Introduction: Switching from originator products to generic equivalents is a key method used by governments to reduce costs and keep their healthcare systems sustainable. The aim of this article is to review generic medicine pricing in Europe by analysing the factors that influence them. Methods: The literature review focused on selected studies that highlighted generic medicine pricing in ambulatory care in Europe. PubMed, the Centre for Reviews and Dissemination databases, Cochrane Database of Systematic Reviews, and EconLit were searched up to August 2011. Search terms included, ‘pharmaceuticals’, ‘generic medicines’, ‘Europe’, ‘pricing’, ‘discount’, and ‘rebate’. Bibliographies of included studies were checked for relevant studies and the status of generic medicines pricing in Europe was also documented via accessing the European Generic medicines Association market survey. Results: Ex-manufacturer prices for generic medicines were found to vary substantially between European countries, which suggests that pricing not only reflects production costs, but is also influenced by the domestic regulatory environment. The penetration of generic medicines is more successful in countries that permit free pricing of medicines than in those that have price regulation. Although tendering systems may reduce (generic) medicine prices in the short term, little is known about the overall long-term impact of such systems. Conclusion: No single approach towards developing generic medicine pricing policies and attaining cost savings was evident
Submitted: 20 April 2011; Revised manuscript received: 7 September 2011; Accepted: 13 October 2011
Introduction
Generic medicines are a key instrument for governments to sustain their healthcare systems and control pharmaceutical expenditures. This contribution of generic medicines to the sustainability of European healthcare systems has been recognised by the High Level Pharmaceutical Forums, ‘Generic medicines provide an opportunity to obtain similar treatments at lower costs for patients and payers, while liberating budgets for financing new innovative medicines’ [1]. WHO also emphasises the cost-saving potential of switching consumption from originator products to generic equivalents [2].
This underlines the importance of gaining insight into generic medicine pricing in Europe, where pricing is an area of national responsibility of the EU Member States. The aim of this brief article is to review generic medicine pricing in Europe. This will be achieved by providing evidence concerning the generic medicine price levels in Europe and the factors that influence price levels and by providing an insight into the international literature on generic medicine pricing policies and their impact. When addressing generic medicine pricing policies, this article focuses on free-pricing systems versus price-regulated systems, reference pricing, price competition and discounts, and tendering procedures.
Methods
This literature review did not focus on summarising and assessing all relevant studies, but rather drew on personally selected studies about generic medicine pricing in Europe. As such, this literature review was not systematic.
Studies were identified by searching PubMed, Centre for Reviews and Dissemination databases, Cochrane Database of Systematic Reviews, and EconLit, up to August 2011. Additionally, the bibliography of included studies was checked for other relevant studies. Search terms included pharmaceuticals, generic medicines, Europe, pricing, policies, regulation, market, competition, reference pricing claw-back, tendering, discount and rebate alone and in combination with each other.
The literature review was restricted to generic medicine pricing in ambulatory care in a European country. Studies of generic medicine pricing in the hospital setting were excluded. Studies could be published in Dutch, English, French, German or Italian. Studies published prior to January 2000 were not included as this is a rapidly changing field. Additionally, the market survey conducted by the European Generic medicines Association was accessed to document the status of generic medicine pricing in Europe in 2011.
Results
Generic medicine pricing Price levels Professor Simoens conducted an international comparison of ex-manufacturer prices of generic medicines in ambulatory care in 2005 [3]. Data on generic medicine prices of 15 molecules/strengths were derived from IMS Health. The analysis was limited to medicines in immediate release, oral, and solid dosage forms. Prices were compared between nine European countries (Belgium, Denmark, France, Germany, The Netherlands, Norway, Spain, Sweden and UK) and with India. India was included because the European generic medicines industry has been facing competition from Indian firms which benefit from lower labour and production costs, and weaker patent protection laws.
Ex-manufacturer prices, i.e. the price at which a pharmaceutical company sells medicines, for generic medicines varied substantially between European countries. For instance, generic medicine prices in the Scandinavian countries were substantially lower than prices in countries such as France, Germany, The Netherlands or UK. Such European variation suggests that the prices of generic medicines not only reflect underlying production costs, but are also influenced by the domestic regulatory environment surrounding registration, pricing, reimbursement and distribution of generic (and originator) medicines. This illustrates the importance of domestic healthcare policies in the pricing strategies of manufacturers. For instance, the introduction of the ‘manufacturer’ and ‘wholesaler’ schemes in UK in 2005 (which purported to increase generic medicine pricing transparency) reduced generic medicine prices by 32% in the first year following policy implementation [4, 5].
This study also indicated that the lowest ex-manufacturer prices of generic medicines were observed in India. Imports from India are likely to put downward pressure on generic medicine price levels in Europe. Indeed, Indian generic medicine prices could give an indication of how much generic medicine prices in Europe could drop in the future.
Factors influencing price levels Generic medicine pricing not only varies between European countries, but it can also differ between medicines within a single country. Adriaen et al. examined the evolution of the retail price of originator and generic medicines from July 2001 to December 2005 in Belgium [6]. Price levels in the Belgian off-patent market were influenced by a large number of issues such as successive reductions in reference prices and prescription status of medicines; by market incentives in the form of price competition between generic medicines, competition between originator and generic medicines or price agreements between originator and generic medicines; by medication class; and by the market power of the originator medicine.
A recent study investigated whether there is a relationship between the market share of generic medicines and the price level in European off-patent markets [7]. Data on 35 oral active substances were derived from IMS Health. Medicine values were calculated on the basis of ex-manufacturer prices. The analysis included countries with a high market share of generic medicines (volume of 40% or more) as well as countries with a low market share of generic medicines (volume of 20% or less), see Figure 1. Data used were from June 2002 until March 2006.
The authors calculated the evolution of off-patent market values, i.e. price x volume, of 35 selected active substances. The decrease of market value in markets with a high share of generic medicines was more substantial (−26.6%) than the decrease in markets with a low share of generic medicines (−0.06%), although this was not statistically evaluated. In high generics market share markets, medicine prices dropped by −43.18% and in low market share markets by −21.56%. Thus, the extent to which price competition from generic medicines leads to price reductions appears to vary according to the market share of generic medicines.
Markets with a high market share of generic medicines tended to see a larger decrease in medicine prices than markets with a low market share of generic medicines. This observation suggests that the generic medicines industry is able to deliver competitive prices if it is ensured a high market share of the off-patent market. This high market share is dependent on demand-side policies. On the one hand, countries with a high market share of generic medicines have incentives in place for physicians, pharmacists, and/or patients to demand generic medicines. On the other hand, there are few incentives to stimulate demand for generic medicines in countries with a low market share of generic medicines [8]. This is corroborated by recent work from Godman et al., which suggests that European countries can enhance prescribing efficiency by implementing measures to lower generic medicine prices in combination with demand-side policies such as prescribing restrictions on originator medicines [9, 10].
Generic medicine pricing policies Free market versus price regulation European generic medicine pricing systems tend to be: a) a free-market approach, where manufacturers are (relatively) free to set generic medicine prices; b) a price-regulated system, where generic medicine prices are set on a regulatory basis, e.g. by law; or c) a combination of these two approaches, e.g. price regulation for the first generic medicine(s) and a free-market approach for following medicines [4, 11, 12].
In Europe, the reimbursement status of a generic medicine tends to determine which pricing system applies to a product. The literature indicates that penetration of generic medicines is more successful in countries that permit free pricing of medicines than in countries that have price regulation [13-15]. In countries where a free-market approach prevails, manufacturers of originator medicines can charge premium prices both before and after patent expiry, thereby attracting market entry of generic medicines. Manufacturers of generic medicines are engaged in price competition and are able to raise their market share by offering price reductions on their products. As a result, in countries with free pricing, the price difference between originator and generic medicines tends to be higher than in countries with price regulation [14, 16].
In contrast, in countries that rely on regulated prices, regulation drives down the price of the originator medicine over the life cycle of the medicine, thus discouraging market entry of generic medicines [15]. The limited diffusion of generic medicines in such markets restricts price competition following patent expiration, although competition in the form of discounts to pharmacists may occur [16]. In response to this, countries such as France have introduced generics substitution targets to sustain generic medicine market entry and price competition [17].
A market survey conducted by the European Generic medicines Association in 2011 revealed that 80% of European countries imposed price regulation and 20% adhered to free-market pricing [18]. Of those countries with pricing regulation, 37% set the price of generic medicines at a predetermined percentage below the price of the originator medicine, 31% set a maximum price for generic medicines, and 16% based the generic medicine price on the average price of medicines in a selection of European countries. The mechanism used to link the prices of generic and originator medicines may produce the following incentive: if a generic medicine needs to be priced at, for example, 55% or more below the price of an originator medicine throughout its life cycle, as is the case in France, then manufacturers of originator medicines can lower prices in an attempt to drive generic medicines out of the market.
The mechanism of price regulation may also have an impact on the extent to which price competition takes place and, hence, can influence generic medicine pricing. A Norwegian study has reported that a reference pricing system, i.e. a system where the regulator establishes a common reimbursement level for a group of interchangeable medicines, stimulated generics competition to a greater extent and led to lower prices than did price-cap regulation, i.e. a system where the regulator sets a maximum price that can be charged for a medicine [19]. The recent literature suggests that mechanisms to regulate prices such as price caps or a reference pricing system reduce prices of originator and generic medicines and may encourage price competition beyond the price reductions imposed by regulation in some countries, e.g. Austria, Lithuania [11, 12], but not in others, such as Slovenia or Spain [20].
Reference pricing The generic medicine price level is likely to be influenced by the operation of a reference pricing system. Given that medicines priced above the reference price are likely to lose market share as a result of the additional patient co-payment, manufacturers have an incentive to price generic and originator medicines at or below the reference price. Also, in some countries such as Belgium, generic medicines need to be priced at or below the reference price if they wish to gain reimbursement [21].
The market survey conducted by the European Generic medicines Association found that 80% of European countries had a reference pricing system in 2011 [18]. When setting reference prices, the majority of countries took into account the prices of existing medicines: the reference price was based on either the lowest priced medicine (47% of countries), the lowest priced generic medicine (21% of countries), the average price of medicines (11% of countries), the average price of generic medicines (5% of countries), or other measures (16% of countries). Reference prices were established by active substance (42% of countries), therapeutic class (31% of countries), pharmacological class (18% of countries), or by another mechanism (9% of countries).
By calculating the reference price as a function of the prices of existing medicines, generic medicine manufacturers may have an incentive to compete, thereby driving down (reference) prices of medicines [22]. Nevertheless, it should be noted that competition does not exist in all countries that have adopted this mechanism of setting reference prices. Therefore, in addition to setting reference prices as a function of the prices of existing medicines, some countries have established a fixed minimum price difference between generic and originator medicines, e.g. France, Italy and Portugal [8]. This approach has the benefit of guaranteeing savings to the third-party payer, although it is not clear at what level maximum prices of generic medicines need to be set. The third-party payer will lose out if reimbursement prices of generic medicines are established at a higher level than would have been observed in a competitive market [22].
Discounting In some European countries, competition between generic medicine manufacturers takes the form of discounting to the distribution chain rather than price competition. Indeed, two studies found that generic medicine discounts ranged from 20–70% off the wholesaler selling price in France and maximum discounts exceeded 50% of the Drug Tariff price in UK [23, 24]. Retail prices overestimate the value of generic medicines if generic medicines manufacturers compete by offering discounts to the distribution chain. This is because retail prices do not take these discounts into account. In the author’s opinion, the practice of discounting is not clear to market actors and is not fair as wholesalers and pharmacists are not rewarded for services rendered, but rather for their ability to negotiate discounts on artificial prices [22].
Such a system may financially benefit wholesalers and pharmacists, but it is not sustainable in the long run given that countries increasingly compare prices across Europe and given that healthcare payers and patients do not capture the potential savings from a generic medicines market where companies compete on price [25]. In response to this, France has regulated the size of discounts awarded in the distribution chain [24] and The Netherlands has introduced claw-back mechanisms that aim to recover the discounts that pharmacists receive. The introduction of the ‘Manufacturer’ and ‘Wholesaler’ schemes in UK made the manufacturing costs and discounts more transparent, leading to lower prices for generic medicines [5].
However, this type of government intervention is unlikely to be as efficient as a market mechanism where generic medicine manufacturers compete on the basis of prices rather than discounts to the distribution chain. Price competition between generic medicines manufacturers is transparent and easy for all market actors to understand, and ensures that prices paid by healthcare payers and patients reflect value [15]. For instance, Poland will introduce legislation in 2012 that outlaws discounting to the distribution chain and promotes price competition. However, such legislation also needs to address the issue of pharmacist remuneration as pharmacists are likely to lose an important source of income if discounts are outlawed.
Tendering Tendering is a mechanism whereby a purchaser buys medicines based on a competitive bidding process where the contract is granted to the pharmaceutical supplier who offers the best bid following strict criteria [26]. Whereas tendering procedures are widely used in the hospital sector, in the last couple of years they are also being rolled out in ambulatory care in an increasing number of European countries with a view to constraining pharmaceutical expenditure [27]. Few data are available to date on the current status and impact of tendering procedures in Europe.
The literature suggests that significant pharmaceutical budget savings can be achieved from tenders, but the overall results are unclear [28]. One study pointed to pharmaceutical budget savings as a result of significant reductions in medicine prices in Denmark, Germany and The Netherlands [29]. However, although physicians and patients have incentives (in the form of lower patient co-payment) to demand medicines that are included in the tender in Germany, physicians still have the right to write ‘do not substitute’ on the prescription form. Furthermore, the Belgian experience indicates that tendering produced savings for one specific medicine, but these savings were offset by the fact that physicians switched their prescribing patterns to medicines with a similar therapeutic indication that did not fall under the tendering procedure, so-called ‘re-allocation of demand’, and total expenditure actually increased [30].
Countries that have implemented tendering procedures have sometimes witnessed a decrease in pharmaceutical investments, a slowdown in the development of the generic medicine market, short-term absences of some medicines due to logistic shortages, a reduction in pharmacist remuneration, and problems with patient compliance [29]. Finally, tendering systems in countries such as Germany are regionally based and are initiated between individual sickness funds and pharmaceutical companies and, therefore, are less transparent than in countries such as Belgium, which has a national tender.
Conclusion
Using evidence from the literature on generic medicine pricing in Europe, this article suggests that competition from Indian generic medicine manufacturers, international comparisons of generic medicine prices, some mechanisms to set (reference) prices, and efforts to move away from competition by discount to competition by price are likely to put pressure on generic medicine prices in European countries and to generate additional savings to healthcare payers and patients. These savings may depend on the implementation of a free-market approach because more generics competitors tend to enter the market and price competition is stronger in less-regulated markets. Although tendering systems may reduce (generic) medicine prices in the short term, little is known about the overall long-term impact of such systems.
For patients
Once the patent of an originator medicine expires, generic medicines can enter the market. Generic medicines have the same quality, safety and therapeutic efficacy as the originator medicine, but are less expensive than originator medicines. In an era of ageing populations and rising healthcare costs, generic medicines allow patients to access safe, effective, high quality medicines at 20–80% of the price of branded originator medicines.
Conflict of interest
No sources of funding were used to assist in the preparation of this manuscript. The author has no conflicts of interest that are directly relevant to the content of this manuscript.
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Author: Professor Steven Simoens, MSc, PhD, 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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Abstract: Biopharmaceuticals are medicines whose active drug substance is made by living cells. Copies of these drugs, called biosimilars, are not identical to their reference drug and therefore specific regulatory requirements for registration apply. Whereas pharmaceutical quality evaluation requires a full dossier and a detailed comparative analysis to the reference drug, non-clinical and clinical requirements are much less extensive compared to the requirements for an innovator. Limited clinical experience and their complex nature exclude biosimilars from being considered interchangeable with the reference drug..
Submitted: 20 April 2011; Revised manuscript received: 22 September 2011; Accepted: 14 October 2011
Introduction
Biopharmaceuticals, also called ‘biological medicinal products’ or ‘biological medicines’, are medicines whose active drug substance is made by a living organism or derived from a living organism by means of recombinant DNA and/or controlled gene expression methods. These products are polypeptides, (glyco-)proteins, and/or nucleic acids and their molecular characteristics are much more complex than traditional chemical drugs.The final biopharmaceutical product is influenced by many variables, such as the type of expression system, e.g. bacteria, yeast, and mammalian cells; the growth conditions, the purification process, the actual formulation and the conditions during storage and transport. Post-translational modifications occur during cellular synthesis, such as glycosylation, phosphorylation, sulphation, methylation, acetylation and hydroxylation which may affect biological activity and which results in an intrinsic molecular heterogeneity. It can be calculated, theoretically, that these modifications may result in more than one million product-related variants. Since this structural variability is substantial and can be very subtle, the currently available analytical techniques are insufficient to fully characterise the end product. In contrast, ‘traditional low molecular weight chemical drugs’ are produced by well-controlled and highly reproducible chemical reactions and are molecules with a small, well-defined and stable chemical structure, which can be completely characterised by analytical methods.The heterogeneity of biopharmaceuticals is further increased by the fact that these products are quite sensitive to ‘external’ conditions. The latter can affect product integrity and stability, leading, for example, to varying degrees of peptide denaturation, aggregation, oxidation, and degradation. Such modifications are less likely to occur in traditional non-biopharmaceutical drugs because they are much smaller and can be better controlled and are more predictable by nature [1-3].Importantly, and in contrast to traditional chemical drugs, biopharmaceuticals are potentially immunogenic. In this respect it is important to note that subtle structural differences, for example, consequent to small differences in the number and type of product variants, may significantly affect the immunogenic potential of the drug product [4-6]. Additionally, product- or process-related impurities can provoke an immune response [2, 7].The main differences between low molecular weight (chemical) drugs and biological drugs are summarised in Table 1.
Biosimilars
After the expiration of patent(s) for the first approved biopharmaceuticals, ‘copying’ and marketing of these biological substances can be offered by other biotech companies and might possibly, as with generics, reduce cost to patients and social security systems. However, biopharmaceuticals are made by living cells. Because of their intrinsic complexity and because no two cell lines, developed independently, can be considered identical, biopharmaceuticals cannot be fully copied. This is recognised by the European regulatory authorities and has resulted in the establishment of the term ‘biosimilar’ in recognition of the fact that, whilst biosimilar products are similar to the original product, they are not exactly the same [8, 9].European legislation has included specific guidelines for the approval of biosimilars since 2005. The Australian Therapeutic Goods Administration has adopted the European guidelines. Canadian health authorities have recently published a guidance document for approval of biosimilars, mainly based on the European guidelines [10]. Adaptation of US legislation concerning biosimilar approval processes is still under development. In March 2010, the Public Health Service Act was amended to create an abbreviated approval pathway for biosimilars [11]. Also WHO has issued guidelines for the evaluation of biosimilars [12].Thus a biosimilar, sometimes called ‘similar biological medicinal product’ or ‘follow-on biologic’ (Japan and USA) or ‘subsequent entry biologic’ (Canada), is a medicine that is similar to a biopharmaceutical that has already been authorised (the ‘reference product’). Since the active substance of a biosimilar is similar but not identical to the active substance of the reference product the regulatory requirements for approval of generics are inadequate to demonstrate the quality, efficacy, and safety of biosimilars.For a generic low molecular weight chemical drug, it is sufficient to demonstrate comparable quality, for example, content and purity, and a comparable clinical pharmacokinetic (PK) profile, i.e. relative bioavailability/bioequivalence, with a reference (innovator) product to obtain regulatory approval [13]. For biosimilars, EMA not only requires comparative quality and clinical PK studies, but also non-clinical studies, clinical pharmacodynamic (PD) studies, and limited toxicology studies, as well as comparative clinical efficacy and tolerability studies [8, 14, 15]. However, non-clinical PKs, safety profile, reproduction toxicology, mutagenicity and carcinogenicity studies are not mandatory for approval of a biosimilar, in contrast to what is required for reference biopharmaceuticals. A comparison of the European regulatory requirements for a marketing authorisation application of a biosimilar versus a reference is shown in Table 2.The guidelines for quality requirements for a biosimilar product claiming to be similar to an approved and marketed biopharmaceutical product published by the Committee for Medicinal Products for Human Use (CHMP) [14] states that the active substance in the biosimilar should be similar to the one in the reference product. Demonstration of similarity requires comparability exercises versus the chosen reference product. This implies the use of appropriately selected state-of-the-art analytical methods that are able to detect ‘slight differences relevant for quality evaluation.’ These comparability exercises also include the comparative evaluation of physicochemical parameters, biological activity using relevant bioassays and a qualitative and quantitative comparative assessment of purity and impurity profiles. The guideline also indicates that ‘… it is not expected that the quality attributes in the similar biological and reference medicinal products will be identical …’. Indeed, the quality attributes of the final biological product inherently vary with the type of host cell, the growth conditions, the purification process, the formulation, and the storage conditions. However, the CHMP requires that any difference in the quality attributes between the biosimilar and its reference product, such as variability in post-translational modifications or differences in impurity profiles should be justified in relation to its potential impact on efficacy and tolerability. The existence of differences in quality attributes between a biosimilar and the reference product is reported in the public assessment reports (EPAR) (visit www.ema.europa.eu) made available upon approval of the biosimilar. For example, for a biosimilar of epoetin alfa, differences are reported with respect to glycosylation (higher levels of phosphorylated high-mannose-type structures, lower levels of N-glycolylneuraminic acid and diacetylated neuramic acids) and oxidation (lower levels of the oxidised variant). For a biosimilar of somatropin, differences in impurities are reported as well as a higher level of deamidated variants.The general non-clinical and clinical requirements for a biological medicinal product claiming to be similar to an approved biopharmaceutical were also published by the CHMP in 2006 [15]. These are much less comprehensive compared to the requirements for an innovator, see Table 2, and evaluation is mainly based upon data obtained by comparative studies—biosimilar versus reference. In addition to the general non-clinical and clinical guidelines, product class-specific annexes to these guidelines have also been adopted for biosimilars containing recombinant interferon alfa, recombinant granulocyte-colony stimulating factor, recombinant somatropin, recombinant insulin, low molecular weight heparins, and recombinant erythropoeitins as the active substance. Draft guidelines for biosimilars containing monoclonal antibodies [16], as well as concept papers for biosimilars containing recombinant interferon beta [17] and recombinant follitropin [18] have been released for consultation.In general, non-clinical comparative tests should comprise in vitro studies, e.g. receptor-binding studies or cell-based assays, as well asin vivo PD studies. In addition, given the immunogenic potential of biopharmaceuticals, at least one repeat dose toxicity study should be performed including toxicokinetic measurements such as determination of antibody titres, cross-reactivity and neutralising capacity[6]. Such tests are particularly useful to detect the presence of hostcell proteins and/or impurities in the product. However, in contrast to the reference products, the approval process of biosimilars does not require safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies, see Table 2.Clinical studies required for regulatory approval of a biosimilar should include comparative PK and PD studies in healthy volunteers, followed by comparative efficacy and tolerability trials. The guideline states specifically, ‘… the clinical comparability exercise is a stepwise procedure that should begin with PK and PD studies followed by clinical efficacy and safety trial(s) or, in certain cases, PK/PD studies for demonstrating clinical comparability.’ The latter studies are usually performed only in the most sensitive and most relevant target patient population(s). In some cases, PK/PD studies alone might be considered sufficient [15] and in other cases, for example, where it is assumed that the mechanism of action of the drug is only dependent on its interaction with one single binding partner as the target, therapeutic similarity demonstrated in one indication may be extrapolated to other indications of the reference product. Extrapolation, however, remains a matter of debate especially when different indications imply the use of significant different doses [19], or different patient populations, for example, children versus adults, or when extrapolation to use in healthy individuals is concerned, for example, use of filgrastim for stem cell mobilisation and collection in healthy donors.On the other hand, the guidelines put special emphasis on assessment of the clinical tolerability of a biosimilar because of its potential immunogenicity. Indeed, differences in quality attributes between the biosimilar and its reference product cannot always be detected during the quality control process, and their clinical consequences cannot always be predicted from non-clinical animal studies [6]. Hence, clinical trials that extensively evaluate the tolerability and immunogenicity of the biosimilar are indispensable. These assessments require optimal antibody testing, characterisation of the observed immune response, and evaluation of the correlation between antibodies and their effects on PKs, PDs, efficacy and tolerability. It is also important to realise that for one product the risk of immunogenicity may differ depending on the therapeutic indication. In most cases, pre-approval data over at least a six-month period are requested and a post-approval commitment to provide data up to 12 months. Since immunogenicity is a long-term event, gathering of immunogenicity data after marketing authorisation remains an important prerequisite. Consequently, within the authorisation procedure, the company applying for regulatory approval of a biosimilar, as for any newly approved biopharmaceutical, should also provide plans for post-marketing surveillance including a risk management programme.
Being biosimilar is not equal to being interchangeable
In general, when copies of chemical drugs (generics) have been approved, approval has been based on demonstrated bioequivalence compared to the reference product. Having an identical structure and a proven bio-equivalence implies that the generics and reference product, as well as any two generics, are interchangeable. For biopharmaceuticals, however, the situation is completely different since two independently developed biopharmaceuticals demonstrated to be bio-equivalent will not have identical pharmaceutical quality attributes and therefore cannot be considered interchangeable in the absence of evidence gathered from adequately designed clinical studies. Indeed, potential differences in immunogenicity can only be observed in large study populations and switching between biological preparations from different origins may increase the risk of antibody development. On the other hand, it should also be realised that, in contrast to various generics of the same reference product which can be considered identical, two biosimilars, independently developed and compared to the same reference product cannot be considered biosimilar to each other. It is obvious that demonstration of similarity between biosimilar A and reference product on the one hand and between biosimilar B and reference product on the other hand does not allow any conclusions with respect to a possible similarity between the two biosimilars, i.e. the degree of similarity between A and B. Thus, from a scientific point of view as well as for the sake of patient safety, biopharmaceuticals, irrespective of their regulatory status as biosimilar or reference, should not be considered interchangeable in the absence of solid clinical data. This is also enforced in the new US Health Care Reform Bill, which clearly states that more data are required for a product to be labelled interchangeable rather than the mere fact of being biosimilar [20]. It must be stressed that if interchangeability has been proven between two biopharmaceuticals, e.g. between two biosimilars or between a biosimilar and its reference, this remains strictly valid only for the two specific products that were evaluated.It may also be of interest to note that, in this context, it is often claimed that approved manufacturing changes form the proof for a generalisation of interchangeability for biosimilars. For a variety of reasons this argument contains some major flaws. Firstly, all independently developed biosimilars have so far been proven to be different from their reference product with respect to particular quality aspects. In contrast, in most cases, manufacturing changes are accompanied by the demonstration that the majority, if not all, quality attributes remain within preset specification limits. In cases where manufacturing changes would have resulted in a significant qualitatively different composition, demonstration of clinical safety will be required [21]. Secondly, any company producing a biopharmaceutical must handle hundreds of various (process-)specific quantitative and qualitative criteria that need to be taken into account in the comparison of the products obtained before and after the manufacturing change. Therefore, a comparison (‘before’ versus ‘after’) can be made at various stages in the process. This is in contrast to the comparability exercises for biosimilars which only involve the end product. Thirdly, introduction of a manufacturing change will, at most result in only one switch for the patient in only one direction, i.e. a drug produced by the ‘old process’ to a drug produced by the ‘new process’, not vice versa. Fourthly, approval of a manufacturing change should not be interpreted as a proof that both versions can be safely switched back and forward. Taken together, even though it needs to be realised that some manufacturing changes could result in safety concerns, the putative safety risk associated with a manufacturing change can, in general, be considered a few orders of magnitude smaller compared to that associated with the differences between two independently developed biopharmaceuticals [22]. It should be stressed that a risk assessment for any biopharmaceutical always needs to be considered on a case-by-case basis.
Conclusion
The production of biopharmaceuticals involves complex processes and includes the development of an engineered cell line, the production of the active substance through large scale culturing of cells, the purification of the protein including a wide variety of downstream processing steps, and its formulation. Consequently, any two independently developed biopharmaceuticals starting from the same DNA sequence will be characterised by particular differences in composition.Approval of biosimilars is contingent upon a full and detailed demonstration of pharmaceutical quality, a comparative analysis with a reference product, limited non-clinical and clinical evaluations, and a post-approval follow-up. In the absence of specific data concerning interchangeability, any measures taken, e.g. by health insurance companies and/or reimbursement authorities, to control budgets by stimulating the use of less expensive biopharmaceuticals should contain a mechanism that prevents switching between products in a patient.For patientsBiopharmaceuticals are complex medicines produced by living cells. Copies of approved biopharmaceuticals have been introduced recently. Because of their intrinsic complexity such copies are similar but not identical to the reference medicine and are therefore called ‘biosimilars’. Approval of biosimilars requires a full quality analysis including a detailed comparison to the reference whereas non-clinical and clinical evaluations are less extensive. It is important to keep in mind that inherently related to the complex nature of biopharmaceuticals, similarity is not equal to interchangeability. Therefore, switching between similar biopharmaceuticals in a patient should be prevented.
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Author: Professor Paul J Declerck, PhD, Laboratory for Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Campus Gasthuisberg, O&N2, PO Box 824, 49 Herestraat, BE-3000 Leuven, Belgium
Abstract: The advent of similar biological medicinal products or ‘biosimilars’ in Europe in the 2000s has led to development of a global biosimilars market and regulatory frameworks designed specifically for approval of biosimilars. Like originator biologicals, biosimilars exhibit greater molecular complexity than small-molecule drugs, including generics. Current estimates suggest that biosimilars are more expensive and require longer development times than generics. Regulatory and industry conferences have addressed how to achieve the appropriate level of regulation for biosimilars. Many originator biologicals feature support programmes or additional services that are designed to improve usage by patients, prescribers, and payers; these are not a mandatory part of the regulatory approval process. We refer to these features collectively as the ‘biologicals experience’ as described and discussed in this paper, and suggest that this experience should be an important element of consideration for the development of public policies on biosimilars.
Submitted: 22 October 2011; Revised manuscript received: 15 November 2011; Accepted: 16 November 2011
Introduction
In the history of medicine, biologicals are relatively new products. Biologicals developed in the 1980s produced an impact in nephrology, oncology, and other therapeutic areas. The expiration of intellectual property rights on originator biologicals created the possibility for development of ‘follow-on biologic’ products, based on the originators. The EU in 2005 initiated public discussion on guidelines for approval of such products [1], which it denominated as ‘similar biological medicinal products’ in the guideline but also referred to as ‘biosimilars’ in subsequent publications [2]. EMA approved its first biosimilar under these guidelines in 2006. Since then, many countries on all continents (besides Antarctica) have adopted similar biosimilar regulatory approval procedures, and the WHO has developed a guideline for development of such regulatory guidelines. Regulatory and industry conferences have addressed how to achieve the appropriate level of regulation for biosimilars [3]. One consulting company recently estimated the combined annual growth rate of the global biosimilars market at 52% for the time period 2010–15 [4].
Special challenges for biologicals and biosimilars
Biosimilar manufactures face unique manufacturing, financing and developmental challenges. As with all biologicals, biosimilars are more structurally complex than small-molecule drugs [5]. Biologicals, including biosimilars, are produced through means which will almost always differ by manufacturer: cell lines, mass production and purification processes, and even issues like temperature and availability of light within a manufacturing facility [6]. The average capital cost for development of a biologicals manufacturing facility is US$250 – US$450 million [7].
Many state-of-the-art techniques are evolving to help characterise biologicals, but cannot yet demonstrate biopharmaceutical equivalence [8]. In the EU and WHO guidelines, biosimilar manufacturers have to demonstrate comparable quality to an originator biological and usually also need a non-clinical and clinical research programme that also demonstrate comparability. This will usually include a phase III clinical trial. A biosimilar manufacturer also cannot benefit from regulatory data protection. Even though it must generate its own data to submit to regulators, most regulations preclude the use of a biosimilar as a reference product [9-11]. Overall, these challenges amount to long development timelines (5–8 years) and overall development costs of US$100 – US$200 million [2].
A potential challenge for the future could concern interaction with physicians and the use of sales representatives to provide information on biosimilars [12]. In the EU, some companies have used sales representatives, but this is a cost not normally associated with the generics industry. The Generic Pharmaceutical Association has expressed concern to FDA that manufacturer promotional efforts might result in a ‘detailing war’ [13].
The biologicals experience
In addition to the manufacturing, research and development challenges for bringing a biosimilar to market, competitive challenges exist when on the market. Although price can be one area of competition [14], originator biologicals often provide a number of supplemental services and programmes that support patient comfort, prescriber concerns, and payers’ desires for proper reimbursement procedures. These services, which we call collectively the ‘biologicals experience’, are not mandated by regulators but can be meaningful to patients, prescribers, and others.
Patient-related aspects • Devices: most biologicals come with some kind of delivery device. The mode of delivery has an impact on how patients feel about the medicine and what they can expect [15]. For people with severe rheumatoid arthritis, for instance, auto-injection devices need to be user-friendly for people with limited dexterity [16]. Patients may also need expert training with the devices in order to achieve the right outcomes.
• Patient support systems: handling patient concerns is especially important for originator biologicals and biosimilars. Systems need to be in place to sort out potentially important adverse events from administration errors or routine questions. Some manufacturers provide telephone lines with dedicated nurses for patients. Considering general consumer frustration with anonymous call centres [17], the quality of the patient support system will be integral to supporting patient comfort and confidence.
• Replacement systems: for retail products, replacement can be a crucial issue, especially if a needle breaks or another quality deficiency is found. Companies will need to develop mechanisms that can get the right replacement to patients in time to address their needs.
• Naming: names of biosimilars will be very important for patients. On the one hand, names will need to be distinct for tracking and tracing purposes, especially when there is a need to distinguish the exact biological product that triggered an adverse event report. On the other hand, they will need to be similar enough to the originator to provide a high level of confidence. Since WHO’s international nonproprietary name (INN) policy does not provide a basis for distinct INN for all biologicals, these issues can be resolved by companies through development of similar but distinct trade names [18].
• Access programmes: some originator programmes ensure that cost will not be an obstacle to biologicals access for patients. This goal can be achieved through direct financial support or support to patients with reimbursement programmes.
Prescriber-related aspects For prescribers as well, biologicals present a very different experience. Infusion-administered biologicals require dedicated facilities and extra staff time, as well as specialised rooms for administration to patients. The cost for biologicals is quite high and can pose cash flow concerns for smaller practices.
• Physician education: originator biologicals companies have been educating physicians for years [19] about their products, and biosimilar companies have only recently started similar efforts in Europe. Research by the National Comprehensive Cancer Network indicates that ‘familiarity with biosimilars is suboptimal and that more clinician education is required’ [20]. Education for nurses has also been identified as an area of need [21].
• Physicians’ need for clinical data: a recent report indicates that the data necessary for marketing authorisation might not suffice for the needs of prescribers. Both payers and prescribers indicated they would want to see additional data on efficacy for biosimilars in order to encourage their uptake [22]. This need is even more pronounced when considering whether a manufacturer can extrapolate from the primary approved indications to others.
• Physician reimbursement services: originator biologicals manufacturers often provide support services for physicians and practices to ensure proper reimbursement decisions [23-25]. Reimbursement rules often dictate when patients can receive the biological, and the biological needs to be present in the exact right amount at the right time [26]. A biosimilar manufacturer that failed to offer this kind of support would have extra difficulty in presenting itself as an attractive option for specialty practices or others who rely on such services.
Another important stakeholder group for biologicals is the payer community, which has to manage the costs of originator biologicals. Patients’ adherence to biologicals is not well researched and a review of rheumatoid arthritis studies suggest that better methods are needed for tracking patients and prescriptions as well as for devising appropriate interventions [27]. Having said that, Blue Cross Blue Shield of North Carolina, USA, has set out to improve adherence for biologicals by developing patient-centred interventions [19]. According to Dr Marissa Blum of Temple University, Philadelphia, USA, in many ways, adherence boils down to the individual patient–provider relationship [19]. To the extent that further research identifies elements of the biologicals experience that improve or sustain adherence, those elements could help payers avoid unnecessary costs from non-adherence.
It should be noted that the individual factors below also can pertain to some small-molecule drugs, especially structurally-complex ones or those involving devices. Patients’ usage of asthma inhalers, for instance, received attention by The NewYork Times, when a widespread shift in the inhalation devices impacted patient behaviours [28]. Generic injectables have also been the object of recent attention owing to shortages in the US [29]. We would not argue that each individual factor is specific solely to biologicals, but that biologicals generally possess many of these features in a way that supports the patient and prescriber’s overall experience with the medicine.
This list is hardly exhaustive, but gives insight into the manifold elements in the biologicals experience that can support optimal health outcomes for patients.
Case study: device improvement
The case of Omnitrope (somatropin) illustrates how commercial success can relate to the biologicals experience. Omnitrope, which was the first biosimilar approved in 2006 by the EU, initially experienced minimal uptake. While the fragmented marketplace appears to have been a key factor [30], much of the blame can also be attributed to the delivery device. In the first Omnitrope delivery system, the multi-step mixing of the Omnitrope and measuring of the dosage were two phases of the process that were much more complex than predicate systems, and discouraged uptake and patient adherence [31].
The manufacturer subsequently initiated a switch from a ‘lyophilised powder form in a vial’ [32], to injector pens ‘Omnitrope Pen 5 and 10, with liquid cartridges in 5 mg/1.5 mL and 10 mg/1.5 mL strengths’ [33]. These new systems represented increased convenience for patients because ‘the liquid is already dissolved in a ready-to-use cartridge and can be loaded into the pen for injection’ [33].
With the implementation of the new delivery system, the manufacturer experienced increased sales. Executives have claimed that the new device represents a ‘commitment to meeting the needs of patients through providing more convenient delivery systems’ [34], as well as its commitment to a fundamental business strategy of ‘focus on difficult-to-make products that provide added patient benefits’ [35].
Discussion: policy implications
Many meetings of regulators and industry officials have taken place since the first EMA consultations in 2005. Most recently, FDA held a public session in November 2010 [36] and EMA held a consultation on monoclonal antibodies in October 2011 [37]. Numerous other industry conferences have been organised by private-sector vendors [38].
Written comments submitted to FDA after the November 2010 consultation provide insight into a wide variety of issues, based on questions posed by FDA [38]. Many of the regulatory policy issues posed by FDA focused on criteria for regulatory approval of biosimilars: use of foreign reference data, factors to assess similarity, and others. By and large, these issues pertain to the question of how to obtain marketing authorisation.
The issue of interchangeability, however, has great relevance for the ‘biologicals experience’. The US Biologics Price Competition and Innovation Act (BPCIA) of 2009 allows an applicant for a biosimilar marketing authorisation to further seek designation as an interchangeable product, which would facilitate pharmacy-level substitution where allowed by state law. ‘The BPCIA requires the FDA to deem a biosimilar ‘interchangeable’ if the biosimilar ‘can be expected to produce the same clinical result as the reference product in any given patient’ … ‘The question of whether an interchangeable biosimilar should be automatically substituted will remain one of state law’ [39].
In its written comments to FDA, the Generic Pharmaceutical Association in the US argued that ‘FDA needs to understand that interchangeability is the engine that most immediately drives competition and supports access through affordability’ [13]. Likewise, a consultant for the Parexel consulting company has publicly claimed that interchangeability would be a critical factor for a biosimilar’s commercial success: ‘the fact is, you need interchangeability in the label to succeed’ [40].
Outside the US, global regulatory policy offers little guidance on this issue. The EU, WHO, Canada and Japan do not provide an approval pathway for interchangeability as part of the marketing authorisation process [41]. Malaysia proscribes automatic substitution, and Saudi Arabia says it is ‘not encouraged’ [42, 43]. While it is possible that FDA or another regulator will develop a test for interchangeability in the future, FDA itself has expressed concern over the limits of determining it via current scientific methods [44]. As Health Canada has noted, significant clinical trial work would need to be undertaken, but such studies are unlikely in most situations [45].
Policy issues on interchangeability are complicated by the different settings in which biologicals are sold. Many biologicals are administered at specialty practices or at hospitals. In these situations, the issue of substitution by pharmacists is less significant, because the practices or hospitals will likely make joint decisions about ensuring availability of a limited number of biologicals. In this setting, prescribers would be part of the decision-making process and could work with their patients to manage key aspects of the biologicals experience [46].
One area for further discussion, however, should focus on how interchangeability policies would affect the biologicals experience. If the primary beneficiaries of the biologicals experience are indeed patients and prescribers, how will their interests and voices be heard in this process? If a pharmacist can substitute a product with a user-friendly device for one with a less user-friendly device, what recourse does a patient have? What are the risks to eliminating elements of the biologicals experience?
We would suggest that a focus on optimal outcomes for patients should be a high priority for policymakers who might encounter this issue. Such an approach would entail consideration of the facets of the biologicals experience that have the most relevant impacts on health outcomes. And we believe that such an approach would ultimately strengthen support for policies that preserve the ability of the physician to choose the best biological for an individual patient—whether that is an originator or a particular biosimilar.
To encourage further savings, policymakers can eliminate market access barriers in order to incentivise biosimilar manufacturers to enter markets. Transparency in expectations for health technology assessments (HTA), for instance, could give meaningful guidance to biosimilar manufacturers, since the use of ‘often-inappropriate methodology creates a very real chance that HTA authorities will reject some biosimilars’ [47]. In Europe, many manufacturers face long delays by Member States for reimbursement approval [48]; in the case of lower-cost biosimilars, such delays would actually postpone potential savings for the Member States.
Conclusion
The entry of biosimilars into the European and other markets in the last decade has been facilitated by the development of regulation designed for unique aspects of biologicals. To meet the demands of this regulation, companies must overcome financial and technical challenges that are not present for small-molecule generic drugs. Beyond regulatory approval, however, originator manufacturers’ support services provide a ‘biologicals experience’ that can be important to patients and prescribers. While this experience poses a further challenge for biosimilar manufacturers, it also provides an opportunity to optimise these lower-cost products for patients. Public policies related to interchangeability and pharmacy-level substitution thus need assessment not only of their scientific grounding, but also of the potential impact of such policies on the biologicals experience and thus on outcomes for patients themselves.
For patients
This paper proposes that public policies on biologicals and biosimilars take into account the ‘biologicals experience’, the variety of support services and programmes provided by originator manufacturers to support patient and prescriber use of existing biologicals. Patients should expect that evaluation of interchangeability and pharmacy-level substitution policies would focus not only on minimising costs but also on ensuring optimal health outcomes.
Disclosure
Dr James N Class is Director of Global Public Policy at Merck US. Ms Lauren Langis is Global Policy Co-Op at Merck US. This article represents the views of the authors and is not necessarily representative of Merck’s public policy views.
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Author for correspondence:James N Class, PhD, Director, Global Public Policy, Merck US, Suite 1200, 601 Pennsylvania Ave NW, Washington, DC 20004, USA
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Author byline as per print journal: Brian Godman1,2,3, BSc, PhD; Bjorn Wettermark1,4, MSc, PhD; Iain Bishop5, BSc; Thomas Burkhardt6, MSc; Jurij Fürst7, PhD; Kristina Garuoliene8, MD; Ott Laius9, MScPharm; Jaana E Martikainen10, Lic Sc(Pharm); Catherine Sermet11, MD; Inês Teixeira12, BA, MSc; Corrine Zara13, PharmD; Lars L Gustafsson1, MD, PhD
Introduction: Pharmaceutical expenditure is increasingly scrutinised by payers of health care in view of its rapid growth resulting in a variety of reforms to help moderate future growth. This includes measures across Europe to enhance the utilisation of generics at low prices. Methods: A narrative review of the extensive number of publications and associated references from the co-authors was conducted, supplemented with known internal health authority or web-based articles. Results: Each European country has instigated different approaches to generic pricing, which can be categorised into three groups, with market forces in Sweden and UK lowering the prices of generics to between 3–13% of pre-patent loss originator prices. Payers have also instigated measures to enhance the utilisation of generics versus originators and patent-protected products in a class or related class. These can be categorised under the 4Es: education, engineering, economics and enforcement, with the measures appearing additive. The combination of low prices for generics coupled with measures to enhance their utilisation has resulted in appreciable cost savings in some European countries with expenditure stable or decreasing alongside increased utilisation of products in a class. Conclusion: Reforms will increase as resource pressures continue to grow with the pace of implementation being likely to accelerate. Care though with the introduction of prescribing restrictions to maximise savings as outcomes may be different from expectations.
Submitted: 7 April 2011; Revised manuscript received: 15 October 2011; Accepted: 19 October 2011
Introduction
Pharmaceutical expenditure is increasingly scrutinised by payers in view of its rapid growth, outstripping growth in other components of health care [1-7]. This growth has resulted in pharmaceutical expenditure in ambulatory care becoming the largest, or equal to the largest, cost component in this sector [1, 3-9], with expenditure on drugs in ambulatory care typically appreciably greater than inpatient drug costs, particularly in Europe. This growth in pharmaceutical expenditure has been driven by well-known factors including changing demographics, rising patient expectations, strict clinical outcome targets, and the continued launch of new and expensive drugs [1, 3, 5, 6, 10].
As a consequence, third-party payers have introduced multiple reforms and initiatives in recent years to optimise the managed entry of new drugs and, in addition, to help control expenditure on existing drugs through encouraging the increased prescribing of generics at low prices [1, 2, 6, 7, 11-13]. The various measures to increase the prescribing of generics among existing molecules and classes, as well as their potential impact, will be appraised in this review article. A list of potential, additional measures that third-party payers could introduce as they seek further measures to help control their rising prescribing costs is also provided.
This review will be divided into two sections: firstly, the measures that have been instigated to lower the prices of generics; secondly, measures to enhance their utilisation. However, we acknowledge that there will be overlap between these two sections. The principal focus will be on Europe.
Pricing policies to help lower the pr ice of generics in Europe
Each European country has introduced different measures to lower the price of generics. However, the variety of measures can be categorised into three distinct approaches [1, 3, 4, 8, 11, 14-17]:
• Prescriptive pricing policies: mandated price reductions for reimbursement, e.g. under the ‘stepped price’ model in Norway, there is an automatic 30% price reduction for the first generic versus the originator pre-patent loss prices, which increases to 55% or 75% reduction six months later depending on overall expenditure. There is a maximum 85% reduction for high expenditure generics after a further 12 months. In France, generics currently have to be 55% below pre-patent loss originator prices to be reimbursed, with further price reductions in subsequent years.
• Market forces: market forces are used in a number of European countries to lower the price of generics. This is achieved by introducing a variety of demand-side measures that encourage the prescribing and dispensing of generics versus originator molecules, as well as lowering their prices. Market forces can be categorised by the 4Es: namely education, engineering, economics and enforcement. Table 1 gives the definition of each category alongside examples, with Table 2 documenting examples of initiatives to enhance the prescribing and dispensing of generics versus originators among European countries with different methods of financing health care, geographies, and epidemiology.
• Mixed approach: a combination of prescriptive pricing for the first generic(s) with market forces after that, e.g. in Austria the first generic must be priced 48% below pre-patent loss originator prices to be reimbursed, second generic 15% below the first generic and the third generic 10% below the second (overall 60% below pre-patent loss prices). Market forces to further lower prices from the fourth generic onwards, with each new generic necessarily priced lower than the last one for reimbursement and physicians financially incentivised to prescribe the cheapest branded generic(s). In Finland, the price of the first generic must be 40% lower than the pre-patent originator price to be reimbursed. Prices of subsequent generics must not be higher than the first generic for reimbursement with market forces, including the need for additional co-payment for more expensive products than the reference priced molecule, helping to reduce prices.
These are in addition to compulsory price cuts for both originators and generics instigated among some European countries as they struggle to contain rising pharmaceutical expenditure [1, 3, 5, 8, 9].
The different approaches to the pricing of generics has led to an appreciable variation in reimbursed prices for generics across countries, with prices varying up to 36-fold depending on the molecule [3, 20].
However, the general trend is for countries to introduce additional measures to lower their generics prices to maximise savings with countries continuing to learn from each other [3, 5, 8], introducing initiatives highlighted in Table 1. For instance, high volume generics in Sweden and UK are priced at between 3–13% of pre-patent loss prices through a variety of market force measures, some of which are highlighted in Table 2 [3, 7, 14, 21]. This is driven by global sales of products likely to lose their patents between 2008 and 2013 estimated at US$50 –US$100 billion (Euros 35 – Euros 70 billion) per year [22, 23], with global sales of pharmaceuticals estimated at US$820 billion (Euros 579 billion) in 2009 [24].
Demand-side measures to enhance the prescribing of generics
Currently, there is also an appreciable variation in the utilisation of generics across Europe. This includes the prescribing and dispensing of generics versus originators, as well as the prescribing of generics versus patent-protected products in a class or related classes. Table 2 contains examples of ongoing demand-side measures across Europe to enhance the prescribing and dispensing of generics versus originators, which resulted in high utilisation rates for generic omeprazole versus the originator and generic simvastatin versus the originator in 2007 in a recent cross-national study, see Table 3; full details of the measures undertaken to increase the utilisation of generics in individual European countries can be found in references 3 and 5.
European countries have also introduced a variety of different measures to encourage the prescribing of generics within a class. The objective is again to take advantage of the availability of lower priced generics in a class. As a result, these measures help fund increased drug volumes and new drugs without having to raise taxes or health insurance premiums. However, recent research has shown that among the proton pump inhibitors (PPIs), 3-hydroxy-3-methil-gluteryl-CoA reductase inhibitors (statins) and renin-angiotensin products, there is considerable variation in the prescribing of generics within a class or related classes once generics become available in a class [5, 8, 15, 26, 27]. Consequently, there are appreciable opportunities for countries to further enhance their prescribing of generics and lower their prescribing costs through learning from each other.
Examples of ongoing initiatives to increase the prescribing of generic products in a class, again broken down by the 4Es building on Tables 1 and 2, include [1, 4-8, 14-17, 27-29]:
• Educational activities: local, regional and national formularies coupled with monitoring of prescribing patterns and academic detailing. One example is the ‘Wise Drug’ list in Stockholm County Council, which contains approximately 200 drugs covering conditions typically encountered in ambulatory care. Prescribing suggestions typically include older well-established and well-documented drugs, which are generally available as generics, rather than newly marketed drugs. Physician-prescribing patterns are continually benchmarked against the list and their colleagues to enhance adherence to the guidance, with the instigation of educational activities if needed.
• Engineering activities: a number of European countries have instigated prescribing targets. These typically include the percentage of generic drugs within a class such as the percentage of generic PPIs versus all PPIs, percentage of generic statins versus all statins and percentage of angiotensin-converting enzyme inhibitors (ACEIs) versus all rennin-angiotensin drugs.
• Economic interventions: financial incentives to physicians for achieving agreed prescribing targets in a class, as well as devolution of drug budgets to local general practitioner groups combined with regular monitoring of prescribing behaviour.
• Enforcement: prescribing restrictions such as restricting the prescribing of patent-protected statins to second-line in Austria, Finland, Norway, and Sweden as well as restricting the prescribing of angiotensin receptor blockers (ARBs) to second-line in Austria and Croatia.
However, in countries with less intensive demand-side measures to combat industry and other pressures to prescribe patent-protected drugs, there is typically an increased prescribing of patent-protected products once multiple sources are available. Examples include increased prescribing of esomeprazole with decreased prescribing of omeprazole as a % of total PPI utilisation, which has been seen in France, Ireland, and Portugal [5, 8]. The reverse was seen in countries that have instigated multiple and intensive demand-side measures such as Spain (Catalonia), Sweden, and UK. A similar situation was seen with the statins, with increased utilisation of atorvastatin and rosuvastatin and decreased utilisation of simvastatin in countries with less intensive demand-side measures, with the exception of Portugal where the utilisation of all three statins increased following the availability of generic simvastatin [5, 8].
The differences in price that can be obtained for generics in countries, coupled with measures to enhance their prescribing versus originators as well as patent protected products in a class, can have a profound impact on overall prescribing costs. Table 4 documents changes in reimbursed expenditure between 2001 and 2007 among western European countries for both PPIs and statins alongside changes in their utilisation [5, 8]. The introduction of reference pricing for both PPIs and statins in Germany appreciably increased the utilisation of omeprazole and simvastatin at the expense of esomeprazole and atorvastatin [5, 19, 25]. However, higher expenditure/defined daily doses for generic omeprazole and generic simvastatin compared with Sweden and UK limited efficiency gains in practice [30, 31].
The different patterns seen in Table 4 resulted in appreciable differences in overall expenditure for the PPIs and statins among European countries in 2007 when adjusted for population sizes, see Table 5.
The quality of care does not appear to be compromised through initiatives to enhance the utilisation of generics. This demonstrates the potential of releasing considerable resources through the increased use of generics, see Table 5, without negatively affecting outcomes. This is further illustrated by health authorities and health insurance agencies typically viewing all PPIs as having similar effectiveness based on available data [5-8, 14, 19, 25]. They also generally believe generic statins can be used as first-line to treat patients with coronary heart disease and hypercholesterolaemia adequately, with patent-protected atorvastatin and rosuvastatin reserved for patients failing to achieve target lipid levels with, e.g. generic simvastatin [5-8, 11, 14, 15, 17, 19, 25]. These beliefs are endorsed by a recent ecological study, which showed that outcomes, in terms of the subsequent impact of drug treatment on lipid levels, were similar whether patients were prescribed formulary drugs (including generic simvastatin) versus non-formulary drugs, which included patent-protected statins [32]. Published studies have also shown that patients can be successfully switched from atorvastatin to simvastatin without compromising care [33], and physicians in UK extensively prescribe generic simvastatin to achieve agreed target lipid levels in the quality and outcomes framework to help maximise their income [14, 21, 34, 35]. Alongside this, pharmaceutical companies have failed to provide reimbursement agencies with any published studies documenting increased effectiveness of ARBs versus ACEIs to support premium prices for ARBs [26, 27]. In addition, only 2–3% of patients in the ACEI clinical trials actually discontinued ACEIs due to coughing [36, 37], and a recent ecological study again showed that outcomes, in terms of the subsequent impact of drug treatment on blood pressure, were similar whether patients were prescribed formulary drugs (including generic ACEIs) versus non-formulary drugs, which included patent-protected ARBs [32]. As a result, generic ACEIs can be prescribed first line with patent-protected ARBs reserved for patients where there are concerns with side effects without compromising outcomes.
Finally, care may be needed when considering the introduction of prescribing restrictions (enforcement). This is because their nature and follow-up appear to influence subsequent utilisation patterns appreciably [4, 15, 17, 26]. For instance, the prescribing restrictions for patent-protected statins, atorvastatin and rosuvastatin, had less influence on increasing the utilisation of generic statins, e.g. simvastatin, in Norway versus Austria and Finland. This was the result of having no prior authorisation scheme in Norway, unlike Austria, or no close scrutiny over prescriptions as seen in Finland [4, 15, 17]. In Austria, atorvastatin and rosuvastatin can only be reimbursed if physicians obtain agreement from the Chief Medical Officer of the patient’s Social Health Insurance Fund [4]. The Norwegian authorities also recently introduced prescribing restrictions for esomeprazole. However, hospital specialists in Norway have to verify the diagnosis and recommend therapy before PPIs are reimbursed, and they are not subject to the same restrictions [15]. This reduced the influence of the prescribing restriction in practice, with physicians generally reluctant to deviate from the initially prescribed drug or the advice for the prescription if this was for esomeprazole [15].
Conclusion
The differences between the extent and intensity of supply- and demand-side measures encouraging the prescribing of generics at low prices led to over tenfold difference in reimbursed expenditure for the PPIs and statins in 2007 between European countries when adjusted for populations, see Table 5. However, there was greater morbidity among the Irish population studied [5, 8]. Consequently, there are considerable opportunities for countries to learn from each other to reduce their prescribing costs, especially with the influence of demand-side measures appearing additive.
Both supply- and demand-side measures are thought to be important to limit costs, with countries limiting the extent of any potential efficiency gain if they principally concentrate on one set of measures. For example, in Germany, the reimbursed prices for generics are appreciably higher than seen in UK, which limited potential savings in reality [38]. The limited number of demand-side measures in Portugal also reduced their efficiency gains from recent initiatives to lower generic prices [3, 5, 8]. This is changing with recent reforms. However, payers are urged to consider the nature of any prescribing restrictions they may seek to introduce, and their follow-up, when they forecast the possible influence of these measures, as there could be appreciable differences from expectations [15, 26, 27].
We are already seeing countries learning from each other to identify new initiatives to enhance their prescribing efficiency, i.e. increased drug utilisation at similar or lower costs. Examples include greater transparency in the pricing of generics, prescribing targets, physicians’ financial incentives, compulsory prescribing with the international non-proprietary name, and prescribing restrictions [1, 3, 5, 6, 8, 18]. It is likely that the pace of implementation of what has been learned will accelerate to maintain the European ideals of universal, affordable, and comprehensive health care, especially given the current financial concerns coupled with ongoing pressures. This will need to be reviewed in future publications.
For patients
The costs of health care are rising across Europe through ageing populations resulting in greater prevalence of patients with chronic diseases, stricter clinical targets for managing patients with long term (chronic) diseases, the continued launch of new and more expensive drugs as well as rising patient expectations. The provision of generics (multiple sourced products once the original product loses its patent) at considerably lower prices than the price of the originator just before it lost its patent, and with similar effectiveness and safety to the originator through strict licensing regulations, allows European governments to continue to provide comprehensive and equitable health care without prohibitive increases in either taxes or health insurance premiums. This paper discusses a number of measures introduced by health authorities or health insurance companies in recent years to increase the prescribing and dispensing of generics, with countries continuing to learn from each other as cost pressures continue growing.
Disclosure of financial interest
The majority of the authors are employed directly by health authorities or health insurance agencies or are advisers to these organisations. No author has any other relevant affiliation or financial involvement with any organisation or entity with a financial interest, in or financial conflict with, the subject matter or materials discussed in the manuscript.
This study was in part supported by grants from the Karolinska Institutet.
Acknowledgement
We acknowledge the help of INFARMED with providing NHS data on Portugal.
Author and co-authors
1Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden 2Prescribing Research Group, University of Liverpool Management School, Chatham Street, Liverpool L69 7ZH, UK 3Institute for Pharmacological Research Mario Negri, 19 Via Giuseppe La Masa, IT-20156 Milan, Italy 4Public Healthcare Services Committee, Stockholm County Council, Sweden 5Information Services Healthcare Information Group, NHS Scotland, 1 South Gyle Crescent, Edinburgh EH12 9EB, UK 6Hauptverband der Österreichischen Sozialversicherungsträger, 21 Kundmanngasse, AT-1031 Wien, Austria 7Health Insurance Institute, 24 Miklosiceva, SI-1507 Ljubljana, Slovenia 8Medicines Reimbursement Department, National Health Insurance Fund, 1 Europas a, LT-03505 Vilnius, Lithuania 9State Agency of Medicines, 1 Nooruse, EE-50411 Tartu, Estonia 10Research Department, The Social Insurance Institution, PO Box 450, FI-00101 Helsinki, Finland 11IRDES, 10 rue Vauvenargues, FR-75018 Paris, France 12CEFAR – Center for Health Evaluation and Research, National Association of Pharmacies (ANF), 1 Rua Marechal Saldanha, PT-1249-069 Lisbon, Portugal 13Barcelona Health Region, Catalan Health Service, 30 Esteve Terrades, ES-08023 Barcelona, Spain
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Author: Brian Godman, BSc, PhD, Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden
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: Helle Håkonsen, MScPharm, PhD; Else-Lydia Toverud, MScPharm, PhD
Introduction: With a few exceptions, generic drug use has been promoted in western countries by allowing pharmacists to substitute drugs defined as therapeutically equivalent generics. The aim of this literature review is to summarise the research on the patients’ perspectives of generics substitution in the western world between 2000 and 2011 with special emphasis on the challenges these attitudes present for optimal drug use. Methods: A literature search was undertaken in MEDLINE (PubMed), Embase (Ovid), and SciVerse Scopus with the aim of identifying all the peer reviewed, original research articles concerning patient perspectives on generics substitution in western countries published between 1 January 2000 and 1 March 2011. Results: The 20 studies included in this review indicate that close to one-third of all patients were uneasy about having their drug(s) substituted generically. Between 8–34% of patients reported poorer effects and/or new side effects after a change—except for antiepileptic drug users from which the number of reports was even higher. Poor awareness of generics substitution caused confusion and reduced the patients’ willingness and ability to take their medication as prescribed. Patients’ acceptance of generics substitution was influenced by age, educational levels, perceptions about disease, generic drug information, and who informed them about the change. The studies consistently suggested a continuing need for information directed at patients and an increased involvement of physicians. Conclusion: This literature review suggests that although generics substitution is well accepted by the majority of patients, about one-third of the patients report negative experiences which may lead to poor adherence and medication errors.
Submitted: 17 April 2011; Revised manuscript received: 3 October 2011; Accepted: 16 October 2011
Introduction
With a few exceptions, e.g. Ireland and the UK, generic drug use has been promoted in western countries by allowing pharmacists to substitute drugs defined as therapeutically equivalent generics. Although this enables cost savings, which can slow growing pharmaceutical budgets, concerns have been raised regarding the possibility of such substitution leading to a higher overall healthcare expenditure [1]. The core of these concerns is that problems may arise when a brand-name drug, with which the patient is familiar, is replaced by a product with a different name and with other physical attributes, e.g. shape, size, and colour. This well-intentioned cost-containment strategy might contribute to suboptimal drug use and thereby increase morbidity and overall costs in a wider perspective depending on the extent that this strategy interferes with patients’ prescription drug-taking behaviour. Currently, patients with chronic medical conditions are increasingly affected by substitution reforms because they consume more drugs over a longer period of time and the generics interchangeable markets are expanding in response to policy changes and expiration of patents.
Since the first studies of generic drug use were published in the 1970s [2, 3], the emphasis on consumer/patient perspectives has increased due to the need to explore the underlying causes for the patients’ decision-making processes. In 2001, Gaither et al. published a literature review of consumers’ knowledge, attitudes, and opinions about the use of generic drugs [4]. The authors summarised the results of studies, which were all American and conducted in the last century, and reported that consumers, in general, were positively inclined to generic drugs, although their views differed according to socio-demographic factors and the extent of knowledge and past experiences with drug therapy. In the conclusion, the need for more research on consumers’ behaviours regarding generic drug use was emphasised [4]. Following the implementation of generics substitution in more and more countries during the last decade, it seems opportune to gather the recent evidence.
The aim of this literature review is to summarise the results of studies on the patients’ perspectives of generics substitution in the western world between 2000 and 2011, with special emphasis on challenges for optimal drug use.
Methods
A literature search was undertaken in MEDLINE (PubMed), Embase (Ovid), and SciVerse Scopus with the purpose of identifying all peer reviewed, original research articles published in English on patients’ perspectives of generics substitution conducted in western countries. Search terms included: ‘generics substitution’, ‘generics prescribing’, ‘generic drugs’, and ‘generic medicines’. All articles were selected for further analysis based on title and abstract. The search was supplemented by a manual review of the reference lists of identified articles.
The time period for publication was limited to 1 January 2000 and 1 March 2011. As the review focused on the patients’ perspectives of generics substitution, register-based studies, and studies which investigated patient perspectives on generic drug use in general and did not include aspects of substitution, were excluded.
Twenty original research articles were included. A data extraction form was developed to systematically extract relevant data from the included articles. Table 1 provides an overview of the included articles listed according to authorship and year of publication, country where the study was undertaken, research method, number of participants (response rates if applicable), and drug class(es). The results were structured thematically and reported in the main text.
The first author of this paper conducted the search, reviewed the articles, and extracted the data; the second author reviewed the interpretation and presentation of the data. Disagreements were resolved by an additional review of the article(s) in question, followed by a discussion.
Results
Patients’ attitudes towards and experiences with generics substitution In Himmel et al. (2005) primary care patients in Germany were surveyed about their thoughts on generic drug use. One-third of the participants considered inexpensive generics to be inferior to, or different from, more expensive brand-name drugs because of their lower price. This view was more frequently expressed by patients who were more than 60 years of age, chronically ill, and/or without higher education. Of those who knew that their drugs had been switched (30% of the total sample), more than half said they were sceptical about the substitution. Twelve percent reported a lower effect of the drug after the change, and 13% claimed that they had experienced new side effects [5].
Heikkilä et al. surveyed Finns on two occasions. In the first study, two groups were recruited: customers who had accepted (28% of the total sample), and customers who had refused (72% of the total sample), generics substitution. Of these, 83% and 66%, respectively, reported that they were satisfied with the substitution reform which took effect in 2003. The main reason for accepting substitution was a desire to save money and, secondly, that the pharmacists recommended it. Positive experiences with drugs used previously and a wish to talk with their physician before substituting were the most cited reasons for refusing substitution [6]. In the second study, 81% of the participants were of the opinion that cheaper generics were effective, and 85% did not consider generics substitution as a threat to drug safety [7]. In both of these Finnish studies, men and patients up to 60 years of age were identified as those most likely to feel positively towards generics substitution [6, 7].
In a Norwegian survey by Kjønniksen et al. (2006), one-third of the participants reported one or more negative experience with generics substitution, e.g. more side effects or a poorer effect, and 21% reported an overall negative experience with the change. The negative experiences were not associated with gender, age, or number of drugs. Forty-one per cent claimed they would only allow substitution if they achieved financial savings [8].
Palagyi and Lassanova (2008) investigated patients’ attitudes towards, and experiences with, generic drugs in Slovakia. Overall, 61% of the participants (predominantly those aged 30 years or younger) did not have any issues with trust regarding generic drugs and more than 50% indicated a preference for a product with a lower co-payment. Seventeen per cent considered generics inferior to brand-name drugs in terms of quality, and 18% preferred being prescribed brand-name drugs despite a higher co-payment [9].
In an American survey, Shrank et al. (2009) reported that one-third of patients were uncomfortable with substitution to some extent. About 10% believed that generic drugs could cause more side effects than brand-name drugs. The participants revealed self-contradictory opinions about generic drugs as more than half reported that Americans should use more generics but only 38% said they would prefer generics for themselves. Female, young, and wealthier patients were the most positive. Beliefs about the use of generic drugs were investigated for the treatment of an acute symptomatic condition compared to a chronic asymptomatic condition and no significant differences were found between the two [10].
In a study from New Zealand, Babar et al. (2010) differentiated between ‘minor’ (such as cold, flu, or hay fever) and ‘major’ (such as asthma, diabetes, or heart problems) illnesses and reported that participants claimed to be more prepared to change to generic drugs for the former than for the latter (78% vs 59%). Moreover, a change was more likely to be accepted if the patient was young, educated, had sufficient knowledge about generic drugs, and/or had previous experience with generics substitution [11].
The case of generics substitution of anti-epileptic drugs Anti-epileptic drugs (AEDs) in particular have been the cause for concern regarding the safety of generics substitution. In a Canadian survey of epileptic patients by Guberman and Corman (2000), the participants had relatively positive attitudes towards generic drugs with regard to effects and safety, although they were not fully informed about whether or not their medication had been changed. Among those who thought that their medication might have been changed, 14% reported that they had experienced a problem [12].
A larger study including several countries was conducted by Haskins et al. (2005). In this study, two-thirds of participants reported concerns about the safety and the effectiveness of generic AEDs, 58% felt uncomfortable receiving a generic drug, and 23% believed that substitution was linked to breakthrough seizures [13].
Even more concern was reported by Berg et al. (2008) where 70% of the patients thought that substitution with a generic AED could have negative treatment outcome consequences, and 34% believed that generics substitution was a reason for breakthrough seizures. Four out of five patients thought pharmacists should not be allowed to generically substitute AEDs without physician consent [14].
In a study by Papsdorf et al. (2009), 80% of the epileptic patients knew that generic versions of certain AEDs are available; 57% had taken a generics version and, among these, 28% reported breakthrough seizures which they believed were a direct consequence of the change. In addition, 34% reported experiencing side effects they believed were related to the switch [15].
The risk of non-adherence and medication errors and the significance of information
Håkonsen et al. (2009) and Håkonsen and Toverud (2011) conducted semi-structured personal interviews in two populations of chronic patients in Norway: (study I) patients from the general Norwegian population [16] and (study II) patients with a Pakistani background [17]. Twenty-nine per cent (study I) and 41% (study II) of the patients reported concerns after receiving the generically substituted drug(s). Eight per cent (study I) and 16% (study II) reported that the effects of the new drug(s) were inferior. Similar findings of new, or more severe, side effects were reported by 15% and 20%, respectively. In both groups, negative attitudes towards generics substitution were significantly associated with low educational levels and lack of information. In the Pakistani population, one in four patients thought that the generics were counterfeit drugs. Generics substitution was stated as an important reason for intentional non-adherence (especially in study II). Also, 33% and 26%, respectively, reported that it was more demanding to keep track of their medication after substitution; this resulted in erroneous drug use (simultaneous use of more than one therapeutically equivalent generics, e.g. one brand name and one generic drug with the same active ingredient) by 5% of the participants in study I and 10% in study II. These findings were made possible because the participants showed the interviewer the drugs they were currently using [16, 17].
Confusion and discontent due to differences in drug name and physical attributes were also detected in a focus group study by Toverud et al. (2011). Although the patients usually accepted substitution by the pharmacy, they considered the inexpensive generics to be of poorer quality than the brand-name products. The following quote illustrates the patients’ concerns: ‘You believe in your doctor, so when you come to the pharmacy and they give you something else than what the doctor has prescribed, you feel insecure. You sit at home and think that the new tablets don’t work as the old ones, because if it is the same thing, why did not the doctor prescribe it?’ [18].
Qualitative studies from other countries show similar results. In semi-structured personal interviews conducted by Hassali et al. (2005), Australian consumers reported that, in addition to the cost of medicines, a recommendation from their physician or pharmacist was decisive for their acceptance of generic drugs. The major barriers to acceptance were confusion, influence from physicians, and perceived side effects of generics. The consumers also emphasised the need for direct educational intervention by health professionals and government bodies [19].
Gill et al. (2010) conducted unstructured personal interviews with customers from Australia, Finland, and Italy. The main, recurrent theme in these interviews was ‘confusion related to why they were being offered something that was different to what their doctor had prescribed’. Confusion and suspicion were associated with poor awareness of generic drugs by the participants when asked whether they were willing to accept substitution by the pharmacy personnel. The participants said that although they had agreed to substitution in the pharmacy, they would check the appropriateness of the intervention with their physician [20].
In a mixed-method study among Australian seniors by Bulsara et al. (2010), generics substitution was identified as a major issue underlying problems of drug non-adherence and erroneous drug use. Reluctance to use generics was explained by a lack of knowledge, changes in packaging, disbelief in the equivalence of generics alternatives, and mistrust in the (foreign) pharmaceutical industry and their relationship with health professionals. The participants thought that physicians should discuss generics substitution more actively with their patients as this would affect their decision to accept the change [21].
Roman (2009) hypothesised that differences in name, appearance, and packaging between brand-name and non-branded drugs would cause anxiety, confusion, and misperceptions in Dutch patients with psychoses/schizophrenia. Among the 87% of such patients who were unwilling to change their medication to a generic drug, one-half attributed this decision to different packaging while 28% said that they did not have any faith in the effect of the generics since it was not prescribed by their psychiatrist [22].
Two studies explored the effects of providing information to patients. Vallès et al. (2003) conducted a Spanish multicentre study on the effect of patient education on acceptability of generics in general practice. The patient education consisted of a session of up to five minutes and included verbal information and providing handout materials on the advantages and disadvantages of generics equivalents and brand-name drugs. The study reported that 99% of participants accepted generics substitution after this intervention, but substitution was less well accepted for drugs acting on the central nervous system [23]. Similarly, Shrank et al. (2009) found that American patients who reported that they communicated with their physician and pharmacist about generics substitution, and felt comfortable doing that, were more likely to use generic drugs than patients who did not [24].
Discussion
Firstly, the main focus of the 20 studies included in this literature review was on the patients’ attitudes towards generics substitution. The studies highlighted negative attitudes in a sizeable minority of the patients—often close to one-third of study participants. Several explanations for the patients’ scepticism were given. First of all, the patients sometimes believed that lower prices meant poorer quality. In fact, the percentages of patients who reported changes in effects/side effects were in the range of 8–34% (except AEDs for which the number of reports was even higher). At the same time, prospects of personal economic savings were identified in some studies as a decisive factor in the patients’ acceptance of generics substitution.
Secondly, changes in physical attributes added to their uncertainty. In the case of chronic drug treatment, patients tend to know their drugs by appearance and it may be more demanding to keep track of their medications. There may also be other practical challenges such as handling different medication containers [17]. Moreover, the studies suggested that patients generally preferred the drugs prescribed by their physician. It was commonly reported that patients called for increased involvement of their physicians and requested information from their physician to support the information they received in the pharmacies. The findings of this review support hypotheses proposed elsewhere: i.e. if physicians were to prescribe by the medication’s generic name, it might be possible to reduce patient insecurity [25].
In the review by Gaither et al. (2001) peoples’ opinions of generic drugs varied according to socio-demographic variables such as ethnicity, educational level, income, and age [9]. The influence of these factors was also identified in this current review. Patients of younger age and/or with higher educational levels were consistently more likely to hold positive attitudes towards generics substitution, while the effects of income and gender were inconsistent. One study explored the influence of being an immigrant from a developing country. The results of that particular study suggested that generics substitution may even be more challenging for patients who may experience language problems and who may also have had previous negative experiences with counterfeit drugs and other issues with respect to pharmaceutical quality [17].
In studies on lay persons’ opinions of generic drugs, people tended to report being more uneasy about generics substitution of drugs used for more serious conditions [4, 26-27]. Ganther and Kreling (2000) reported that, as the perceived risk of a condition increased, the higher the cost savings needed to be in order for the patients to accept a generic drug [27]. This current review suggests that the data we currently have on patients’ views on the relevance of medical conditions are inconclusive, with the exception of epilepsy and psychiatric diseases.
The likelihood that treatment outcome may vary with the stated monetary value of the drug therapy has been found to be significant in a randomised, controlled trial by Waber et al. [28]. Research has also indicated that tablet appearance seems to influence the effectiveness of drugs [29]. As mentioned above, confusion and misunderstanding that substitution may cause are further exacerbated by changes in physical attributes and name. As this review suggests, generics substitution may reduce the patients’ ability to take drugs appropriately, e.g. the patients may erroneously take more than one therapeutically equivalent generic drug at the same time. It was also reported that negative attitudes towards and experiences with generics substitution were associated with intentional non-adherence. In this regard, the studies in the current review are important complements to the register-based studies performed by van Wijk et al. (2006), Chapman et al. (2009), and Briesacher et al. (2009) which, on the whole, did not find any evidence that adherence was negatively affected by generics substitution and rather tended to point in the opposite direction [30-32].
Conclusion
This literature review suggests that although generics substitution is well accepted by a majority of patients, about one-third report negative experiences which may lead to poor adherence and medication errors. Patients’ acceptance of generics substitution is influenced by age, educational levels, perceptions of disease, generic drug information, and who informed them about the change. Furthermore, poor awareness of generics substitution is associated with confusion which reduces the patients’ ability to take their medication as prescribed. The studies reviewed consistently suggest a continuing need for patient information and an increased involvement of physicians.
For patients
In many countries pharmacists are encouraged to substitute brand-name drugs with cheaper but equivalent drugs, produced by different companies, for cost-saving purposes. Although the drugs are equal in respect of effect as well as quality and safety, they may differ by name, shape, colour, and taste.
Research shows that many patients get confused or feel apprehensive about having their drugs changed and report negative experiences such as poorer effect or more side effects. As a consequence, patients may use their drugs inappropriately or even end up not taking their drugs at all.
More information directed at patients and increased involvement of physicians are needed.
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Author for correspondence: Helle Håkonsen, MScPharm, PhD, Department of Social Pharmacy, School of Pharmacy, University of Oslo, PO Box 1068, Blindern NO-0316 Oslo, Norway
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Abstract:
This paper describes the design of currently available matrix models and assesses the experience with these models to date. Matrix models provide a valuable tool to facilitate transparent and interactive evidence-based medicine prescribing. In many cases, generically available drugs perform well because of the documented effects on clinically relevant endpoints, good clinical efficacy, extensive experience, and documented long-term safety. Taking the lower acquisition cost of generic drugs into account as well, matrix models can be used effectively to promote the use of generic drugs.
Submitted: 23 March 2011; Revised manuscript received: 29 September 2011; Accepted: 9 October 2011
Introduction
The increased use of generic medicines is one of the most important elements in terms of the creation and maintenance of sustainable healthcare systems in Europe. Generic medicine prescribing by physicians in European countries has been supported by a variety of initiatives. However, despite these efforts, the use of generic drugs is still limited in many countries. Policymakers, insurers, and governments have focused on the low cost of generic drugs, but most physicians do not consider cost to be an important criterion; they want to prescribe a drug which is primarily effective and safe.
Prescribing is a complex process and, ideally, should be a rational process based on evidence-based criteria such as clinical efficacy, safety, tolerability, drug interactions, dosage frequency and ultimately cost. However, in practice, numerous other factors can play a role in medicine prescribing including emotional factors, the influence of pharmaceutical companies, personal financial interests, and unconscious criteria [1]. As a result, the medicine prescribing process is not always evidence based, transparent or reproducible.
In the last 20 years, matrix models have been developed to inform decisions in medicine prescribing in a transparent and reproducible way [2]. A matrix model, in essence, is an interactive computer program that identifies the most appropriate medicine to prescribe, taking into account clinically relevant and evidence-based selection criteria. Such matrix models have been implemented in The Netherlands [2] and in Northern Ireland, UK [3].
As the introduction of matrix models is likely to have an impact on the prescribing of originator and generic medicines, the aim of this paper is to describe the design of available matrix models and to assess the experience with these models to date. This will aid physicians, health insurance companies, and policy makers to gain a better understanding of both how matrix models can support generic medicine prescribing and how they can be used as a tool to support further population health improvements whilst optimising pharmaceutical expenditure.
Matrix models in The Netherlands
Two matrix models have been developed in The Netherlands: the System of Objectified Judgement Analysis (SOJA) [2] and InforMatrix [4]. These matrix models are used for assessing medicines within a certain pharmaceutical class.
The SOJA matrix model The SOJA matrix model defines a number of selection criteria for a given group of medicines and scores the extent to which each individual medicine fulfills the requirements for each criterion. The most important selection criteria are: clinical efficacy, documented effects on clinically relevant endpoints, incidence and severity of side effects, tolerability, dosage frequency, drug interactions, costs, and documentation. Each criterion is given a relative weight, i.e. more important selection criteria are assigned a higher relative weight.
The scores of a medicine on each selection criterion are determined by a panel of experts in the field. The scores of all medicines are compared to the hypothetical ‘ideal’ medicine from that group, which is assigned the full relative weight for each criterion. This ideal medicine will be 100% effective in all patients, have optimal effects in terms of clinically relevant endpoints and quality of life, have no side effects, is given once daily, shows no drug interactions, is well documented concerning randomised double-blind comparative clinical studies, has a very low acquisition cost, and there must be extensive clinical experience with the drug. The scores for the other medicines for each selection criterion are expressed as a percentage of the relative weight for that criterion. One medicine may therefore score 70% on efficacy, 80% for side effects, 100% for dosage frequency, 30% for medicine interactions, and 20% for cost, as compared with the ‘ideal’ medicine that is used as a reference.
In the published SOJA scores, 1,000 points are divided over the criteria that are considered to be relevant for a particular group of medicines. An example of a SOJA score for antipsychotics in the treatment of schizophrenia is presented in Table 1. Once generic olanzapine becomes available, this drug will also perform well in a future SOJA update.
Interactive program In the interactive program, the percentages scores for each medicine per criterion have been determined by a panel of experts, but users of the program, e.g. physicians, pharmacists, are free to assign their own relative weight to each criterion. The program then computes the ranking scores for the medicines in the group.
The InforMatrix model The InforMatrix model was developed in the early 1990s [5]. The InforMatrix model is an instrument that enables the users of the program to determine, on the basis of agreed criteria, an order of merit for the various medicines available in a specific category. The criteria used are: effectiveness, safety, tolerability, ease of use, applicability, and costs. Safety refers to the incidence of severe to life-threatening side effects and tolerability the incidence of mild to moderate side effects, such as nausea, headache or skin reactions. Relative weights are applied to these six criteria by the users of the program. Next, the medicines are compared to each other per criterion. This evaluation of the medicines is informed by data from the literature and by clinical experience. The weighted score of a medicine per criterion is determined by multiplying the score of a medicine for the criterion by the relative weight of the criterion. To compute the final score of a medicine, the weighted scores are totalled across the six criteria. The most important differences and similarities of both methods are summarised in Table 2.
Validation Various validation steps are used for matrix productions. For InforMatrix, a standard set of criteria is used in all productions. The same is true for SOJA, although extra criteria may be added when this is considered relevant, such as risk of development of resistance to antibiotics.
All matrix authors are asked to provide information on links with pharmaceutical companies or other conflicts of interest, which may affect their judgement. All discussions with individual authors are visible to all other authors in order to improve a transparent decision-making process.
Matrix models are a step towards objective medicine prescribing, but it should be noted that there is still some subjectivity involved in these models. For example, although there is usually agreement on the fact that medicine A has a lower incidence of side effects than medicine B as proven in clinical trials, any assessment of the importance of the observed difference, as is done in SOJA, is subjective. Therefore, a number of peer reviewers critically assess the evidence integrated in the matrix model. The matrix productions are sent to all pharmaceutical companies that are marketing drugs in that specific drug class (including generics) for their comments on the scientific correctness and completeness. All articles are then published in peer reviewed journals, necessitating comments by independent reviewers.
How SOJA and InforMatrix can influence generics prescribing SOJA is designed for use in primary care and for drug classes with large numbers of randomised clinical trials, allowing judgement of the relative efficacy and safety. Informatrix is used primarily in hospital care and for drug classes for which few or no direct double-blind comparative studies have been performed, such as for the tumour necrosis factor-alpha blockers, which have only been compared to placebo, but not between the drugs.
The experience with the SOJA and InforMatrix models suggests that users of the program usually assign high relative weights to criteria such as clinical efficacy, documented effects on clinical endpoints, safety, and dosage frequency. Medicines that perform well on these criteria therefore show a high score for almost all users. In general, generic medicines score very well in the SOJA and InforMatrix models. Their high scores do not originate from their low cost—as physicians and pharmacists do not consider cost to be an important criterion, but instead from their proven clinical efficacy, proven effects on clinically relevant endpoints— morbidity and mortality, extensive and long-term clinical experience with the medicine, and documented long-term safety. Examples of pharmaceutical classes where generic medicines perform well in the most recent updates of published SOJA scores are presented in Table 3. These scores are based on the weightings assigned by the authors of the original publications.
Discussion
As physicians tend to have few incentives to prescribe generic medicines in most European countries, this paper has identified matrix models to be an instrument to support generic medicine prescribing. Matrix models provide a tool to facilitate rational and evidence-based medicine prescribing. Such models can be applied by physicians, pharmacists, formulary committees in hospitals, health insurance companies, and policymakers to inform medicinal selection.
Matrix models ensure that medicine prescribing is founded upon multiple rational and evidence-based criteria; other non-rational selection criteria do not play a role in the decision-making process. As a result, medicine prescribing becomes transparent and reproducible as the criteria and weightings on which decisions are based are known. A matrix model also avoids the situation where a decision is taken solely on one criterion and therefore supports a comprehensive approach towards medicine prescribing. The use of matrix models in The Netherlands and Northern Ireland suggests that this method for medicine prescribing greatly aids discussion in pharmacotherapy audit meetings between general practitioners and/or pharmacists, local or regional formulary committees, pricing, and reimbursement negotiations.
Matrix models allow the active participation of physicians, pharmacists and other stakeholders in informing medicine prescribing. These models tend to integrate ‘top-down’ and ‘bottom-up’ methods of decision making. The ‘top-down’ contents of matrix models, i.e. assessment of medicines based on a thorough evaluation of the evidence, are combined with the high compliance of the ‘bottom-up’ decision-making process as the final decision is made by, for example, the formulary committee in a hospital. This is likely to increase the acceptability of the matrix model’s outcome—namely the identification of the most appropriate medicine to prescribe.
Matrix models suffer from a number of limitations; they are time-dependent in that the evidence on the efficacy, safety, costs, pharmacokinetic and pharmaceutical aspects of medicines change continuously. Also, new products are introduced over time and older products are withdrawn from the market. Regular updates of the information needed by matrix models are therefore necessary. For instance, the Dutch SOJA matrix model is updated every six months.
It could be argued that matrix models may inhibit the introduction of innovative medicines due to the limited documentation of evidence on such medicines. If a new medicine has no added benefit as compared to existing medicines in terms of the selection criteria used in matrix models, it will almost certainly show a low score because of its poorer documentation and usually higher acquisition cost. However, such medicines are not innovative, but are in essence ‘me too’ medicines. Generically available drugs will show higher scores compared to the ‘me too’ drugs. A truly innovative medicine would exhibit an added benefit compared to existing medicines, thus generating a high score in a matrix model, especially when effects on clinically relevant endpoints have been documented.
The operation of matrix models in practice—based on unpublished results from hundreds of interactive sessions in The Netherlands and Northern Ireland—shows that users of the program tend to assign high relative weights to the clinical efficacy, documented effects on clinical endpoints, safety and dosage frequency of medicines. Pharmaceutical factors, pharmacokinetics and acquisition cost are usually given a low relative weight. During these sessions, generic medicines showed favourable overall scores because they have the same quality, safety, and efficacy as originator medicines, but have a lower cost. Compared to newer drugs from the same class, they have the advantage of wider clinical experience, documented effects on clinical endpoints and better documentation concerning randomised controlled clinical trials.
Other scores such as for erythropoiesis-stimulating factors and granulocyte colony-stimulating factor showed favourable results for drugs, which are also available as biosimilars. Again, the preference for these drugs is based on quality aspects instead of cost. Therefore, matrix models may also be useful to promote the use of (good quality) biosimilars.
How to implement matrix models in other countries
A variety of interactive tools are available on the Internet [6], which allow active participation of physicians and pharmacists in the preparation of the score. The existing programs are specific for the Dutch and UK situation. Several adjustments to criteria need to be made to make these programs suitable for use in other countries such as available formulations, trade names, approved indications, dosage frequency, and acquisition cost. These adjustments can be made in a couple of hours per program, so country-specific matrices can be made at very short notice. Besides this, it is highly recommended to use a local expert group in each country to increase ‘ownership’; translation into the local language is also recommended for most countries.
Conclusion
Matrix models may serve as an instrument to support generic medicine prescribing. The experience of The Netherlands and Northern Ireland indicates that generic medicines perform well in matrix models. In Northern Ireland, generic drugs showed the highest scores for the first five drug classes—statins, proton pump inhibitors, ACE inhibitors, angiotensin II antagonists, and selective serotonin reuptake inhibitors—investigated by the matrix methodology [7]. In the Dutch situation, generics showed the highest scores for many pharmaceutical classes. The main advantage of matrix models is that the high scores for drugs available as generics are based on clinically relevant criteria, such as efficacy, documented effects on clinical endpoints, safety and dosage frequency of medicines and not solely on acquisition cost. Therefore the outcomes of matrix models are accepted much better by physicians, rather than choosing generic drugs on the basis of cost. All matrices are available in an interactive format, thereby allowing active participation of physicians and pharmacists.
For patients
Use of generic drugs instead of patented drugs can save major amounts of money. However, many physicians do not consider cost an important selection criterion. This paper describes interactive matrix models to promote rational drug selection within a drug class, based on criteria such as efficacy, safety, tolerability, dosage frequency, drug interactions, documentation and cost. When all these criteria are taken into consideration and weighted, generic drugs are very interesting alternatives to much more expensive patented drugs.
References 1. Scott M, Janknegt R, Brenninkmeijer R. A prelude to the matrix models supplement. Expert Opin Pharmacother. 2007;8(Suppl 1):S1-4.
2. Janknegt R, Scott M, Mairs J, Timoney M, McElnay J, Brenninkmeijer R. System of Objectified Judgement Analysis (SOJA) as a tool in rational and transparent drug-decision making. Expert Opin Pharmacother. 2007;8(Suppl 1):S5-14.
3. Scott M, Timoney M, Mairs J, Crealey G, Al Abaddi I, Brenninkmeijer R, et al. Safe Therapeutic Economic Pharmaceutical Selection (STEPS): development, introduction and use in Northern Ireland. Expert Opin Pharmacother. 2007;8(Suppl 1):S57-63.
4. Brenninkmeijer R, Mairs J, Timoney M, Scott M, McElnay J, Janknegt R. InforMatrix as an alternative tool in rational and transparent drug-decision making. Expert Opin Pharmacother. 2007;8(Suppl 1):S31-6.
5. Brenninkmeijer R, Vermeij D, Hes R. InforMatrix: therapeutisch beleid, informatiesynthese en consensusontwikkeling. Pharmaceutisch Weekblad. 1994;129: 1185-90.
6. Brenninkmeijer R, Janknegt R. Application of SOJA and InforMatrix in practice: interactive web and workshop tools. Expert Opin Pharmacother. 2007 Oct;8 (Suppl 1):S49-55.
7. STEPSelect Knowledge Management [cited 2011 Dec 11]. Available from: http://www.medicines-management.ie/en/mx/stepselect
Author: Robert Janknegt, PharmD, PhD , Director of Pharmacy and Clinical Pharmacology, Orbis Medisch Centrum, 1 Dr H van der Hoffplein, NL-6162 BG Sittard-Geleen, The Netherlands
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Abstract: Despite biopharmaceuticals having an enormous potential value for our health, they have also become a serious threat to our healthcare systems.
Submitted: 22 June 2011; Revised manuscript received: 6 October 2011; Accepted: 11 October 2011
Recombinant drugs, or biologicals as they are widely termed, are highly complex drug substances that have added tremendous treatment opportunities to modern medicine. However, introducing these highly complex molecules into a patient is a high-risk medical intervention, particularly because recombinant proteins have additional immunological risks compared to most, if not all, small molecules. This is certainly the case when an original product is clinically tested in first-in-human trials. Fortunately, we have learned that the risks far outweigh the benefits for conditions where no other treatments are available.
Most recombinant drugs are very expensive, which can only be explained in part by the costs accrued during their development and manufacture. These costs put a tremendous burden on healthcare systems and it is clear that many patients who could benefit from such therapy with a recombinant drug are left untreated if neither they nor their healthcare system can afford to pay. Some therapies can cost up to Euros 500,000 or more per patient per year of therapy [1]. This cost may be warranted due to the potential benefits the drug can deliver and the initial investment when the medicine is innovative and new, but such high costs cannot be justified in the very long term.
Without a doubt, developing a biosimilar is much more complex than developing a generic version of non-biological drugs [2]. A highly controlled manufacturing process is intrinsically important to biotech medicines as even minor variations in manufacturing or production can result in vastly different products with deleterious, or in some cases highly favourable results, such as better tolerability or efficacy [3].
Once the possibility of efficacious treatment within an acceptable safety profile has been demonstrated, competitors may enter the market, occasionally even while the original molecule is still protected by patents. This is possible because, in many cases, a whole variety of different proteins can solve the same clinical problem. For example, six structurally very different tumour necrosis factor-alpha antagonists compete in the market for the treatment of chronic inflammatory diseases and several more are in the pipeline [4]. All these molecules are innovations as the molecules are structurally very different, but all have turned out to be reasonably well tolerated and more or less equally efficacious and all were consequently approved by authorities in Europe and the US.
Due to the less stringent regulatory requirements of biosimilars and the time required for research, the price of these can be significantly lower than the innovator. By introducing these less expensive biosimilars into the market, the price of the innovator is also often reduced due to this market competition and is a reasonable tool to keep medicines at an affordable cost.
In my opinion, innovator companies should concentrate on innovations—and the potential for innovation is enormous. There are many unmet medical needs waiting for innovative intervention options and there is always a potential for improving on the characteristics of the molecules towards second or third generation drugs. This is both an opportunity for seriously ill patients and a chance for our healthcare system as well.
References 1. Bailey L. An overview of enzyme replacement therapy for dysosomal storage diseases. OJIN. 2008;13(1):3. doi:10.3912/OJIN.Vol13No01Man03
2. Crommelin D, et al. Pharmaceutical evaluation of biosimilars: important differences from generic low-molecular-weight pharmaceuticals. Eur J Hosp Pharm Sci. 2005;11(1):11-7.
3. Robinson CJ, Jones C. Quality control and analytical techniques for biopharmaceuticals. Bioanalysis. 2011;3:81-95.
4. Nam JL, Winthrop KL, van Vollenhoven RF, et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis. 2010;69:976-86.
Author: Professor Theodor Dingermann, PhD, Institute of Pharmaceutical Biology, Biocenter, Gebaeude N230, 306, 9 Max-von-Laue Strasse, DE-60438 Frankfurt/Main, Germany
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Abstract: There are many variables responsible for the pricing of generic medicines in Europe. This editorial looks at the many policy initiatives currently being undertaken.
Submitted: 3 November 2011; Revised manuscript received: 23 November 2011; Accepted: 14 December 2011
In this first issue of the Generics and Biosimilars Initiative Journal, Professor Steven Simoens describes the pricing of generic medicines in ambulatory care in Europe for the period 2000–11, pages 8 to 12. The author makes a number of interesting observations, a few of which will be discussed here.
First, Professor Simoens observed that both the prices and market shares of generics vary substantially across European countries. In an attempt to explain these differences he stresses the importance of price regulation imposed by the government versus free-market pricing, where the penetration of generics is higher in the case of free pricing. This is because, in countries with free pricing, the manufacturers of originator medicines can charge premium prices, thereby attracting the market entry of generic medicines. Manufacturers of generics are thus able to raise their market share by offering price reductions.
This observation of Professor Simoens might be true in many cases, but the probability of other entry barriers to enter the market should not be underestimated. Other such barriers include the registration of multiple patents on drugs (even on the route of administration), biased marketing, financial offers by originator companies to buy-off potential generic producers and cartels of existing generic producers might frustrate or slow down market entry of new generic producers and hence limit the price reduction.
Professor Simoens cited a market survey from 2011 that states that 80% of European countries impose price regulation and 20% adhere to free-market pricing. Many price regulating countries have established a fixed minimum price difference between generic and originator medicines and this approach has the benefit of guaranteeing savings to the third-party payer. However, these savings might be less than what could have been observed in a competitive market. This opinion was also shared by Dr Andreas Seiter of the World Bank in a keynote presentation at the Pharmaceutical Pricing and Reimbursement Information Conference in 2011 in Vienna, Austria [1].
The potentially larger savings of a competitive market can only materialise when such a market truly exists. As long as governments do not have the power to model the market institutions towards increased competition, they might prefer a more certain, but lower amount of savings as a result of regulation, as governments are assumed to be risk averse.
In addition, recent examples of Portugal and Ireland, both of which apply price regulation, show that the Euro crisis created a sense of urgency. Under Troika pressure, both governments achieved a considerable reduction in the pricing of generics. Ireland also reduced the wholesale and retail mark-ups and dispensing fees and Portugal lowered the reimbursement value of generics to the value of the cheapest five generics. In addition, the market share of generic medicine was seen to increase substantially in Portugal during 2006–11 [2, 3].
Professor Simoens also discusses tendering, that is, a purchaser buys medicines based on a competitive bidding process and the contract is granted to the supplier who offers the best bid. He states that although tendering systems may reduce (generic) medicine prices in the short term, little is known about the overall long-term impact. Although I agree with this cautious statement, medium term results for The Netherlands make me more optimistic. If the preferential policy of Dutch health insurers can be viewed as tendering, we can conclude that it resulted in a 60% structural price reduction of preferential generics (90% of all generics) since 2008. The market share of generics in The Netherlands increased to 59% of prescriptions in 2010. The savings on drug costs due to the preferential policy were estimated to be Euros 300 million for 2008 and Euros 500 million for 2010 [4].
In conclusion, many policy initiatives are currently being undertaken to reduce prices of generic medicine to affordable levels. Although free-market pricing based on competition might be preferable from an economic point of view, this might be limited by institutional and/or political barriers. The euro crisis clearly has increased the sense of urgency to undertake drastic policy steps in several countries.
References 1. Seiter A. The World Bank. Balancing pharmaceutical policies between equity and cost-containment –a critical discussion and lessons learned. Pharmaceutical pricing and reimbursement – a global perspective. PPRI Conference 2011; 2011 Sep 30; Vienna, Austria. Available from: http://whocc.goeg.at/Downloads/Conference2011/PraesentationenPPRIKonferenz/Day2_afternoon_Festsaal_1400_Seiter.pdf
2. Mulvenna K. P & R in the light of the financial crisis: Ireland. Pharmaceutical pricing and reimbursement– a global perspective. PPRI Conference 2011; 2011 Sep 30; Vienna, Austria. Available from: http://whocc.goeg.at/Downloads/Conference2011/PraesentationenPPRIKonferenz/Day1_afternoon_Festsaal_1300_Mulvenna.pdf
3. Gomes MV. Medicine Policy: surviving the crisis. Pharmaceutical pricing and reimbursement – a global perspective. PPRI Conference 2011; 2011 Sep 30; Vienna, Austria. Available from: http://whocc.goeg.at/Downloads/Conference2011/PraesentationenPPRIKonferenz/Day1_afternoon_Festsaal_1300_Gomes.pdf
4. College voor zorgverzekeringen (CVZ) [homepage on the Internet]. [cited 2011 Dec 11]. GIPeilingen 2010, Diemen 2011.
Author: Associate Professor Marc A Koopmanschap, PhD, Health Economist, Associate Professor of Health Economics, Institute of Health Policy and Management and Institute for Medical Technology Assessment, Erasmus University Rotterdam, PO Box 1738, NL-3000 DR Rotterdam, The Netherlands
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I am proud and pleased to be able to write the introduction to this first issue of the Generics and Biosimilars Initiative Journal (GaBI Journal).
This journal is designed to complement GaBI Online which has successfully covered generic and biosimilar issues since 2009. The Publisher, the members of our Editorial Boards, and I, that is, ‘we’; all became convinced some time ago of the need for a traditional hard copy journal dedicated to publishing articles on generic versions of drugs and biologicals. We feel that the growth of the generic drug and biological industry as well as the technical, regulatory, political and economic issues associated with this industry would benefit from the introduction of such a journal.
The GaBI Journal Editorial Boards, and I owe a debt of gratitude to Professor Arnold G Vulto, PharmD, PhD, and our Publisher, Ms Lasia Tang. They both made the original GaBI Online so successful. They then conceived the idea of this published version and worked tirelessly to make this journal a reality. Their continued work, support and inspiration have been and will continue to be largely responsible for the success of this journal.
We recognise that it is not always easy or even possible for authors to get generic and biosimilar manuscripts such as comparative bioavailability studies of new generic products published in peer reviewed, English language journals. It can be even more difficult to publish negative studies, opinion pieces or letters. However, all such work should be available for review and discussion. We believe that publication of such work in a single journal will facilitate important evaluation and impact. Any such work, as long as it involves some aspect of generics or biosimilars and conforms to our instructions to authors, will be considered for peer review.
We want the journal to be a single place where editorials, commentaries, reviews, perspectives, reports, news, letters and original research articles concerning every aspect of generic drugs and biologicals can be published. We hope to present issues in an objective and unbiased manner and to publish all appropriate articles including both pro and con views, opinions and data. We welcome submissions from both the generic and non-generic pharmaceutical industry as well as all others including regulators, payers, governments, economists, healthcare providers, patients and their families or caregivers. We also hope to eventually include articles on important non-human medicines, e.g. veterinary medicines, as well as non-physician/pharmacy, e.g. dental, nursing; and non-traditional medications, e.g. herbal products.
While the journal will be published in English we hope to be a truly global journal presenting data, publications, and perspectives from all countries of the world. We offer English language publication support in an attempt to make this possible.
We encourage our readers and their colleagues to submit manuscripts to the journal. We also ask for your continuous feedback and suggestions both for individual articles we publish as well as for our format and philosophy. Together we can provide helpful dialogue and data concerning this important and rapidly changing aspect of therapeutics.
Disclosure of Conflict of Interest Statement is available upon request.
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Abstract: Many generic drugs are now being prescribed and the trend is increasing. For example, in Austria, the number of all generics prescriptions has more than doubled from 11% in 2000 to 23% in 2010. However, many myths and questions about generic drugs remain and information may be difficult to come by. It is therefore not surprising, as we have discovered in recent years, that even physicians and pharmacists are not always fully up to date in their understanding of generic drugs. Some of their questions centre on issues such as: are generic drugs really as good as the original; are we really dealing with an adequately tested, high quality medicinal product.
Today, generic drugs present an equally well-tolerated and efficacious alternative to established medicinal products, which contain well-known, rigorously tested active ingredients. An established originator product undergoes expensive and protracted development (up to 15 years) with inherently high preclinical and clinical research costs in order to be given market approval. The development of generic drugs, on the other hand, is relatively quick and inexpensive, which allows generic drugs to be sold at a distinctly cheaper price. This is due to the waiving of new preclinical and clinical studies, aside from some bioequivalence studies. Their lower price however should not be equated with ‘cheap quality’. In fact, generic medicines undergo the same strict scrutiny by the European or national medicines authorities as reference products.
At AGES PharmMed, the Austrian competent authority for marketing authorisation of human medicinal products, generic drugs are subjected to detailed assessment, during which the safety profile and efficacy data of the active substances, as well as the proof of bioequivalence, are thoroughly examined. This is also the case for all other national competent authorities of the EU and EMA. The Austrian Federal Office for Safety in Healthcare issues a marketing authorisation only if all legal and scientific requirements are fulfilled. This marketing authorisation validates the safety, efficacy, and quality of a generic drug.
Submitted: 20 May 2011; Revised manuscript received: 16 November 2011; Accepted: 25 November 2011
What makes a generic medicinal product generic?
The definition, according to Austrian drug law/the Medicinal Products Act as well as to EU Directive 2001/83/EC, is that a generic medicinal product ‘is a product which has the same qualitative’, i.e. kind of active substance, ‘and quantitative’, i.e. amount of active substance, ‘composition as the reference medicinal product’. For the sake of simplicity, the reference product is often also referred to as the originator. The different salts, esters, or derivatives of an active substance are considered to be the same active substance, unless they differ significantly in their safety and/or efficacy properties. In these cases, the manufacturer of a generic drug has to submit further proof of efficacy and safety.
The pharmaceutical form, which means the distinct way a product is to be administered, of the generic medicinal product has to be the same as for the reference medicinal product [1]. However, remarkably the various types of immediate release oral pharmaceutical forms, e.g. tablets, capsules and dragées, are considered to be one and the same pharmaceutical form. A patient prescribed with a particular medicinal product may therefore be prescribed either a film-coated tablet or a capsule of the same drug by his physician. This in itself does not pose a problem, as the galenic formulation may indeed be different, but the impact on the safety and efficacy profile of the whole product has been judged to be comparable during the approval procedure.
Are different compositions possible?
Differences in composition between the generic and reference medicinal product are possible, but only regarding the excipients, e.g. bulking agents, colouring agents; and not for the active substances. For example, corn starch may be used instead of lactose as an excipient. However, it has to be demonstrated by the applicant of the generic drug that these differences in composition do not influence the therapeutic efficacy and safety or how the drug is absorbed, distributed, metabolised or eliminated by the body, i.e. the drug’s pharmacokinetics must also remain more or less the same.
Bioavailability or bioequivalence trials need to be conducted in order to demonstrate the equivalence between the generic medicinal product and the reference medicinal product. Differences in the manufacturing process compared to the originator are allowed, but the same strict general quality criteria, e.g. controlled production under good manufacturing practice (GMP), apply to the production of the generic medicinal product as well as for the reference product. Also a medicinal product can only be considered as the reference product if it has been granted market approval in at least one Member State of the European Economic Area. However, only the so-called originator can serve as the reference product in bioequivalence testing, but never another generic drug, as this would otherwise mean the allowance of a copy of a copy.
How soon can generic medicinal products appear on the market?
The applicant needs to provide proof that the originator product has been authorised for at least eight years, or that the originator company has issued a written informed consent stating that the generics company is permitted to apply for its generic drugs sooner. As a rule however, the earliest a generic medicinal product is allowed to go on sale is 10 years after the first European originator is granted marketing authorisation. This 10-year market exclusivity can be extended by an additional year if, during the first eight years, the marketing authorisation holder of the originator obtains an additional authorisation for one or more new relevant therapeutic indications [2]. Figure 1 shows the ‘8+2 (+1) Formula’ applicable to generic medicinal products entering the market.
Some originators, however, hold patents—in some cases up to 1,000 patents for one single product were found—which can further postpone the launch of a generic drug. Such delay in market access is therefore possible, even if the marketing authorisation has already been granted to the generic drug. Notably, some misuse of patent strategies was described in the final report of the 2009 sector inquiry of the European Commission for Competition [3]. In a sample of 219 molecules from 2000 to 2007 there were reportedly 1,300 patent-related out-of-court disputes related to the launch of a generics. The number of patent litigations brought to court totalled nearly 700 cases in these seven years and the number of cases increased by a factor of four between 2000 and 2007. The report reached the conclusion that the behaviour and practices of originators contribute to generics delay as well as to difficulties in innovation itself because originators may even block each other.
What is a bioequivalence study?
Bioequivalence studies are often the demanded basis for granting marketing authorisation for a generic medicinal product. They are clinical studies conducted in accordance with Austrian drug law as well as to EU Directive 2001/20/EC and provide data to demonstrate bioequivalence between a test product, i.e. the generic medicinal product, and a reference product, i.e. the originator. The rate and extent of absorption of the medicinal products and therefore the bioavailability of the active substance(s) are determined. It is a widely accepted regulatory assumption, even sometimes challenged by generics disputants, that equivalent plasma concentration time curves represent equivalent efficacy and safety. Therefore, if bioequivalence can be shown after the administration of the same molar dose, equivalence or assumption of so-called essential similarity of the two products in terms of efficacy and safety can be concluded.
How is a bioequivalence study conducted?
The simplest design for a bioequivalence study is the ‘two-way crossover’. In this design, a subject receives one product first (for example, the generic test (T) product) and then, following a sufficiently long wash-out period to ensure that no residual active substance remains in the subject’s body, is given the other product (in this case, the originator reference (R) product). Usually 20–30 healthy volunteer subjects are used for such a study. Subjects can belong to either sex, although the risk to women of childbearing potential should be considered and an existing pregnancy must be ruled out. Repeated blood samples are taken to monitor plasma concentrations of the active substance or its active metabolites, see Figure 2.
More complex designs like bioequivalence studies with a fully-replicate design, meaning a double crossover approach with for example T-R-T-R may be chosen if one wants to evaluate the intra-individual variability of a medicinal product. This becomes necessary when a company wants to apply for an authorisation for a so-called highly-variable drug, which means that the intra-individual variance of a reference product is higher than 30%, which could make the generic drug eligible to somewhat broadened bioequivalence criteria. However, in certain cases of so-called Biopharmaceutics Classification System (BCS) class I drug substances, the bioequivalence study may be waived. These BCS class I substances are highly soluble, completely absorbed and are not considered to have a narrow therapeutic index. Occasionally, BCS class III drugs substances, which have a high solubility but limited absorption can qualify for such waivers but only if they have qualitatively the same excipients at a quantitatively very similar amount as a reference product.
Parameters
The most important parameters, which are evaluated during a bioequivalence study, are as follows, see also Figure 3:
Area under the curve (AUC): that is the area under the plasma concentration time curve, which represents the extent of exposure. Usually the AUC0-t is evaluated, which means that a measurement from the time (0) of the drug administration until the last (t) blood sample was drawn. To show that blood samples were drawn for a sufficiently long time period, the measured AUC0-t has to cover at least 80% of the AUC0-inf, which means the AUC extrapolated to infinity. In cases where a drug has a very long half-life, a measurement until a maximum of 72 hours after drug administration (AUC0-72) is considered sufficient, as the absorption phase of immediate release products is fully covered by this approach.
Maximum plasma concentration of the active substance (Cmax): Cmax provides information on pharmacodynamic and pharmacokinetic properties and is fundamental in the evaluation of adverse events.
Time to maximum plasma concentration (Tmax): Tmax allows inferences to be drawn, to a certain degree, on the speed of release from the pharmaceutical form and on the absorption from the gastrointestinal tract as well as a raw estimate of the onset of action.
Acceptance limits
The data collected during the bioequivalence study undergo exacting statistical analyses, for which a 90% confidence interval is used. To put it simply, the 90% confidence interval provides a range within which one can be 90% confident the true effect lies. The agreed acceptance limits are valid throughout the EU and can be found in the ‘Guideline on the Investigation of Bioequivalence’ of EMA [1]:
For the AUC, the 90% confidence interval has to be contained within the acceptance interval of 0.80–1.25. Substances with a narrow therapeutic range, e.g. immunosuppressive drugs such as ciclosporin, may be tightened to an acceptance interval of 0.90–1.11. The need for such tightening is decided case-by-case based on clinical considerations either by the applicant or by the EMA Pharmacokinetic Working Party (PKWP).
For Cmax the 90% confidence interval also needs to be within the acceptance interval of 0.80–1.25. As before, the acceptance interval may be tightened to 0.90–1.11 for substances with a narrow therapeutic range. However, for drug substances falling under the definition of a highly variable drug, which must always be proven in a fully replicate design bioequivalence study, the interval for Cmax on the other hand can gradually be broadened up to a maximum of 0.70–1.43. This maximum interval is only eligible if intra-individual variance amounts to more than 50%. Intra-individual variance bigger than 30% but smaller than 50% would yield regulatory acceptance intervals between conventional 0.80–1.25 and the maximum tolerable 0.70–1.43 [1].
Why are studies carried out using healthy subjects, rather than patients?
Bioequivalence studies have a special experimental approach: the aim is to enable a comparison of the bioavailability to determine the equivalence of the two drugs, or in other words, to exclude a statistically significant difference between two formulations. Inherently, every study has ‘background noise’, which makes it harder to discern the actual effect. The background noise, also known as ‘bionoise’, is caused by random fluctuations of biological measurements and can be likened to static on the radio. By chance, it is possible that a difference in effect can be masked by this bionoise. The bionoise fluctuations can be caused by the ‘intra-subject variability’ (the physiological variability within a single individual) or can be due to the ‘inter-subject variability’, which describes variability between different subjects. Due to their differences in constitution, co-morbidities and co-medication, patients present as a distinctly heterogeneous population. This heterogeneity makes direct comparisons difficult and is accompanied by profound bionoise. Therefore, subjects for bioequivalence studies are ‘standardised’ as far as possible with the aim of permitting the detection of each and every small difference between the formulations. Healthy volunteers are selected in accordance with strict inclusion criteria, such as being healthy, 18–55 years of age, normal body weight, and non-smokers. The homogeneity of the selected study subjects helps validating the results of the study. Throughout the study, diet, fluid intake, and exercise are standardised and concomitant medication or alcohol is not allowed [4]. The subjects are closely monitored in a clinical setting. All these conditions are maintained to ensure reliable results and to permit the identification of any possible differences between the two pharmaceutical products under test.
Are the acceptance limits strict enough?
The approvable acceptance range from 0.80–1.25, i.e. 80–125%, is sometimes incorrectly thought to represent a difference in efficacy. In fact, acceptance limits define a statistical range and the actual mean lies much closer to 1 (or 100%). Numerous studies have reported that generic drugs’ AUC and Cmax differed only by 3–4% on average from those of the originator [5-8]. They also reported that, in general, the poorer manufactured products, where the bioavailability differed by more than 5–10% from the originator, no longer fulfilled the key criteria for bioequivalence and were not granted marketing authorisation as generic drugs. It should also be noted that most pharmaceuticals rely on the law of mass action. In this non-linear system, an 80% or 125% change in concentration in the range of the dissociation constant—the area where half of all receptors are bound to the active substance—results merely in a +/- 6% change in receptor binding. Moreover, in therapeutics, dosage is sometimes chosen where nearly all receptors, e.g. 90%, are bound. At these dosages, the changes in concentration described above result in an even smaller change, approximately 2%, in receptor binding. A difference in efficacy is therefore close to impossible and will usually not be detectable, either therapeutically or statistically.
What are the rules for conducting bioequivalence studies?
How exactly a bioequivalence study has to be conducted, and which requirements need to be taken into consideration, is laid out in detail in the European bioequivalence guideline, the revised version of which came into effect mid-2010. The guideline clearly specifies the requirements for the design, conduct, and evaluation of bioequivalence studies for all EU countries. Since 2001, when the first bioequivalence guideline was published, many additional aspects were identified which needed to be amended and improved. Minor issues were addressed in interim question and answer documents. After a three-year preparation period, the comprehensively revised version of the guideline came into effect in August 2010. The comments and suggestions of over 50 expert organisations and associations were worked into the 22 draft versions. The revised version therefore now reflects the most up-to-date state of knowledge, which is essential in issuing harmonised and standardised marketing authorisations across Europe. The aim of the guideline was to do away with the ambiguities of the past, which often led to lengthy discussions and differences in professional opinion between the countries and competent authorities of the EU. This also ensures the safety and efficacy of all generic drugs being granted marketing authorisation.
Are bioequivalence studies only used in the development of generic drugs?
Since the task of bioequivalence studies is to detect differences between formulations or pharmaceutical forms, they are indeed not only used as a basis for the licensing of generic medicinal products. In fact, originators may also use bioequivalence studies during their own development since the formulation first used in clinical trials is often not the same which later goes into large-scale market production. Bioequivalence studies are used in these cases to allow bridging of the results obtained in the clinical trials. The same principles in study conduct, data evaluation, and assessment of results by the authority are applied in such originator studies as in the above-described studies for generic drugs. Remarkably, essential similarity between an originator small-scale clinical trial product and a large-scale originator product later to be for sale has never been put in question by anyone. Considering media coverage sometimes casts massive doubt about generics and the way they are authorised, obviously there seems to be an unfounded contrast in the perception dependent on who—the originator company or the generics company—makes use of the bio – equivalence concept for the authorisation of one of their products. Assuming that the bioequivalence concept is valid and trustworthy for authorisation of a new originator product, the same should be applied to the authorisation of a generic drug.
Is the manufacturing quality the same for generic and originator products?
The same quality requirements apply to the manufacturing of generic drugs as for any other medicinal product. Production has to be performed in accordance with GMP and is strictly controlled by evaluating the manufacturing data and by inspections performed not only in Austria and the EU, but also all over the world including countries such as India and South Africa. As for any other medicinal product, quality deficiencies in individual batches are theoretically possible and therefore the Austrian Federal Office for Safety in Health Care as well as the other competent EU authorities closely monitor the quality of all authorised medicinal products on the market. This is achieved by the legal obligation of authorisation holders to inform the authority about every out-of-specification results or other problems in manufacturing and an additional quality-defect notification system involving all healthcare professionals. This guarantees that only high quality medicinal products are available, regardless of whether these products are originators or generics.
When is a generic drug granted market authorisation?
An Austrian or an EU marketing authorisation is only issued when the pharmacokinetic parameters of the generic drug are comparable to those of the reference product and bioequivalence has been successfully demonstrated. Furthermore, the overall benefits of the generic medicine need to outweigh its risks (positive risk–benefit ratio) and its excipients and the manufacturing process must have been demonstrated to not negatively influence its safety and efficacy. Last but not least, all internationally relevant quality standards and legal requirements have to be fulfilled before marketing authorisation can be granted.
Are generic drugs as efficacious as the original?
Since the generic medicinal product contains the same active substance as the originator and comparability has been demonstrated in a successful bioequivalence study, the generic drug is assumed to behave in the same way as the originator. This equality also implies equal efficacy and safety. Austria, as well as other EU Member States, due to its contribution of experts in scientific councils, e.g. the EMA PKWP, also plays a significant role in keeping generics standards high and ensuring that only generic drugs with the same safety and efficacy profiles as their reference products are brought onto the market. A follow-up control is also established by means such as the evaluation of recent scientific literature, clinical trials, pharmacovigilance provisions, manufacturing inspections, quality controls, and an obligatory renewal of the marketing authorisation after a five-year period. Despite these facts there have been repeated attempts by originators and some medical societies to cast doubts on generics efficacy in fields such as osteoporosis medications (bisphosphonates), antipsychotics [9], platelet inhibitors [10] and opioid pain relievers [11]. Taking this into account the final report of the 2009 sector inquiry of the European Commission for Competition states, therefore that any campaigns which put this fact in question (namely that all medicinal products, whether originator or generics, are subject to the same strict requirements of quality, safety and efficacy) ignore the key principles for marketing authorisation in the EU and may mislead the public. The Commission hence urges Member States to take appropriate action if such campaigns are detected in their territory. In Austria, appropriate actions were taken in 2010 when the Austrian Federal Office for Safety in Health Care released a public letter which detailed facts about clopidogrel generics [12], and afterwards published a more detailed, pharmacologically-based article in several physician and pharmacist journals [13] as well as in official journals of the Main Association of Austrian Social Security Institutions and Austrian Health Insurances [14]. Furthermore, recent international scientific publications confirm once more the similar efficacy of generics in this and various other therapeutic fields [15-19].
Do generic drugs antagonise innovation?
It is sometimes said that generic drugs prevent innovation. In fact, the opposite is true. As seen in other areas of research and development, a careful balance must be struck between patent protection and free competition. The current rules regarding patent protection and market exclusivity ensure a sufficiently long period of market protection for originators, while ensuring at the same time a fairly good access to market for generics competitors, at least after the 10-year market exclusivity has expired, and occasionally much more tricky, the patent issues were resolved. Although originator companies repeatedly bemoan a dwindling return of investment due to generics competition [20], data investigating the duration for development and gaining market approval have shown that originators nowadays have, compared to 1990, an additional three and a half years due to faster development and expeditious registration procedures in which to reap the rewards of being the sole market authorisation holder [21, 22]. It is a noteworthy fact that some countries with high rates of generics penetration like Germany or US also have high rates of pharmaceutical innovation and spending in research and development [23]. It would seem, therefore, that generics competition indeed contributes and gives stimulus to the discovery of new medicines. Generic drugs therefore not only help national health services by reducing its costs, they can in fact cause pressure for innovation.
For patients
Many generic drugs are nowadays being prescribed to patients and the trend is increasing. However, some people still feel that myths and questions about generic medicines remain and information may be difficult to come by. In fact, generic drugs are well-tested, high quality medicinal products. They are strictly regulated by the National and European Competent Authorities and they are only granted approval by going through an extensive authorisation process. This process ensures adequate safety and efficacy of generic medicines available on the European market.
References
European Medicines Agency. CPMP/EWP/QWP/1401/98 Rev.1. Guide line on the investigation on bioequivalence. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf
European Commission. Guidance on elements required to support the significant clinical benefit in comparison with existing therapies of a new therapeutic indication in order to benefit from an extended (11 years) marketing protection period, 2007. Available from: http://ec.europa.eu/health/files/eudralex/vol-2/c/guideline_14-11-2007_en.pdf
European Commission Competition, EU Sector inquiry, 8 July 2009. Available from: http://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/communication_en.pdf
Tschabitscher D, Platzer P, Baumgärtel C, Müllner M. Generic drugs: quality, efficacy, safety and interchangeability. Wien Klin Wochenschr. 2008;120:63-9.
American Medical Association. Summaries and recommendations of Council on Scientific Affairs Reports. Generic drugs (CSA Rep 6, A-02). 2002 Annual Meeting of the American Medical Association. 2002:13-4.
Henney JE. Review of generic bioequivalence studies from the food and drug administration. JAMA. 1999;282:1995.
Nwakama PE. Generic drug products demonstrate small differences in bioavailability relative to brand name counterparts: review of approved ANDAs, FDA. 2005.
Davit BM, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the FDA. Ann Pharmacother. 2009 Oct; 43(10):1583-97.
Statement of the Austrian Society of Cardiology (ÖKG) regarding Clopidogrel-Generics. 2010. Available from: http://kardiologie-gefaessmedizin.universimed.com/artikel/stellungnahme-der-%C3%B6sterr-kardiologischen-gesellschaft-%C3%B6kg-zu-clo
Consensus statement of Austrian Society of Biologic Psychiatry (ÖGBP), Generics and originators in psychiatry, 2008. Available from: http://www.medizin-medien.at/mm/mm011/low-generika.pdf
Statement of Austrian Society of Pain regarding opioid generic switching due to economic reasons, 2011. Available from: http://www.expertenstatement.com/
Statement of Austrian Agency for Health and Food Safety, Austrian Medicines and Medical Devices Agency, AGES PharmMed and Austrian Federal Office for Safety in Health Care regarding Clopidogrel Generics. 2010 March 26. Available from: http://www.basg.at/uploads/media/100325_Stellungnahme__Clopidogrel_Generika_1.pdf and http://www.basg.at/uploads/media/100325_Stellungnahme_Clopidogrel_Generika__2.pdf
Baumgaertel C. Clopidogrel-generics. Austrian Pharmacists Journal, ÖAZ, Ausgabe. 2010;64(11): 666-8. Available from: http://www3.apoverlag.at/pdf/files/OAZ/OAZ-2010/OAZ-2010-11.pdf
Baumgaertel C. Generics of clopidogrel are equivalent. Publication of Vienna Health Insurance Fund and Austrian Health Insurance, WGKK, Therapie Info. 2010;22(3). Available from: https://www.sozialversicherung.at/mediaDB/692427_therapieinfo_nr3_07_2010.pdf
Kim SD, et al. Bioequivalence and tolerability of two clopidogrel salt preparations, besylate and bisulfate: A randomized, open-label, crossover study in healthy Korean male subjects. Clin Ther. 2009;31(4):798-803.
Neubauer H, et al. Comparing the antiplatelet effect of clopidogrel hydrogensulfate and clopidogrel besylate: a crossover study. Clin Res Cardiol. 2009 Sep;98(9):533-40.
Gagne JJ, et al. Refilling and switching of antiepileptic drugs and seizure-related events. Clin Pharmacol Ther. 2010 Sep;88(3):347-53.
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Author: Christoph Baumgärtel, MD, Department Head, Department Safety and Efficacy Assessment of Medicinal Products, Institute Marketing Authorisation of Medicinal Products & LCM, AGES PharmMed, Austrian Medicines and Medical Devices Agency, 9 Schnirchgasse, AT-1030 Vienna, Austria
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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.
Clinical studies required for regulatory approval of a biosimilar should include comparative PK and PD studies in healthy volunteers, followed by comparative efficacy and tolerability trials. The guideline states specifically, ‘… the clinical comparability exercise is a stepwise procedure that should begin with PK and PD studies followed by clinical efficacy and safety trial(s) or, in certain cases, PK/PD studies for demonstrating clinical comparability.’ The latter studies are usually performed only in the most sensitive and most relevant target patient population(s). In some cases, PK/PD studies alone might be considered sufficient [15] and in other cases, for example, where it is assumed that the mechanism of action of the drug is only dependent on its interaction with one single binding partner as the target, therapeutic similarity demonstrated in one indication may be extrapolated to other indications of the reference product. Extrapolation, however, remains a matter of debate especially when different indications imply the use of significant different doses [19], or different patient populations, for example, children versus adults, or when extrapolation to use in healthy individuals is concerned, for example, use of filgrastim for stem cell mobilisation and collection in healthy donors.On the other hand, the guidelines put special emphasis on assessment of the clinical tolerability of a biosimilar because of its potential immunogenicity. Indeed, differences in quality attributes between the biosimilar and its reference product cannot always be detected during the quality control process, and their clinical consequences cannot always be predicted from non-clinical animal studies [6]. Hence, clinical trials that extensively evaluate the tolerability and immunogenicity of the biosimilar are indispensable. These assessments require optimal antibody testing, characterisation of the observed immune response, and evaluation of the correlation between antibodies and their effects on PKs, PDs, efficacy and tolerability. It is also important to realise that for one product the risk of immunogenicity may differ depending on the therapeutic indication. In most cases, pre-approval data over at least a six-month period are requested and a post-approval commitment to provide data up to 12 months. Since immunogenicity is a long-term event, gathering of immunogenicity data after marketing authorisation remains an important prerequisite. Consequently, within the authorisation procedure, the company applying for regulatory approval of a biosimilar, as for any newly approved biopharmaceutical, should also provide plans for post-marketing surveillance including a risk management programme.
