these standards of comparability cannot be referred to as biosimilars [6].

Since it is assumed that potential differences might lie not only in the current biosimilar guidelines on non-clinical and clinical aspects, differences in the definitions of biological products between EMA and FDA are outlined prior to the comparison of documents, see Table 1.

Safety issues of biological drugs

As most biological medicinal products, including biosimilars, are intended for long-term use to treat chronic diseases, safety concerns are likely to arise outside the time course of controlled clinical trials. A study of safety-related regulatory issues of biologicals approved in the EU and US investigated 174 approved products and identified 82 safety-related regulatory actions concerning 41 products [7].

Biologicals developed first had a higher risk for safety related regulatory actions compared with later approved products of the same class, indicating that the experience gained over time reduced safety concerns.

The most important general safety concern of biosimilars and follow-on biologics is their potential to trigger immunogenic responses in humans [811]. Therefore, the immunogenicity issue has become a focus area in their development and approval [12]. In the case of monoclonal antibodies (mAbs), these may cause safety issues, alter activity or have an impact on both parameters. For example, antibodies neutralizing endogenous erythropoietin (EPO) can result in a rare condition known as antibody-mediated pure red cell aplasia (PRCA) [8], which was observed inter alia after a manufacturing change initially considered to be minor to the originator product Eprex in 1998 [13].

Regarding biosimilar products currently approved by EMA, there are still some concerns in the long-term evaluation of these products, particularly the limited experience at the time of approval in terms of safety and their potential to trigger immunogenicity. Even if similar efficacy is proven in the comparability exercises conducted during biosimilar development, the safety profile might differ from that of the reference product. Therefore, the particular need for safety surveillance by rigorous pharmacovigilance (PV) is stressed also for biosimilars [8]. Only effective post-marketing PV including post-authorization safety studies (PASS) will provide sufficient evidence that a biosimilar is comparable to the reference product in terms of its safety profile [14]. Side effects related to use in daily practice, e.g. medication errors, off-label use, drug interactions or co-morbidities, can only be detected during post-approval exposure. A crucial point to consider in this context is the need for traceability of the products after launch and in daily practice [15].

The assessment of toxicity and safety of mAbs becomes more challenging due to the higher complexity and size of these products, giving rise to higher variability. The manufacture of biosimilar mAbs can lead to differences in glycosylation pattern, resulting in a high level of micro-heterogeneity. In addition, mAbs often have a complex mode of action as they comprise multifunctional molecules with biological properties involving both their Fab and Fc fragments. Many challenges are associated with the approval process of biosimilar mAbs [16].

Recently, EMA issued two guidelines dealing with non-clinical/clinical issues as well as with the immunogenicity assessment of biosimilar mAbs [17, 18]. In contrast, no specific requirements for the approval of biosimilar mAbs are addressed by FDA in their draft guidance documents so far. In June 2013, first approvals for biosimilar mABs have been granted in the EU for infliximab; however, it will be interesting to follow how future applications will be assessed by EMA and FDA (CHMP 2013 Summary of positive opinion for Remsima (infliximab). EMA/CHMP/363689/2013. released 27 June 2013; CHMP 2013 Summary of positive opinion for Inflectra (infliximab). EMA/CHMP/364710/2013. released 27 June 2013).

Comparison of regulatory requirements covering toxicity and safety

Overall, the regulatory requirements in both regions are comparable regarding their scientific content. However, the most obvious discrepancy is the structure and number of guidance documents. In contrast to the US, guidance documents in the EU are available for different product classes such as somatropins, EPO, granulocyte colony-stimulating factor (G-CSF) and insulin [5]. Content-related differences between the EU and US guidelines regarding distinct parameters with possible impact on toxicity and safety of biosimilar products are outlined below.

General requirements with a possible impact on toxicity and safety of biosimilars
General topics with a possible impact on toxicity and safety of the proposed biosimilar product include: the reference product; definitions of biological drugs and the resulting regulatory pathway; and naming and labelling.

Comparison of provisions determining the reference product.
In principle, only a reference product licensed in the EU or US, respectively, is accepted for any kind of testing during the approval process of a biosimilar drug. Furthermore, the same product has to be used throughout the entire development programme [12]. In certain cases, the use of non-EU or non-US reference products, respectively, is accepted for distinct non-clinical and clinical investigations and results may be bridged for final evaluation [19]. Under this approach, it is the applicant’s responsibility to establish that the batches sourced outside the European Economic Area (EEA) are representative of the reference medicinal product authorized in the EEA through an extensive analytical comparison.

According to the May 2013 EMA’s overarching guideline the use of foreign reference material to conduct the immunogenicity and clinical efficacy programme marketing is in principle possible in both regions which is considered a key advantage (CHMP 2013. Guideline on Similar Biological Medicinal Products. CHMP/437/04-Rev 1. Released 22 May 2013). This is considered by biosimilar developers as a key advantage since they can use the EU programme also for US filing [20]. However, FDA Q&A document (Q.1.8) states that ‘At this time, as a scientific matter, it is unlikely that clinical comparisons with a non-US licensed product would be an adequate basis to support the additional criteria required for a determination of interchangeability with the US licensed reference product’ [21]. In this context, interchangeability means that the biological product is biosimilar to the reference product, it can be expected to produce the same clinical result as the reference product in any given patient; and for a product administered more than once, the safety and reduced efficacy risks of alternating or switching are not greater than with repeated use of the reference product without alternating or switching [22]. This concept of interchangeability, however, is only applied in the US and not the EU [23]. Recently, it was reported that FDA accepts substitution of interchangeable biosimilars [24], while, for example, the Greek medicines agency released a document in March 2013 that it did not recommend automatic substitution or interchangeability of biological [25]. Automatic substitution will make post-marketing surveillance more difficult due to potential issues with traceability and identification of the products.

The reliable bridging of data derived from studies with a non-EU or non-US licensed product to the respective licensed reference product remains challenging. This has been followed in the May 2013 drafted revision of EMA’s Overarching guideline. As is stated in the response to Question 4 of the Q&A document of EMA [19], a close collaboration with FDA is foreseen in the upcoming revision of the biosimilar guideline CHMP/437/04 to ensure harmonization of requirements of reference products for the comparability exercise. It should be noted that bridging data between studies gathered by the use of different reference products may result in potential bias regarding safety data.

During the development programme, sponsors are encouraged to discuss with the authorities the adequacy of the scientific justification of such an approach, particularly the bridging to reference material authorized in another ICH region applying respective approval standards proving biosimilarity similar to that of the EU and the US [26].

Comparison of biological drug definitions for approval of biosimilars
In the US, for historical reasons and due to the definition of biological drugs, certain biologicals are regulated under the Federal Food, Drug, and Cosmetic (FD&C) Act and are therefore open to the so-called Hatch–Waxman generic drug pathway (The Hatch–Waxman Act, a 1984 amendment to the FD&C Act, created an abbreviated approval process for generic versions of conventional drugs while still protecting the patent rights of brand-name drug manufacturers). Such biological products include insulin, glucagon, somatropin, and low molecular weight heparins (LMWHs). Recently, FDA published requirements to be fulfilled by a biosimilar, thus offering the possibility of authorization by an abbreviated new drug application (ANDA) procedure [27].

In contrast, EU regulation does not allow for the use of classical generics application procedures for marketing authorization of biosimilars for these classes of biologicals [28].

Since there are different requirements to be fulfilled when the same drug is approved in either the US or the EU, e.g. the extent of non-clinical and clinical testing, the characterization of the safety profile of biosimilars may be affected. This applies, for example, to the product class of LMWHs. These are classified as generic drugs in the US and therefore become approved as generics under the FD&C Act using an ANDA [29]. The generic drug approval procedure in the US results in a less extensive development programme omitting studies evaluating non-clinical and clinical safety and efficacy. Only bioequivalence to the originator product has to be proven in company-sponsored studies [30]. In contrast, LMWHs are classified as biosimilars in the EU. Since heparins are derived from biological source material and are labelled according to potency rather than according to weight, these products are regulated as biologicals rather than generics. Consequently, mere physico-chemical similarity between a biosimilar such as LMWH and the originator product will be insufficient for a successful licensing application in the EU [31] and additional clinical studies assessing comparability with respect to pharmacokinetics (PK), efficacy and safety are required [32, 33]. Similarly, while insulins, glugacon, and human growth hormone (somatropin) are regulated under the FD&C Act (generics procedure) in the US, they are treated as biologicals or biosimilars in the EU.

In conclusion, when comparing the different regulatory approaches for distinct biological product classes in the EU and US, there is an obvious need for global harmonization of the available regulatory pathways.

Comparison of guidelines for biosimilar labelling
The impact of naming and labelling on the safety of already approved biosimilar products has been widely discussed because biosimilars are marketed under the same International Nonproprietary Names (INN) as the reference product. In this regard, it was outlined by the European Biopharmaceutical Enterprises (EBE) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) that, for example, the labelling for Omnitrope is effectively indistinguishable to that of its reference product (Genotropin). It is not clearly highlighted that Omnitrope is a biosimilar, or which data quoted in the labelling were generated with Omnitrope and which data with Genotropin. EBE and EFPIA strongly recommended a consistent approach concerning the labelling of future biosimilars by providing the respective information about the origin of data in sections 4.8 and 5.1 of the product’s Summary of Product Characteristics [34].

The European Commission issued a directive by end of 2012 requiring biological products to be identified by brand name and not by INN [35]. Measures are described which should facilitate the recognition of medical prescriptions of biologicals and, thus, also of biosimilars issued in another Member State. However, FDA is less precise in this context only saying that naming and labelling of the drug should facilitate decision making by the prescribing healthcare professional [22].

Therefore, biologicals should be marketed with the brand name or at least with the INN together with the manufacturer’s name for a definite identification of the product by prescribers [35]. Unique, dissimilar names can help to prevent prescription mix-ups and can support reporting and tracking of adverse events. Identical or similar names may contribute to prescription mix-ups and complicated post-marketing surveillance [36].

Comparison of non-clinical testing strategies
There is no substantial difference in the general non-clinical approach between the EU and the US regarding the scientific content. Both regions require an extensive set of in vitro data which in principle are comparable. In the US draft guidances, residual uncertainty after every single study milestone is addressed within the scope of the next studies to be conducted. However, individual testing strategies are likewise applied in the EU approach providing product-class specific guidelines.

In the EU and US, in vivo studies are usually required in relevant species based on state-of-the-art technology. However, slight differences exist concerning the structural approach. In the US, some of the non-clinical tests are described in the quality guideline [37]. The step-wise procedure of the so-called ‘totality of the evidence’ approach is described in more detail in the US draft guidance documents compared with EMA’s general guideline on non-clinical and clinical issues, particularly regarding structural characterization of the product [12, 22]. Furthermore, consistent with the recommendations of EMA, non-clinical safety pharmacology, reproductive and developmental toxicity as well as carcinogenicity studies are not warranted in the US when the proposed product and reference product have been demonstrated to be highly similar by extensive structural and functional characterisation. In August 2012, FDA proposed a risk-based approach stating that animal repeated-dose toxicity studies may not be required, and may only be useful if safety uncertainties remain before first-in-man studies [38].

Both EMA and FDA agree that animal immunogenicity studies do not predict potential immunogenic responses to protein products in humans. However, if differences in manufacturing, e.g. the presence of impurities or excipients, between the proposed product and the reference product result in altered immunogenicity, measurement of anti-protein antibody responses in animals may provide useful information relevant to patient safety [26]. Overall, a step-wise testing approach before entering the clinical phase is required in both the US and EU.

Comparison of clinical testing strategies
Both, the EU guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/42832/05) and the US draft guidance for industry, scientific considerations in demonstrating biosimilarity to a reference product [26], propose in general that the clinical comparability exercise is a stepwise procedure that should start with PK and pharmacodynamics (PD) studies followed by clinical efficacy and safety trials or, in certain cases, PK/PD studies. Both regions recommend selecting PD parameters on the basis of their relevance to demonstrate therapeutic efficacy of the product. Although reference-controlled clinical trials are usually required to demonstrate clinical comparability of safety, in certain cases PK/PD studies may be sufficient. For this purpose, there must be a high level of physico-chemical characterization of the biosimilar product in comparison with all the information collected with the originator during the development process or through post-marketing experience. If there are several potential indications, the most sensitive disease model to detect differences should be chosen in a homogeneous patient population. If efficacy and safety has been shown in this indication, the extrapolation to other indications is possible under certain circumstances [12, 26].

Overall, FDA and EMA recommendations for clinical testing of PK/PD and efficacy trials are highly similar.

Comparison of clinical safety and pharmacovigilance requirements
In terms of clinical safety and PV requirements there are no significant differences between FDA and EMA recommendations. In principle, study populations should be of sufficient size to detect possible safety concerns. Usually it is recommended to evaluate safety data within the scope of combined safety and efficacy trials. However, since the need for such clinical trials depends on the extent and relevance of data derived from non-clinical testing and PK/PD studies in humans, and particularly on the relevance of PD markers used, the size of the safety population to be evaluated may vary. Even if extensive phase III clinical trials are performed, the study population will be too small to allow the detection of rare side effects. Therefore, both FDA and EMA focus on post-marketing safety programmes according to the respective PV laws applicable in either region. To detect possible differences between reference and biosimilar products, it is crucially important to compare the frequency and severity of known side effects of the reference product with any differences or new side effects not yet observed with the reference product [12, 26].

Comparison of immunogenicity assessment
Both authorities, FDA and EMA, explicitly state the importance of the assessment of clinical immunogenicity in both pre- and post-approval settings. FDA and EMA agree that non-clinical data are not able to predict the immunogenic potential of a molecule. To date, current guidance documents focus on chronic administration in humans with a minimum follow-up period of one year being expected in both regions [12, 26]. However, FDA explains in more detail that the requirements depend on the extent and period of administration. EMA also addressed this aspect in a concept paper regarding non-clinical and clinical issues of biosimilars [39].

The regulatory approaches differ regarding extrapolation of immunogenicity data to other indications. While EMA clearly states that immunogenicity should be assessed for each indication separately [12], FDA in principle provides the possibility of extrapolating data to other indications [26]. However, caution is advised regarding the extrapolation of data to other indications and the applicant is recommended to discuss these aspects with the agency [20].

The possibility of extrapolating immunogenicity data depends on several factors, including understanding the mode of action, experience with the reference product, the extent of characterization of the reference and proposed product, and the amount and relevance of data collected so far. In principle, the most sensitive disease model with regard to immunogenicity should be used [26], and extrapolation is only possible from high-risk to low-risk patient populations and clinical settings [40]. However, testing for only one indication may not be sufficient to adequately explore the immunogenic potential of a biosimilar drug throughout several indications. This issue is of particular importance as biosimilar mAbs are already in the development pipeline, making the immunogenicity issue even more challenging [18, 41].

While the possibility of altered efficacy and safety of a product is outlined by both EMA and FDA, EMA provides examples of reactions possibly related to immunogenicity that should be closely monitored, such as hypersensitivity, infusion reactions, autoimmunity and loss of efficacy. Both agencies recommend defining certain PV measures depending on the specific characteristics of the product.

Discussion and conclusions

EMA was the first competent authority to issue guidelines for biosimilar approval in 2005 [2]. In February 2012, FDA issued draft guidance documents regarding the approval of biosimilars; however, no biosimilar drug has yet reached approval in the US. By March 2013, FDA’s drugs centre had received 51 requests for pre-Investigational New Drug (IND) meetings covering 12 different biological reference products. This is interesting to compare with Europe, where to date 14 biosimilars have been approved covering only three reference products [42].

The purpose of this review article was to compare EU with US regulatory approaches to biosimilar approval, evaluating the potential extent to which the safety profile of a proposed biosimilar product is characterized. Major issues comparing regulatory approaches with regard to a harmonized characterization of safety profiles of biosimilars in the two regions of interest are displayed in Table 2.

Overall, the requirements are similar; however, the language is different [20]. This fact makes it more complicated to identify relevant differences with respect to potential safety issues.

Despite differences in the structural approach and the language chosen, major differences possibly affecting understanding of the safety profile of the proposed products concern the general requirements, i.e. the choice of the reference product, the definition of biologicals and the resulting regulatory pathways, and to some extent the naming and labelling requirements. Regarding non-clinical and clinical testing strategies, substantial differences were identified concerning the extrapolation of immunogenicity data from one indication to another, which is precluded in the EU and in principle allowed in the US.

The naming and labelling of biosimilars is a topic under continuous discussion. With the new EC Directive 2012/52/EU, consensus was found in the EU regarding the naming of biologicals by brand name and not by INN. In contrast, until now no precise requirements are scheduled in the US. For PV in a global setting, harmonization in naming is crucial as different naming systems in different countries, particularly outside the scope of the EC directive and FDA regulations, may hamper clear data analysis for a specific biosimilar product.

Physicians need to be informed about the scientific principles of the biosimilar approval. In this context, there is no reason to assume that biosimilars would behave differently from the reference product in clinical practice if the respective regulatory and scientific principles have been properly applied [40]. In addition, according to a review of an extensive set of clinical trials and post-authorization safety data, no specific safety concerns have yet been identified for switching from one authorized biological to another for the same indication [43, 44]. However, since many safety-related issues of biological drugs only occur in very rare situations, which often relate to long-term use, more experience is needed with distinct product classes.

To help manufacturers provide reliable efficacy and safety data for their biosimilar products in the most cost-effective way, and in order to give physicians and patients’ confidence in globally comparable safety profiles, harmonization regarding these topics is highly desirable.

Competing interests: The authors are employees of PharmaLex GmbH. The authors declare that there are no conflicts of interest that are directly relevant to the content of this manuscript. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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

Authors

Tobias Blank, PhD
Tilo Netzer, PhD
Wolfram Hildebrandt, MSc, MA
Angela Vogt-Eisele, PhD
Professor Marietta Kaszkin-Bettag, PhD
PharmaLex GmbH,13-15 Joseph-Meyer-Straße, DE-68167 Mannheim, Germany

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Author for correspondence: Professor Marietta Kaszkin-Bettag, PhD, Head of Preclinical and Medical Aff airs, PharmaLex GmbH, 13-15 Joseph-Meyer-Straße, DE-68167 Mannheim, Germany

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Assessing biosimilarity using the method of generalized pivotal quantities

Author byline as per print journal: Shih-Ting Chiu, PhD, Chen Chen, MSc, Professor Shein-Chung Chow, PhD, Eric Chi, PhD

Introduction: For generic approval of small-molecule (chemical) drug products, US Food and Drug Administration requires evidence of equivalence in average bioavailability from bioavailability and bioequivalence studies. To address drug interchangeability, population bioequivalence (PBE) for drug prescribability and individual bioequivalence (IBE) for drug switchability under replicated crossover designs have been proposed.
Methods: In this manuscript, we assess the biosimilarity through a 95% upper confidence bound based on the recommended individual bioequivalence criterion based on method of generalized pivotal quantities (GPQs) under a 2 × 3 extra-reference crossover design. A simulation study is conducted to evaluate performance of GPQ-based approach by using bootstrap procedure. Both methods have almost the same power but GPQ approach controls type I error within the pre-specified significant level.
Discussion: It is recognized that standard methods for bioequivalence assessment of small-molecule drug products cannot be directly applied to assessing biosimilarity of biosimilar products owing to some fundamental differences between small-molecule generic and large-molecule biosimilar drug products.GPQ is an appropriate method for assessing biosimilarity of biosimilar drug products under the 2 × 3 extra-reference crossover design.

Submitted: 18 March 2013; Revised: 19 May 2013; Accepted: 3 June 2013; Published online first: 17 June 2013

Introduction

Biological products are therapeutic moiety manufactured by a living system or organism, such as human, plant, animal, or micro-organism. Many best-selling biological products will expire in years to come. Therefore, innovative biological products can be generically reproduced and marketed.

When an innovative (brand-name) small-molecule (chemical) drug product is going off patent, pharmaceutical or generic drug companies can file an abbreviated new drug application for generic approval. For approval of generic drug products, US Food and Drug Administration (FDA) requires that evidence of equivalence in average bioavailability (in terms of drug absorption) is provided from bioavailability or bioequivalence studies [1].

The assessment of bioequivalence in average bioavailability is usually referred to as the assessment of average bioequivalence (ABE), which focuses on average bioavailability but ignores variability, e.g. intra-subject variability, inter-subject variability, and variability caused by subject-by-drug interaction, associated with the observed responses. As a result, generic drug products are becoming increasingly available. It is a concern that an ABE for generic approval can equate to quality, safety, and efficacy. To address drug interchangeability, the concept of population bioequivalence for drug prescribability and individual bioequivalence (IBE) for drug switchability under replicated crossover design have also been proposed [2].

Unlike small-molecule drug products, the generic versions of biological products are similar biological drug products. These are not generic drug products, which are usually referred to as drug products with identical active ingredient(s) as the innovative drug product, but are similar to the innovative biological products. They are made in living cells or organisms, which is different from (small molecule) generic drug products. Generic drug products are fundamentally different from those of biosimilar (large molecule) drug products [3]. For example, biosimilar products have a heterogeneous structure (usually mixtures of related molecules), which is difficult to characterize. In addition, biosimilar products are often variable and sensitive to environmental conditions, such as light and temperature. A small change or variation at any critical stage of the manufacturing process of a biological product could result in a drastic change in clinical outcomes.

Because of these fundamental differences, current standard methods for bioequivalence assessment of generic drug products may not be appropriate for assessing biosimilar products [4, 5].

In this manuscript, we focus on the assessment of biosimilarity by using IBE rather than the assessment ABE, because biosimilar products are known to be variable and sensitive to small changes (variations) in environmental factors during the manufacturing process. For assessment of IBE, the method proposed by Hyslop et al. [6] is recommended under a replicated crossover design, e.g. TRTR, RTRT or TRT, RTR, where t is the test product and r is the reference product. Chow et al. [7] proposed a 2 × 3 extra-reference design, i.e. TRR, RTR, which was shown to be the most efficient design among 2 × 3 replicated crossover design for assessing IBE. Thus, in this manuscript, we focus on assessing biosimilarity of biosimilar products by constructing a 95% upper confidence bound for the IBE criterion recommended by FDA using the generalized pivotal quantities (GPQs) method under the 2 × 3 extra-reference crossover design. We conduct a simulation study to evaluate the performance of the proposed method under various scenarios.

Study design, statistical model, and hypotheses

Study design
For assessment of IBE, Chow et al. [7] indicated that the following 2 × 3 extra-reference design given in Table 1 is the most efficient design among the 2 × 3 crossover designs. In some cases, the 2 × 3 extra-reference design is also more efficient than the 2 × 4 replicated crossover design. We, therefore, focus on the 2 × 3 extra-reference design.

Under the 2 × 3 extra-reference design, qualified subjects will be randomly assigned to either sequence 1 or sequence 2 with equal probability. For example, subjects who are assigned to sequence 1 will receive test treatment first, then are crossed-over to receive the reference product after a sufficient length of washout, then get crossed-over to receive the reference product after another sufficient length of washout.

Statistical model
Let yijk be the response from subject i in sequence k at period j of the experiment. The statistical model for the 2 × 3 extra-reference design can be described as follows:

l = T, R (treatment: T (test product), R (reference product)); k = 1, 2 (sequence); i = 1,…,nk (subject); j = 1, 2, 3 (period)

μlis the mean of the l treatment

Fl is the fixed effect of formulation l

Wljk’s are nuisance parameters and can include fixed period, sequence, and interaction effects.

Slik is the random effect of subject i in sequence k under formulation l and (STik, SRik). They are independent and identically distributed bivariate normal random vectors with mean and an unknown covariance matrix .

where are between-subject variances and ρ is the covariance of two formulations under model (1). εlijkis the random error for subject i within sequence k on period j of treatment l and assumed to be mutually independent and identically distributed as where are within-subject variances under model (1).

Individual bioequivalence criterion, hypothesis, and modified large sample method
According to the 2001 FDA guidance [8], let FT be the average pharmacokinetics (PK) response from the test formulation, and FR and FR′ be two identically distributed average responses from an individual under the reference formulation.

Then the drug switchability can be measured by

Under the 2 × 3 extra-reference design, θ is equal to

where and , which is the difference of effect between the two formulations.

Note that are within-subject variances for test and reference formulation separately. is the variance of subject-by-interaction and is the minimum within-subject variance of reference formulation specified by FDA.

When , θ is referred to as the constant-scale and , θ is referred to as the reference-scale by FDA. IBE can be claimed if the following null hypothesis H0 is rejected at the 5% level of significance:

where θ0 = 2.4938 is an upper limit specified in the 2001 FDA guidance [8]. On the basis of the hypothesis in (4), the IBE criterion can be expressed as the following linearized criteria:

As the result, the testing hypothesis based on the linearized criteria (5) will be given as:

Under the same accuracy of estimation on , the 2 × 3 extra-reference design needs fewer observations than 2 × 4 crossover design, and even provides more efficiency as the same number of observations. To avoid the estimation of , the following decomposition of γ in criteria (5) can been shown equal to

where

Let be the mean of average observations xlik under the formulation l in sequence k and be the mean of zlik, which is the difference between the two observations under the l formulation in sequence k.

Then unbiased estimators of

And an unbiased estimator of δ is

have been given by Chow et al. [7]. They proposed the confidence bound based on the hypothesis (6). For the reference-scale:

where U is the sum of the following three quantities

and

For the constant-scale, the confidence bound will be

where U0 is the same as U expect that the quantity in Equation (11) should be replaced by

Proposed method based on the generalized pivotal quantity

One of the major disadvantages of the method described above is that the estimate may depend on unknown nuisance parameters that may affect the size and power of the IBE hypothesis testing. To overcome this drawback, alternatively, we may consider the GPQ method, which can avoid the inference of nuisance parameters [9]. Assume that Y is a random variable whose distribution depends on a vector of unknown parameters ζ = (θ, η), wherev θ is a parameter of interest and η is a vector of nuisance parameters. Let Y be a random sample from Y and y be the observed value of Y. Furthermore, let R = R(Y; y, ζ) be a function of Y, y, and ζ. The random quantity R is said to be a GPQ, satisfying the following two conditions:

a) The distribution of R does not depend on any unknown parameters.

b) The observed value of R, say r = R(y; y, ζ) is free of the vector of nuisance parameters η.

In other words, r is only a function of (y, θ). The distribution of GPQ of a vector that contains parameters of interest and nuisance parameters does not depend on any unknown parameters, and the observed value of GPQ is free of the vector of the nuisance parameters. On the basis of the GPQ concept, we can find the GPQ for γ in Equation (7).

For the GPQ of , let .

We can find the GPQ for is given as

which does not depend on any unknown parameters.

Also, let , then we can find the GPQ for is given as

Since, , may not be a good estimator for , and let as and

then the GPQ for δ2 can be given as .

Therefore, we can get by substituting with equation (14), and with equation (15) with equation (16) into the following equations:

are GPQ for γ’ in reference scale and constant scale in reference scale and constant scale.

Generalized upper confidence limit A 100(1–α)% generalized upper confidence limit for γ’ is given by R1–α, where R1–α is the 100(1–α)th percentiles of the distribution of . The percentiles of can be analytically estimated using Monte Carlo algorithm.

Step 1: Choose a large simulation size, say B = 10,000. For b equal to 1 through B, carry out the following steps.

Step 2: Independent generate univariate standard normal random variable , and central chi-square variables and with degrees of freedom , respectively.

Step 3: For the realized values of and , compute as defined in Equation (17) and (18).

The required upper 100(1–α)th percentiles of the distribution of GPQ for γ’, which is also the upper 100(1–α)th generalized confidence limit for γ’, is then estimated by the 100(1–α)th sample R,percentiles of the collection of B = 10,000 realizations .

The upper 100(1–α)% generalized confidence limit for γ based on GPQ can be used to test the statistical hypothesis for the IBE test. The null hypothesis is rejected and the individual bioequivalence is concluded at the α significance level if the upper 100(1–α)% generalized confidence limit for γ is less than 0.

Simulation study

The following simulation study aims to compare the empirical size between two upper confidences bound on testing the IBE we have already described. The first approach was proposed by Chow et al. [7], which is based on the method recommended by Hyslop et al. [6] in FDA guidance. The second one is our proposed GPQ approach. To compare the two methods, we conducted a simulation study. The whole simulation procedure is presented in Figure 1. On the basis of Equation (7), we specify the different parameter combinations. For sample size per arm, we consider the sample size allocation as n = n1 = n2 = 10, 15, 20, 25, 30, 35 and 40. Let the variance of subject-by-interaction as σD = 0, within-subject variances for test as σWT = 0.15, 0.2, 0.3, 0.5, within-subject variances for reference as σWR = 0.15, 0.2, 0.3, 0.5. And upper limit as θ0 = 2.4948, the minimum within-subject variance σ0 = 0.2, which are referred to the regulation by FDA guidance.

We aimed to study the empirical size between two upper confidences bound when the linearized criteria γ′ are set equal to 0. The result for both constant and reference scales are presented in Table 2. The power curves are shown in Figure 2. At the 5% significance level, 10,000 random samples each parameter combination will be conducted to compute type I error probability and power for IBE test based on the two methods. In additional, for obtaining GPQ confidence bound, , will be generated in each distribution independently by the rnorm() function in R programme. Whole simulation is calculated and random samples are generated by using R version 2.15.2 [10].

On the basis of the results presented in Table 2, overall type I error rate of the GPQ approach is more stable than the method recommended by FDA. The empirical size of our proposed method can always keep within the significant level we pre-specified, i.e. 0.05. In Figure 2, we have only slight difference on the power curves between two methods. The empirical power comparison was almost the same in the two methods. Both methods have 80% power when the sample size was over 35 per arm in most of our cases. The power decreases to lower than 20%, however, when σWT increases to 0.5, even when we have 40 samples per arm. How the power decreases with γ is shown in Figure 3. As two curves are also close to each other in Figure 3, it means the sample sizes required for the same power by two methods are almost the same.

Discussion

In the 2001 guidance [8], FDA recommended 2 × 3 or 2 × 4 replicated crossover design to assess IBE. In this manuscript, we consider 2 × 3 extra-reference design with the GPQ approach, which requires the same number of observations as the 2 × 3 crossover design and the same reference sample size as the 2 × 4 crossover design. FDA’s method can estimate more components, but our method with the GPQ approach is more efficient than 2 × 3 or 2 × 4 crossover design [7]. The GPQ approach, however, needs a longer calculation process than the method proposed by FDA. The distribution of proposed GPQ could approach the true distribution of γ very well by the bootstrap distribution procedure. As biological products are sensitive to manufacturing process changes, the variance could be larger than the common small-molecule drugs. In additional, the criterion γ is composed of serious parameters that may destabilize the estimation. On the basis of our results in the simulation section, the GPQ-based approach has smaller type I error rates than the method proposed by Chow et al. [7]. Both methods have almost the same power with equal sample size. By using the GPQ approach, the influence of the nuisance factor could be reduced. GPQ method can focus on the interesting parameter because GPQ is free of nuisance parameters. Therefore, GPQ is an appropriate method for assessing biosimilarity of biosimilar products that have higher variability than small-molecule drugs.

To assess interchangeability, FDA recommends 2 × 3 crossover design, e.g. TRT, RTR or TRR, RTT, or a 2 × 4 crossover design, e.g. TRTR, RTRT in the 2001 guidance. The TRR, RTT 2 × 3 crossover design can estimate the carryover effect by repeating formulation in the last period of each sequence. The 2 × 3 extra-reference design (TRR, RTR) repeats only in the first sequence to estimate the carryover effect of the reference sample. Addition of the third sequence (RRT) to 2 × 3 extra-reference design to include all possible ‘two references and one test’ cases, and 3 × 3 complete design. Note that the decomposition of γ of 2 × 3 extra-reference design and 3 × 3 complete design are the same. Therefore, we can propose similar GPQ of 3 × 3 complete design. The 3 × 3 complete design can provide a more accurate estimate if we have enough reference samples, but 2 ×3 extra-reference can also estimate the with less sample size than 3 × 3 complete design. And for both 2 × 3 extra-reference design and 3 × 3 complete design, can be avoided by the decomplosition of γ in the Equation (7).

With the design described above, GPQ can be easily applied to assessing interchangeability of biosimilar products, i.e. alternating and switching by knowing the improved decomposition of and its unbiased estimator.

Competing interests: Dr Shih-Ting Chiu, Chen Chen and Professor Shein-Chung Chow are the primary authors of the article. Dr Eric Chi provided some comments for this study. This manuscript was not funded by Amgen Inc.

Dr Eric Chi is Director of Biostatistics in the Biosimilar Division at Amgen Inc.

This manuscript represents the views of the author and is not necessarily representative of Amgen’s.

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

Authors

Shih-Ting Chiu, PhD
Chen Chen, MSc
Professor Shein-Chung Chow, PhD
Duke University School of Medicine, Durham, North Carolina, USA

Eric Chi, PhD
Amgen, Inc, Thousand Oaks, California, USA

References
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2. Chow SC, Liu JP. Design and analysis of bioavailability and bioequivalence studies.3rd ed. New York:Marcel Dekker;2008.
3. Chow SC, Ju C. Assessing biosimilarity and interchangeability of biosimilar products under the Biologics Price Competition and Innovation Act. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(1):20-5. doi:10.5639/gabij.2013.0201.004
4. Chow SC. Quantitative evaluation of bioequivalence/biosimilarity. J Bioequiv Availab, S1. 002. 2011.
5. Chow SC. Biosimilars: design and analysis of follow-on biologics. New York: Chapman and Hall/CRC Press, Taylor and Francis; 2013.
6. Hyslop T, Hsuan F, Holder DJ. A small sample confidence interval approach to assess individual bioequivalence. Stat Med. 2000;19(20):
2885-97.
7. Chow SC, Shao J, Wang H. Individual bioequivalence testing under 2 × 3 design. Stat Med. 2002;21(5):629-48.
8. US Food and Drug Administration. Guidance for Industry. Statistical approaches to establishing bioequivalence [homepage on the Internet]. 2001 [cited 2013 May 19]. Available from: http://www.fda.gov/downloads/
Drugs/Guidances/ucm070244.pdf
9. Chiu ST, Tsai PY, Liu JP. Statistical evaluation of non-profile analyses for the in vitro bioequivalence. J Chemometr. 2010;24(10):617-25.
10. R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria: 2008 [cited 2013 May 19]. ISBN 3-900051-07-0. Available from: http://www.R-project.org

Author for correspondence: Shih-Ting Chiu, PhD, Postdoctoral Associate, Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Duke Box 2721, Suite 1102, 2424 Erwin Road, 11069 Hock Plaza, Durham, NC 27705, USA

Disclosure of Conflict of Interest Statement is available upon request.

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What lessons can be learned from the launch of generic clopidogrel?

Author byline as per print journal: Christoph Baumgärtel1, MD; Brian Godman2,3,4, BSc, PhD; Rickard E Malmstrom5, MD, PhD; Morten Andersen6, MD, PhD; Mohammed Abuelkhair7, PharmD; Shajahan Abdu7, MD; Marion Bennie8,9, MSc; Iain Bishop9, BSc; Thomas Burkhardt10, MSc; Sahar Fahmy7, PhD; Jurij Furst11; Kristina Garuoliene12, MD, PhD; Harald Herholz13, MPH; Marija Kalaba14, MD, MHM; Hanna Koskinen15, PhD; Ott Laius16, MScPharm; Julie Lonsdale17, BSc; Kamila Malinowska18, MD; Anne M Ringerud19, MScPharm; Ulrich Schwabe20, MD, PhD; Catherine Sermet21, MD; Peter Skiold22, MSc, PhD; Ines Teixeira23, BA, MSc; Menno van Woerkom24, MSc; Agnes Vitry25, PharmD, PhD; Luka Vončina26, MD, MSc; Corrine Zara27, PharmD; Professor Lars L Gustafsson4, MD, PhD

Introduction and study objectives: Resource pressures will continue to grow. Consequently, health authorities and health insurance agencies need to take full advantage of the availability of generics in order to continue funding comprehensive health care particularly in Europe. Generic clopidogrel provides such an opportunity in view of appreciable worldwide sales of the originator. However, early formulations contained different salts and only limited indications. Consequently, there is a need to assess responses by the authorities to the early availability of generic clopidogrel including potential reasons preventing them from taking full advantage of the situation. In addition, it is necessary to determine the extent of initial price reductions obtained in practice to guide future activities.
Methods: Feedback from health authorities and health insurance personnel involved with the reforms surrounding generic clopidogrel was principally used to assess authority responses as there is limited information in the public domain. Abu Dhabi has been included as a representative of the Middle East since it has introduced compulsory international non-proprietary name (INN) prescribing except for limited situations. Generic clopidogrel is not one of these – providing direction to other health authorities alongside, e.g. Lithuania. Australia has also been included in view of the high court ruling in favour of generic clopidogrel.
Results: Authorities from across Australia, Europe and the Middle East typically adopted a pragmatic approach to the availability of generic clopidogrel to enhance its prescribing and dispensing once approved by regulatory agencies such as EMA. This included guidance to enhance its utilisation such as academic publications, co-payment incentives and compulsory INN prescribing. However, this was not always possible with challenges to the availability of generics in some countries. Again, there was appreciable variation in the initial price reductions for generic clopidogrel versus the originator.
Conclusion: Authorities can take full advantage of the early availability of generics despite different formulations and indications. Pharmaceutical companies need to accept this in order to help fund new premium price products as resource pressures grow.

Submitted: 13 September 2011; Revised manuscript received: 2 December 2011; Accepted: 5 March 2012

Introduction and study objectives

There is increasing focus on pharmaceutical expenditure globally [1], driven by factors including changing demographics and the continued launch of new premium priced medicines [17]. This has stimulated a number of initiatives surrounding generics, with European countries learning from each other as they continually search for additional measures to further enhance prescribing efficiency [13467]. Initiatives include measures to enhance the utilisation of generics versus originators and patent protected products in the class or related class, as well as measures to obtain low prices for generics [13468]. This includes generic clopidogrel, with global sales of the originator at US$9.8 billon in 2009 and US$9.7 billion in 2010 [910]. However, there have been concerns with different salts and indications between the originator and early generic clopidogrel formulations, which could reduce potential health authority and health insurance agency savings from the availability of generic clopidogrel. In addition in the US, the originator manufacturer also instigated a range of activities to delay the entry of generic clopidogrel. These included a recent successful and prolonged legal battle against a Canadian generics manufacturer [1112].

These issues regarding generic clopidogrel have arisen because manufacturers have been able to address the technicalities of Plavix’s European patent protection early by producing clopidogrel in a different salt, such as the besylate salt, and initially, only launching for secondary prevention of atherosclerotic events post myocardial infarction or post ischaemic stroke, i.e. without the acute coronary syndrome (ACS) indication [111314].

The Swiss generics company Acino has been able to market its generic clopidogrel in Germany since August 2008. By the end of 2008, Acino’s generic clopidogrel accounted for approximately one quarter of total clopidogrel utilisation [1314]. Other generics versions were also launched in Austria in 2008. However, it was not until mid 2009 that EMA was able to approve various generic clopidogrel preparations through its centralised procedure [111314]. This included more than 20 generic clopidogrel products, which contained the besilate and hydrogen sulphate salts, of which eight were approved for both indications, i.e. both secondary prevention and ACS indications [15]. However, in the UK for instance, initial generics typically only included the secondary prevention indication in their submissions [1516].

Health authority or health insurance agencies faced similar issues to drug licensing authorities when considering reimbursement and/or recommending the prescribing of generic clopidogrel versus the originator potentially impacting on outcomes. These included whether changing the salt would alter the rate of absorption, toxicity and stability of the active drug. In addition, efficacy questions were raised by the fact that bioequivalence studies measured only the parent compound or inactive metabolite rather than the low and transient concentrations of the active metabolite, present only briefly after dosing, as well as possible concerns with inter-patient variability [1722]. There have also been concerns among some authorities that any putative interaction between clopidogrel and proton pump inhibitors will be less well known initially for the generic salts. These concerns were in addition to patent issues in each European country, the latter leading to widely different dates when generics become available for prescribing [34]. Additionally, there have been issues regarding the functional integrity of CYP2C19 in patients as this could potentially affect the availability of the clopidogrel and hence outcomes in practice [2324]. As such, personalised medicine using tailored individualised antiplatelet treatment based on pharmacogenetic testing could be helpful in identifying which patients should be treated with clopidogrel and which with newer drugs such as prasugrel and ticagrelor. However, other studies have questioned this [2529]. In any event, this should not impact on the debate of whether generic or originator clopidogrel should be prescribed. Of potential greater importance is the widely different timescales that currently exists among European countries when authorising reimbursement for generics [1330].

The situation for health authorities and health insurance agencies was further complicated by the EMA recall in March 2010 of clopidogrel besylate produced by Glochem Industry Ltd’s manufacturing facility in India [3134]. The medicines concerned included Clopidogrel 1A Pharma, Clopidogrel Acino, Clopidogrel Acino Pharma, Clopidogrel Acino Pharma GmbH, Clopidogrel Hexal, Clopidogrel Ratiopharm, Clopidogrel Ratiopharm GmbH and Clopidogrel Sandoz. The marketing authorisation holder of all these products was Acino Pharma GmbH [3134], which held the market authorisation for the majority of early generics formulations. However, Acino and other companies have been able to source generic clopidogrel from other companies to overcome possible supply problems, with multiple companies and formulations now typically available across Europe. The originator manufacturer tried to take advantage of these recalls through pointing out the known quality of Plavix [35]. The impact of this approach though was reduced in reality by EMA approval of a number of generic clopidogrel formulations from different manufacturers. In addition, European health authorities and health insurance companies are continually seeking ways to fund new premium priced drugs and increased drug volumes from ageing populations within finite resources through encouraging greater generics utilisation, Table 1 as well as references 1 and 36 contain examples of different authority approaches across Europe to enhance generics utilisation with similar approaches among managed care organisations in the US [145836].

Consequently, the principal objective of this paper is to document health authority and health insurance agency responses to take advantage of the early availability of generic clopidogrel products. Secondly, to assess potential reasons preventing health authorities and health insurance agencies from taking full advantage of the early availability of generic clopidogrel, and potential ways to address this in the future. Finally, to determine the extent of price reductions that have been obtained by a range of countries for generic clopidogrel versus pre-patent loss originator prices in the initial months following generics availability. This aims to provide knowledge of how the future availability of generics in high expenditure areas can be accelerated, combined with measures to enhance their rapid uptake versus originators, to rapidly release valuable resources.

Table 1: 4E methodology of demand-side initiatives across Europe

Methods

We first performed a literature review of English language papers in PubMed, MEDLINE and Embase between 2005 and April 2011 using the keywords ‘generic clopidogrel’. But because this resulted in only a limited number of publications, e.g. only seven relevant English language papers were cited in PubMed, the literature search was supplemented by additional information, papers and web-based articles known to the many co-authors from health authorities, health insurance agencies and their advisers from across Australia, Europe and the Middle East regarding generic clopidogrel. This information was subsequently re-confirmed with each co-author by the lead co-author Dr Brian Godman to ensure the accuracy of the data provided, hence its robustness. This is an accepted technique where there is limited information publically available to achieve study aims [24673742]. No attempt was made to review the quality of the published studies using the methodology of the Cochrane Collaboration [43] in view of the paucity of peer-reviewed published studies.

Reimbursed prices for generic clopidogrel were either provided directly from the co-authors from their own internal sources based on the 75 mg tablet (Personal communications from: Mr Iain Bishop, Mr Thomas Burkhardt, Dr Jurij Furst, Dr Kristina Garuoliene, Dr Hanna Koskinen, Mr Ott Laius, Dr Catherine Sermet, Dr Peter Skiöld, Professor Ulrich Schwabe, Dr Agnes Vitry); alternatively from administrative databases (Republic of Serbia’s Health Insurance Fund database, Dr Marija Kalaba). The findings were again validated with pertinent co-authors to ensure accuracy. Data from administrative databases included reimbursed expenditure/defined daily dose (DDD)–with DDDs defined as ‘the average maintenance dose of the drug when used on its major indication in adults’ [44]–for both the originator and generics. This approach has been successfully used in previous publications when reviewing the impact of ongoing reforms to reduce generics prices versus originators to enhance future prescribing efficiency in Europe [24673740]. The countries reviewed were selected based on their different geographies, financial base for the healthcare system (taxation or insurance based) and population size to enable comprehensive comparisons of payer activities as well as reimbursed prices to provide examples to others. In addition in some countries, generic clopidogrel has only recently been reimbursed, see Table 2.

The demand-side measures initiated in each selected country to enhance the utilisation of generic clopidogrel have been taken from published sources supplemented with additional information from the co-authors. The latter approach providing most data in view of, as stated, limited available information in the public domain. Demand-side activities were again checked with pertinent co-authors to ensure the accuracy of the information provided. The various demand-side measures were subsequently collated using the 4E methodology, i.e. education, engineering, economics and enforcement, to simplify comparisons between countries, see Table 1. This approach has been successfully used in other settings to compare and contrast the influence of different demand-side interventions in practice [3463840].

Table 2: Individual countries’ health authorities and health insurance companies’ responses to enhance the prescribing and dispensing of generic clopidogrel

Table 2: (Continued)

Table 2: (Continued)

Table 2: (Continued)

Table 2: (Continued)

Results

Most health authorities and insurers have adopted a pragmatic approach towards differences in the salt and indications between the generic and the originator drug to enhance the prescribing of generic clopidogrel, see Table 2; with examples of pragmatic approaches documented in Table 3. However, this has not always been possible. For example, activities in Norway, Portugal and Slovenia have resulted in all or some versions of generic clopidogrel being removed from the market place for a period of time, see Table 2.

There has also been extensive education of physicians in some European countries to allay their fears about prescribing generic clopidogrel with different salts and indications, see Table 2. As a result, utilisation of generic clopidogrel has been enhanced thereby helping health authorities and health insurance agencies gain savings from the early availability of generic clopidogrel given the global expenditure on Plavix pre-patent loss [910].

The various measures instigated among countries to obtain low price of generics [24] has already resulted in appreciable price reductions in some countries. However, this was not universal with a 20-fold difference in reimbursed prices existing between countries in April to July 2011, see Table 4.

Conclusion

Health authorities and health insurance agencies have typically adopted a pragmatic approach to enhance the prescribing and dispensing of generic clopidogrel once available. As a result, valuable resources have been released from the early availability of generic clopidogrel. This is despite different salts and more limited indications initially versus the originator, coupled with the withdrawal of some formulations of generic clopidogrel from the market place due to manufacturing concerns.

Activities undertaken by health authorities and health insurance agencies to enhance the prescribing of generic clopidogrel, see Table 2, mirror those undertaken for other generics [24673740]. They also included extensive education among key stakeholder groups in some countries to enable health authorities and health insurance agencies to fully realise the finan-cial benefits from the early availability of generic clopidogrel. However, activities in some countries have not always been possible following successful challenges to the availability of generic clopidogrel, which led to the removal of all or some formulations for a period of time, see Table 2.

It may well be in the long term that compliance is a greater issue to maximise outcomes from clopidogrel than any perceived differences in bioavailability between formulations, mirroring the situation with other cardiovascular drugs [51]. Consequently, some of the resources released from the availability of generic clopidogrel could be used to address this issue to maximise the health gain from clopidogrel alone or in combination with aspirin among pertinent patients.

Table 3: Individual countries’ examples of pragmatic approaches towards the availability of generic clopidogrel

Table 4: Reimbursed/dispensed prices for generic clopidogrel among countries in April to July 2011

Alongside this, recent studies [6162] have further questioned the clinical utility of measuring CYP2C19 endorsing our earlier comments that this measurement should not impact on the debate of whether to prescribe generic or originator clopidogrel.

There was already considerable variation in reimbursed prices for generic clopidogrel versus the originator, see Table 4, mirroring the findings in other studies [2346]. Again the size of the country’s population does not appear to be responsible for these differences, confirming previous publications [37]. Price reductions appear to be determined largely by ongoing policies to enhance generics utilisation [1452]. It is likely though that in time reimbursed prices for clopidogrel will converge, driven largely by countries striving to release further resources from the increasing availability of generics [53]. This will be researched in future studies alongside the impact of the various policies in each country to enhance the prescribing of generic clopidogrel versus the originator, see Table 2.

In conclusion, payers across Europe are learning from each other how best to take full advantage of the early availability of generics, even when there are different salts and indications, to maximise the use of available resources. This will continue. However, as we have seen this is not always possible. We believe pharmaceutical companies should accept generics availability to enable continued funding of new premium priced products, and not try to delay their introduction through challenging reimbursement decisions. The alternative, as resource pressures continue growing, is limited or no funding for new drugs, which is not in the future interests of all key stakeholder groups [14854].

For patients

Pharmaceutical expenditure is typically the largest or equalling the largest component of expenditure in ambulatory, i.e. non-hospital, care. Consequently, the increasing availability of multiple sourced products (generics) once a product loses its patent is welcomed by health authorities and health insurance agencies as these can be provided at considerably lower costs than the originator. This is the case with generic clopidogrel with its price already only 12% of the cost of the originator within a few months in some European countries, with prices expected to fall further.

However, there can be concerns among physicians and patients with the effectiveness of a generic drug if this is provided as a different salt to the originator. The availability, and hence effectiveness of a generic drug, is tested though by the European authorities before such medications can become available to help address such fears. In this case, the European authorities found no bioavailability problems with different salts of generic clopidogrel compared to the originator substance. The European authorities go on testing generics to ensure trust in the system, and will remove generics if there are justified concerns. This happened with some of the manufacturers of generic clopidogrel giving further confidence in the system.

Health authorities and health insurance companies across Europe also typically found no issue with early formulations of generic clopidogrel despite different salts indications than the originator drug. Consequently, they typically took a pragmatic approach to encourage physicians to prescribe generic clopidogrel versus the originator to release considerable monies. Patients can also play their part by accepting generics that have been approved by the European authorities rather than the originators, with the monies released used to help maintain the European ideals of comprehensive and equitable health care in these difficult economic times especially in Europe.

Disclosure of financial interest

The majority of the authors are employed directly by health authorities or health insurance agencies or are advisers to these organisations. No author has any other relevant affiliation or financial involvement with any organisation or entity with a financial interest in, or financial conflict with, the subject matter or materials discussed in the manuscript.

Acknowledgements

The study was in part supported by grants from the Karolinska Institutet and the Swedish Reimbursement Agency. We thank Ms Margaret Ewan from HAI Global for her help with reimbursed prices in New Zealand.

No writing assistance was utilised in the production of this manuscript.

Provenance and peer review: Commissioned; externally peer reviewed.

Authors 

1Austrian Medicines and Medical Devices Agency, 9 Schnirchgasse, AT-1030 Wien, Austria
2 Institute for Pharmacological Research Mario Negri, 19 Via Giuseppe La Masa, IT-20156 Milan, Italy
3 Prescribing Research Group, University of Liverpool Management School, Chatham Street, Liverpool L69 7ZH, UK
4 Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden
5 Department of Medicine Solna, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Solna, SE-17176, Stockholm, Sweden
6 Centre for Pharmacoepidemiology, Karolinska Institute, Karolinska University Hospital, Stockholm, Solna, Sweden
7 Drugs and Medical Products Regulation, Health Authority Abu Dhabi (HAAD), PO Box 5674, Abu Dhabi, United Arab Emirates
8 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
9 Information Services Division, NHS National Services Scotland, 1 South Gyle Crescent, Edinburgh EH12 9EB, UK
10 Hauptverband der Österreichischen Sozialversicherungsträger, 21 Kundmanngasse, AT-1031 Wien, Austria
11 Health Insurance Institute, 24 Miklosiceva, SI-1507 Ljubljana, Slovenia
12 Medicines Reimbursement Department, National Health Insurance Fund, 147 Kalvarijų Str, LT-08221 Vilnius, Lithuania
13 Kassenärztliche Vereinigung Hessen, 15 Georg Voigt Strasse, DE-60325 Frankfurt am Main, Germany
14 Republic Institute for Health Insurance, 2 Jovana Marinovica, 11000 Belgrade, Serbia
15 Research Department, The Social Insurance Institution, PO Box 450, FI-00101 Helsinki, Finland
16 State Agency of Medicines, 1 Nooruse, EE-50411 Tartu, Estonia
17 Medicines Management, NHS North Lancashire, Moor Lane Mills, Moor Lane, Lancaster LA1 1QD, UK
18 HTA Consulting, 17/3 Starowiślna Str, PL-31038 Cracow, Poland
19 Norwegian Medicines Agency, 8 Sven Oftedals vei, NO-0950 Oslo, Norway
20 University of Heidelberg, Institute of Pharmacology, DE-69120 Heidelberg, Germany
21 IRDES, 10 rue Vauvenargues, FR-75018 Paris, France
22 Dental and Pharmaceuticals Benefits Agency (TLV), PO Box 22520, 7 Flemingatan, SE-10422 Stockholm, Sweden
23 CEFAR – Center for Health Evaluation & Research, National Association of Pharmacies (ANF), 1 Rua Marechal Saldanha, PT-1249-069 Lisbon, Portugal
24 Instituut voor Verantwoord Medicijngebruik, Postbus 3089, 3502 GB Utrecht, The Netherlands
25 Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide SA 5001, Australia
26 Ministry of Health, Republic of Croatia, Ksaver 200a, Zagreb, Croatia
27 Barcelona Health Region, Catalan Health Service, 30 Esteve Terrades, ES-08023 Barcelona, Spain

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Author for correspondence: Brian Godman, BSc, PhD, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden

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European payer initiatives to reduce prescribing costs through use of generics

Author byline as per print journal:  Brian Godman1,2,3, BSc, PhD; Bjorn Wettermark1,4, MSc, PhD; Iain Bishop5, BSc; Thomas Burkhardt6, MSc; Jurij Fürst7, PhD; Kristina Garuoliene8, MD; Ott Laius9, MScPharm; Jaana E Martikainen10, Lic Sc(Pharm); Catherine Sermet11, MD; Inês Teixeira12, BA, MSc; Corrine Zara13, PharmD; Lars L Gustafsson1, MD, PhD

Introduction: Pharmaceutical expenditure is increasingly scrutinised by payers of health care in view of its rapid growth resulting in a variety of reforms to help moderate future growth. This includes measures across Europe to enhance the utilisation of generics at low prices.
Methods: A narrative review of the extensive number of publications and associated references from the co-authors was conducted, supplemented with known internal health authority or web-based articles.
Results: Each European country has instigated different approaches to generic pricing, which can be categorised into three groups, with market forces in Sweden and UK lowering the prices of generics to between 3–13% of pre-patent loss originator prices. Payers have also instigated measures to enhance the utilisation of generics versus originators and patent-protected products in a class or related class. These can be categorised under the 4Es: education, engineering, economics and enforcement, with the measures appearing additive. The combination of low prices for generics coupled with measures to enhance their utilisation has resulted in appreciable cost savings in some European countries with expenditure stable or decreasing alongside increased utilisation of products in a class.
Conclusion: Reforms will increase as resource pressures continue to grow with the pace of implementation being likely to accelerate. Care though with the introduction of prescribing restrictions to maximise savings as outcomes may be different from expectations.

Submitted: 7 April 2011; Revised manuscript received: 15 October 2011; Accepted: 19 October 2011

Introduction

Pharmaceutical expenditure is increasingly scrutinised by payers in view of its rapid growth, outstripping growth in other components of health care [1-7]. This growth has resulted in pharmaceutical expenditure in ambulatory care becoming the largest, or equal to the largest, cost component in this sector [1, 3-9], with expenditure on drugs in ambulatory care typically appreciably greater than inpatient drug costs, particularly in Europe. This growth in pharmaceutical expenditure has been driven by well-known factors including changing demographics, rising patient expectations, strict clinical outcome targets, and the continued launch of new and expensive drugs [1, 3, 5, 6, 10].

As a consequence, third-party payers have introduced multiple reforms and initiatives in recent years to optimise the managed entry of new drugs and, in addition, to help control expenditure on existing drugs through encouraging the increased prescribing of generics at low prices [1, 2, 6, 7, 11-13]. The various measures to increase the prescribing of generics among existing molecules and classes, as well as their potential impact, will be appraised in this review article. A list of potential, additional measures that third-party payers could introduce as they seek further measures to help control their rising prescribing costs is also provided.

This review will be divided into two sections: firstly, the measures that have been instigated to lower the prices of generics; secondly, measures to enhance their utilisation. However, we acknowledge that there will be overlap between these two sections. The principal focus will be on Europe.

Pricing policies to help lower the pr ice of generics in Europe

Each European country has introduced different measures to lower the price of generics. However, the variety of measures can be categorised into three distinct approaches [1, 3, 4, 8, 11, 14-17]:
Prescriptive pricing policies: mandated price reductions for reimbursement, e.g. under the ‘stepped price’ model in Norway, there is an automatic 30% price reduction for the first generic versus the originator pre-patent loss prices, which increases to 55% or 75% reduction six months later depending on overall expenditure. There is a maximum 85% reduction for high expenditure generics after a further 12 months. In France, generics currently have to be 55% below pre-patent loss originator prices to be reimbursed, with further price reductions in subsequent years.
Market forces: market forces are used in a number of European countries to lower the price of generics. This is achieved by introducing a variety of demand-side measures that encourage the prescribing and dispensing of generics versus originator molecules, as well as lowering their prices. Market forces can be categorised by the 4Es: namely education, engineering, economics and enforcement. Table 1 gives the definition of each category alongside examples, with Table 2 documenting examples of initiatives to enhance the prescribing and dispensing of generics versus originators among European countries with different methods of financing health care, geographies, and epidemiology.
Mixed approach: a combination of prescriptive pricing for the first generic(s) with market forces after that, e.g. in Austria the first generic must be priced 48% below pre-patent loss originator prices to be reimbursed, second generic 15% below the first generic and the third generic 10% below the second (overall 60% below pre-patent loss prices). Market forces to further lower prices from the fourth generic onwards, with each new generic necessarily priced lower than the last one for reimbursement and physicians financially incentivised to prescribe the cheapest branded generic(s). In Finland, the price of the first generic must be 40% lower than the pre-patent originator price to be reimbursed. Prices of subsequent generics must not be higher than the first generic for reimbursement with market forces, including the need for additional co-payment for more expensive products than the reference priced molecule, helping to reduce prices.

Table 1: Definition and examples of the 4 Es
These are in addition to compulsory price cuts for both originators and generics instigated among some European countries as they struggle to contain rising pharmaceutical expenditure [1, 3, 5, 8, 9].

The different approaches to the pricing of generics has led to an appreciable variation in reimbursed prices for generics across countries, with prices varying up to 36-fold depending on the molecule [3, 20].

However, the general trend is for countries to introduce additional measures to lower their generics prices to maximise savings with countries continuing to learn from each other [3, 5, 8], introducing initiatives highlighted in Table 1. For instance, high volume generics in Sweden and UK are priced at between 3–13% of pre-patent loss prices through a variety of market force measures, some of which are highlighted in Table 2 [3, 7, 14, 21]. This is driven by global sales of products likely to lose their patents between 2008 and 2013 estimated at US$50 –US$100 billion (Euros 35 – Euros 70 billion) per year [22, 23], with global sales of pharmaceuticals estimated at US$820 billion (Euros 579 billion) in 2009 [24].

Demand-side measures to enhance the prescribing of generics

Currently, there is also an appreciable variation in the utilisation of generics across Europe. This includes the prescribing and dispensing of generics versus originators, as well as the prescribing of generics versus patent-protected products in a class or related classes. Table 2 contains examples of ongoing demand-side measures across Europe to enhance the prescribing and dispensing of generics versus originators, which resulted in high utilisation rates for generic omeprazole versus the originator and generic simvastatin versus the originator in 2007 in a recent cross-national study, see Table 3; full details of the measures undertaken to increase the utilisation of generics in individual European countries can be found in references 3 and 5.

European countries have also introduced a variety of different measures to encourage the prescribing of generics within a class. The objective is again to take advantage of the availability of lower priced generics in a class. As a result, these measures help fund increased drug volumes and new drugs without having to raise taxes or health insurance premiums. However, recent research has shown that among the proton pump inhibitors (PPIs), 3-hydroxy-3-methil-gluteryl-CoA reductase inhibitors (statins) and renin-angiotensin products, there is considerable variation in the prescribing of generics within a class or related classes once generics become available in a class [5, 8, 15, 26, 27]. Consequently, there are appreciable opportunities for countries to further enhance their prescribing of generics and lower their prescribing costs through learning from each other.

Table 2: Examples of market forces across Europe to enhance the prescribing and dispensing of generics collated under the 4Es

Examples of ongoing initiatives to increase the prescribing of generic products in a class, again broken down by the 4Es building on Tables 1 and 2, include [1, 4-8, 14-17, 27-29]:
Educational activities: local, regional and national formularies coupled with monitoring of prescribing patterns and academic detailing. One example is the ‘Wise Drug’ list in Stockholm County Council, which contains approximately 200 drugs covering conditions typically encountered in ambulatory care. Prescribing suggestions typically include older well-established and well-documented drugs, which are generally available as generics, rather than newly marketed drugs. Physician-prescribing patterns are continually benchmarked against the list and their colleagues to enhance adherence to the guidance, with the instigation of educational activities if needed.
Engineering activities: a number of European countries have instigated prescribing targets. These typically include the percentage of generic drugs within a class such as the percentage of generic PPIs versus all PPIs, percentage of generic statins versus all statins and percentage of angiotensin-converting enzyme inhibitors (ACEIs) versus all rennin-angiotensin drugs.
Economic interventions: financial incentives to physicians for achieving agreed prescribing targets in a class, as well as devolution of drug budgets to local general practitioner groups combined with regular monitoring of prescribing behaviour.
Enforcement: prescribing restrictions such as restricting the prescribing of patent-protected statins to second-line in Austria, Finland, Norway, and Sweden as well as restricting the prescribing of angiotensin receptor blockers (ARBs) to second-line in Austria and Croatia.

However, in countries with less intensive demand-side measures to combat industry and other pressures to prescribe patent-protected drugs, there is typically an increased prescribing of patent-protected products once multiple sources are available. Examples include increased prescribing of esomeprazole with decreased prescribing of omeprazole as a % of total PPI utilisation, which has been seen in France, Ireland, and Portugal [5, 8]. The reverse was seen in countries that have instigated multiple and intensive demand-side measures such as Spain (Catalonia), Sweden, and UK. A similar situation was seen with the statins, with increased utilisation of atorvastatin and rosuvastatin and decreased utilisation of simvastatin in countries with less intensive demand-side measures, with the exception of Portugal where the utilisation of all three statins increased following the availability of generic simvastatin [5, 8].

Table 3: Percentage utilisation of generics: two examples

The differences in price that can be obtained for generics in countries, coupled with measures to enhance their prescribing versus originators as well as patent protected products in a class, can have a profound impact on overall prescribing costs. Table 4 documents changes in reimbursed expenditure between 2001 and 2007 among western European countries for both PPIs and statins alongside changes in their utilisation [5, 8]. The introduction of reference pricing for both PPIs and statins in Germany appreciably increased the utilisation of omeprazole and simvastatin at the expense of esomeprazole and atorvastatin [5, 19, 25]. However, higher expenditure/defined daily doses for generic omeprazole and generic simvastatin compared with Sweden and UK limited efficiency gains in practice [30, 31].

Table 4: Differences in utilisation and reimbursed expenditure for proton pump inhibitors and statins

The different patterns seen in Table 4 resulted in appreciable differences in overall expenditure for the PPIs and statins among European countries in 2007 when adjusted for population sizes, see Table 5.

Table 5: Reimbursed expenditure in 2007 for proton pump inhibitors and statins

The quality of care does not appear to be compromised through initiatives to enhance the utilisation of generics. This demonstrates the potential of releasing considerable resources through the increased use of generics, see Table 5, without negatively affecting outcomes. This is further illustrated by health authorities and health insurance agencies typically viewing all PPIs as having similar effectiveness based on available data [5-8, 14, 19, 25]. They also generally believe generic statins can be used as first-line to treat patients with coronary heart disease and hypercholesterolaemia adequately, with patent-protected atorvastatin and rosuvastatin reserved for patients failing to achieve target lipid levels with, e.g. generic simvastatin [5-8, 11, 14, 15, 17, 19, 25]. These beliefs are endorsed by a recent ecological study, which showed that outcomes, in terms of the subsequent impact of drug treatment on lipid levels, were similar whether patients were prescribed formulary drugs (including generic simvastatin) versus non-formulary drugs, which included patent-protected statins [32]. Published studies have also shown that patients can be successfully switched from atorvastatin to simvastatin without compromising care [33], and physicians in UK extensively prescribe generic simvastatin to achieve agreed target lipid levels in the quality and outcomes framework to help maximise their income [14, 21, 34, 35]. Alongside this, pharmaceutical companies have failed to provide reimbursement agencies with any published studies documenting increased effectiveness of ARBs versus ACEIs to support premium prices for ARBs [26, 27]. In addition, only 2–3% of patients in the ACEI clinical trials actually discontinued ACEIs due to coughing [36, 37], and a recent ecological study again showed that outcomes, in terms of the subsequent impact of drug treatment on blood pressure, were similar whether patients were prescribed formulary drugs (including generic ACEIs) versus non-formulary drugs, which included patent-protected ARBs [32]. As a result, generic ACEIs can be prescribed first line with patent-protected ARBs reserved for patients where there are concerns with side effects without compromising outcomes.

Finally, care may be needed when considering the introduction of prescribing restrictions (enforcement). This is because their nature and follow-up appear to influence subsequent utilisation patterns appreciably [4, 15, 17, 26]. For instance, the prescribing restrictions for patent-protected statins, atorvastatin and rosuvastatin, had less influence on increasing the utilisation of generic statins, e.g. simvastatin, in Norway versus Austria and Finland. This was the result of having no prior authorisation scheme in Norway, unlike Austria, or no close scrutiny over prescriptions as seen in Finland [4, 15, 17]. In Austria, atorvastatin and rosuvastatin can only be reimbursed if physicians obtain agreement from the Chief Medical Officer of the patient’s Social Health Insurance Fund [4]. The Norwegian authorities also recently introduced prescribing restrictions for esomeprazole. However, hospital specialists in Norway have to verify the diagnosis and recommend therapy before PPIs are reimbursed, and they are not subject to the same restrictions [15]. This reduced the influence of the prescribing restriction in practice, with physicians generally reluctant to deviate from the initially prescribed drug or the advice for the prescription if this was for esomeprazole [15].

Conclusion

The differences between the extent and intensity of supply- and demand-side measures encouraging the prescribing of generics at low prices led to over tenfold difference in reimbursed expenditure for the PPIs and statins in 2007 between European countries when adjusted for populations, see Table 5. However, there was greater morbidity among the Irish population studied [5, 8]. Consequently, there are considerable opportunities for countries to learn from each other to reduce their prescribing costs, especially with the influence of demand-side measures appearing additive.

Both supply- and demand-side measures are thought to be important to limit costs, with countries limiting the extent of any potential efficiency gain if they principally concentrate on one set of measures. For example, in Germany, the reimbursed prices for generics are appreciably higher than seen in UK, which limited potential savings in reality [38]. The limited number of demand-side measures in Portugal also reduced their efficiency gains from recent initiatives to lower generic prices [3, 5, 8]. This is changing with recent reforms. However, payers are urged to consider the nature of any prescribing restrictions they may seek to introduce, and their follow-up, when they forecast the possible influence of these measures, as there could be appreciable differences from expectations [15, 26, 27].

We are already seeing countries learning from each other to identify new initiatives to enhance their prescribing efficiency, i.e. increased drug utilisation at similar or lower costs. Examples include greater transparency in the pricing of generics, prescribing targets, physicians’ financial incentives, compulsory prescribing with the international non-proprietary name, and prescribing restrictions [1, 3, 5, 6, 8, 18]. It is likely that the pace of implementation of what has been learned will accelerate to maintain the European ideals of universal, affordable, and comprehensive health care, especially given the current financial concerns coupled with ongoing pressures. This will need to be reviewed in future publications.

For patients

The costs of health care are rising across Europe through ageing populations resulting in greater prevalence of patients with chronic diseases, stricter clinical targets for managing patients with long term (chronic) diseases, the continued launch of new and more expensive drugs as well as rising patient expectations. The provision of generics (multiple sourced products once the original product loses its patent) at considerably lower prices than the price of the originator just before it lost its patent, and with similar effectiveness and safety to the originator through strict licensing regulations, allows European governments to continue to provide comprehensive and equitable health care without prohibitive increases in either taxes or health insurance premiums. This paper discusses a number of measures introduced by health authorities or health insurance companies in recent years to increase the prescribing and dispensing of generics, with countries continuing to learn from each other as cost pressures continue growing.

Disclosure of financial interest

The majority of the authors are employed directly by health authorities or health insurance agencies or are advisers to these organisations. No author has any other relevant affiliation or financial involvement with any organisation or entity with a financial interest, in or financial conflict with, the subject matter or materials discussed in the manuscript.

This study was in part supported by grants from the Karolinska Institutet.

Acknowledgement

We acknowledge the help of INFARMED with providing NHS data on Portugal.

Author and co-authors

1Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden
2Prescribing Research Group, University of Liverpool Management School, Chatham Street, Liverpool L69 7ZH, UK
3Institute for Pharmacological Research Mario Negri, 19 Via Giuseppe La Masa, IT-20156 Milan, Italy
4Public Healthcare Services Committee, Stockholm County Council, Sweden
5Information Services Healthcare Information Group, NHS Scotland, 1 South Gyle Crescent, Edinburgh EH12 9EB, UK
6Hauptverband der Österreichischen Sozialversicherungsträger, 21 Kundmanngasse, AT-1031 Wien, Austria
7Health Insurance Institute, 24 Miklosiceva, SI-1507 Ljubljana, Slovenia
8Medicines Reimbursement Department, National Health Insurance Fund, 1 Europas a, LT-03505 Vilnius, Lithuania
9State Agency of Medicines, 1 Nooruse, EE-50411 Tartu, Estonia
10Research Department, The Social Insurance Institution, PO Box 450, FI-00101 Helsinki, Finland
11IRDES, 10 rue Vauvenargues, FR-75018 Paris, France
12CEFAR – Center for Health Evaluation and Research, National Association of Pharmacies (ANF), 1 Rua Marechal Saldanha, PT-1249-069 Lisbon, Portugal
13Barcelona Health Region, Catalan Health Service, 30 Esteve Terrades, ES-08023 Barcelona, Spain

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Author: Brian Godman, BSc, PhD, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden

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Source URL: http://gabi-journal.net/european-payer-initiatives-to-reduce-prescribing-costs-through-use-of-generics.html


Payers endorse generics to enhance prescribing efficiency: impact and future implications, a case history approach

Author byline as per print journal: Brian Godman1,2,3, BSc, PhD; Mohammed Abuelkhair4, PharmD; Agnes Vitry5, PharmD, PhD; Shajahan Abdu4, MD; Marion Bennie6,7, MSc; Iain Bishop7, BSc; Sahar Fahmy4, PhD; Kristina Garuoliene8, MD, PhD; Harald Herholz9, MPH; Andrew Martin10, BSc, MPharmS; Rickard E Malmstrom11, MD, PhD; Professor Saira Jan12,13, PharmD, PhD; Ulrich Schwabe14, MD, PhD; Catherine Sermet15, MD; Peter Skiold16, MSc, PhD; Luka Voncina17, MD, MSc, Professor Lars L Gustaffson3, MD, PhD

Introduction: Pharmaceutical expenditure continues to rise driven by a number of factors including ageing populations and the continued launch of new premium-priced drugs. Increasing use of generics versus originators and patent-protected products of the same or related classes can help conserve valuable resources. However, concerns with their effectiveness and safety compared to originators as well as only limited introduction of measures to promote their demand in some countries have led to variable use among countries. Countries need to learn from each other to further enhance their prescribing efficiency.
Study Objectives: Firstly to review successful case histories from different countries, and secondly, raise awareness about potential pitfalls that could undermine the success of future measures in order to provide future guidance on conserving resources in relation to generics.
Methods: A narrative review of case histories selected by co-authors using a range of different approaches. Systematic reviews are published elsewhere.
Results: Twelve case histories were selected depicting both supply- and demand-side measures. These include Croatia where the introduction of additional measures helped reduce drug expenditure as well as debt whilst improving access to new medicines, Lithuania where recent reforms decreased pharmaceutical expenditure in 2010 whilst the number of prescriptions increased by 9% versus 2009; Scotland where despite a 6.2 fold increase in statin utilisation, multiple measures limited the increase in reimbursed expenditure to just 7% in 2010 vs 2001; Sweden where the introduction of monthly auctions for generics has helped lower prices; and the US where managed care organisations actively encourage cross therapeutic opportunities for generics substitution where the safety and efficacy of a generic drug is similar to a patent-protected product in the class or related class to conserve resources.
Conclusion: Payers across Australia, Europe, Middle East (United Arab Emirates), and US have introduced multiple measures to both enhance the prescribing of generics and obtain lower prices, with the result that they are increasingly able to take advantage of the availability of generics. However, due to growing pressures on healthcare resources, it is important that countries accelerate the sharing of lessons learned about which policies and new measures are most effective in controlling costs.

Submitted: 13 September 2011; Revised manuscript received: 24 April 2012; Accepted: 6 May 2012 

Introduction

There is increasing scrutiny over pharmaceutical expenditure in view of its greater growth compared with other components of health care [1]. Pharmaceutical expenditure currently accounts for up to 60% of total healthcare costs in some countries [2]. This increasing scrutiny has stimulated many reforms and initiatives to moderate future growth. These include measures to increase the prescribing of generics versus originators at lower prices than originators; other measures aim to increase the prescribing of generics versus patent-protected products in the same or related classes [3-18]. Our paper in the first issue of the GaBI Journal gave examples of the different supply- and demand-side measures that are being used by health authorities and health insurance agencies to achieve these aims [1]. The objective of these measures is to help maintain comprehensive health care, particularly in Europe where there is continued pressure on resources, without prohibitive increases in taxes or health insurance premiums. One reason for the pressure on resources is the continued funding of new innovative premium-priced drugs. Additional measures stem from an increased volume of drugs being used due to stricter clinical targets, rising patient expectations and ageing populations [3-5, 8, 9, 11, 19].

In Europe, in order to receive market authorisation, generic medicines have to demonstrate they have the same qualitative and quantitative composition as well as the same pharmaceutical formulation and bioavailability, as the originator medicine [20-23]. In addition, there must be no prior intellectual property associated with the generic drug [20, 22, 23]. In view of this, payers typically assume that if two medicines have the same bioavailability they should have a similar therapeutic effect. This appears generally to be the case and applies even when the generic drug is in the form of a different salt to the originator as well as different indications initially, as seen with generic clopidogrel [24]. Two recent comprehensive reviews illustrate this by comparing the outcomes between generic and originator drugs for the treatment of two widely different dis­eases [25, 26]. The first review considered treatments for epi­lepsy and found no evidence of association between loss of seizure control and treatment with at least three types of anti­epileptic drugs, one of which was phenytoin [25]. Similarly, the second review, which focused on the treatment of cardio­vascular disease, did not demonstrate superiority in outcomes for originators compared to generic drugs [26]. This included drugs with a narrow therapeutic index such as propafenone and warfarin [26]. Therefore, generic medicines can help con­serve valuable resources without compromising the quality of care [1, 3-6, 8, 13-17, 20, 27].

Many different measures and initiatives have increased prescribing efficiency in Europe, and are summarised in a previous edition of the GaBI Journal [1, 27].

These resulted in generic medicines in Europe comprising 50% of the volume of dispensed drugs but only 18% of the expen­diture on drugs in 2006 [19, 28], leading to estimated annual savings of Euros 25 billion per year among the 27 nations in the EU [28]. Expenditure on generics in Europe was 21% in 2007, with the EU accounting for 30% of worldwide sales of generics in 2007 [28]. The extent of the savings is helped by estimated price reductions of between 30% to 90% for generics versus originator prices just prior to patent loss, with typically between 10 to 30 manufacturers competing to supply the differ­ent generic products in each market [20, 27, 28].

In the US, the prescribing of generics is also gaining ground. For example, published studies have consistently shown that among managed care organisations (MCOs) co-payment tier levels three and four are associated with decreased use of pre­scription drugs [29]. This even applies to patients with chronic conditions with higher morbidity and mortality such as dia­betes, hypertension and hypercholesterolemia [29]. On the other hand, there is improved adherence to drug therapy if patients are prescribed generic drugs with typically the lowest co-payment levels—Tier One [29]. These findings [29] are fur­ther substantiated with recent research reporting that ‘dispense as written’ requests from physicians in the US, aimed at reduc­ing generics substitution leading to higher co-payments, were again associated with decreased rates of prescription filling [30].

However, there are concerns with the effectiveness and tolerability of generics compared with originator drugs [3, 7, 24, 31-37], with some originator companies questioning the quality of generics as part of their marketing strategies to reduce the ero­sion of sales which follow patent loss [38]. Whilst these con­cerns typically only apply to a minority of situations [34, 36, 39], as demonstrated for instance by ‘dispense as written’ prescrip­tions only accounting for 2.7% of prescriptions written by phy­sicians in the US [30], failure by health authorities, physicians and pharmacists to adequately address these concerns will mean reduced savings in reality [3-5, 17, 40]. Potential concerns regarding the effectiveness and tolerability of generics, and associated reduced savings from lower utilisation rates, have stimulated health authorities and health insurance agencies to instigate new initiatives to address these concerns, see Tables 1, 2 and 3.

There are also concerns among payers at the considerable varia­tion in the price of generics. These can vary up to 36 fold among European countries and India, and greater than 50 fold among developing countries, depending on the molecule [2, 4, 20]. The price differences are independent of the population size of the country or levels of income [10, 41], and are leading some countries to continually review their generics pricing strategies so as to enhance resource savings [3, 4, 7, 9-16]. There is also wide variation across Europe in the utilisation of generics versus patent-protected products in the same class or related class [4, 5, 8, 11]. Reducing this variation will likewise enable payers to conserve additional resources as generic drugs become increasingly available [4, 8, 12, 13].

In the future it is likely there will be further expansion in the manufacture and availability of generics, given the likely size of the market. For example, global sales of pharmaceuticals were estimated at US$820 billion in 2009 [1]. However between 2011 and 2016, products with current sales of US$255 billion per year are likely to lose their patents [42]. This is in addition to high volume products that have already lost their patents in the past decade including various proton pump inhibitors (PPIs), statins, selective serotonin re-uptake inhibitors (SSRIs) and angiotensin converting enzyme inhibitors (ACEIs), helping to conserve resources [1, 4, 5-9, 11, 16, 18, 43].

As a result of the burgeoning availability of generics, and the concerns outlined above, payers need to continue to learn from each other regarding potential additional measures to further conserve costs as resource pressures grow.

Study objectives

The principal objective of this paper is to produce guidance on potential ways to conserve resources around the use of generics especially to payers of health care. To this end, this paper firstly reviews measures that have been successfully introduced in dif­ferent countries; secondly, potential pitfalls that could arise. The latter needs to be heeded to optimise potential savings from the increasing availability of generics.

Methods

This is a narrative review of case histories. There is no system­atic review of initiatives to enhance the utilisation of generics at low prices since these reviews have already been undertaken and published elsewhere including those by the co-authors [4, 5, 8, 11, 18, 27].

The case histories have been selected by co-authors to meet the objectives of the paper rather than document a specific number of case histories from each continent. They have been divided into those predominantly concerned with supply-side measures, those predominantly discussing demand-side measures, those combining both approaches, and finally those where payers have not always been able to fully realise potential savings.

Table 1: Selected successful country case histories principally dealing with supply-side measures
Table 1: Selected successful country case histories principally dealing with supply-side measures (continued)

Where possible, each case history documents the measures undertaken as well as the outcomes. No set format has been used to document the measures undertaken as their nature varies by country depending on the current situation and circumstances. In addition, in some countries there is an iterative approach to successive reforms such as Australia.

Whilst this may represent a limitation to the study design, we have counter-balanced this by including as co-authors those directly involved in implementing the reforms. Consequently, we believe this approach provides the most comprehensive and accurate insight into the situation in the respective coun­tries. This approach has worked well in previous publications [1, 3-11, 14-18], and is seen as preferable to obtaining informa­tion solely through interviews.

Results

As discussed under methodology, selected case histories have been divided into those predominantly concerned with supply­side measures, see Table 1; those documenting predominantly demand-side measures, see Table 2; as well as those combining both approaches, see Table 3.

However, there have been situations where health authorities and health insurance agencies have failed to realise the full resource benefits from the availability of generics, although this is changing through the instigation of additional measures, see Table 4.

Discussion

As can be seen in Tables 1 to 4, payers across Europe, Middle East (United Arab Emirates), Australia and the US have intro­duced a range of measures to try and enhance the utilisation of generics as well as obtain lower prices, in order to try and maximise the opportunity that generics provide for conserving valuable resources.

Successful supply-side measures include aggressive pricing of the generics as seen in Lithuania, see Table 3, as well as increased transparency in the pricing of generics to further lower generics prices. The latter is seen in the UK, see Table 3. As discussed, the situation in Lithuania, see Table 3, demon­strates that it is possible for European countries with small populations to obtain low prices for their drugs despite the rhetoric [10, 60]. As a result, this helps to continue providing access to drugs even though drug budgets are being cut. This is also seen in Croatia with their extensive range of princi­pally supply-side measures, see Table 1, regarding the pricing of generic and other drugs for the molecule (ATC Level 5) as well as the class (ATC Level 3 and 4). The various measures in Croatia helped engineer sufficient budgetary space to reduce the budget arrears to pharmacies as well as increase the avail­ability to new drugs [13].

The monthly auction for generics prices in Sweden is a novel approach, which can potentially be transferable across countries. However, more analysis needs to be undertaken before this can occur, see Table 1. The specific contracting between pharma­ceutical companies and individual sickness funds in Germany is also an interesting development, see Table 1. However, poten­tially greater savings could occur through more aggressive pric­ing policies for generics, see Table 1A. These though may take considerable time to implement; consequently, current practices in Germany could be a good compromise.

Table 1A: Price comparison of 50 leading generics and out of patent drugs with products reimbursed in Germany and UK (England and Wales)
Table 1A: Price comparison of 50 leading generics and out of patent drugs with products reimbursed in Germany and UK (England and Wales) (continued)
Table 1A: Price comparison of 50 leading generics and out of patent drugs with products reimbursed in Germany and UK (England and Wales) (continued)

Demand-side measures to address physician and patient con­cerns have been successfully introduced in France leading to appreciable savings when combined with prescriptive pricing policies for generics, see Table 2. As a result, this provides direc­tion to other countries faced with similar concerns. Similarly, the recent initiatives among MCOs in the US to enhance the use of generics within a class to improve both the quality and efficiency of care, especially where the outcome and safety of new drugs has not been established, also provides direction to other countries. This mirrors the situation in for instance Stockholm in Sweden with its ‘Wise List’ of approximately 200 recommended drugs in ambulatory care [64]. These are predom­inantly well-established generic drugs, with a recent ecological study showing no difference in surrogate measures in patients with diabetes, hypertension of hypercholesterolaemia between patients prescribed well-established generic drugs compared with those prescribed patent-protected drugs; however consid­erable differences in costs [65].

Table 2: Selected successful country case histories principally dealing with demand-side measures to enhance the prescribing of generics

Table 2: Selected successful country case histories principally dealing with demand-side measures to enhance the prescribing of generics (continued)

The combination of multiple supply- and demand-side measures has appreciably improved prescribing efficiency for high volume drugs in Scotland, also providing direction to other countries, see Table 3. An important message, based on the experiences of NHS Bury, is for health authorities and health insurance agen­cies to pro-actively monitor products shortly losing their patent and plan for this through switching and other activities where this is possible, see Table 3. As a result, fully capitalise on gener­ics as soon as they become available.

Table 3: Selected successful country case histories principally dealing with both supply- and demand-side measures
Table 3: Selected successful country case histories principally dealing with both supply- and demand-side measures (continued)
Table 3: Selected successful country case histories principally dealing with both supply- and demand-side measures (continued)

Additional measures to enhance the prescribing of generics include compulsory or voluntary INN prescribing. This has the potential to reduce patient confusion where patients are prescribed a different brand of generics at each pre­scription [9, 66] as well as the potential for duplication of prescriptions. In addition, reduce the need for pharmacists to spend time addressing possible confusion among patients with associated costs. These issues will be explored further in future issues of this journal.

Potential pitfalls to avoid, based on the experiences of the co-authors, include not fully addressing all key stakeholders when initiating reforms to encourage the prescribing and dis­pensing of generics as seen in Abu Dhabi, see Table 4. However, this is now being addressed. In addition, not allowing phar­macists to dispense the cheapest drug once multiple sources are available, which is typically a generic versus an originator drug, in all but a minority of situations that could compromise patient care. Alongside this, delaying the instigation of measures to enhance INN prescribing, compulsory substitution, as well as other measures to enhance the prescribing of particular generics need to be discussed and agreed in advance of their availability, to enhance physician acceptance as seen in Abu Dhabi, Austria and Sweden [7, 14, 17, 49].

Table 4: Country case histories where health authorities have failed to realise the full benefits from the availability of generics
Table 4: Country case histories where health authorities have failed to realise the full benefits from the availability of generics (continued)

Other pitfalls to avoid include long delays between marketing authorisation and the reimbursement of a generic drug [19]. These issues are also currently being addressed to enable payers to take full financial advantage of the availability of generics. There have also been situations where generics companies have been able to launch new generics ahead of patent loss by launching them in different salts to those of the originator such as generic clopidogrel. This is outside the scope of this paper, but has been explored elsewhere in this issue of the GaBI Journal.

As discussed, we accept there are limitations with the study design. However, we believe the selected case histories provide useful lessons to other countries regarding which measures could potentially further enhance their prescribing efficiency. The sharing of information about potential policies and measures is vital if Europe is to maintain the ideals of comprehensive and equitable health care. Similarly, in the US, given current finan­cial concerns, there is a greater need than ever before for further measures to help stem the rise in pharmaceutical expenditure.

Conclusion

Payers across countries have successfully introduced multiple supply- and demand-side measures to improve prescribing efficiency through increased use of generics versus originators and patent-protected products in the same or related classes as well as measures to obtain low prices for generics. As a result, they are increasingly able to take full advantage of the availability of generics.

However, this has not always been possible. It is important though that countries continually share their experiences, and even start to accelerate the sharing of lessons learned about which policies and new measures appear the most effective, as resource pressures grow. The alternative is insufficient funds to cover the costs of increased drug volumes or new innova­tive drugs, both of which are not in the best interests of all key stakeholder groups.

For patients

Expenditure on pharmaceuticals is a growing concern among health authorities and health insurance agencies as it is now the largest or equalling the largest component of expenditure in ambulatory, i.e. non-hospital, care. In addition, utilisation and expenditure on pharmaceuticals will continue growing driven by a number of factors including ageing populations, and hence a growing prevalence of chronic diseases leading to greater use of drugs, as well as new drugs being launched that are typically more expensive than existing drugs.

Consequently, health authorities and health insurance agencies welcome the availability of generics as these are priced lower than the originators to help ease resource pressures especially in these difficult economic times. However, the extent of the pre­scribing and dispensing of generics versus originators, as well as similar patent protected drugs in the same class to treat the same patients, varies considerably among countries. This can be due to concerns with the effectiveness of generics versus originators. However, this has been found not to be the case in extensive studies, especially with the tests required by the authorities to demonstrate similar bioavailability between generics and origi­nators before products are launched onto the market. There are also considerable differences in the prices of generics among countries.

Health authorities and health insurance agencies need to tackle both these issue to release considerable resources to help fund comprehensive and equitable health care particularly in Europe without prohibitive increases in either taxes or health insurance premiums. Consequently, they need to learn from each other with respect to measures that have been successful in other countries to enhance the prescribing and dispensing of generics at increasingly lower prices, as well as the pitfalls to avoid. The case histories described in this paper help them to achieve this aim.

Disclosure of financial and competing interests

All authors have been especially invited for their direct role in introducing policy initiatives with regard to generics in their regions or countries, drawn from relevant health authorities or health insurance companies and their advisers. All authors have taken full part in the compilation and production of this paper.

Mohammed Abuelkhair (Abu Dhabi), Agnes Vitry (Australia), Shajahan Abdu (Abu Dhabi), Marion Bennie (Scotland, UK), Iain Bishop (Scotland, UK), Sahar Fahmy (Abu Dhabi), Karuoliene Garuoliene (Lithuania), Harald Herholz (Germany), Saira Jan (USA), Andrew Martin (UK), Rickard Malmström (Sweden), Ulrich Schwabe (Germany), Catherine Sermet (France), Peter Skiöld (Sweden), Luka Von ina (Croatia), are employed directly by health authorities, physician associations (Germany) or health insurance agencies, or are advisers to these organisations.

No author has any other relevant affiliation or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

No writing assistance from commercial organisations was utilised in the production of this manuscript.

This study was in part supported by grants from the Karolinska Institutet.

Provenance and peer review: Commissioned; externally peer reviewed.

Authors

Institute for Pharmacological Research Mario Negri, 19 Via Giuseppe La Masa, IT-20156 Milan, Italy
Prescribing Research Group, University of Liverpool Management School, Chatham Street, Liverpool L69 7ZH, UK
3 Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden
Drugs and Medical Products Regulation, Health Authority Abu Dhabi (HAAD), PO Box 5674, Abu Dhabi, United Arab Emirates
5 Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide SA 5001, Australia
6 Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
7  Information Services Division, NHS National Services Scotland, 1 South Gyle Crescent, Edinburgh EH12 9EB, UK
Medicines Reimbursement Department, National Health Insur­ance Fund, Europos a., LT-03505 Vilnius, Lithuania
Kassenärztliche Vereinigung Hessen, 15 Georg Voigt Strasse, DE-60325 Frankfurt am Main, Germany
10 NHS Bury, 21 Silver Street, Bury BL9 0EN, UK
11 Department of Medicine, Clinical Pharmacology Unit, Karolin­ska Institutet, Karolinska niversity Hospital Solna, SE-17176 Stockholm, Sweden
12 Department of Pharmacy Practice and Administration, William Levine Hall, Rm 416, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, NJ 08854, USA
13 Horizon Blue Cross Blue Shield of New Jersey, New Jersey, USA
14 University of Heidelberg, Institute of Pharmacology, DE-69120 Heidelberg, Germany
15 IRDES, 10 rue Vauvenargues, FR-75018 Paris, France
16 Dental and Pharmaceuticals Benefits Agency (TLV), PO Box 22520, 7 Flemingatan, SE-10422 Stockholm, Sweden
17 Ministry of Health, Republic of Croatia, 200a Ksaver, HR-10000, Zagreb, Croatia

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Author for correspondence: Brian Godman, BSc, PhD, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden

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