The editors and publisher wish to express their gratitude to the colleagues listed below for their valuable contribution to the peer review process for the Generics and Biosimilars Initiative Journal(GaBI Journal) in 2012.
Ms Arpah Abas, Malaysia
Dr Ibrahim Alshwaier, Saudi Arabia
Professor Saleh Alsuwayeh, Saudi Arabia
Dr Christoph Baumgärtel, Austria
Professor Daniel Benjamin, USA
Professor Majid Cheraghali, Iran
Professor Moses Chow, USA
Dr Joshua Cohen, USA
Mr Alessandro Curto, Italy
Professor Theodor Dingermann, Germany
Professor Wolfgang Frieß, Germany
Professor Livio Garattini, Italy
Dr Brian Godman, UK
Mr Andy Gray, South Africa
Professor Lars Gustafsson, Sweden
Dr Kalle Hoppu, Finland
Dr Toru Kawanishi, Japan
Dr Nana Kawasaki, Japan
Professor Marc Koopmanschap, The Netherlands
Dr Ged Lee, UK
Dr Frits Lekkerkerker, The Netherlands
Professor Bryan Liang, USA
Professor Alan Lyles, USA
Dr Janice Reichert, USA
Professor Martin Schultz, Germany
Dr Andreas Seiter, Germany/USA
Professor Hannsjörg Seyberth, Germany
Professor Steven Simoens, Belgium
Professor Fatima Suleman, South Africa
Dr Robin Thorpe, UK
Ms Katelijne van de Vooren, Italy
Professor Robert van der Stichele, Belgium
Dr Sabine Vogler, Austria
Professor Arnold Vulto, The Netherlands
Professor Philip Walson, USA/Germany
Professor Markus Zeitlinger, Austria
Abstract:
The European Organisation for Research and Treatment of Cancer (EORTC) has updated its 2006 guideline on the use of granulocyte colony-stimulating factor (G-CSF) for the prevention of febrile neutropenia (FN), a sometimes fatal condition in which a loss of neutrophils in patients receiving chemotherapy leads to infections and fever. The guideline provides recommendations on the assessment of risk factors for FN, and the choice of G-CSF formulation.
Submitted: 4 February 2013; Revised: 6 February 2013; Accepted: 7 February 2013; Published online first: 12 February 2013
Background
Patients undergoing chemotherapy for cancer are at risk of developing febrile neutropenia (FN), a condition in which a loss of neutrophils leads to infection, fever and sepsis, and is fatal in 9.5 to 12.5 per cent of cases. Patients aged over 65, and those undergoing myelosuppressive therapy appear to be most at risk, and may have their chemotherapy delayed, or treatment doses reduced, to minimize the effects of FN. As a consequence, they are then more prone to treatment failure and poorer clinical outcome with regard to their cancer, particularly solid tumours and lymphoma.
Prophylactic treatment is available in the form of G-CSF, which boosts and replenishes the body’s supply of neutrophils. This preventive measure reduces hospital admissions, antibiotic use and the need for dose-reduction. Treatment can be with one of several approved forms of recombinant G-CSF, including filgrastim and its biosimilars, or the pegylated version of filgrastim. All three are considered equivalent in clinical efficacy and safety. Their use, however, requires caution, and needs to be limited to patients who are deemed to be most at risk of FN.
To help guide the decision-making process for managing patient treatment and care, EORTC set up a working party in 2005 to systematically review available data and derive evidence-based recommendations on the most appropriate way to use G-CSF in adult patients undergoing chemotherapy. This European Guidelines Working Party published its first set of recommendations in 2006. These guidelines were revised in 2010 following a new systematic review owing to several developments, including the understanding of the factors that predispose patients to the onset of FN, and the availability of new models for assessing risk [1].
Issues considered for the guideline updates
The updated guideline, which is intended to complement the previously published European Society for Medical Oncology (ESMO) guideline on the use of G-CSF for prevention of chemotherapy-induced FN in patients with cancer, takes into account a range of issues regarding different potential risk factors that affect the likelihood of patients developing FN.
Febrile neutropenia is defined as an absolute neutrophil count of < 0.5 x 109/L, or 1.0 x 109/L predicted to fall below 0.5 x 109/L within 48 hours, with fever or clinical signs of sepsis. Fever is defined as a rise in auxiliary temperature to > 38.5°C sustained for at least one hour.
Among the issues considered for the guideline update was the assessment of risk that a patient will develop FN. Risk factors which affect the likelihood of this include the tumour type, chemotherapy regime such as the type, frequency and dosage of chemotherapeutic agents, and patient-related factors such as whether they have experienced FN previously. Various risk indices are available for assessing who is most likely to develop FN, including that produced by the Multinational Association for Supportive Care in Cancer (MASCC) in which a score of 21 or above indicates low risk.
There is consensus that treatment with G-CSF should be given to a patient with solid tumour or lymphoma if their risk goes above a threshold of 20 per cent, according to guidelines from Canada, Europe (EORTC and ESMO) and USA (American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN)).
Another issue that clinicians have to contend with is whether or not to give prophylactic antibiotic medication instead of, or in combination with, G-CSF. Caution is generally stressed with regard to antibiotics owing to the need to minimize the development of antibiotic resistant infections. G-CSF may therefore appeal as an alternative way to minimize the risk of infections and fever in patients undergoing chemotherapy, but then clinicians must weigh up the potential adverse effects of G-CSF treatment. These include a small risk that patients may develop secondary cancer, such as myelodysplastic syndrome, acute myeloid leukaemia, or acute lymphoblastic leukaemia.
Updating the guideline involved a new review of literature published between 2006 and July 2009, on studies concerning adults aged 18 and over, with solid tumours or lymphoma, as well as evidence presented at meetings held between April 2006 and December 2009. EORTC also took into account the 2009 NCCN and 2006 ASCO guidelines.
Summary of the 2010 EORTC guideline updates
Recommendation 1: patient-related risk factors for increased incidence of FN and complications of FN
The updated guideline confirms that patients are at increased risk of FN if the patient:
is aged 65 years or over
is at an advanced stage of disease
has had previous experience of FN
has had prior chemotherapy or has intense chemotherapy scheduled.
The recommendations on the process of evaluating risk factors remain in line with previously published guidelines.
Recommendation 2: chemotherapy regimens associated with increased risk of FN
New targeted agents added to chemotherapy regimens can exacerbate myelosuppression and hence febrile neutropenia, for example, in patients with non-small cell lung cancer given cetuximab or bevacizumab. The updated guideline lists some of the various drug combinations that have a potentially elevated risk of FN and note that, ‘Consideration should be given to the elevated risk of FN when using certain chemotherapy regimens.’ Furthermore, they stress, ‘this list is not comprehensive and there may be other drugs or regimens associated with an increased risk of FN.’
Recommendation 3: G-CSF to support intensive chemotherapy regimens
Based on consistent findings in the more recent literature, the updated guideline continues to support the use of prophylactic G-CSF to facilitate the delivery of dose-dense (increased frequency) and dose-intense (increased dose) chemotherapy in an attempt to improve long-term clinical outcomes. This is particularly recommended when more frequent and intensive chemotherapy is likely to have survival benefits.
Recommendation 4: impact of the overall FN risk on G-CSF use
Recent literature confirms the benefits of G-CSF treatment for preventing FN in patients with a wide range of malignancies, including breast cancer and lymphoma. Physicians should assess the patient’s risk for FN case-by-case in order to make treatment decisions, taking into account patient-related risk factors, the chemotherapy regimen and associated complications and treatment intent. This should be done at the beginning of each treatment cycle. Recent studies confirm that G-CSF has clinical benefits for patients whose FN risk is equal to, or greater than, 20 per cent. The authors note, however, that this guidance is not intended to supersede national guidelines.
Recommendation 5: G-CSF in patients with existing FN
There are only a limited number of sufficiently powered studies on the effects of G-CSF treatment in patients with an ongoing episode of FN. The EORTC guideline update, in line with ASCO, continues to recommend that ‘Treatment with G-CSF for patients with solid tumours and malignant lymphoma and ongoing FN is indicated only in special situations. These are limited to those patients who are not responding to appropriate antibiotic management and who are developing life-threatening infectious complications (such as severe sepsis or septic shock).’
Recommendation 6: choice of formulation
The updated guideline recommends the use of filgrastim and lenograstim (daily injections) and pegfilgrastim (once per cycle administration) to prevent FN and FN-related complications, where indicated. Filgrastim biosimilars are also included in this recommendation.
In conclusion, the 2010 update of EORTC guideline aims to help optimise local protocols and patient management strategies in hospitals across Europe, in order to improve patient care and clinical outcomes.
Competing interests: None.
Provenance and peer review: Article prepared based on published scientific or research papers recommended by members of Editorial Board; internally peer reviewed.
Editor’s comments
The EORTC guideline is based on a comprehensive literature review, and concludes that all three G-CSF’s are considered therapeutic equivalent choices.
Julie Clayton, PhD, GaBI Journal Editor
Reference 1. Aapro MS, Bohlius J, Cameron DA, et al. 2010 update of EORTC guidelines for the use of granulocytecolony-stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 47 2011;47(1):8-32.
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We start off the second year of GaBI Journal with articles covering a wide range of issues.
In Letters to the Editor, Dr Christian K Schneider discusses and expands on a previously published article by a bioethicist [1] on the ethics of biosimilars. Dr Schneider applauds the inclusion of ethicists in the debates concerning biosimilars but points out some problems created by questioning the safety or efficacy of properly approved biosimilars. He discusses the biosimilars approval processes in Europe and asks ‘How ethical is it to question their safety, and can we afford questioning it?’ Unfortunately, he does not discuss the very real problems posed by inadequately studied copies of biological products that are being produced in many countries such as the problems discussed in an article by Professor Abdol Majid Cheraghali from Iran. In another Letters to the Editor, Dr Christoph Baumgärtel is in response to two previously published articles by Dr Julie Clayton, GaBI Journal Science Editor; asking for increased physician involvement in the use of biosimilars [2, 3], Dr Baumgärtel discusses attempts by the Austrian Regulatory Authority to do this.
Biosimilars are discussed both from a payer’s perspective by Mr Gustaf Befrits Hälsoekonon in a Commentary as well as by Dr Brian Godman in an Editorial on health authority’s perspective.
Original Research by Fereshteh Barei et al. discuss their view of how generics manufacturers can move from incremental innovation to ‘re-innovation’, and on the future of biosimilars.
Three Review Articles are presented discussing how biosimilars are approved for use or interchangeability in different countries. Professor Shein-Chung Chow and Ms Christine Ju discuss US review processes included in the US Biologics Price and Competition Act. In contrast to the rigorous US processes, Professor Abdol Majid Cheraghali discusses the use and monitoring of biological products in Iran, including inadequately controlled biological copies. A related discussion of how ‘similar biologics’ are approved and marketed in India is included as a news item. In the third review, Professor Joan Rovira et al. discuss the biosimilars development processes used in 24 European Union Member States, plus Norway and Switzerland.
A Perspective by Dr Richard O Dolinar discusses concerns that he, the Alliance for Safe Biologic Medicines – the group that funds the organization he works for, and various other ‘stakeholders’ including treating physicians and patients have about the use of biosimilars. Some concerns expressed about biosimilars also apply to originator products whenever any production method changes are made. This suggests, at least to this reader, that even new batches of originator products perhaps should be subjected to expanded retesting or restricted use. Unfortunately, neither this nor the possibility that biosimilars can actually be ‘biobetters’ was adequately covered.
Diverse Regulatory and practice Guidelines articles are presented as well. Dr Toshiyoshi Tominaga, Dr Tatsuya Kondo, and Ms Yuki Ando present a less detailed discussion of the Japanese Pharmaceuticals and Medical Devices Agency. Dr Robin Thorpe and Dr Meenu Wadhwa review the European Medicines Agency’s Committee for Medicinal Products for Human Use ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’. One very relevant cancer treatment practice guidelines from the European Organisation for Research and Treatment of Cancer concerning the use of biosimilars is reviewed by our editors.
A For Patients paper by Ms Yasemin Dil directed at patients discusses relevant patient-centred healthcare indicators. Finally, in Abstracted Scientific Content, a paper describes some publications concerning the use of generic anticonvulsant medications was abstracted by Dr Julie Clayton, GaBI Journal Science Editor.
The wide range of topics presented in this issue emphasizes the complexity of the use of generics and biosimilars. Readers are encouraged to submit both comments on these and other published articles as well as their own relevant manuscripts.
Professor Philip Walson, MD
Editor-in-Chief, GaBI Journal
References 1. Petrini C. A bioethicist’s view of the use of biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3–4):110–1. doi:10.5639/gabij.2012.0103–4.034 2. Clayton J. The potential for doctors to contribute to biosimilar guidelines. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3–4):152. doi:10.5639/gabij.2012.0103–4.039 3. GaBI Online – Generics and Biosimilars Initiative. Dialogue needed to build confidence in biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Dec 3]. Available from: www.gabionline.net/Biosimilars/Research/Dialogue-needed-to-build-confidence-in-biosimilars?
Disclosure of Conflict of Interest Statement is available upon request.
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Abstract: Dr Brian Godman reviews Mr Gustaf Befrits’ paper on the case for biosimilars from a payer’s perspective. Biosimilars are increasingly important to payers with growing resource pressures. However, key issues need addressing to fully capture their benefits.
Submitted: 17 January 2013; Revised: 4 February 2013; Accepted: 8 February 2013; Published online first: 11 March 2013
Gustaf Befrits has provided us with an important insight into biosimilars from a payer’s perspective [1]. Key areas include the fact that healthcare systems are under increasing resource pressures due to well-known factors, including an ageing population, stricter clinical treatment targets and the continued launch of new premium priced drugs [2, 3]. The latter includes new biological drugs, with almost 300 identified in a quick internet search [1]. These can cost up to US$25,000/patient/month [4], in part, due to the complexity of production [1]. Their costs have become more visible in recent years with many standard oral drugs now available as low cost generics [2, 3]. Sweden has seen low prices for generics with mandatory generics substitution with the lowest cost generics [1, 3], and more recently with monthly auctions [3]. Demand-side measures have also appreciably enhanced the prescribing of generics versus patented products in a class or related class [2, 3]. As pointed out, this builds on the accepted premise of substitution as well as similarity of the products in a class [1]. However, further reforms are needed [1].
Consequently, as noted by Befrits, biosimilars are an attractive proposition among payers to create headroom for increased volumes as well as new premium priced drugs, acknowledging that price reductions will not be of the same magnitude as with small molecule oral drugs. This is in view of the complexities involved with their production process as well as clinical trial and post-marketing surveillance requirements [1]. Prices for small molecule oral generics can be as low as 4% of the originator price in Sweden [3]. Typically, price reductions for biosimilars are not as great, averaging between 15% to 30% of the originator price in both Europe and US [5, 6]. In Austria, price reductions are 48% for the first multiple sourced biosimilar; mirroring the situation for small molecule oral generics [2]. As a result of the high prices of originators, there is considerable potential to save costs even at these discounts [6, 7]. In Europe, projected sales for filgrastim (with six biosimilars) are envisaged to exceed those of Neupogen (originator) during 2012 at US$156 million vs US$129 million for the originator [5]. Overall, biosimilars are expected to save between Euros 11.8 billion and Euros 33.4 billion between 2007 and 2020 across a range of European countries [7]. This will be helped by the growing number of biosimilars–14 approved for marketing by the European Medicines Agency by mid-2012 [8].
However, a number of key issues need to be addressed or else it will be increasingly difficult for health authorities in Europe to maintain comprehensive and equitable health care, argues Befrits. Otherwise, there could be negative attitudes towards new expensive biological drugs [1].
One major issue highlighted is substitutability. Currently, there is typically no substitution among ambulatory care pharmacies in Europe, enhanced by recent EU pharmacovigilance legislation that came into effect in July 2012 [8, 9]. This is due to differences in manufacturing processes, and biosimilars cannot be assumed to share an identical safety profile with the originator [8]. Compulsory international non-proprietary name prescribing is also waivered for biopharmaceutical products [10]. The only exception is Germany where there is currently a short list of ‘bioidenticals’ that can be substituted [11]. This came into effect in October 2011. These products can be substituted as their production processes are considered identical. There are also prescribing targets for biosimilars among physicians in Germany [12].
Data on the frequency of switching is scarce, although seen most frequently with erythropoietins [13]. A recent study found no evidence from trials or post-marketing surveillance that switching to and from different biopharmaceuticals leads to safety concerns [13], with similar safety profiles between recombinant erythropoietins [14]. However, others have concerns [8]. Confidence in biosimilars should be enhanced by recent tightening on EU regulations [8] as well as further studies in this area [14].
In conclusion, Befrits highlights key issues surrounding biosimilars. As mentioned, there is an urgent need among health authorities and health insurance companies to enhance the utilisation of biosimilars at prices acceptable to all key stakeholder groups. This will build on current measures in Austria and Germany, as well as potential activities and incentives [15]. This will be explored further in future articles.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. Befrits G. The case for biosimilars–a payer’s perspective. Generics and Biosimilars Initiative Journal (GaBI Journal). 2013;2(1):12. doi:10.5639/gabij.2013.0201.010 2. Godman B, Wettermark B, Bishop I, Burkhardt T, Fürst J, et al. European payer initiatives to reduce prescribing costs through use of generics. Generics and Biosimilars Initiative Journal (GaBI Journal).2012;1(1):22-7. doi:10.5639/gabij.2012.0101.007 3. Godman B, Abuelkhair M, Vitry A, Abdu S, et al. Payers endorse generics to enhance prescribing efficiency; impact and future implications, a case history approach. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):69-83. doi:10.5639/gabij.2012.0102.017 4. Kaiser J. Personalized medicine. New cystic fibrosis drug offers hope, at a price. Science. 2012 Feb 10;335(6069):645. 5. Reinke T. Biosimilars might not measure up to health plan expectations. Manag Care. 2012 Oct;21(10):12-3. 6. Declerck P, Simoens S. A European perspective on the market accessibility of biosimilars. Biosimilars. 2012;2:33-40. 7. Höer H, de Millas C, Häussler B, Haustein R. Saving money in the European healthcare systems with biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4).120-6. doi:10.5639/gabij.2012.0103-4.036 8. Clayton J. Tighter EU rules on pharmacovigilance for biologicals. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):56-7. doi: 10.5639/gabij.2012.0102.015 9. Rovira J, Espin J, Garcia L, de Labry A. The impact of biosimilars’ entry in the EU market. EMINT January 2011. 2011 [cited 2013 Feb 4]. Available from: http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_market_012011_en.pdf 10. Garuoliene K, Godman B, Gulbinovi J, Wettermark B, Haycox A. European countries with small populations can obtain low prices for drugs: Lithuania as a case history. Expert Rev Pharmacoecon Outcomes Res. 2011 Jun;11(3):343-9. 11. Anon. Anlage 1 zum Rahmenvertrag nach § 129 SGB V zu § 4 Absatz 1 Buchstabe a). 2011 [cited 2013 Feb 4]. German. Available from: http://www.pharmatrix.de/cms/upload/pdf/Recht/apothekenrecht/Rahmenvertrag_129_Abs_2_Anlage_1_111001.pdf 12. Kassenärztliche Bundesvereinigung. Rahmenvorgaben nach § 84 Abs. 7 SGB V – Arzneimittel – für das Jahr 2012 vereinbart zwischen dem Spitzenverband Bund der Krankenkassen (GKV-Spitzenverband) und der Kassenärztlichen Bundesereinigung – nachstehend Bundesvertragspartner genannt – Bekanntgaben der Herausgeber: Kassenärztliche Bundesvereinigung; Dtsch Arztebl 2011;108(47): A-2565/B-2145/C-2117. [cited 2013 Feb 4]. German. Available from: http://m.aerzteblatt.de/print/114221.htm 13. Ebbers H, Muenzberg M, Schellekens H. The safety of switching between therapeutic proteins. Expert Opin Biol Ther. 2012;12(11):1473-85. 14. Abraham I, MacDonald K. Clinical safety of biosimilar recombinant human erythropoietins. Expert Opin Drug Saf. 2012;11:819-40. 15. Mackay T, Liang B. Promoting access to biosimilars: a public-private partnership model for biosimilar development in underserved populations. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):84-8. doi:10.5639/gabij.2012.0102.018
Author: Brian Godman, BSc, PhD, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden; Strathclyde Institute of Pharmacy and Biological Science, University of Strathclyde, Glsagow UK
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Author byline as per print journal: Robin Thorpe, PhD, FRCPath; Meenu Wadhwa, PhD
Abstract: The importance of monoclonal antibodies as a product class and the challenge of assessing unwanted immunogenicity for these products have prompted the drafting of a new CHMP (Committee for Medicinal Products for Human Use) guideline. The ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’ is intended as an annex to the existing general immunogenicity guideline. This guidance in conjunction with other relevant CHMP guidelines should assist manufacturers and regulators who are involved with producing or assessing marketing authorization applications for monoclonal antibody products.
Submitted: 4 February 2013; Revised: 6 February 2013; Accepted: 7 February 2013; Published online first: 12 February 2013
Unwanted immunogenicity remains a major concern for biological products including biosimilars. Assessing the immunogenicity of biologicals and the possible clinical consequences of this is a considerable challenge and requires carefully planned, prospective immunogenicity studies, conducted using appropriate patient groups. Regulatory guidance on this has been published by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) (Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins; EMEA/CHMP/BMWP/14327/2006). This guideline, which came into effect in 2008, has been used by manufacturers of biologicals and regulators especially at the marketing authorization stage of regulatory product approval. Although it has been generally well received, one criticism of it is that it is ‘too general’ and does not provide specific guidance for particular products or classes of products. The latter point is indeed true, as the guideline was intentionally drafted to provide general guidance relating to all biological products. Drafting guidelines dealing with immunogenicity issues for specific products is possible, but has been considered unnecessary or even undesirable. It would be a major task to produce specific guidelines covering the very wide range of biological products now being produced or in development and there would be much overlap in the content of many of the specific guidelines as several aspects of unwanted immunogenicity are common to all biologicals. But, in some cases there are issues that affect some products more than others or are different for different biologicals. Normally, this has to be dealt with on a case-by-case basis. However, in some cases for specific products or product classes, generalities pertaining to their immunogenicity may apply, which may merit the preparation of specific immunogenicity guidelines. One such large class of products is monoclonal antibodies (mAbs). This is clearly a very important class of biotherapeutics and in vitro diagnostics, for which there are several approved products in the EU and elsewhere; many more are in development.
In view of this situation, and following internal and external consultation, the decision was taken to draft a mAb specific CHMP immunogenicity guideline. This guidance, titled ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’ (EMA/CHMP/BMWP/86289/2010) has now been adopted by CHMP (again following public consultations) and came into effect in December 2012. It is intended as an addendum to the ‘Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins’ (EMEA/CHMP/BMWP/14327/2006), i.e. that it should be read in conjunction with the general guideline. The new guideline includes sections addressing problems experienced with screening and confirmatory assays used in assessing immunogenicity of mAbs (assays for antibody detection, presence of mAb product in samples for analysis, confirmatory assays and controls), assessment of the neutralising capacity of antibodies induced against mAbs and considerations on immunogenicity risk management of mAbs (risk identification, risk management and risk monitoring and mitigation). The guideline concentrates on specific issues, problems and technicalities that relate to mAbs and products that have similarities to mAbs, such as IgFc fusion proteins. However, some parts of the guideline contain useful information that can also apply to other biologicals. The new immunogenicity of mAbs guideline will apply to all mAbs, including biosimilar mAbs, but treats biosimilars as just a subclass of biologicals (which they clearly are) with no specific requirements from the immunogenicity perspective. This follows the approach taken in the ‘Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins’.
However, immunogenicity assessment for biosimilars does differ in one important aspect from immunogenicity assessment of stand-alone biologicals, as comparative immunogenicity, which is an essential element of the comparability studies, has to be assessed for the candidate biosimilar and the innovator (reference) product. Non-clinical and clinical issues relating to biosimilar mAbs are addressed in another new guideline, ‘Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues’ (EMA/CHMP/BMWP/403543/2010); which includes sections that address these aspects of immunogenicity for biosimilar mAbs. This guideline is specific to the mAb product class and therefore needs to be read alongside the ‘Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use’. Of note, the biosimilar mAb guideline does not reflect on the quality aspects of mAbs as a guideline dealing with this particular aspect is already in place (Guideline on development, production, characterization and specifications for monoclonal antibodies and related products; EMEA/CHMP/BWP/157653/2007) although this does not include any considerations for specific assessment of immunogenicity of biosimilars (this was not thought to be necessary at the time when the guideline was drafted). From the immunogenicity perspective, it is clear that the methodology and strategy for assessment of immunogenicity of biosimilar products including mAbs needs careful evaluation to ensure that this is appropriate for the required comparative assessment. In particular, it is important to ensure that screening procedures identify all patients who develop antibodies against the product that they receive, i.e. the candidate biosimilar or the reference product. This implies that at least screening assays need to be tailored to include the use of the biosimilar and the reference product as antigens (usually conducted as separate assays) and samples from treated patients are screened against the antigen relating to the product that they received. If the trials are double blind (as is normally required for mAbs), then this means that samples will have to be screened against both antigens, as the identity of the product that the patients have received is unlikely to be known at the time of screening. If this strategy is not adopted, it is possible that false negative results may be generated for some patients as one or more epitopes present on the biosimilar and reference products may not be shared. This aspect of immunogenicity assessment strategy is likely to receive considerable attention as more experience is gained with immunogenicity assessment of biosimilar products including mAbs. It is also important to understand the underlying causes of immunogenicity when comparing the incidence of immunogenicity. For example, it may be that differences observed with immunogenicity between a candidate biosimilar and the reference product are due to differences in impurity profiles due to a change in the expression system.
The new immunogenicity of monoclonal antibodies guideline stresses the importance of risk assessment for immunogenicity management, but emphasises the need to take account of the numerous factors that may contribute to immunogenicity, e.g. the production system used, the patient population treated, the clinical indication(s) selected for treatment and the antigen target of the mAb. It is not possible to assign a single ‘risk level’ for mAbs as a product class, as each product needs to be assessed on a case-by-case basis, taking account of all the risk factors.
For patients
Monoclonal antibody products are potentially very valuable medicines and several are approved for the treatment of a range of clinical problems. Many more such products are in development. Unwanted immunogenicity associated with mAb products can be a problem, occasionally resulting in adverse effects and more often a reduction in clinical efficacy. The new guideline described in this article will help manufacturers of mAb products in assessing unwanted immunogenicity of mAbs and will also aid regulators in their evaluation of mAb products for approval for marketing.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
Co-author
Meenu Wadhwa, PhD, Cytokines and Growth Factors Section, Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK
Author for correspondence: Robin Thorpe, PhD, FRCPath, Head – Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK
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There have been established guidelines for approving generic versions of small molecule chemical drugs in India for some time already. However, no specific guidelines for ‘similar biologics’, as the Indian regulatory authorities call these products, have existed in India until recently. This has been the case despite the fact that the requirements for granting regulatory approval for such ‘similar biologics’ required more data than for a simple generic drug application [1].
India announced the release of draft regulatory guidelines for ‘similar biologics’ at the BIO industry conference in Boston, USA, on 19 June 2012, and implemented them from 15 September 2012. The guidelines outline a simple abridged procedure for evaluation of ‘similar biologics’ which have been approved and marketed in India, Europe or USA for more than four years [2].
Biosimilars are firmly established in the EU as copy biologicals with a clear and effective route for approval [3]. It should be noted, however, that ‘similar biologics’ approved and marketed in India have not been subjected to the same rigorous controls and have not necessarily been compared in direct clinical trials to the reference product as is demanded in Europe by the European Medicines Agency. They should not therefore be referred to as biosimilars according to the definition proposed by EMA:
‘A biosimilar is a copy version of an already authorized biological medicinal product with demonstrated similarity in physicochemical characteristics, efficacy and safety, based on a comprehensive comparability exercise’ [4].
The Central Drugs Standard Control Organization is responsible for the approval, i.e. marketing authorisation of medicinal products, including these so-called ‘similar biologics’, in India.
India has, by far, demonstrated the greatest acceptance of ‘similar biologics’. According to our research at GaBI Online, the first ‘similar biologic’ was approved and marketed in India for a hepatitis B vaccine in 2000. In recent years over 50 biopharmaceutical products have been approved for marketing in India, with more than half of them being ‘similar biologics’ [5], see Table 1.
Competing interests: None.
Provenance and peer review: Article prepared based on extensive research; internally peer reviewed.
Michelle Derbyshire, PhD, GaBI Online Editor
References 1. Joshi SR, Biosimilar peptides: need for pharmacovigilance. J Assoc Physicians India. 2011;59 Suppl:44-7. 2. GaBI Online – Generics and Biosimilars Initiative. India releases draft ‘similar biologic’ guidelines [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Sep 21]. Available from: www.gabionline.net/Guidelines/India-releases-draft-similar-biologic-guidelines 3. GaBI Online – Generics and Biosimilars Initiative. EMA proposes more precise definition for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Sep 21]. Available from: www.gabionline.net/Biosimilars/Research/EMA-proposes-more-precise-definition-for-biosimilars 4. Wadhwa M, Thorpe R. Terminology for biosimilars-a confusing minefield. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):132-4. doi:10.5639/gabij.2012.0103-4.023 5. Jayaraman K. India’s Cipla sets sights on Avastin, Herceptin and Enbrel. Nature Biotechnol. 2010 Sep;28(9):883-4. 6. Mody R, et al. How similar are biosimilars in India? Pharmafocus Asia [monograph on Internet]. c2004–2012 Ochre media; [cited 2012 Sep 21]; Available from: www.pharmafocusasia.com/research_development/blind-comparative-study.html 7. Som N. India on biologics trail. Biospectrum. 13 Feb 2012.
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Background: Due to the declining innovativeness of the classic R & D model in the original pharmaceutical industry, the generic pharmaceutical industry is aiming to become an innovation generator itself. Objective: The objective of this article is to gain insight into the re-innovation model in some of the innovative generic pharmaceutical firms. To this effect, we show how some of the generic pharmaceutical firms attempt to achieve competitive advantages either by improving existing product attributes or by replacing new components, reshaping their configuration, and using new technology platforms to produce new innovative products. Methods: We used a qualitative method to examine re-innovation at several levels within these companies, in their management systems, business models and product portfolios. The research was conducted by a series of semi-structured interviews with chief executive officers, consultants, researchers, patent attorneys, pharmacists and medics in different countries. Results: Those generic pharmaceutical firms that implement new competitive strategies have integrated re-innovation design into their product portfolio to provide more personalized, cost-effective products to meet the healthcare systems’, policymakers’ and patients’ demand for high quality accessible treatments. This re-orientation hopes to better face the changing competition challenges in both mature and developing markets. Conclusion: A new approach to innovativeness together with a value proposition strategy aims to deliver high quality products to patients.
Submitted: 17 December 2012; Revised: 4 February 2013; Accepted: 11 March 2013; Published online first: 15 March 2013
Introduction
Innovation is widely regarded as an instrument to create competitive advantage. Different types of innovation exist, including incremental innovation, re-innovation and radical innovation. Incremental innovation deals with creating minor improvements or simple adjustments in a product’s current state [1, 2]. Re-innovation has been defined as: ‘the process of innovation and product development that occurs after a new product is launched, building upon early success but improving the next generation with revised and refined features’ [3]. Finally, radical innovation refers to radical, new inventions that produce milestones, new products or services, and as a result lead to the development of new industries [4]. Today there is less radical product innovation in the original pharmaceutical industry. Moreover, the concept of ‘new product’ has also evolved by the application of strategies such as incremental innovation and re-innovation. In the past, radical or disruptive innovation changed the pharmaceutical market, whereas today generic pharmaceutical firms attempt to innovate in a less costly way in a shorter time with less regulatory obstacles due to the substantial R & D costs to achieve a radical new product. Incremental innovation and re-innovation meet these objectives.
The generic pharmaceutical industry is now evolving in an innovative way. Some firms are applying strategic changes in their management systems and business models and creating new product portfolios fortified with ‘super generics’, new chemical entities and novel drug delivery systems. A super generic drug is an improved version of an original drug which has lost product patent protection. The product patent for the original drug will have expired or have been circumvented by the company developing the super generics. The nature of the improvement may include drug delivery, manufacturing or reformulation technology. This kind of value-added version is manufactured in a re-innovation framework. This innovative design is between incremental and radical innovation. Companies producing super generics have a greater regulatory risk in gaining marketing approval compared to strict generics manufacturers [5]. Without getting into the details, there are three regulatory pathways for drug approval in Europe and the US.
The US Food and Drug Administration (FDA) does not recognize the term ‘super generics’. These products are also referred to as ‘added value generics, new therapeutic entities or hybrids’. These products differ from the original product in formulation or method of delivery. These products are improved formulation of a known product.
This group of generics needs a completely New Drug Application (NDA) in order to gain FDA approval. The regulatory pathway in Europe appears to be very similar to that in the US and was introduced within the Directive 2001/83/EC in November 2001 and in the Regulation (EC) No 726/2004. These products are not interchangeable with the brand-name drugs. Those regulatory pathways are summarized in Table 1.
With a NDA, innovative drug therapies are reaching the market in a specific dosage form for one or more clinically proven indications of which, after expiration of the patent or the data exclusivity, copies are launched using Abbreviated New Drug Applications (ANDA). Advanced therapies that emerged from launched molecules during their product life cycle have gained considerable attention as clinical practice provides evidence for additional therapeutic values; patient centric delivery systems show improved therapeutic outcomes or emerging technologies offer efficiency gains in manufacturing or access to emerging markets. The US and European regulatory framework has set reasonable regulations in place for these super generics or hybrid applications. While these regulations are relatively recent the pharmaceutical industry is just starting to use this route for its product development [6, 7].
However, super generics take an average of three to four years development time to registration, and enjoy reduced development and regulatory risks compared to new chemical entities. The end product may gain a significant price premium to conventional generics once marketing approval is received. Depending on the type of modification to the original formulation and whether the super generic drug is being developed for the same or a different indication will also have an impact on the level of additional research that is needed to gain approval for the reformulated product [8]. The quantity of issued patents highlights the technical knowledge and skill sets that are available in generic pharmaceutical firms. The success of these pharmaceutical firms has illustrated the possibility of changing from the classic model of ‘copy maker’ towards a model of creating new value-added products, manufacturing strategies and new business models [9, 10].
Meanwhile, the demand side for pharmaceutical treatments has also evolved. ‘New’ customers have emerged, i.e. a better informed, web data empowered generation of patients searching for cost-effective treatments. The generic pharmaceutical industry is reacting to this by applying new business models.
By applying a patient-centred and quality-based perspective into their business models, the generic pharmaceutical industry is attempting to offer new less risky and cost-effective products. The most important aspect is that innovation is no longer just about the product itself, it is also centred on how a company contributes to improving the health of patients. This process has required the out-licensing of innovative generic drug products and has also involved the establishment of new partnerships and alliances to better utilize technological platforms and manufacturing facilities [11]. As an example, Teva Pharmaceuticals acquired Ivax in 2006, Barr Laboratories in 2008, and Ratiopharm in 2010.
The aim of this article is to gain insight into re-innovation in the generic pharmaceutical industry by focusing on product innovation, and a business model based on value proposition employed by some of the innovative generic pharmaceutical firms. This is an alternative model between hybrid and classic R & D companies.
Methods
This research complies with the procedure of Paris Dauphine University not to require consent from an institutional review board when subjects cannot be identified. Also, there are no personal identifiers in the data files or in the results.
We applied a qualitative approach. Semi-structured interviews [12] were conducted because they offer the opportunity to ask experts about their views and experiences of the recent changes. In the absence of studies and documentation on this topic due to its novelty, we conducted interviews with managers, industry consultants, lawyers, physicians, pharmacists, patent attorneys, and researchers to gather more views and share their experiences in this area. We prepared two questionnaires; the original questionnaire was more focused on the intellectual aspect of innovation, trying to investigate about the type of innovation in this industry. In Table 2 we have presented a list of our sources in this qualitative research.
The questionnaire had three parts: the first part was about innovation strategy and how it has influenced the generic drug form; the second part was about innovation in their business model, and how do they boost their model by value proposition to customers; the third part was about innovation in the product portfolio and the reasons of product selection and the use of new technology platforms and new statistical methods to reduce risks and optimize product manufacturing in a shorter time to a quicker access to market. We checked the questions with two researchers who were specialists in survey design and we consulted with an American economist who conducts this type of research in order to validate our questionnaire, some of the questions were added during or after some interviews.
Some new topics emerged during the interviews.From April to October of 2011, a total of 20 interviews were conducted in Basel,Budapest, Paris, at the forum on ‘Biopharmaceuticals and Supergenerics’, and in Frankfurt. There are also some interviews that were conducted by telephone calls to Australia, India, UK and US.
We have also followed relevant forums and conferences in France, Hungary, and International Fairs like the CPhI Worldwide in Frankfurt, Germany, to get up-to-date information.
During the first forum on super generics in Budapest, Hungary, we discussed the regulatory aspect of this innovation in the companies manufacturing innovative products known as super generics, hybrid products and value added generics. In Frankfurt, we met for the first time the specialists we contacted via LinkedIn and by email. It was a unique occasion to meet and discuss with the representatives of the super generics manufacturers worldwide.
We studied almost every day every piece of news related directly or indirectly to our research coming from reliable references. This shows that quality by design (QbD) is a very important concept and that innovative generic drug firms may apply QbD not only to reduce the risk of product failure but also to respond to the demands of FDA.
Several economic and financial reports from Business Insight, Data Monitor, IMS, Ernest & Young, Markets and Research were also reviewed before and during the interviews. The companies that accepted participation in this research are: Mayne Pharma (Australia), Capsugel (Belgium), Biogaran (France), Gedeon Richter (Hungary), Dr Reddy (India) and Hanmi (Korea). The other participants were from drug development companies, consultancy companies, and formulation scientists. Other information was collected using the websites of the associations of generic drugs, such as the European Generic medicines Association (EGA); the generic drug industry association in France (GEMME, Association des professionnels du médicament générique); the American Generic Pharmaceutical Association (GPhA); and the International Generic Pharmaceutical Alliance (IGPA) as part of their insights into 2010 on the generics markets in Europe.
Data analysis We have constructed a database of our data collected from the interviews. Interviews were recorded, transcribed verbatim and analyzed using the software NVivo 9.2 software according to the Matrix Framework approach. We used NVivo Dataset and survey to explore our findings. In practice we began by coding the ‘raw’ data at nodes representing themes in our text-data. Alternatively, we ran ‘Text’ search query or ‘Word’ frequency to identify common themes in survey responses before coding them. Matrix coding analysis helped us to associate the main results to the three main axes of our research work: Innovation in management system, Business model innovation and Product portfolio innovation. Framework matrices provided a way to summarize or condense the source materials in a grid. Subsequently, we launched questions and found patterns based on our coding and checked for coding consistency among interviewees. This method helped us to compare results, and to identify new perspectives of the survey results that could not be acquired without running the queries and coding the results.
Results
Producing novel products is defined as the part of new product development strategy which explores the extension of existing innovations, which can only happen after the first generation of a new product is launched [13]. This is, for example, the case with the development of super generics and bio-superior products that follow on from reference biopharmaceutical products. Being built upon early successful products, re-innovative products are created through applying new platforms, new components, or new configurations with breakthrough technologies to previous products or manufacturing processes [14, 15]. The new re-innovated medicines are focusing on improving health outcomes for patients.
‘… In the past, successful pharmaceuticals stemmed from having good clinical trial data which companies owned and controlled. In the future, their success in the market will instead be evaluated by post marketing data resulting from patients’ satisfaction, of which they will no longer have sole possession …’ (Pharma Researcher, UK)
At the industrial level, through re-innovation attempts, generic pharmaceutical firms aim to minimize the new product failure rate [7], reduce the cost of developing a new product and decrease the lead time in bringing it to market. A pharmaceutical product developed and manufactured with less excipients and unit operation, while maintaining the product therapeutic performance compared to the originator, could be considered as an improved therapeutic entity as it reduces the overall costs of manufacturing that could lead to reduced healthcare spending [16].
Innovative generic pharmaceutical firms may apply QbD and design of experiment methods to optimize their production outcome and minimize the risk. Quality by design means designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the manufacturing process [17]. Statistical methods are becoming increasingly vital for pharmaceutical firms. Design of experiments is a tool for determining the relationship between the factors that have an effect on a process and the response of that process [18].
The re-innovative product (as compared to an incremental new product) can be defined as a product that provides new features, benefits, or improvements through existing technology. As such, re-innovation and incremental innovation are different in two aspects: 1) incremental products are improved only by incremental technologies while breakthrough technologies can be used in re-innovative products; and 2) incremental products must be based on the current platform but re-innovative products are either (mostly) based on a new platform or (occasionally) based on an existing platform [19].
‘… As to technology platforms, if for example you consider aerosolization as a platform, then using such a platform to create new, better forms of an existing entity are part of re-innovation …’ (US Manager, 2012)
Re-innovation by the generic pharmaceutical industry can be observed in drug product design, formulation, process development and manufacturing processes going back to the early stages of the product development cycle.
Some product examples are:
1-Abraxane, super generic form of Taxol (FDA, 2005), which uses albumin to deliver the chemotherapy, not Cremophor, and so avoids hypersensitivity and claims a greater tumour response rate than Taxol. The drug Abraxane (nanoparticle albumin bound paclitaxel) uses the approach of coating Taxol with albumin to reduce the side effects associated with standard Taxol (paclitaxel), making it possible to give it without steroids (which can be a rather bothersome issue for many patients, causing problems from severe insomnia to very high blood sugars and more) and also reducing some other Taxol-associated side effects like joint and muscle aches [20, 21].
2-SUBACAP is an improved version of the conventional itraconazole formulation used to treat fungal infections. In June 2012, Mayne Pharma announced that the UK Medicines and Healthcare products Regulatory Agency (MHRA) had reversed its previous decision on SUBACAP and advised that the SUBACAP marketing authorization application was approvable in the UK. Mayne Pharma is in the process of submitting the response to re-activate the ‘Decentralized Procedure’ to seek approval in Germany, Spain and Sweden. Following approval in these countries, the company will seek a second round of approvals in other European countries, including Belgium, Italy, Greece, Portugal and The Netherlands. The total European market sales of itraconazole in 2011 were US$85 million (companies communication and annual report 2012). SUBACAP provides enhancements to patients and prescribers with reduced inter- and intra-patient variability and therefore a more predictable clinical response enabling a reduction in active drug quantity to deliver therapeutic blood levels. Itraconazole is one of the broadest spectrum antifungal drugs on the market and can be used to treat both superficial fungal infections such as onychomycosis (nail infection) and systemic fungal infections such as histoplasmosis, aspergillosis and candidiasis which can be life threatening to immunocompromised patients [22].
Another example of novel technology platform used in super generic drug manufacturing is the application of nanoparticle technology to address challenges associated with the delivery of poorly soluble compounds. Re-innovation has, for example, led to the development of a tablet dosage form that incorporated candesartan cilexetil nanoparticles [23–28] to reduce dosage, reduce toxicity, improve bioavailability and enhance solubility. The original candesartan cilexetil is used for the treatment of hypertension. The major drawback in the therapeutic efficacy of candesartan cilexetil is its very low aqueous solubility leading to low and variable bioavailability. Low bioavailability may lead to variability in therapeutic response. The formulation change resulting from Design of Experiments and nanoparticle technology resulted in better solubility. Using Design of Experiments for process optimization resulted in a robust scalable manufacturing process with design space established for critical process parameters that can balance milling time, particles size and yield. Design of Experiments studies indicated that, out of the three parameters tested in the experimental design, disc speed, pump speed and bead volume were found to affect the critical product attributes either through non-linear, quadratic or interaction effects [29, 30].
The robustness of the model was validated based on confirmatory trials that indicated statistically no difference between predicted and experimental values. The rate and extent of drug dissolution from tablet dosage form incorporating drug nanoparticles was significantly higher than in the tablet containing micronized drug and marketed product.
The increase in drug dissolution resulted in significant enhancement in rate (Cmax) and extent of drug absorption (AUC).
The manufacturing process used is simple and scalable indicating general applicability of the approach to develop oral dosage forms of sparingly soluble drug.
The formulation approach used provides a viable approach to enhance dissolution and bioavailability of sparingly soluble compounds (BCS class II) that may translate into improved therapeutic outcome [23].
This innovative change is also illustrated by the following quote:
‘Super-generic [drug] products, mostly nano- and micro-sized drug delivery systems, focus on improving active principles which were previously commercialized in another formulation. These new formulations are certainly not bioequivalent in the generic [drug] industry’s sense of the term, they are therefore not generics. They are new, i.e. innovative, drugs, which can replace treatment with the previous entity.’ (Drug Delivery Manager, USA)
Another example of re-innovation in super generic drugs relates to the development of a per oral [29] dosage form for a sparingly soluble camptothecin analogue. This was achieved by formulating it as a drug complex [30]. This formulation approach addressed limitations of the currently marketed product that is only amenable for intravenous administration. The drug complex following oral administration demonstrated safety and efficacy comparable to marketed product in athymic mice with implanted tumours. The manufacturing process used is simple and scalable indicating general applicability of the approach to develop oral dosage forms of sparingly soluble drugs. An oral dosage form should result in lower treatment cost, better patient compliance and improved therapeutic outcome for better disease management [23].
In a recent compliance review for antihypertensive drug treatments it was found that some drug classes have significantly poorer adherence performance by patients than other drug classes. Only one third of patients were adherent to b-blockers and diuretics, while two thirds of patients were adherent to angiotension converting enzyme inhibitors and angiotensin II Receptor blockers [31]. Even an adherence of two-thirds of patients still remains at an unsatisfactory low level and leaves considerable room for improvement.
Modifying the release of drugs that have a short biological half-life by extending their release, circumvents high plasma peaks, reduces fluctuations in plasma levels and allows for a once-daily intake that can optimize therapy. This can avoid the daily oral intake for people with dysphagia or dementia. In this new business model, therapy is moving away from a clinical parameter oriented treatment to an outcome oriented disease management programme [32].
Discussion
The low price of generic drugs threatens to undermine the sustainability of the generic pharmaceutical industry in regards to its low margins, number of competitors, increased requirements for pharmacovigilance, the mature markets in developed countries, and the post-patent cliff arena after 2015 [8]. Meanwhile, medical and technological changes push the pharmaceutical industry to implement new business models. These changes coincide with a growing demand from ageing populations, and better-informed patients who have a substantial need for individualized cost-effective treatments.
Several generic pharmaceutical firms have evolved their traditional business models into innovative models. These models are key to maintaining market position. They are focused on patients’ unmet medical needs and a high quality approach to the manufacturing process.
The innovative business models emerge from new management systems. The challenge of new management systems in these innovative generic pharmaceutical firms is on product innovation: how to manage a better organization to achieve a maximum product differentiation through value proposition to patients? How to optimize product quality? How to reduce manufacturing costs? How to reduce the time to market?
The generic pharmaceutical industry is evolving into a less generic, but more innovative format. In this respect, it should be noted that many generic pharmaceutical firms have the capacity to re-innovate. They have experience, good knowledge and the technical possibility to re-innovate. Alternatively, new alliances can provide the necessary financial resources for technical and marketing requirements.
Implementing re-innovation as a strategy strives to convert price-focused competition into product quality competition, this is central to an innovative business model. Some generic pharmaceutical firms are re-innovating their product portfolio by using new technology platforms, new components and new configurations. These attempts have mainly resulted in super generic drugs; value added products or hybrid products and biosimilars. These super generic drugs and improved therapeutic entities are an important source for innovation in drug therapy in the coming decades.
The so-called super generics are a promising alternative. The value added products resulting from re-innovation strategy by using new ‘technology platforms’, new components and new services will be a strategic element for affordable and individualized medicines.
According to our findings:
The classic innovation model of R & D in Big Pharma is no longer able to provide sufficient results, because it is too costly, too time-consuming and too risky. There are more regulatory barriers, changing demographic and economic features, and Big Pharma is becoming too big to manage innovation. Generic pharmaceutical company aims to provide innovative products to meet: price pressure, low margins, government’s pressure, competition, mature markets, and tendering.
The generic pharmaceutical industry is facing now unmet medical needs of a new generation of patients (demand-side is evolved), there is a real demand for high quality geriatric pharmaceuticals for a rapidly ageing population in some developed countries such as Japan.
Better results will be obtained by using novel technology platforms to achieve new formulations, reducing costs and time by applying QbD.
These new products produced by some generics companies are only one example; they try to switch to biosimilars, and new chemical entities. The future is related to a new kind of disease management requiring more value for more affordable treatments.
This research may be followed by further investigation in innovative business models adapted by an evolving generic pharmaceutical industry that has not yet been studied. A quantitative study of R & D investment and strategic alliances in an innovative generic pharmaceutical industry will reveal more.
Conclusion
Due to evolution in the pharmaceutical industry landscape, some generic pharmaceutical companies are restructuring their business models. In this new industrial design, some of the generics manufactures are re-inventing their product portfolio through a re-innovation strategy. New technology platforms, new components and new configurations are adopted to provide patient compliance and increase patient quality of life. Super generics, biosimilars, bio-superiors and value added versions are some of the new product alternatives resulting from this innovative evolution. The product itself is not the only target; the conversion of competition from price to product quality ensures the value proposition and provides product differentiation. New innovative product portfolios are the evidence that innovative generics companies are not only mastering incremental innovation but are also adopting re-innovation in their new strategies. In this perspective, biotechnology, nanosciences and nanotechnology are ‘strategic’ areas for its scientific and commercial development.
For patients
For patients, the innovative changes in product portfolios struggle to improve patient’s quality of life, reduce side effects and enhance efficiency by new product alternatives. These new product alternatives are developed by applying new technology platforms like nanotechnology. Enhancing drug solubility is often key to improving a product’s formulation. New nanotechnologiesa are now being used to solubilize drugs with the aim of improving bioavailability and activity, and reducing in vivo variabilityb.
The re-innovated product portfolios propose more personalized products according to patient’s unmet medical needs. Non-compliance can be attributed to poor taste, difficulty in administration or swallowing, and the inconvenience of multiple doses per day. Non-compliance is a frequent issue (see Cap Gemini Ernest & Young, Compliance Discovery Workshop, 2003). General reasons for non-compliance include: side effects/adverse events, lack of access, financial constraints and lack of communication or information, poor taste and difficulty to swallow (inconvenience in administration). Compliance is dependent on the class of drugs. Some of the new super generics have the advantage of a lower dose, they have the same positive effect provided by the original version, and have significantly reduced adverse side effects [33]. The importance of the oral route of administration [34] from both a clinician and patient acceptance point of view means there has been a vast amount of development and research in drug delivery via this route. Pharmaceutical devices will continue to drive patient compliance and acceptability. The convergence of microelectromechanical systems and nanotechnology with biological applications offers breakthrough in drug developments [35]. As such, improved therapeutic entities could bring innovation faster and at lower risk to society and help to improve health outcomes [36].
For further reading, please refer to references 37 to 47.
Competing interests: Professor Claude Le Pen is professor of health economics at Paris Dauphine University. He has also several organizational, scientific and governmental responsibilities. Professor Steven Simoens holds the EGA Chair ‘European policy towards generic medicines’. The authors have 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.
Co-authors
Professor Claude Le Pen, PhD
LEGOS, Laboratory of Economics and Management of Health Organizations, Paris Dauphine University, Place du Maréchal de Lattre de Tassigny, FR-75775 Paris Cedex 16, France
Professor Steven Simoens, MSc, PhD
Department of Pharmaceutical and Pharmacological Sciences, Research Centre for Pharmaceutical Care and Pharmacoeconomics, Katholieke Universiteit Leuven, Onderwijs en Navorsing 2, PO Box 521, 49 Herestraat, BE-3000 Leuven, Belgium
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IDrugs. 2010 Apr;13(4):243-7. 36. Gassmann O, Reepmeyer G, Zedtwitz M. Leading pharmaceutical innovation. 2nd ed. Berlin: Springer Verlag; 2004. Chapter 2: Pharmaceutical innovation: the case of Switzerland, p. 23-52, chapter 3: The science and technology challenges, how to find new drugs? P. 53-77. 37. Kale D. Learning to innovate: the Indian pharmaceutical industry response to emerging TRIPs regime. DRUID Academy Winter 2005 PhD Conference; 2005: Aalborg, Denmark. 38. Simoens S, De Coster S. Sustaining generic medicines markets in Europe. Journal of Generic Medicines. 2006;3(4):257-68. 39. Le Pen C. Consommation pharmaceutique et indicateurs de santé publique. Leem. 2009. 40. Ring in generics in 2012 and beyond. Zacks Equity Research – 2011 Dec 29 [cited 2013 Feb 4]. Available from: http://www.zacks.com/stock/news/67042/Ring+in+Generics+in+2012+and+Beyond 41. Dingermann T. Innovator companies should focus on innovations. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):6. doi:10.5639/gabij.2012.0101.003 42. Class JN, Langis l. A patient-centred paradigm for the biosimilar market? Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(1):17-21. doi:10.5639/gabij.2012.0101.006 43. Van Lerberghe W. The world health report 2008. Primary health care [homepage on the Internet]. 2013 [cited 2013 Feb 4]. Available from: http://www.who.int/whr/2008/en 44. Shaw B. The role of the interaction between the user and the manufacturer in medical equipment innovation. R & D Management. 1985;15(4):283-92. 45. Terziovski M. Building innovation capability in organizations: an international cross-case perspective. Imperial College Press, London; 2007. p. 157-75. 46. Cheng CJ, Shiu E. Re-innovation: the construct, measurement, and validation. Technovation. 2008;28(10):658-66. 47. Miele E, Spinelli GP, Miele E, Tomao F, Tomao S. Albuminbound formulation of paclitaxel (Abraxane ABI-007) in the treatment of cancer. Int J Nanomedicine. 2009;4:99-105.
aNanotechnology is the science of manipulating materials on a scale so small that they cannot be seen with a regular microscope. The technology could have a broad range of applications, such as increasing the effectiveness of a particular drug, improving the packaging of food, or altering the look and feel of a cosmetic. Nanotechnology could also be used in medicines designed for the detection, treatment, and prevention of disease; food production and preservation; water decontamination and purification; environmental remediation; lighter and stronger materials for construction and transportation; and energy resources such as solar cells and fuel-efficiency additives, just to name a few. Paul C Howard, PhD, Director of the Office of Scientific Coordination and Director of the Nanotechnology Core Facility at FDA’s National Center for Toxicological Research, FDA website, 2011. bSkyepharma and Elan have developed technologies that have been used to reposition well-known drugs (fenofibrate, megestrol and sirolimus).
Author for correspondence: Fereshteh Barei, PhD, LEGOS – Laboratory of Economics and Management of Health Organizations, Paris Dauphine University, Place du Maréchal de Lattre de Tassigny, FR-75775 Paris Cedex 16, France
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Abstract: Comment on the GaBI Journal article titled The potential for doctors to contribute to biosimilar guidelines [1] and the GaBI Online article titled Dialogue needed to build confidence in biosimilars [2], both by GaBI Journal Editor, Dr Julie Clayton.
Submitted: 18 November 2012; Revised: 3 December 2012; Accepted: 4 December 2012; Published online first: 7 December 2012
In September 2012, Austrian doctors were given reassurance that pharmacists would not make the decision to automatically switch patients from brand-name drugs to biosimilars without the involvement of doctors, and that stringent regulations were in place regarding the safety and efficacy of biosimilars.
In September 2012, the Austrian Society for Pharmaceutical Medicine together with representatives of the Austrian Regulatory Authority and the Austrian Main Association of Social Health Insurance gave hospital and resident doctors an information update about the meaning and potential use of biosimilars, particularly for the benefit of those who are hesitant about prescribing biosimilars. The meeting took place at the largest hospital and medical school in Austria, the General Hospital Vienna, and provided information about the registration and authorisation processes and the mandatory comparability testing against the reference product. Many new biosimilars are likely to be authorised and made available soon, following tests for safety and efficacy via the centralised procedure, leading to upright authorisations in all 27 EU-Member States. As common reluctance to use biosimilars is mainly based on lack of information, this session was an opportunity to answer as many questions as possible.
One major issue was the automatic substitution with biosimilars. Representing the Austrian Regulatory Authority I explained that it is currently not advised that pharmacists automatically substitute a reference product with a biosimilar. Rather, the European Medicines Agency (EMA) states that the decision to use a biosimilar should always involve a well-informed physician.
In the US, automatic substitution with biosimilars is at least a theoretical possibility, owing to a specific, step-wise approval process which first requires biosimilarity to be shown and then interchangeability. In contrast, EMA does not take responsibility for decisions on interchangeability and/or substitution. Instead, it is for the national competent authorities of EU-Member States to decide based on the scientific evaluation performed by EMA. This could potentially lead to different approaches in the different Member States. However, there seems to be unanimous disapproval of the idea of automatic switching by pharmacists without the involvement of doctors.
I underscored that even by now there is a good opportunity for increasing the uptake of biosimilars in Austria by promoting their use as a starting treatment for new patients rather than by switching existing therapies to biosimilars. Austria already has a very high penetration with biosimilars, ranking third in the EU in 2011, with a defined daily dose of 0.09 per population head. In the case of generics, research by the social insurance system had shown that merely starting new patients on treatment with generics could have a marked effect on raising the penetration rate. Similar effects can be expected for biosimilars.
Hearing that they would remain directly involved in decisions over treatment with a biosimilar seemed to alleviate a major concern for the participating Austrian physicians [1]. However, they will be obliged to choose biosimilars more often in order to save a huge amount of money for the public health system. Mag Jutta Piessnegger of the Austrian Main Association of Social Health Insurance explained that biosimilars will be priced in Austria in the same way generics are priced, meaning that in a complex system of price reductions, after biosimilar market entry, biosimilars must be priced at 48 to 60 per cent below the cost of the originator, allowing room for substantial savings.
The Austrian Regulatory Authority is interested in continuing to cooperate and seek to have further dialogue with Austrian physicians so that they can make well-informed decisions regarding biosimilar use [2].
Competing interests: None.
Provenance and peer review: Not commissioned, internally peer reviewed.
Author: Christoph Baumgärtel, MD, Department Head, Department Safety and Effi cacy Assessment of Medicinal Products, Institute Marketing Authorisation of Medicinal Products & LCM, AGES PharmMed–Austrian Medicines and Medical Devices Agency, and Austrian Federal Offi ce for Safety in Health Care, European Expert in Pharmacokinetics Working Party and Safety Working Party of EMA, Member of Austrian Prescription Commission, 5 Traisengasse, AT-1200 Vienna, Austria
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Epilepsy features the unpredictable onset of seizures that can be devastating to a patient’s quality of life. Fortunately there are medications available to control the onset of seizures. But because these have to be taken over the long term, healthcare providers need to consider whether to take advantage of cheap generic alternatives to brand-name antiepileptic drugs (AEDs).
Generic AEDs have been the subject of controversy since anecdotal reports and observational studies indicated adverse consequences in some patients who switched from branded to generic AEDs. The UK medical journal The Lancet, for example, warned, ‘Until firm evidence supporting the safety of generics switching becomes available, we should err on the side of caution and ensure that AEDs are excluded from any sweeping policies that promote automatic generics substitution’ [1].
Several recent publications have tried to disentangle the factors involved, to see whether such doubts are valid, or whether generic AEDs have been misrepresented through the use of too much anecdote and not enough scientifically rigorous investigation.
A commentary in the journal Clinical Pharmacology & Therapeutics examines reasons why generic AEDs are cause for concern [2], and provides potentially reassuring explanations for recent observations regarding their use. First, Professor Moore and co-authors consider general issues around the use of generic drugs, such as the plasma concentration of the drug’s active substance which, in order to meet the US FDA approval, must be within 80 to 125 per cent of that obtained with the originator product—a range known as the equivalence boundary. While this range may be acceptable for the treatment of some conditions, such as cardiovascular disease, when it comes to AEDs, such a difference in plasma concentration could, in theory, cause over- or under-dosing resulting in toxicity or treatment failure. As Professor Moore and co-authors point out, however, even individual tablets of the same medication can produce as much as a 40 per cent difference in the amount of active ingredient absorbed by the patient. If a seizure occurs following fluctuations between tablets of the same drug, rather than following a switch between brands, such incidents may go under-reported compared to when it occurs after generics substitution.
Other potential differences between branded products and generics include the presence of different ratios of isomers in a racemic mixture, which may show the same pharmacokinetic profile but may have a different activity profile, as well as the possible confusion or mistrust for patients from different appearance, colour, and so on, which again could lead to non-compliance and treatment failure or toxicity. In the meantime, both branded and generic products can vary in quality, depending on where they were manufactured, and so switching between even branded medications can also potentially have adverse consequences for patients.
Regarding clinical effects, as Professor Moore and co-authors outline, there are few formal, scientifically sound studies on the consequences of switching from brand-name to generic drugs and back. In favour of generics, they point to a meta-analysis by Kesselheim et al. comparing brand-name AEDs to generics, and found no clinical difference in randomised clinical trials. They also highlight an observational study by Gagne et al. revealing that prescription refilling itself is associated with an increased risk of seizure, with no statistically significant difference between seizures after refill with branded products compared to a switch to generic drug alternatives, or from generics back to brand-name originator. It appears, therefore, that the event of prescription refilling can itself create circumstances leading to seizures, possibly through causing confusion or upset to a patient’s routine, delaying the timing of medication, and transiently reducing the level of systemically active drug. The problem, therefore, is not necessarily anything to do with generics. [3, 4].
A more recent study in 2011 supports the use of generic AEDs by looking at bioequivalence, or availability of active ingredient in the blood circulation—assessed as total drug exposure and peak concentration during fasting and fed bioequivalence studies. Kraus et al. obtained data on Abbreviated New Drug Application through a freedom of information request, and found that the total drug exposure was similar between generic AEDs and reference products. Peak plasma concentrations varied more.
Curiously, the study found that switches between generic products cause greater variation in plasma concentration than generics substitutions of reference products, indicating that generics substitution may not be such a problem after all [5].
In 2012, a systematic review of clinical studies of innovator versus generic AEDs adds to the debate. Talati et al. found that while there appears to be a similar efficacy, tolerability and safety after initiating treatment with either innovator or generic AEDs, a switch from one form to the other may result in more hospitalisations and longer hospital stays. The study was underpowered, however, limited by trial size and the range and quality of drugs considered [6].
As Professor Moore and co-authors suggest, more adequately controlled and powered clinical trials and meta-analyses are required to enable scientifically sound decisions to be made over the safety of generics substitution for the treatment of epilepsy.
Competing interests: None.
Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.
Julie Clayton, PhD, GaBI Journal Editor
References 1. Antiepileptic drugs: the drawbacks of generic substitution. Lancet Neurol. 2010 Mar;9(3):227. doi:10.1016/S1474-4422(10)70044-2 2. Moore N, Berdai D, Begaud B. Are generic drugs really inferior medicines? Clinical Pharmacol Ther. 2010;88(3):302-4. 3. Gagne JJ, et al. Refilling and switching of antiepileptic drugs and seizure-related events. Clin Pharmacol Ther. 2010;88(3):347-53. Epub 2010 Jul 14. 4. GaBI Online – Generics and Biosimilars Initiative. Switching from a brand-name antiepileptic drug to a generic is not associated with a higher risk of seizures [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Nov 14]. Available from: http://www.gabionline.net/Generics/Research/Switching-from-a-brand-name-antiepileptic-drug-to-a-generic-is-not-associated-with-a-higher-risk-of-seizures/. 5. Kraus GL, et al. Assessing bioequivalence of generic antiepilepsy drugs. Ann Neurol. 2011 Aug;70(2):221-8. doi:10.1002/ana.22452. Epub 2011 Jun 29. 6. Talati R, et al. Efficacy and safety of innovator versus generic drugs in patients with epilepsy: a systematic review. Pharmacotherapy. 2012 Apr;32(4):314-22.
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Abstract: The clinical importance of biopharmaceuticals for the management of life threatening diseases is increasing but costs have become a major obstacle to the administration of these medicines, especially in resource limited healthcare systems. Introduction of biosimilars as a cost-effective alternative to innovator biopharmaceuticals has attracted the attention of both industry and policymakers. However, due to the complex structures of biopharmaceuticals, the regulation of biosimilars has become challenging for national regulatory authorities. In the past decade, national pharmaceutical companies in Iran have manufactured copies of several brand-name biopharmaceuticals. Although copied biopharmaceuticals produced by Iranian companies have received marketing authorization for the local market, none has been evaluated using internationally recognized guidelines for the approval of biosimilars. Therefore, effective pharmacovigilance programmes are essential to evaluate whether the safety and efficacy profiles of these locally produced biopharmaceuticals are different from those of either the original brand biopharmaceuticals or their biosimilar versions.
Submitted: 21 November 2012; Revised: 11 February 2013; Accepted: 13 February 2012; Published online first: 19 February 2013
Introduction
The population of Iran is now over 74 million. The country’s gross domestic product (GDP) per capita in 2011 was reported to be over US$12,000 and the country spends about 6% of its GDP on health. In the past three decades the government of Iran has devoted substantial resources for improving the national health system. Through implementation of many long-term initiatives Iran has achieved substantial success in extending health care to every corner of the country and most of the major healthcare indicators have significantly improved during the past decades [1–2]. The availability of World Health Organization (WHO) designated essential medicines in Iranian health centre pharmacies is reported to be over 92% [3]. The healthcare system in Iran was established in response to its primary healthcare needs. However, recent changes in the Iranian lifestyle have caused a shift in mortality and morbidity patterns towards a predominance of the non-communicable diseases of an ageing population [1].
After the 1979 Islamic revolution, Iran adopted a full generic-based medicine policy and prioritized local production of medicines. A formulation based national industry focused on self-sufficiency is one of the main goals of Iran’s medicine policy. The policy is mainly based on generic medicines, in which all medicines are only registered by their generic identity. In 2002, however, Iranian policymakers introduced the concept of branded generics in order to promote competition within the national pharmaceutical industry [4–5].
Although local Iranian pharmaceutical companies are able to produce small molecule medicines for the domestic market, the national health system depends on certain imported life-saving or disease-modifying patented medicines including biopharmaceuticals [6]. Although modern Iranian pharmaceutical companies were established 80 years ago, departure of international pharmaceutical companies following the 1979 Islamic revolution limited the access of the local pharmaceutical industry to both new technology and needed raw materials [4–6]. Although due to its population size, Iran has one of the largest pharmaceutical markets in the Middle East, its per capita spending on medicines is low. However, the Iranian pharmaceutical market has experienced rapid growth in recent years, increasing on average more than 30% annually in the period 1993–2003. Most of this increase is attributed to the cost of imported medicines and devaluation of the national currency. The cost is mostly because local manufacturers do not produce the new, hi-tech medicines being demanded from prescribers by consumers. Currently locally produced medicines provide only about 65% of the Iran pharmaceutical market needs and this percentage has been declining substantially in recent years. Despite a substantial decrease in the country’s population growth rate in the past decade, drug expenditures have drastically increased to over US$4 billion [4–6].
The increasing costs of health care, including the costs of pharmaceuticals, pose challenges for all nations. In developing countries including Iran, pharmaceutical expenditures account for 25–65% of total public and private health expenditures, and for 60–90% of household out-of-pocket expenditures on health. In order to improve affordability of the medicines in Iran, the government has implemented a direct and not targeted subsidy mechanism for medicines. The main goal of this strategy is to reduce the price of medicines on the market. Obviously this universal subsidy mechanism can cause corruption. Direct subsidization of some very expensive imported medicines by the government has promoted smuggling of these medicines into the neighbouring countries, where they can be sold with a very high profit [7]. Therefore, this strategy was stopped and now only a few, mainly hi-tech medicines are receiving direct subsidy from the government. Currently the national health insurance system is the main tool in Iran for improving the affordability of medicines. Local production of copies of biopharmaceuticals is a new development in the Iranian pharmaceutical sector. In recent years some small science-based pharmaceutical companies have started to manufacture biological pharmaceuticals using modern biotechnology methods [5].
Importance of biopharmaceutical medicines
Biopharmaceuticals are large and complex biological molecules. Their final biological activities very much depend on the methods used for their production. Recombinant proteins such as blood coagulating factors, erythropoietins, gonadotrophins, granulocyte colony-stimulating factors (G-CSF), human growth hormones, interferons, interleukins and monoclonal antibodies are among the most important biopharmaceuticals marketed in past decades [8].
Biopharmaceuticals represent a rapidly growing market. It is reported that 32% of the products in development pipelines and 7.5% of marketed medicines are biopharmaceuticals. By 2020, biopharmaceuticals are forecasted to sell for around US$23 billion in the EU and US$29 billion in the US [9]. Although currently many original brand-name biopharmaceuticals are protected by intellectual property laws and regulations, with expiration of their patent protection in the next few years the pharmaceutical industry faces a unique business challenge from both well regulated rival biosimilars as well as less regulated copied biopharmaceutical. Despite the increasing clinical significance of biopharmaceutical medicines, economic barriers limit their use for many patients, especially in developing countries. In the World Trade Organization (WTO) member countries, failure of the pharmaceutical industry to meet the needs of national health services may result in compulsory licensing regulation changes in order to permit local industries to produce and market copies of such patented medicines to be sold at more affordable prices.
‘Biosimilars’ are biopharmaceuticals that are manufactured and marketed, usually by non-originator pharmaceutical companies, following expiration of the originator patents. Currently, marketing authorization of such biosimilars for highly regulated markets depends on demonstration of ‘similarity’ between a biosimilar and its corresponding originator biopharmaceutical. In the next few years substantial numbers of biopharmaceuticals will lose their patent protection and therefore will be open to the production and competitive marketing of such medicines. However, in contrast to small molecule medicines the replication of the biopharmaceuticals is not an easy task. In many cases even small changes in the structure of the final molecule can create a different safety and efficacy profile. This is why adequate evaluation of biosimilars has become such a challenge for both the scientific community and regulatory agencies.
Generic small molecule medicines are usually approved on the basis of their established bioavailability compared to the originator brand comparator. In most cases, generic medicines are also considered as interchangeable with their corresponding original brand medicines. In contrast to small molecule medicines, biopharmaceuticals are manufactured in living systems, e.g. plant or animal cells. The methods used to produce the biopharmaceuticals; including cloning, expression system, expansion, recovery, purification and formulation of the final product, determine the ultimate biological activity of these products. Therefore, any change in any of these steps could create substantial changes in the efficacy or safety profile of the medicine, including its immunogenicity. Despite the introduction of biosimilars into world pharmaceutical markets many years ago some countries still lack regulations for registration of these medicines. The European Medicines Agency (EMA) was the first well-established regulatory authority to develop comprehensive guidelines in 2004 [10]. WHO has also published its guidelines for the evaluation of biosimilars in 2010 [11]. These guidelines are mainly focused on a head-to-head demonstration of biosimilarity with a registered original brand biopharmaceutical through both preclinical and clinical trials. The clinical studies must be designed in a way that can demonstrate comparable safety and efficacy between biosimilar and the reference biopharmaceutical.
With the increasing importance of biopharmaceuticals in disease therapy and their high costs, the lower costs of their alternatives, biosimilars, is a driving force for their marketing. Due to very high costs both for each treatment, and over a full treatment time period, even a slight cost reduction through the marketing of biosimilars could facilitate access to biopharmaceuticals; especially in resource limited healthcare systems [12–14]. As has happened with generic versions of small molecule medicines, the introduction of biosimilars is expected to create substantial reductions in national healthcare expenditures. Published data show that these medicines will result in savings of about US$9–12 billion for the US Medicare program in a decade [15]. It is also reported that biosimilars could create savings of between Euros 11.8 and Euros 33.4 billion between 2007 and 2020 for European healthcare systems. The savings for erythropoietins alone could be between Euros 9.4 and Euros 11.2 billion. However, most of these savings will come from administration of biosimilar monoclonal antibodies. [16].
It is estimated that developing a biosimilar for highly regulated markets such as the EU and the US will cost between US$75 and US$250 million [17]. Since many pharmaceutical companies in developing countries cannot afford such costs, national companies try to meet local demand by manufacturing copied biopharmaceutical medicines without actual demonstration of biosimilarity. Obviously, these copied biopharmaceuticals cannot be compared to the original brand biopharmaceuticals approved in highly regulated markets. These countries instead must perform close pharmacovigilance of copied biopharmaceuticals for both patient safety and proving efficacy of these medicines [18].
Registration of biopharmaceuticals in Iran
Iran’s national pharmaceutical industry is mostly a generic-based industry that produces small molecule chemical medicines. Since a decade ago some newly established science-based Iranian pharmaceutical companies began developing biopharmaceuticals. Iran’s Government has also allocated substantial resources including financial and administrative support for improving the capability of local pharmaceutical companies to manufacture biopharmaceuticals. Because they do not have access to the production procedures of originators, including cell type, fermentation and purification procedures, they cannot claim ‘similarity’ to originator brands. These copied biopharmaceutical including IFNs, G-CSF and GH have received marketing authorization for the local Iranian market, but none have received evaluation according to internationally recognized guidelines for biosimilars. Registration has mainly followed the path for ‘biogeneric’ medicines, and their application for marketing authorization has been handled on a case by case basis. Since 2003, about 20 locally manufactured biopharmaceuticals either entered the market or are awaiting marketing authorization, see Table 1; from Iran’s national regulatory authority (NRA). This table shows that the most clinically important biopharmaceuticals, especially recombinant proteins, are manufactured locally by Iran’s national industry. Some additional monoclonal antibodies have already been filed for registration and are expected to enter the market in 2013–2014. All medicines, including biopharmaceuticals in Iran, have their prices set by national authorities, and have to be sold at a fixed price all over the country. The prices of locally manufactured biopharmaceuticals are between 27–72% lower than their corresponding imported original brands. Obviously, this could significantly improve affordability and accessibility of the biopharmaceuticals for both patients and the national health service.
In 2001, Iran became a member of the World Intellectual Property Organization and registers trademarks for medicines. However, there is no patent protection for imported medicines in Iran [5]. As of mid 2005, Iran became an observer member of WTO. However, due to the current international political situation full WTO membership is unlikely to happen in the near future. Iran’s local industry does not consider WTO membership to be an eminent concern with regard to producing copies of patented biopharmaceuticals. Therefore, the local pharmaceutical companies would be able to manufacture both patented and off-patent biopharmaceuticals provided that they gain access to their production procedures.
In order to support local manufacturers, Iranian officials impose a tariff on imported original brand medicines as soon as a local version enters the market. This tariff can be as high as 65% and therefore substantially increases the price of imported medicines, enabling locally made products to dominate the market. However, if either local manufacturers or authorities overestimate production capability, there may be a shortage of cheaper, locally manufactured biopharmaceuticals, thus causing a huge economic burden on patients who then have to buy more expensive original brand medicines.
The process of registration of biopharmaceuticals in Iran
Iran established its NRA in the 1950s, and passed the first laws for the regulation of the national pharmaceutical market in 1955. The Ministry of Health and Education of Iran is responsible for regulation of the market. Although the registration of small molecule medicines is a well-developed system it is not always as transparent as it should be according to NRA’s guidelines for the marketing of locally produced copied biopharmaceuticals [5]. In 2006, the Iranian NRA announced national guidelines for the marketing of biosimilars. These guidelines, which are mainly adapted from the WHO guidelines, specify the need for a clinical trial with a small sample size comparing locally manufactured biopharmaceuticals with the original brand. However, there are clear differences between the WHO guidelines and current Iranian national guidelines for the registration of locally produced biopharmaceuticals [19–20]. Currently, the Iranian NRA does not ask for comprehensive new preclinical or clinical data for proving similarity between locally produced biopharmaceuticals and original brand medicines.
The Iranian NRA has so far relied on national post-marketing surveillance to produce data on the ‘safety’ of all marketed, copied biopharmaceuticals. Iran has a fairly well-established national adverse drug reaction (ADR) reporting system and so far no serious or unexpected ADRs related to administration of locally manufactured biopharmaceuticals have been reported to the national health authorities [20–21].
Discussion
Healthcare expenditures in Iran have risen dramatically in recent years, due mainly to an increase in expenditure on biopharmaceuticals. Iran’s policymakers believe that although biosimilars are a cost-effective intervention for the treatment of patients, the regulatory approaches for their marketing used by organizations such as EMA, US Food and Drug Administration (FDA) or even WHO may not suit the needs of the Iranian market [20–21].
Although highly regulated markets such as the EU and the US have specific requirements for marketing of biosimilars, these might not be appropriate for the marketing of biopharmaceuticals in less regulated markets. Biosimilars in these markets therefore have different definitions. While they may have acceptable safety and efficacy profiles based on local requirements these ‘copied biopharmaceuticals’ manufactured in these countries are not ‘biosimilars’ as defined by EMA, FDA and WHO guidelines.
In order to create a balance between the regulation and affordability of locally produced biopharmaceuticals, Iran’s NRA tries to use its national pharmacovigilance system as a tool for assessing the safety of the marketed locally manufactured biopharmaceuticals, including the incidence of ADRs associated with their use. There is a general consensus that patient’s safety should not be compromised in exchange for access to the less expensive biosimilars [22]. Iran’s NRA mainly accepts evidence of pharmacokinetic and pharmacodynamic equivalence between the originator and locally manufactured biopharmaceuticals and a small size clinical trial as a measure of clinical comparability for copied biopharmaceuticals. However, biopharmaceuticals have varying potential for immunogenicity that can change based on a number of factors, including manufacturing processes. Although small differences between copied biopharmaceuticals and original brand medicines might not cause significant differences in clinical efficacy, in rare cases these differences might lead to safety problems. Therefore, post-marketing surveillance could be used as an effective tool to detect any adverse reactions which could be considered as a breach of safety profile of these biopharmaceuticals. Since biological medicines have unique characteristics the surveillance system must be both very sensitive and reliable if it is to detect and assess any adverse event in a timely manner [22].
The Iranian pharmaceutical market is susceptible to the use of counterfeit medicines. Iran is one of the major transit routes for illicit narcotics produced in Afghanistan. It is assumed that the same transit pathways could also be used for counterfeit medicines including biopharmaceuticals. Indeed, illegal medicines and supplements now comprise up to 10% of the total pharmaceutical market [7]. There is a danger that the ambiguity and uncertainty in the regulatory requirements for the marketing of biopharmaceuticals in Iran will encourage manufacturers to avoid doing the clinical trials necessary for proving the comparable efficacy and safety of their products. The use of clinically not comparable biopharmaceuticals could then impose extra medical and financial burdens on patients and the national health system if this leads to treatment failure, toxicity, and the need for corrective interventions. This also raises the possibility of yet unidentified short- and long-term safety concerns. The government of Iran currently supports the local pharmaceutical industry by imposing high tariffs on imported medicines. Therefore, it is expected that patients should benefit from the availability of copied biopharmaceuticals through improved access for effective treatment of chronic and lifelong diseases.
Conclusion
In the past few years, the Iranian national industry has manufactured copies of biopharmaceuticals. Although granted marketing authorization in Iran, none of these medicines has had comprehensive evaluation according to FDA or EMA guidelines. The lower cost of these copied biopharmaceuticals could improve the affordability of these clinically important medicines. However, authorities need to perform close vigilance of these biopharmaceuticals in order to evaluate their safety and efficacy.
Editor’s comments
The manuscript by Professor Majid Cheraghali in this edition of the GaBI Journal raises two important issues that need to be considered. First, economic pressures exist that will encourage some countries to pursue copied biologics which will not be adequately tested for ‘biosimilarity’. This may or may not result in additional risks or cost savings. Second, the article illustrates how politically motivated sanctions, whether or not justified, can have major (hopefully unintended) negative effects on public health even in a resource rich, developed country like Iran. Finally, the article mentions the impact of drug smuggling and counterfeit medicines, both of which have major public health implications throughout the developing and developed world.
Our readers are encouraged to submit manuscripts that explore these important aspects of the use of generics and biosimilars.
Acknowledgement
The author wishes to thank Dr Shekoufeh Nikfar for her valuable assistance on providing some data.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
References 1. Asadi-Lari M, Sayyari AA, Akbari ME, Gray D. Public health improvement in Iran–lessons from the last 20 years. Public Health. 2004 Sep;118(6):395-402. 2. Goudarzi S, Kameli ME, Hatami H. Improvement in health indicators of Islamic Republic of Iran in the years 2004 and 2008. Iran Red Crescent Med J. 2011;13(8):574-7. 3. Cheraghali AM, Nikfar S, Behmanesh Y, Rahimi V, Habibipour F, Tirdad R, et al. Evaluation of availability, accessibility and prescribing pattern of medicines in the Islamic Republic of Iran. East Mediterr Health J. 2004 May;10(3):406-15. 4. Basmenji K. Pharmaceuticals in Iran: an overview. Arch Iranian Med. 2004;7(2):158-64. 5. Cheraghali AM. Iran Pharmaceutical Market. Iran J Pharm Res. 2006;1:1-7. 6. Dinarvand R. New national drug policy in Iran leading to expanded pharmaceutical market and extended access of public to medicines. Iranian J Publ Health. 2009;38 Suppl 1:158-61. 7. Hosseini SA, Darbooy Sh, Tehrani Banihashemi SA, Naseri SM, Dinarvand R. Counterfeit medicines: report of a cross-sectional retrospective study in Iran. Public Health. 2011;125(3):165-71. 8. Brockmeyer C, Seidl A. Binocrit: assemssment of quality, safety and efficacy of biopharmaceuticals. Eur J Hosp Pharm Prac. 2009;15(2):34-40. 9. GaBI Online – Generics and Biosimilars Initiative. Biosimilars: barriers to entry and profitability in the EU and US [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2013 February 11]. Available from: www.gabionline.net/Biosimilars/Research/Biosimilars-barriers-to-entry-and-profitability-in-the-EU-and-US 10. World Health Organization [homepage on the Internet]. Guidelines on evaluation of similar biotherapeutic products (SBPs). 2009 [cited 2013 Feb 11]. Available from: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22 APRIL2010.pdf 11. European Medicines Agency [homepage on the Internet]. Annex guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. Guidance on similar medicinal products containing somatropin. 2006 [cited 2013 Feb 11]. Available from: http://www.ema.europa.eu/pdfs/human/biosimilar/9452805en.pdf 12. Stewart A, Aubrey P, Belsey J. Addressing the health technology assessment of biosimilar pharmaceuticals. Curr Med Res Opin. 2010;26(9):2119-26. 13. Bruce ES, Armour K, Romiti R, Smith C, Tebbey PW, Menter A, et al. Biopharmaceuticals and biosimilars in psoriasis: what the dermatologist needs to know. J Am Acad Dermatol. 2012;66(2):317-22. 14. Simoens S. Biosimilar medicines and cost-effectiveness. Clinicoecon Outcomes Res. 2011;3:29-36. 15. Hackbarth GM, Crosson FJ, Miller ME. Report to the Congress: improving incentives in the Medicare program, Medicare Payment Advisory Commission, Washington (DC) [homepage on the Internet]. 2009 [cited 2013 Feb 11]. Available from: http://www.medpac.gov/documents/jun09_entirereport.pdf 16. Höer A, de Millas C, Häussler B, Haustein R. Saving money in the European healthcare systems with biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):120-6. doi:10.5639/gabij.2012.0103-4.036 17. McCamish M, Woollett G. Worldwide experience with biosimilar development. MAbs. 2011;3(2):209-17. 18. Joshi SR. Biosimilar peptides: need for pharmacovigilance. J Assoc Physicians India. 2011 Apr;59 Suppl:44-7. 19. Hadavand N, Valadkhani M, Zarbakhsh A. Current regulatory and scientific considerations for approving biosimilars in Iran. Biologicals. 2011;39(5):325-7. 20. Cheraghali AM. Biosimilars; a unique opportunity for Iran national health sector and national pharmaceutical industry. Daru. 2012 Sep 10;20(1):35. 21. GaBI Online – Generics and Biosimilars Initiative. Significance of locally produced biosimilars in Iran [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2013 February 11]. Available from: www.gabionline.net/Biosimilars/Research/Significance-of-locally-produced-biosimilars-in-Iran 22. Straus SMJM, Giezen TJ. Pharmacovigilance of biosimilars: challenges and possible solutions. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):118-9. doi:10.5639/gabij.2012.0103-4.033
Author: Professor Abdol Majid Cheraghali, PharmD, PhD, Department of Pharmacology, University of Baqiyatallah Medical Sciences, Tehran, Iran
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal: Richard O Dolinar, MD; Michael S Reilly
Abstract
Biologicals are advanced prescription drugs to treat cancer, rheumatoid arthritis HIV/AIDS, multiple sclerosis and other debilitating diseases. In November 2010, the US Food and Drug Administration (FDA) began consultation with patient groups, physicians and industry on how to approve the first copies of these drugs, known as follow-on biologics in the US or biosimilars. As FDA moves forward in implementing this pathway, it is essential that all stakeholders work together to ensure patient safety remains the top priority to achieve safe and efficacious patient care.
Submitted: 15 October 2012; Revised: 4 March 2013; Accepted: 29 March 2013; Published online first: 8 April 2013
Introduction
Biologicals are large, complex molecule drugs that treat serious illnesses. They are created using proprietary and unique processes involving living cells, and range from sugars and proteins to tissues and nucleic acids [1]. Examples of biologicals can be found in vaccines, certain blood treatments, and gene therapy [2]. Biological medicines are unique because, unlike more established drugs, they are not chemically synthesized. According to the US Food and Drug Administration (FDA), biologicals ‘often represent the cutting-edge of biomedical research and, in time, may offer the most effective means to treat a variety of medical illnesses and conditions that presently have no other treatments available’ [2]. In fact, it is estimated that by 2016, biological medicines will comprise 48 per cent of the top 100 best-selling drugs [3].
Continued improvements in manufacturing efficiency, increasing access to these drugs and reducing costs are as important as new discoveries. Most importantly, with FDA outlining its latest guidance at the end of 2012 for the future of biological medicines, patient safety must be the primary focus of all stakeholders.
Biologicals meet biosimilars
Although the breakthroughs in biologicals have been groundbreaking, the future of health care is not just about new molecules. It is also about the new and exciting frontier of biosimilars, also known as ‘follow-on biologics’ in the US; biosimilars are products that enter the marketplace after the patent of an ‘innovator drug’ expires, in this case a certain biological.
Biosimilars have similar properties to existing biological products (hence the term ‘biosimilar’), therefore, patients can rest assure of the efficacy of these biological therapies. As the Generics and Biosimilars Initiative (GaBI) points out, FDA states that there are ‘no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product’ [4].
Importantly, however, due to the complexity of biologicals, a ‘follow-on biologic’ can only be made similar, rather than identical. Most of the discussion between biologicals and biosimilars contained herein this paper, moreover, is about switching, rather than the initial selection of these medicines.
It is always important to frame a discussion of biosimilars by remembering that there is no such thing as a generic biological. ‘Big’ molecules (biologicals) are more than just a larger version of ‘small’ chemically synthesized ones. Biologicals are created from living organisms and are not as simple to replicate as traditional drugs, such as aspirin and antihistamines. A biosimilar is not a generic drug, and that is more than just a detail.
Because of the complexity of manufacturing a biosimilar, it is imperative that FDA implements a system – a pathway – which provides complete transparency to patients and their physicians. An example of this patient-centered pathway is encouraging US States to require pharmacists to secure a patient’s consent prior to substituting an interchangeable biological product for the one prescribed, or at a minimum to ensure that treating physicians are notified when a substitution has occurred. Undoubtedly, it is in the patient’s best interest to have the pharmacist and physician work together.
The prescribing physician should be notified of the switch in a timely manner. Additionally, a strong track and trace system is needed to detect side effects, both to determine the rate at which rare events occur and to identify those not known at the time of market entry. Keeping patients and physicians in the healthcare decision-making process ameliorates potential harm to the patient in the event a product is found to have adverse side effects after it enters the market.
Today’s biologicals defined
Novel biologicals act by novel targets, technology platforms and/or mechanisms of action compared with previously approved biologicals.
Next-generation biologicals (‘biobetters’) have the same target or mechanism of action as a previously approved biological but include structural changes, bi-functional targeting (with or without a biosimilar core) or an improved formulation that may result in an expected improvement in clinical profile.
Because biological therapeutics are highly complex and large protein molecules, they require a wide variety of analytical methods to ensure consistent quality. Indeed, given the complexity of biologicals and their manufacture (in which living cells produce the core molecule and make post-translational modifications), the innovator product has inherent lot-to-lot variability. In light of this inherent variability and the diverse and complex analytical methodologies required to characterize the molecules, it is not realistic to exactly replicate an innovator molecule. Therefore, the concept of a biosimilar is to make a molecule that is as similar to the innovator as possible. Accordingly, follow-on molecules in the biological space are termed biosimilars, rather than biogenerics.
Biosimilars are structurally highly similar versions of marketed biological medicines. They will have been evaluated and approved by a regulatory authority on the basis of analytical and clinical comparison to the already marketed product.
Across the globe, with the goal of making biologicals more accessible, regulators either have adopted or are considering legislation or regulations to establish pathways for the approval of biosimilars. Because biosimilars are never exact copies of the innovator medicine, establishing appropriate standards for biosimilarity remains an important area for scientific, legislative and regulatory debate [5].
It is important for legislators and regulators to promote safety and science when crafting new policy pertaining to these life-saving medicines. That is why the Alliance for Safe Biologic Medicines (ASBM) works to promote four key principles as US regulators implement an approval pathway for biosimilars:
prioritizing patient safety
leveraging what we know
promoting pharmacovigilance
keeping physicians engaged.
Prioritizing patient safety
Biotechnology companies that seek FDA approval for an interchangeable biosimilar need to demonstrate, through de novo clinical trials, that switches from the biosimilar to the reference innovator product (and vice versa) have no negative effect on safety and/or effectiveness, particularly as a result of immunogenicity. It is also important to realize that for one product, the risk of immunogenicity may differ depending on the therapeutic indication [6].
In fact, when it comes to biosimilars, the most important issues facing global drug regulators are the scientific and technical factors related to a determination of biosimilarity. Minor differences in manufacturing processes, such as different host cells, cell culture and purification methods, can have a clinically significant impact on a biological’s safety and effectiveness. It is not just whether or not a biosimilar ‘works’, it is about whether or not it works as well or in the same way once it is administered to a patient. Just as no two patients are exactly alike, neither are biosimilars identical to the innovator product.
The age of ‘personalized medicine’ is predicated on the ‘four rights’—being able to administer the right medicine to the right patient in the right dose at the right time [7].
One issue at the forefront of the biosimilars debate is that of ‘switching’—changing a patient’s therapy from the innovator product to a biosimilar. Since biosimilars are not identical to their innovator products, many nations around the world have clearly stated that automatic substitution is inappropriate. Because biosimilars generally cost less than innovator drugs, there is significant economic pressure to switch patients to lower cost biosimilars. But when cost-centric concerns are allowed to trump the practice of patient-centric medicine, there is a potential negative impact on both patient safety and clinical effectiveness. The decision to switch a patient must be a clinical one made by the treating physician rather than a legislator, regulator, or insurance provider.
The United States is the only nation that requires its regulatory authority to evaluate whether a biosimilar is similar enough to the already marketed ‘reference’ product that it can be substituted without physician intervention, permission or authorization. Under US law, FDA would designate such products ‘interchangeable’. In addition to scientific challenges associated with making such a designation, there are substantial administrative hurdles that, if not effectively addressed, could jeopardize patient safety.
Leveraging what we know
Regardless of whether you live in the EU, US or Canada, people might see the prescription drug approval process as mysterious and arcane and have never heard of biosimilars, follow-on biologics or subsequent entry biologics (SEBs). In the US, the regulatory pathway for approval of biosimilars is still in its very early stages, lagging behind the regulatory bodies in the EU and Canada. There are many contentious issues surrounding the ‘biosimilar pathway’. Some are economic and focus on legal concerns such as patents and data exclusivity, but these are not within the purview of FDA. What rightly concerns the US drug regulator is safety and efficacy.
The Patient Protection and Affordable Care Act empowered FDA to develop a biosimilar pathway. Having the authority is one thing, getting it done in a timely, suitable, and scientifically robust manner is something else altogether. While FDA retains many of the best regulatory scientists in the world, its human and capital resources are severely limited. Rather than creating a biosimilar pathway from scratch, the US needs not reinvent the wheel. The European Medicines Agency (EMA) began to establish the first formal regulatory pathway for biosimilars in 2003, and that process can serve as a baseline model upon which the US can build.
In February 2012, FDA issued three highly anticipated documents providing guidance on its biosimilar approval pathway. This guidance set forth FDA’s current thoughts on ‘key scientific and regulatory factors involved in submitting an application for biosimilar products’ [8]. The documents help clarify application processes mandated under the new abbreviated regulatory pathway that was included in the Patient Protection and Affordable Care Act.
According to the agency, ‘Healthcare professionals and consumers can be assured that the FDA will require licensed biosimilar and interchangeable biological products to meet the Agency’s exacting standards of safety and efficacy’ [9].
Any biosimilar approval should be based upon the overall assessment of biosimilarity to the innovator through robust analytical, non-clinical and clinical data. For some biological molecules, certain studies may not be necessary. In the event that a biosimilar manufacturer is seeking approval for multiple indications, extrapolation of data should be scientifically justified.
By pioneering in this regulatory area for the last eight years, the EU has gathered much data, which can, at a minimum, help inform policymakers. US policymakers should take advantage of this opportunity to learn from the experiences of their counterparts, both the positive and negative.
Promoting pharmacovigilance
Pharmacovigilance is the surveillance of a drug’s performance, particularly of adverse reactions, after it has been released for marketing. As biosimilars may be approved based on less data, pharmacovigilance plays an even more important role. Before biosimilars are thoroughly introduced into the US marketplace, a robust traceability system – including distinctive labels, distinguishable names, product tracking codes, and a way to report adverse events – must be in place to facilitate accurate surveillance.
Through enhanced, 21st century pharmacovigilance, the US can do a better job analyzing data and drawing conclusions relative to many unknown differences between innovator products and biosimilars. The forces of globalization have enabled many other nations to work together to promote pharmacovigilance. As of 2010, 134 nations are party to the World Health Organization (WHO) pharmacovigilance programme [10]. This WHO pharmacovigilance initiative ‘aims … to enhance patient care and patient safety in relation to the use of medicines; and to support public health programmes by providing reliable, balanced information for the effective assessment of the risk–benefit profile of medicines’ [10]. It is only by embracing this type of understanding of how biosimilars impact patient health in this ‘real world’ that patients will be able to use them in the most appropriate way to achieve the best outcomes for their personalized needs. As former Eli Lilly & Co CEO, Mr Sidney Taurel stated at the Cleveland Clinic, ‘The time is ripe for FDA, the healthcare industry, and the medical community to collaborate on a reform of our nation’s pharmacovigilance system. Such reform will allow us to speed up the recognition of safety signals and understand the true efficacy of new medicines more quickly’ [11].
Automatic substitution complicates the pharmacovigilance that is needed for all biological and biosimilar medicines to ensure safety for patients. Pharmacovigilance is facilitated when physicians make the decision to substitute a biosimilar product. Automatic substitution makes biosimilar pharmacovigilance significantly more difficult. There should be greater clarity and transparency in state substitution laws, and attention must be paid to any prospective policies that infringe physicians’ freedom to prescribe the medicines that they deem most appropriate for a particular patient. The need to improve and expand pharmacovigilance systems must also be applied to any changes made in originator biologicals since they may also cause unintended outcomes. To quote Dr Woodcock, ‘Our improving the use of marketed drugs, to a great extent, is going to involve partnering with the growing patient safety movement. The vast majority of harm from approved drugs comes from misuse, inappropriate use … failure to use, abuse and medical mix-ups’ [8].
When it comes to biosimilars—primum non nocere (first do no harm).
Complex and extreme challenges often require creative solutions. An excellent example of this is the development of biobetters. Biobetters are to biosimilars what Apple’s iPod Touch is to its iPod Shuffle. Where a biosimilar will be a mere structural imitation, a biobetter will possess some molecular or chemical modification that constitutes an improvement over the originator drug. As such, it must be evaluated and approved through the traditional pathway.
Such enhancements may range from a longer half-life, allowing for less frequent dosing, to more potency or less toxicity. That is innovation driven by the new reality of biosimilar competition. And it should not be surprising since, among other things, competition drives innovation.
Keeping physicians engaged
Sir William Osler, widely regarded as the father of modern medicine, wrote ‘If you listen carefully to the patient they will tell you the diagnosis.’ Arriving at a diagnosis and appropriate treatment plan has always represented intimate collaboration between patients and physicians.
But today, physicians are increasingly seeing the decisions that they and their patients reach about specific treatment plans second guessed by distant ‘third parties’, working for government agencies or insurance providers, who may not be aware of the unique individual circumstances of a particular patient.
Physicians must practice both the art and science of medicine, but the issue of cost threatens to interpose itself between physicians and patients. While cost is certainly a crucial topic when it comes to health care, it cannot trump patient safety.
And nowhere is this debate more immediate, urgent, or profound than when it comes to the issue of therapeutic switching, that is, switching patients between products not considered interchangeable. Physicians carefully collaborate with their patients to choose the most appropriate treatment, considering the patient’s disease state, ability to tolerate side effects, and stage of life. The crucial differences between biosimilars and small molecule generics are that biosimilars are difficult and expensive to get approved, complicated and challenging to manufacture, and generally have a short shelf life. The savings are expected to track the experience in Europe to date and reflect a 10–30% discount from the originator product rather than 90%, as with chemical drugs.
Reformers need to recognize that policies giving healthcare administrators control over treatment regimes are hazardous to patient health, and actually inflate overall costs.
In Europe, regulatory authorities understand that the successful adoption of biosimilars requires physician buy-in and for that reason EMA advises that the physician should be in charge of the decision to switch between the reference product and biosimilar, or vice versa [12]. Physician confidence translates into increased utilization and in fact, biosimilar medicines have gained a foothold in some European countries as a result of a strategy to persuade physicians to start new patients on a biosimilar rather than switch existing patients [13].
There is a need of enhancing the ‘biological experience’ for physicians/prescribers. Adequate physician education, sufficient clinical data and appropriate reimbursement services for physicians will result in greater use of biologicals and biosimilars [14].
The repercussions of choosing short-term savings over long-term results, of cost-based choices over patient-centric care, of ‘fail first’ policies over the right treatment for the right patient at the right time—are pernicious to both the public purse and the public health.
Conclusion
The explosive growth of biological medicines, and the emergence of biosimilars as revolutionary tools to fight the most difficult of diseases, is cause for great celebration in the fight to provide advanced health care to patients worldwide. By abiding by the general principles of prioritizing patient safety, leveraging the information we know, promoting pharmacovigilance and keeping physicians engaged, a golden age for innovative and affordable health care is within reach.
As indicated in an FDA hearing on its biosimilar guidelines in Washington DC, USA, in May 2012, the debate over the future of the biosimilar approval pathway is far from over [15]. Issues in need of further consideration include, among others, defining proteins, stricter methodology in labelling and naming biosimilars.
It is important to note that, although beyond the scope of this paper – which focused on switching between biological products – biosimilars can sometimes be used as the initial and only therapy. Also, the manufacture of innovator products can involve changes that require tracking of outcomes.
In fact, biosimilar medicines have gained a foothold in some European countries as a result of a strategy to persuade physicians to start new patients on a biosimilar rather than switch existing patients [14].
The future of biological medicines will be bright if patients, physicians, biotechnology companies, and other stakeholders work together to ensure patient safety is the foremost priority of the biosimilar policy discussion. Then, the future of healthcare debate can move beyond partisan discussion over healthcare access and cost, to a discussion of the diseases that biological medicines can successfully conquer next.
For patients
Biologicals and biosimilars are not covered under the 1984 Hatch-Waxman Act, which created an abbreviated approval process for generic versions of conventional drugs. On 23 March 2010, however, the Patient Protection and Affordable Care Act was signed in to law and included a pathway for the approval of biosimilars (also referred to as the Biologics Price Competition and Innovation Act). This abbreviated approval pathway for biosimilars gives FDA the authority to define the implementation process. The law also gives FDA the authority to further define the detail regarding scientific standards and the extent of analytical, preclinical and clinical data necessary for the approval biosimilars to ensure patient safety and the effectiveness of the biosimilar.
As FDA moves forward with the process it is important for patients, physicians, pharmacists, and all other stakeholders to be engaged in these efforts to ensure that the top priority for US regulators is patient safety. Our hope is that the principles outlined in this paper will help them to achieve this worthy goal for patients.
Acknowledgement
Dr Brett Johnson with the International Cancer Advocacy Network (ICAN) also contributed to the production of this paper.
Funding sources
The Alliance for Safe Biologic Medicines (ASBM) is an organization composed of diverse healthcare groups and individuals—from patients to physicians, innovative medical biotechnology companies and others who are working together to ensure patient safety is at the forefront of the biosimilars policy discussion. The activities of ASBM are funded by its member partners, who contribute to ASBM’s activities, with the primary funding provided by the Steering Committee, funds the ASBM’s efforts. ASBM’s Steering Committee is comprised of Alliance for Patient Access, American Academy of Dermatology, American Association of People with Disabilities, Association of Clinical Research Organizations, Colon Cancer Alliance, Genentech, Global Healthy Living Foundation, Health HIV and Kidney Cancer Association. It is the mission of the ASBM to serve as an authoritative resource center of information for the public, medical community, FDA and other government staff during the implementation of the biosimilars approval pathway and beyond.
Disclosure of financial and competing interests: Dr Richard O Dolinar, Chairman of the Alliance for Safe Biologic Medicines (ASBM) and Mr Michael S Reilly, Executive Director of the Alliance for Safe Biologic Medicines; are the primary authors of the paper. Both authors are employed by ASBM.
This paper was funded by the Alliance for Safe Biologic Medicines and represents the policies of the organization.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Richard O Dolinar, MD, Chairman
Michael S Reilly, Executive Director
Alliance for Safe Biologic Medicines, PO Box 3691 Arlington, VA 22203, USA
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Author for correspondence: Michael S Reilly, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691 Arlington, VA 22203, USA
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
GaBI Journal is an independent and peer reviewed academic journal. GaBI Journal encompasses all aspects of generic and biosimilar medicines development and use, from fundamental research up to clinical application and policies.
