This issue of the GaBI Journal uses a number of article formats to cover a range of issues related to generics and biosimilars.
In Letters to the Editor, Dr Carlo Petrini presents and defends the suggestion that the clinical use of biosimilars poses ethical concerns that differ from those of other pharmaceutical products. He even suggests that perhaps the ‘advice’ of an ethics committee should be sought before such products are used. In another Letters to the Editor Dr Kalle Hoppu presents an opposing, practitioner’s view.
In Editorial, Mr Andy Gray challenges and extends some of the points made in the Pharmaceutical Pricing and Reimbursement Information (PPRI) Conference held in Vienna, Austria, and points out that the issues raised extend far beyond the European region; while Dr Sabine Vogler provides comments concerning the review by Dylst et al.
In a Commentary, Dr Christoph Baumgärtel discusses how data from a 2010 study abstract presentation were misleadingly used to suggest that an increased cardiovascular risk would result if patients were switched from an innovator brand lipid lowering ‘statin’ (atorvastatin) to a different but generic statin (simvastatin). In fact the theoretical risks were based not on a brand to generic switch of the same product but rather the switch from an effective dose of atorvastatin to a therapeutically non-equivalent dose of simvastatin. Unfortunately it is unlikely that this will be the last misleading analysis raising concerns about generic or biosimilar products. Another Commentary by Dr Sabine MJM Straus and Dr Thijs J Giezen presents a summary of a presentation these authors gave at the Conference of the Drug Information Association (DIA) in Copenhagen, Denmark, on the challenges, and possible solutions, associated with biosimilar pharmacovigilance programmes. They stress that such programmes will be both informed by data collected for innovator products and useful to evaluate events that are not likely to be uncovered during limited, pre-marketing, double-blind, randomized, and controlled trials.
Original Research by Haustein et al presents some biosimilar savings data. It would be interesting to see how these calculations would change if the price of innovator products decreased in an attempt by innovator sponsors to maintain market share.
The Review Article by Dylst et al presents a detailed description of the design, popularity, and effectiveness of reference price systems used in Europe.
A Perspective by Dr Robin Thorpe and Dr Meenu Wadhwa presents examples of the confusion that can and has resulted from inconsistent biosimilars terminology. The authors provide definitions they believe should be adopted to decrease this confusion. The other Perspective by Mr Luc Besançon discusses the role of health professionals in communicating the risks associated with counterfeit medicines. However, it is not clear how or even whether the use of generic drugs or biosimilars affect this risk or the content of such communications.
A Special Report by Dr Susanne Keitel describes the MEDCRIME Convention designed to deal with the growing, global criminal trade in falsified/counterfeit medical products.
In Guidelines, Mr Keith McDonald and Dr Kowid Ho use a question and answer format to provide readers with an overview of the background of the ICH Q11 guidelines on the development and manufacture of drugs and biologicals and the relevance of these guidelines for biosimilars and generic drugs.
Finally, in a Conference Report, Dr Sabine Vogler and Ms Nina Zimmerman provide a summary of presentations made at the 2011 PPRI Conference. They discuss the effects and unmet potential of generic policies in a number of European countries.
In the Abstracted Scientific Content, our editor summarizes a recently published science manuscript titled ‘Effective pharmaceutical regulation needs alignment with doctors’, Ebbers et al. discuss the role physicians should play in the development of biosimilars guidelines. It is hoped that these will stimulate discussion and perhaps submission of related manuscripts and letters from our readers.
Some of the formats in this issue are new and not all are routine in scientific journals. The editors, editorial staff and I would be interested in feedback from our readers on the usefulness and acceptability of these as well as the articles themselves.
Professor Philip Walson, MD
Editor-in-Chief, GaBI Journal
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Many healthcare professionals remain concerned about the safety and efficacy of biosimilars, and are hence reluctant to prescribe them for patients, despite the publication of guidelines for their approval by European regulatory authorities. This level of distrust may reflect a lack of engagement by the regulatory authorities with the medical community during the development of the guidelines, with the result that their views were not taken into account before publication of the guidelines, according to Hans C Ebbers and co-authors. The authors suggest that the situation can be resolved by doing more to build confidence among physicians and patients in the regulatory process by encouraging representatives of medical associations to contribute more to public consultations. This would ensure guidelines for the approval of biosimilars meet the needs of all stakeholders, and enable more patients to gain access to them.
EMA has developed guidelines for the regulatory approval of ‘generic’ biotechnology derived proteins, or ‘biosimilars’. The first product-specific version of these guidelines has gone through two rounds of public consultation, including for the approval of biosimilar erythropoietins for the treatment of renal anaemia, and serves as a test bed for the development of other specific guidelines.
The issue of safety came sharply into focus in 2002 after adverse effects became apparent in patients receiving an innovator brand of the erythropoietin, epoetin-alfa (Eprex), for the treatment of renal anaemia. Although the drug had been used safely for both intravenous and subcutaneous delivery, a change in formulation led to the development of antibodies against endogenous erythropoietin in around 200 patients who received the drug subcutaneously. This caused a worsening of their anaemia by triggering the condition of pure red cell aplasia. The precise reason for the immunogenicity of the product is still under debate but is thought to have resulted from the replacement of albumin with a synthetic surface active agent (Tween) during its manufacture. While Eprex manufacture has been revised, and the ban on its subcutaneous use lifted, the incident left many prescribers wary about switching to alternative versions of erythropoietin, particularly if they involve a new manufacturing process.
In 2005, EMA released a draft version of regulatory guidelines on specific types of biosimilars, including erythropoietin, for public consultation. Various stakeholders gave feedback, including representatives of regulatory agencies, innovator companies, generics companies, academia, and a patient organisation. But as outlined by Ebbers and co-authors [1], none of the European medical associations took part. EMA’s Committee for Medical Products for Human Use (CHMP) adopted a revised set of the guidelines in 2006, specifying that biosimilars would need to undergo clinical comparability testing, to ensure similar safety (including lack of immunogenicity) and efficacy, compared to the innovator product. Despite the existence of the new guidelines, when biosimilar erythropoietin was approved in 2006, several European medical associations expressed concerns about safety.
In 2008, EMA proposed amendments to the guidelines regarding safety testing, and again received feedback from innovator and generics companies, but not national or European medical associations. Discussions took into account renewed concerns after a new biosimilar version of erythropoietin, HX575, caused two incidences of pure red cell aplasia during clinical testing. EMA adopted the revised guidelines in March 2010 giving further recommendations for safety testing of biosimilar erythropoietin. Key features of the revised guidelines included the type of patients considered to be the most sensitive indicator for study, the number and duration of studies required for comparability testing, and the need to check for immunogenicity.
However, as Ebbers and co-authors state, ‘To date, medical associations have not responded to the revised guideline, but it does not seem likely that it will change the views of physicians who are already concerned.’ The question remains then, how to generate confidence and trust in the biosimilar approval process among physicians? The authors recommend that regulators should do more to involve medical organisations in the consultation process for developing new guidelines. They note that while individual medical experts may be involved in CHMP and scientific advisory groups, ‘the absence of the major European medical associations in the regulatory process is a telltale of a misalignment of the clinical and regulatory communities.’
Ebbers and co-authors highlight other cases in which the medical profession has been more actively involved, as in the drafting of guidelines for biosimilar low molecular weight heparins. It is therefore a matter of broadening the active participation of European medical associations rather than introducing this as an entirely novel concept, and ensuring that participation occurs early, according to the authors. In future, other types of biosimilars such as biosimilar interferon beta and monoclonal antibodies will become available. The authors state, ‘If these products are to succeed on the market, trust in the regulatory system by prescribers and patients is crucial.’
Questions remain as to why the medical profession is more involved in the development of some regulatory guidelines than others, and point to the US where the FDA is involving speakers of patient associations and representatives of medical associations in the development of guidance on biosimilars.
The authors suggest that ‘Establishing a platform to facilitate dialogue with European medical associations on issues of common interest could promote the acceptance of regulation.’ They conclude, ‘When regulators fail to involve doctors in their activities, this will impede the acceptance of the cost-effective and innovative medicinal products of the future.’
Competing interests: None.
Provenance and peer review: Article abstracted based on published scientific or research papers recommended by members of the Editorial Board; internally peer reviewed.
Julie Clayton, PhD, GaBI Journal Editor
References 1. Ebbers HC, Pieters T, Leufkens HG, Schellekens H. Effective pharmaceutical regulation needs alignment with doctors. Drug Discov Today. 2012;17(3-4):
100-3.
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A recent study by IMS Health Austria (IMS) revealed that in Austria healthcare payers could have saved more than a quarter billion Euros during 2011 if physicians would have prescribed more generics to their patients.
The total reimbursed medicines market in Austria totals Euros 1.89 billion. IMS estimates that 89% of the total market by volume is theoretically replaceable by generics. However, of the total more than 7 million counting units (CU : dosages per day) prescribed in 2011 only 38% were replaced by generics (2.7 million CU).
IMS considered that the average price of an originator drug is at least three Euros 3 more expensive than the average generic drug, meaning that an average generic drug CU costs Euros 0.13 whereas an originator with a price of Euros 0.20 per CU is at least 54% more expensive. If every originator in the replaceable segment were switched to a generic drug, the country would reap savings of more than 3.6 million CU that would result in Euros 256 million in savings per year. This value is however only theoretical as it would mean a 100% generics penetration rate in the replaceable segment.
Since in Austria physicians are only advised, but not obliged, to prescribe generics; and pharmacists are also not obliged to substitute an originator by a generic drug as is common practice in other countries, e.g. Germany with its ‘aut-idem’ system, such penetration rates are just wishful thinking. In fact, at the moment Austria is at the lower end regarding generics penetration. According to 2010 data from IMS, generics in Austria had a market share of only 26% of the total retail market, visit the article link below to view the data on generics uptake rates in Europe.
The Austrian Generics Association (Österreichische Generikaverband) and the Austrian Medicines Authority indeed think that it may be possible to increase the generics share up to 60% during the next years. These opinions, along with the size of the potential savings in Austria, have led to huge media and television coverage in Austria. One crucial point however will remain – providing information to and convincing both physicians and patients of the safety and quality of generics.
Christoph Baumgärtel, MD
Member of International Editorial Advisory Board, GaBI Journal
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Abstract:
Comment on the Letters to the Editor by Dr Carlo Petrini: A bioethicist’s view of the use of biosimilars
Submitted: 8 October 2012; Revised: 9 October 2012; Accepted: 9 October 2012; Published online first: 11 October 2012
In the European Union the word ‘biosimilar’ denotes a copy version of an already authorized biological medicinal product with demonstrated similarity in physicochemical characteristics, efficacy and safety, based on a comprehensive comparability exercise [1]. The ‘comprehensive comparability exercise’ is more extensive and complex than what is required for market authorisation of generics to account for the more complex nature of biopharmaceuticals compared to ‘conventional’ small molecule medicinal products. The particular risks that make the more complex regulatory process necessary are mostly related to the manufacturing process used for biologicals. Similar risks are associated with the changes that are not infrequently made to the manufacturing process of originator (reference) biological medicinal products during their life cycle, and when this occurs a regulatory comparability exercise is also required for the originator [1].
There is no evidence that the benefit–risk ratio of biosimilars authorized after successfully passing the regulatory ‘comprehensive comparability exercise’ would be notably different from that of the originator biological during its life cycle. It is also important to note, that the comprehensive comparability exercise requirement is not limited to quality and safety, but also covers efficacy.
The physician prescribing a medicine, and the patient taking it, should be able to trust that during the regulatory approval process, be it for a ‘conventional’ pharmaceutical product or a biological one, the benefit–risk ratio in relation to quality, safety, and efficacy of the product has been properly evaluated and found favourable. In the case of both generics and biosimilars, regulatory approval should be a sign that benefits and risks are similar enough to the originator. With time, new evidence may emerge, that requires re-evaluation of the risks and benefits of a product. This happens for all types of pharmaceutical products, even some very old ones.
For me the possibility that there are unknown clinical safety issues associated with the use of authorised biosimilars is a research question, not an ethical question. The ethical question may then be a research ethics question. Or if put, as the author of the letter suggests [2], that ‘biosimilars, or any other medicinal products, are approved for use to save money for the society, without appropriate knowledge of safety consequently putting individuals at risk’, then the key ethical question concerns the inappropriate regulatory approval, not the product’s safety. If biosimilars are used without appropriate approval, the ethical question is the same as in any other unlicensed/off-label use, use without appropriate knowledge of quality, safety, efficacy. When approved medicinal products are given for the benefit of somebody other than the person receiving the therapeutic benefit, the intervention, e.g. stem-cell donation; has to be ethically acceptable, the safety of any medicinal product to be given has to be based on data and assessed as acceptable compared to its demonstrated efficacy (in relation to the intervention). The ethical questions are not different whether a biosimilar, or an innovator biological product, or a small molecule medicinal product is given.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Narayanan G, et al. Biosimilars-why terminology matters. Nat Biotechnol. 2011;29(8):690-3. Epub 2011 Oct 09. 2. Petrini C. A bioethicist’s view of the use of biosimilars. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):110-1. doi:10.5639/gabij.2012.0103-4.034
Author: Kalle Hoppu, MD, PhD, Medical Director, Poison Information Centre, Helsinki University Central Hospital, PO Box 790, 17 Tukholmankatu, FI-00029 Helsinki, Finland
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Abstract:
In recognition of the many ethically sensitive issues raised by the production and use of biosimilar medicinal products, the author imagines having to answer the non-multiple choice question ‘From the ethical point of view, what is the most important issue raised by biosimilars?’, and endeavours to explain why the proposed answer is ‘safety’.
Submitted: 8 October 2012; Revised: 9 October 2012; Accepted: 9 October 2012; Published online first: 11 October 2012
The objective of this article is to discuss some of the ethical issues that arise when biosimilars are used in clinical practice.
As the Committee for Medicinal Products for Human Use states ‘it should be recognised that, by definition, similar biological medicinal products are not generic medicinal products, since it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers or compared with reference products, which may not be fully apparent until greater experience in their use has been established’ [1]. For this reason the processes of evaluation and authorisation are more complex for biosimilars than for generic drugs and their quality, efficacy and safety need to be very thoroughly weighed [2].
The production and use of biosimilars involve a multitude of issues that range from those such as safety, risk, efficacy and informed consent, that concern individual users, to others that affect society at large, such as the organisation of healthcare services, the allocation of resources, industrial and commercial rights, conflicts of interest. All are ethically relevant.
A careful examination of the doxography of bioethics (from the seventies, when the term was coined [3] to the present) offers evidence of an evolution in the approach to this discipline. A probably early bias towards the principle of beneficence–the legacy of a centuries-old tradition of medical paternalism–was followed in the eighties by the emergence of greater emphasis on the principle of autonomy and its companions, individual freedom and self-determination. Today, at a time when organisation is a priority, the focus has perhaps shifted towards the principle of justice, the deal between providers and users of health care, negotiation. This is obviously a somewhat simplistic analysis, with all the limits that implies, since neither the various problems nor the various bioethical arguments are watertight compartments. The close interconnections are perfectly exemplified by the debate concerning the procedures for authorising the marketing of biosimilars [4, 5]. These procedures involve both ‘collective’ organisational issues (including questions of justice) and ‘individual’ clinical issues (which embrace such aspects as risk–benefit ratios).
Faced with such a varied scenario, a bioethicist might ask: ‘What is the key ethical problem posed by biosimilars?’. There is no absolute answer to this question, as the weight of each problem will vary according to individual cases. At times the clinical aspect may seem the most important, while in different circumstances the legal aspect may appear to prevail. Notwithstanding this, if I were required to answer this question in a non-multiple choice quiz, my personal reply would be: ‘The single most important issue is safety’.
While I believe that many aspects of so-called ‘biolaw’ are of great importance, for me the well-being of the individual must be the priority consideration. Establishing the level of acceptability of a risk is certainly a technical matter, but it is also a social problem. Sadly, scientific data are not always helpful, and it is sometimes extremely difficult to quantify the entity and probability of a given risk.
The whole question of risk acceptability is further compounded when biosimilars are used for the therapeutic benefit of somebody other than the person receiving them, as is the case with granulocyte-colony stimulating factor (G-CSF) for stem cell mobilisation in related and unrelated healthy donors [6]. This procedure raises a number of ethical questions [7]: i) the person being treated with a biosimilar product is not the person for whose therapeutic benefit the treatment is administered; ii) there could be concerns that a biosimilar G-CSF may be associated with greater risks than a brand product; iii) the main reason for using a biosimilar G-CSF is economic (the cost to the healthcare service will be lower than in the case of a brand-name drug).
There is no easy solution to these problems. It is some comfort that the regulatory authorities are generally of the opinion that the efficacy and safety of authorised biosimilars are comparable to those of the reference product [8, 9]. The Italian Medicines Agency (AIFA), in its Concept Paper ‘Biosimilar Drugs’ notes that ‘biosimilar drugs are produced in accordance with the same quantitative standards that apply to other medicines’ and therefore offer ample guarantees of safety [10]. However, long-term data are often not available and, as Dr Witts wrote, back in 1965, ‘the final test of the safety of a drug is in fact its release for general use’ [11].
The problem of risk is complex and there are no universal solutions, which is why we must be especially vigil in at least two areas.
The first is at the level of authorisation by regulatory authorities, in the knowledge that, as stated in a key document published by FDA, ‘We are in the beginning of a new era for drug safety where protecting public health means that [the FDA’s] responsibility doesn’t end when we grant a product market approval; that is merely the first check point in ensuring safety’ [12].
The second level is use. While the Concept Paper published by AIFA notes that ‘the choice of treating with a biological or with a biosimilar drug remains a clinical decision entrusted to the specialist physician’, it might be as well, where appropriate and feasible, for the specialist physician to receive advice from an ethics committee before making a final decision.
For patients
The processes of evaluation and authorisation are more complex for biosimilars than for generic drugs, and the ethical problems they raise are similarly more numerous and more complex. The present article points to safety as being of particular importance from the ethical viewpoint, and suggests that it should receive priority consideration when the admissibility of biosimilars is being assessed.
Competing interests: None.
Provenance and peer review: Commissioned; externally peer-reviewed.
References 1. European Medicines Agency [homepage on the Internet]. Committee for Medicinal Products for Human Use (CHMP). Guideline on similar biological medicinal products. CHMP/437/04.30 October 2005. [cited 2012 Sep 18]. Available from: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf 2. World Health Organization [homepage on the Internet]. Guidelines on evaluation of similar biotherapeutic products (SBPs). Expert Committee on Biological Standardization. Geneva, 19–23 October 2009. [cited 2012 Sep 18]. Available from: www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22 APRIL2010.pdf 3. Potter VR. Bioethics: the science of survival. Perspect Biol Med. 1970;14(1):127-53. 4. Schellekens H, Moors E. Clinical comparability and European biosimilar regulations. Nat Biotechnol. 2010:28(1):28-31. 5. Schneider CK, Borg JJ, Ehmann F, Ekman N, Heinonen E, Ho K, et al. In support of the European Union biosimilar framework. Nat Biotechnol. 2012;30(8):745-8. 6. Shaw BE, Confer DL, Hwang WY, Pamphilon DH, Pulsipher MA. World Marrow Donor Association. Concerns about the use of biosimilar granulocyte colony-stimulating factors for the mobilization of stem cells in normal donors: position of the World Marrow Donor Association. Haematologica. 2011;96(7):942-7. 7. European Group for Blood Marrow Transplantation (EBMT), Niederwieser D. Biosimilar granulocyte-colony stimulating factor (G-CSF) for stem cell mobilization in related and unrelated donors. 2011. [cited 2012 Sep 18]. Available from: www.gitmo.net/Biosimilars_in%20mobilization%20of %20unrelated%20and%20related%20donors.pdf 8. Giezen TJ, Straus SMM. Pharmacovigilance of biosimilars: challenges and possible solutions. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):118-9. doi:10.5639/gabij.2012. 0103-4.033. 9. Giezen TJ, Mantel-Teeuwisse AK, Straus SMJM, Schellekens H, Leufkens HGM, Egberts ACG. Safety-related regulatory actions for biologicals approved in the United States and the European Union. JAMA. 2008;300(16):1887-96. 10. Agenzia Italiana del Farmaco [homepage on the Internet]. I farmaci biosimilari. AIFA concept paper (Draft). 1 August 2012. [cited 2012 Sep 18]. Available from: www.agenziafarmaco.gov.it/sites/default/files/concept_paper_biosimilari_.pdf 11. Witts LJ. Adverse reactions to drugs. Br Med J. 1965;2(5470):1081-6. 12. Food and Drug Administration [homepage on the Internet]. Strategic priorities, 2011-2015. Washington, DC: US Food and Drug Administration. 2011 [cited 2012 Sep 18]. Available from: www.fda.gov/aboutfda/reportsmanualsforms/reports/ucm227527.htm
Author: Carlo Petrini, PhD, Head of the Bioethics Unit, Offi ce of the President, National Institute of Health – Istituto Superiore di Sanità, 34 Via Giano della Bella, IT-00162 Rome, Italy
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Abstract:
Dylst et al. provide a detailed overview about the characteristics of reference price systems in Europe and discuss their possible impact. The role of stakeholders in the implementation of this policy measure requires further attention.
Submitted: 16 September 2012; Revised: 17 September 2012; Accepted: 19 September 2012; Published online first: 21 September 2012
Dylst et al. show that a reference price system is a broadly used policy in European countries: the majority of the EU Member States have implemented such a system [1].
A key sentence by Dylst et al. is: ‘Unlike its name suggests, a reference pricing system is not a pricing system, but in fact a reimbursement system.’ This statement is key and contributes to a better understanding of this policy. The authors correctly define a reference price system as ‘a system that establishes a reimbursement level or reference price for a group of interchangeable medicines’: terminology clarity is important also because reference price systems are sometimes confused with a pricing policy called external price referencing. That policy is a ‘practice of using the price(s) of a medicine in one or several countries in order to derive a benchmark or reference price for the purposes of setting or negotiating the price of the product in a given country’ [2], and it is also very common in European countries [3].
As a reimbursement policy, a reference price system requires a specific design, in particular with regard to the clustering of the reference groups and the definition of the reimbursement limits (reference limits). The article describes the different approaches to organizing the reference price systems in the European countries and their possible consequences. Dylst et al. highlight that different approaches are recommended for different environments: while, in principle, the relationship ‘the lower reference price, the higher savings’ appears logical, there are settings, particularly in developing generics markets, where a higher reference price appears to achieve better results. A general lesson for policymakers can be drawn: when implementing policy measures, the context needs to be taken into consideration, and, though it is important to learn from the experiences of other countries, successful policy measures cannot be simply copied from one country to another but have to be adapted to the country specific environment [4].
Further, good timing and implementation planning is important when this policy measure is introduced or further developed. Regarding generics substitution, World Health Organization strongly recommends introducing this policy as a voluntary measure, i.e. legal framework allowing it; then encouraging it, e.g. via incentives, and in a final stage having mandatory generics substitution [5]. The implementation of a reference price system should follow a similar approach: the clusters should be defined in a more limited way in the beginning [Anatomical Therapeutic Chemical (ATC)-level 5] and can, after experience is gained, be broadened over the course of time (to the ATC-level 4 and even ATC-level 3).
This approach is recommended firstly because it facilitates the technical process for the staff administrating the system and secondly because stakeholders are more likely to accept the reference price system during a phased introduction. The stakeholder aspect was not addressed by Dylst et al. However, bringing stakeholders on board, as early as possible, is a major prerequisite for a successful policy implementation. The implementation of a reference price system, particularly when introduced in connection with generics substitution and/or with prescribing by the international non-proprietary name, may raise concerns to physicians who might be concerned about a loss of their ‘therapeutic freedom’. A good communication policy could facilitate the acceptance by stakeholders of the measures introduced. A study from Greece suggested that doctors would be willing to prescribe more generically if there was a clear generics promotion policy [6]. Having said this, it must be pointed out that the reference price system is a policy which has the potential to increase possible conflicts between prescribers and pharmacists. Nonetheless, good practice examples exist: a successful cooperation between the two groups was reported from Denmark where pharmacists and prescribers stressed the importance of having a clear understanding of their roles in the system which they consider as complementary and not conflicting [7].
Dialogue and information are therefore both of major importance also, and especially, when addressing the concerns of patients. In a study performed to explore prerequisites for successful implementation of a reference price system in Austria [8] (where it has yet not been introduced), case studies highlighted that in some European countries difficulties were encountered after the introduction of a reference price system because rumours about the low quality of generics had been spread and were not responded to appropriately. As a result, patients were confused and concerned.
Dylst et al. also addressed the issue of socio-economic equity concerns related to reference price systems. Though there are few studies on this topic available, evidence could dispel concerns about possible inequity. In fact, patients might even become strong partners in supporting generics policies. They have the purchasing power to ask for generics if incentivized to do so. But they need to understand the policy. Therefore, a policy providing clear information to patients about the function and benefits of a reference price system and about generics in general is required.
Reference price systems have been introduced in several European countries as a reimbursement policy. All of these have a publicly funded health and pharmaceutical system (either social health insurance or national health service). A recently published article on pro-generic drug policies in low- and middle-income countries (LMIC) also described reference pricing systems [9]. Because of the continuing investment into insurance systems in LMIC, reference pricing systems are a policy option that must be explored by these countries. The prerequisites for successful implementation (appropriate design of the system, stakeholder involvement, and an information policy) are the same as in European countries.
For patients
The editorial refers to the article of Dylst et al. whose findings suggest that reference price systems generate savings for healthcare budgets in the short term without a negative impact on the health of patients. This editorial highlights the role of stakeholders, including patients. Patients can become strong partners in supporting reference price systems and other generic drug policies but they need to have a good understanding of the policies. Therefore, a policy providing clear information to patients was stressed as key in the editorial.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. Dylst P, Vulto A, Simoens S. Reference pricing systems in Europe: characteristics and consequences. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):127-31. doi:10.5639/gabij.2012.0103-4.028 2. Folino-Gallo P, Muscolo L, Vogler S, Morak S. PHIS Glossary: Glossary for pharmaceutical policies/systems developed in the Pharmaceutical Health Information System (PHIS) Project. 2009, latest update of print version: 2011; regularly updated online. Vienna: WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies; 2011. 3. Leopold C, Vogler S, Mantel-Teeuwisse AK, de Joncheere K, Leufkens HG, Laing R. Differences in external price referencing in Europe: a descriptive overview. Health Policy. 2012;104(1):50-60. Epub 2011 Oct 19. 4. Vogler S, Habl C, Leopold C, Rosian-Schikuta, et al. PPRI Report. Vienna: Gesundheit Österreich GmbH/Geschäftsbereich ÖBIG; 2008. 5. World Health Organization [homepage on the Internet]. How to develop and implement a national drug policy. 2nd ed. Geneva: World Health Organization; 2001. [cited 2012 Sep 17]. Available from: http://apps.who.int/medicinedocs/en/d/Js2283e/ 6. Tsiantou V, Zavras D, Kousoulakou H, Geitona M, Kyriopoulos J. Generic medicines: Greek physicians’ perceptions and prescribing practices. J Clin Pharm Ther. 2009;34(5):547-54. 7. Leopold C, Habl C, Vogler S, Rosian-Schikuta I. Steuerung des Arzneimittelverbrauchs am Beispiel Dänemark. Gesundheit Österreich GmbH. 2008 Dec. German. 8. Habl C, Vogler S, Leopold C, Schmickl B, Fröschl B. Referenzpreissysteme in Europa. Analyse und Umsetzungsvoraussetzungen für Österreich. ÖBIG Forschungs- und Planungsgesellschaft mbH. 2008 Feb. German. 9. Kaplan WA, Ritz LS, Vitello M, Wirtz VJ. Policies to promote use of generic medicines in low and middle income countries: a review of published literature, 2000–2010. Health Policy. 2012;106(3):211-24.
Author: Sabine Vogler, PhD, Head of WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies, Health Economics Department, Gesundheit Österreich GmbH/Geschäftsbereich ÖBIG – Austrian Health Institute, 6 Stubenring, AT-1010 Vienna, Austria
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Abstract:
A study presented at the 2010 Congress of the European Society of Cardiology, had created a considerable stir. Its abstract allegedly showed that the originator drug Lipitor was more beneficial than any of its generic statin equivalents. But, in fact the study merely showed that the different potencies of statins were not taken adequately into consideration during the generics switch. The conclusions underscore that statin generics do have essentially the same safety and efficacy as Lipitor and may have implications for new atorvastatin generics that have recently entered the market and will increasingly be prescribed in future.
Submitted: 27 July 2012; Revised: 3 September 2012; Accepted: 3 September 2012; Published online first: 5 September 2012
A notable abstract on generics substitution of statins was presented at the 2010 Congress of the European Society of Cardiology [1]. Some of the resulting media coverage was equally interesting, stating, for example, that ‘Patients should stay on Pfizer’s Lipitor, and not switch to generics’ [2]. What the abstract predicted was an increased potential risk for serious cardiovascular events following a switch to generic statins. Despite this interesting finding, the question of whether generic statins should be considered inferior to the atorvastatin brand leader, however, can be answered with a resounding ‘No’.
Nonetheless, what may appear initially to be a paradoxical conclusion makes perfect sense when considering that the study’s aim was not to see if generics act differently to branded products. Instead, the study showed that following a government-mandated switch to generic statins in The Netherlands, doctors–intentionally or unintentionally–prescribed inadequate doses of the generic drug when switching. Notably, the Dutch doctors were not prescribing generics with the identical active pharmaceutical substance, but instead were switching from branded atorvastatin (Sortis/Lipitor) to various generic versions with simvastatin. This switch makes sense considering the high costs of originator atorvastatin and the remarkably lower costs of generic simvastatin. However, the change of active substances means that it was not a true generics switch because another active substance was prescribed. More importantly, the two active substances are not of equal potency: atorvastatin is more potent than the same molar quantity of simvastatin [3]. The dose equivalence therefore is set at a ratio of at least 1:2 to 1:4, as indicated in the product information leaflets.
Nevertheless, not all prescribing physicians are aware of this fact, and as a result, 20 mg atorvastatin is often substituted by just 20 mg simvastatin. An analysis of the Dutch database revealed, that out of 39,031 patients, more than a third (33.7%) received less than an equipotent dose of simvastatin after the switch. These figures were calculated under the assumption of a potency ratio of 1:2. If the authors had used a ratio of 1:4, the numbers would have been even higher. Statistical models suggested that this inadequate dosing would lead to a 5.6% increase in LDL-cholesterol levels. This, together with the findings of a meta-regression study [4] showing that every 25 mg/dL (0.65 mmol/L) reduction in LDL-cholesterol lowers the risk of serious cardiovascular events by 14%, indicates that inadequate simvastatin dosing might increase cardiovascular risk by at least 5.5% [1].
It remains uncertain whether these dose reductions were intentional or not. But an intentional dose reduction is unlikely due to the high numbers of patients involved, which does not reflect everyday clinical practice. Worryingly, our conclusion is that a substantial number of switches in The Netherlands were performed by physicians who were unaware of the different potencies of statins. This occurred after a government-mandated change in policy in which physicians would have to justify their prescriptions of branded statins. The result was an economically beneficial increased switch to generics. At the time of the policy change, however, atorvastatin generics were not yet licensed, and so patients were switched to generic simvastatin instead as the available alternative.
Fortunately, this situation has not occurred in Austria, for example. Here, the guideline for economic prescribing [5] stipulates that in the case of two equally effective treatments the cheaper one should be chosen. To do so, Austrian doctors can access an online ‘Info-tool’ [6] which indicates alternatives to an originator product and their prices. This tool takes the potency difference of statins into account correctly. A search for alternatives to atorvastatin, e.g. to Sortis 20 mg tablets, produces a list of several simvastatin generics, all at an appropriate dosage form of 80 mg tablets, some of them even with a score line. This takes into account dose equivalence in the range of 1:2 to 1:4. The product information leaflets affirm the difference in potency: the indicated dosage of atorvastatin for the prevention of cardiovascular disease is 10 mg per day, while for simvastatin it is 20–40 mg per day.
The Dutch study shows the importance of thoroughly checking product information and using additional info-tools. The erroneous switch to less than equivalent doses of simvastatin, two to four times below the recommended dosage, could have been detected and presumably avoided if the prescribing physicians had consulted these resources properly.
In conclusion, the media coverage that generic statins might be inferior per se, and that switching should be avoided, can be refuted. In support of this, a Korean study [7] examined the efficacy of atorvastatin generics to reduce LDL-cholesterol and total cholesterol compared to its atorvastatin originator. Reduction after eight weeks from baseline for LDL-cholesterol was about 44% for the generics and 46% for the originator, showing no significant difference. Corresponding values for total cholesterol were about 30% and 31%, respectively, and not significantly different. In addition, a Slovenian trial [8] similarly revealed that generic atorvastatin leads to an equal reduction in LDL-cholesterol compared to the originator after 12 weeks (37.8% vs 38.4%, p = ns). Both drugs reduced the absolute coronary risk by 13% and 13.3% for the generic and reference atorvastatin, respectively.
These findings are important as a number of atorvastatin generics have recently entered the market that will increasingly be prescribed in future, as was already seen with other drug substances [9, 10], giving assurance to physicians that atorvastatin generics are equally as safe and effective as the originator. Physicians who choose to switch from atorvastatin to simvastatin may do so, but must consider the different potency of these two statins and take care to prescribe the correctly adjusted dose.
For patients
A misunderstood study about the statin drug Lipitor and its generic alternatives caused a media storm, with the notion that generics were inferior. A closer examination, however, reveals that physicians had mistakenly prescribed inadequate doses of the generic drug alternatives, putting patients at higher risk of cardiovascular disease.
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
References 1. Liew D, et al. The cardiovascular consequences of switching from atorvastatin to generic simvastatin in the Netherlands. Abstract n° 3562. ESC; 2010 Aug 28–Sep 1; Stockholm, Sweden. 2. Bloomberg News, 2010-08-20 [homepage on the Internet]. Patients should stay on Pfizer’s Lipitor, not switch to generic, study say. [cited 2012 Sep 3]. Available from: www.bloomberg.com/news/2010-08-20/cholesterol-drug-study-shows-heart-risks-in-switch-to-generic-from-lipitor.html 3. Rogers, et al. A dose-specific meta-analysis of lipid changes in randomized controlled trials of atorvastatin and simvastatins. Clin Ther. 2007 Feb; 29(2):242-52. 4. Delahoy PJ, et al. The relationship between reduction in low-density lipoprotein cholesterol by statins and reduction in risk of cardiovascular outcomes: an updated meta-analysis, Clin Ther. 2009 Feb;31(2):236-44. 5. Hauptverband der österreichischen Sozialversicherungsträger [homepage on the Internet]. [Austrian instructions on economic prescribing of medicines (RÖV)]. [cited 2012 Sep 3] German. Available from: www.hauptverband.at/portal27/portal/hvbportal/channel_content/cmsWindow?action=2&p_menuid=58307&p_tabid=4 6. Hauptverband der österreichischen Sozialversicherungsträger [homepage on the Internet]. [Infotool to the Austrian Reimbursement-Code]. [cited 2012 Sep 3] German. Available from: www.hauptverband.at/portal27/portal/hvbportal/emed/ 7. Kim SH, et al. Efficacy and tolerability of a generic and a branded formulation of atorvastatin 20 mg/d in hypercholesterolemic Korean adults at high risk for cardiovascular disease: a multicenter, prospective, randomized, double-blind, double-dummy clinical trial. Clin Ther. 2010 Oct;32(11):1896-905. 8. Boh M, et al. Therapeutic equivalence of the generic and the reference atorvastatin in patients with increased coronary risk. Int Angiol. 2011 Aug;30(4):366-74. 9. Baumgartel C, Godman B, Malmstrom R, et al. What lessons can be learned from the launch of generic clopidogrel? Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):58-68. doi:10.5639/gabij.2012.0102.016 10. Baumgartel C. Generic clopidogrel–the medicines agency’s perspective. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(2):89-91. doi:10.5639/gabij.2012.0102.019
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, and Austrian Federal Office for Safety in Health Care, European Expert in Pharmacokinetics Working Party and Safety Working Party of EMA, Member of Austrian Prescription Commission, 5 Traisengasse, AT-1200 Vienna, Austria
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.
Abstract:
Vogler and Zimmerman, reporting on the 2011 Pharmaceutical Pricing and Reimbursement Information (PPRI) Conference, have noted the incomplete application of generics policies in many settings, and have called for more consistent policies. While many of the basic building blocks of such policies are well described, some elements required renewed attention.
Submitted: 23 July 2012; Revised: 1 August 2012; Accepted: 1 August 2012; Published online first: 2 August 2012
In this issue of the GaBI Journal, Vogler and Zimmerman report on the Pharmaceutical Pricing and Reimbursement Information (PPRI) Conference held in Vienna, Austria, in September 2011 [1]. They have identified issues relating to generic medicines policies as having emerged as a recurring topic throughout that conference, despite not being defined beforehand as an explicit strand of the event. The critical lesson they have extracted, predominantly (but not exclusively) from evidence generated in Europe, is that generics policies have not yet been implemented to their full extent. The conference called for ‘more consistent generics policies’.
The basic building blocks of such a policy have been outlined for more than a decade in the World Health Organization’s (WHO) guideline ‘How to develop and implement a national drug policy’ 2001 [2]. The WHO document emphasised four key elements: supportive legislation; quality assurance capacity; acceptance by prescribers and the public; and economic incentives. It also noted that most countries would go through four possible stages of policy and implementation: generics substitution not allowed; generics substitution allowed; generics substitution encouraged; generics substitution obligatory. WHO warned against attempting to ‘jump from the first phase into a system of obligatory generics prescribing’. Vogler and Zimmermann’s report highlights some important examples of where poorly planned policies have failed. These include policies that fix the price difference between originator and generic products, poorly-designed reference pricing systems that entrench higher than necessary prices, and obligatory generics prescribing in the absence of other elements (notably demand-side measures).
An element that perhaps did not receive sufficient attention was that of ensuring public and professional confidence in the quality of generic products approved by national or regional medicines regulatory authorities. This may not be as much of a challenge in Europe as it is in developing and transitional countries in other regions. However, in far too many countries, it is precisely the lack of transparency about medicines registration processes that feeds both corruption and a lack of confidence in the decisions made [3]. Far too few countries provide public access to an electronic medicines register that discloses the basis for generics registration including, where appropriate, the identity of the reference product used in bioequivalence testing. This is a crucial element of a comprehensive and consistent generics policy.
There are also important issues to consider in relation to intellectual property law, such as avoiding unnecessary linkages between patent and medicines registration processes and limiting data protection provisions that may delay generics entry.
Appropriate medicines pricing policies are key to enhancing generics uptake. Examples cited by WHO included making comparative medicines price information available, reimbursement policies in insurance schemes, favourable margins for generic medicines, and tax incentives for the generics industry. The issue of reimbursement policies is of increasing importance as more countries, particularly in the developing world, attempt to introduce universal health coverage (UHC). UHC has been defined as ‘ensuring that all people have access to needed promotive, preventive, curative and rehabilitative health services, of sufficient quality to be effective, while also ensuring that the use of these services does not expose the user to financial hardship’ [4]. Such policies imply a major shift in the procurement and reimbursement policies generally followed in such countries. This challenge was recognised by the WHO-hosted Alliance for Health Policy and Systems Research, which issued a call for research proposals in May 2012, directed specifically at generating and increasing the use of policy-relevant evidence in low- and middle-income countries [5]. Specifically, the Alliance identified three research questions:
In risk protection schemes, which innovations and policies improve equitable access to and appropriate use of quality medicines, sustainability of the scheme, and financial impact on beneficiaries?
How do policies and other interventions into private markets impact on access to and appropriate use of quality medicines?
How can stakeholders use information and data routinely collected and available in the system in a transparent way towards improving access to and use of quality medicines?
Fundamentally, these three questions echo the concerns expressed by Vogler and Zimmermann in relation to generics policies, but also emphasise their global relevance. Generic policies will be critical in ensuring access to affordable medicines in all settings, but poorly designed and implemented policies can hamper progress towards achieving universal health coverage.
Disclosure of financial and competing interests: In 2009, author attended continuing education events as guest speaker, to the extent of costs of travel and accommodation, use of hire care, honorarium, from Fresenius Kabi. The author has full control of the content in the manuscript.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. Vogler S, Zimmermann N. The potential of generics policies: more room for exploitation–PPRI Conference Report. Generics and Biosimilars Initiative Journal (GaBI Journal). 2012;1(3-4):146-9. doi:10.5639/gabij.2012.0103-4.030 2. World Health Organization [homepage on the Internet]. How to develop and implement a national drug policy. 2nd ed. Geneva: World Health Organization; 2001. [cited 2012 Aug 1]. Available from: http://apps.who.int/medicinedocs/en/d/Js2283e/ 3. Kohler JC, Baghdadi-Sabeti G. Good governance for the pharmaceutical sector. In: The world medicines situation 2011. 3rd ed. (WHO/EMP/MIE/2011.2.5). Geneva: World Health Organization; 2011. 4. World Health Organization [homepage on the Internet]. What is universal coverage? [cited 2012 Aug 1]. Available from: http://www.who.int/entity/health_financing/universal_coverage_definition/en/index.html 5. World Health Organization [homepage on the Internet]. Alliance for health policy and systems research. Call for expressions of interest: health policy and systems research in the field of access to medicines in low- and middle-income countries. 7 May 2012 [cited 2012 Aug 1]. Available from: http://www.who.int/alliance-hpsr/alliancehpsr_atmcall_for_eoi.pdf
Author: Andy Gray MSc (Pharm), FPS, Senior Lecturer, Division of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences; Consultant Pharmacist, Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Private Bag 7 Congella 4013, South Africa
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.
Abstract:
Communication is a key component in the fight against counterfeit medicines affecting the lives of patients. Two types of risk communication should be distinguished: pro-active and reactive. Reactive communication can be facilitated by appropriate pro-active communication strategies, and healthcare professionals can be powerful allies in communication activities targeting patients.
Submitted: 27 July 2012; Revised: 30 July 2012; Accepted: 30 July 2012; Published online first: 1 August 2012
Over the last few decades, an increasing number of counterfeit copies of both branded and generic products have been detected in developed and developing countries.
A coordinated approach that combines legal, technical and enforcement tools, as well as effective communication is needed to counteract the dangers of counterfeit medicines.
The focus of this article is on the role of communication about counterfeit medicines to and from healthcare professionals. A communication programme requires effective transmission of a message from someone through a conveyor of the message to someone else in a defined environment.
With respect to counterfeit medicines such a communication system must involve drug regulatory authorities, the distribution chain (industry, wholesalers, pharmacies…), healthcare professionals, the Media, and patients as well as International partners.
The communication interactions between these groups can be summarized in Figure 1.
Arrows represent the flow of communication (in some cases, it is a two-way communication, while in others, it is primarily a one-way process). Moreover, some communication channels are weaker than others and are therefore represented by hashed arrows.
Communication concerning counterfeit medicines requires an understanding of the current risks of counterfeit medicines that is based on actual data. Design of a communication programme must include consideration of the environment in which the communication will take place (including previous cases of counterfeit medicines).
Once the environment is properly analysed, objectives of the communication programme should be defined based on a risk assessment analysis. This will naturally lead to the selection of a few target audiences. A good understanding of these targets should be built into the programme design. This requires consideration of their characteristics including culture, literacy, habits. etc. This understanding will help to determine the key messages and appropriate communication methods (including conveyors of the message) to be used.
As defined by the Council of Europe [1], two main types of communication activities should be distinguished: pro-active risk communication and reactive risk communication.
Pro-active risk communication
Pro-active risk communication primarily aims to inform individuals (patients, healthcare professionals…) about the risks of counterfeit medicines. It is not based on any particular case involving a particular country.
Communication to healthcare professionals When a communication programme targets healthcare professionals, it is usually designed to empower them to help prevent the introduction of counterfeit medicines into the supply chain. However, such programmes are also designed to prepare them to play a role in future health promotion campaigns involving a specific product as well as to be effectively involved in detection of suspicious cases and to react appropriately when suspicious cases are detected.
Since 2010, WHPA—which brings together the global organizations representing dentists (FDI), nurses (ICN), medical doctors (WMA), pharmacists (FIP), and physiotherapists (WCPT)—has been engaged in activities designed to support healthcare professional associations in organizing such communication programmes. These have targeted healthcare professionals through model campaigns (with examples of posters, postcards, guidance, etc.), regional workshops, and through personalized support of their professional group activities. Similarly, in 2009 the FIP developed a framework for establishing national guidelines to assist pharmacists in combating counterfeit medicines. This document was designed to facilitate the development of national guidelines, by providing a model for a structured approach.
WHPA: World Health Professions Alliance
FDI: World Dental Federation
ICN: International Council of Nurses
WMA: World Medical Association
FIP*: International Pharmaceutical Federation
WCPT: World Confederation for Physical Therapy
*The International Pharmaceutical Federation (FIP) is the global federation of 127 national associations of pharmacists and pharmaceutical scientists that was established in 1912. It is one of the founding members of the World Health Professions Alliance (WHPA). FIP coordinates WHPA activities involving counterfeit medicines.
At a national level, many healthcare professional organizations have developed specific activities, such as training programmes and documents as well as guidelines, e.g. in France, Lebanon or UK. These activities are based on a strong collaboration between healthcare professional associations and drug regulatory authorities and stress two points: providing information about the current situation with respect to counterfeit medicines (including how to prevent their introduction into the supply chain) and providing procedures describing what to do if a healthcare professional has a suspicion that a product might be counterfeit.
Communication to patients There are some especially important aspects of communication campaigns that must be considered when developing programmes that target patients (or certain groups of patients).
First, the target audience must be carefully defined and completely understood. Second, simple messages are usually preferable and the medium used to convey messages should be matched with the target audience. Last, but not least, an evaluation process should be put in place, in order to assess the impact of the communication activity and the results used to improve future communication campaigns.
Many successful campaigns targeting the public have been developed by pharmacists’ organizations throughout the world. Examples include:
In 2009, Federal Union of German Associations of Pharmacists (ABDA) organized a communication campaign targeting youngsters to stress the risks associated with buying medicines over the Internet. Postcards were disseminated in bars and restaurants in 48 German cities and a video was broadcasted over the Internet and in cinemas and theatres (www.youtube.com/watch?v=kJVoIUrpsHk).
In 2010, the Austrian Chamber of Pharmacists together with the Ministry of Finances organized a communication campaign stressing how counterfeit medicines are manufactured and shipped. A website (www.auf-der-sicheren-seite.at) was developed and a video was promoted through social media, e.g. Facebook. Leaflets and brochures were also distributed in community pharmacies.
In 2008 and then again in 2011, the Swiss Association of Pharmacists ( pharmaSuisse) partnered with governmental agencies and the private sector on a project involving 520 community pharmacies. A communication campaign on the dangers of buying medicines over the Internet also included free testing by pharmacies of medicines bought over the Internet during a ‘Stop Piracy Day’. This programme’s aim was to increase detection of counterfeit medicines.
In 2008, the Pharmaceutical Society in Lebanon (Ordre des Pharmaciens du Liban) organized a broad communication campaign using several media, e.g. TV advertisements, billboards, leaflets, etc.; to stress that counterfeit medicines kill and that the individuals behind such operations are criminals.
Finally, in 2009 in the UK, a campaign was conducted by a partnership involving Pfizer, the Royal Pharmaceutical Society of Great Britain, the Medicines and Healthcare products Regulatory Agency (MHRA) and other partners. This campaign consisted of posters displayed in over 3,000 UK cities, advertisements in newspapers, exhibitions in eight major cities, and a dedicated website: www.realdanger.co.uk
For more information on these campaigns and access to the related videos, visit www.fip.org/menu_counterfeitmedicines_publications
Reactive risk communication
Despite all efforts to prevent this, it is still possible for counterfeit medicines to appear within or outside the distribution chain.
When this happens, a reactive risk communication approach is needed. This requires two-way communication.
Bottom-up communication: detection of signals It is crucial for healthcare professionals, regulatory authorities, and any other stakeholder to make sure that their reactive system of communication allows for the detection and reporting of signals that suggest counterfeit medicines.
Possible causes of reporting might be a patient complaining (or mentioning) a difference in taste, physical characteristics or effectiveness of their medicines.
Similarly, healthcare professionals may notice differences in packaging or unexpected patient responses.
Most signals are not strong and therefore it is crucial that all stakeholders remain alert to possible signals and that healthcare professionals listen to patient concerns, and relay any suspicions to relevant authorities, e.g. pharmacovigilance department of industry, drug regulatory authorities, etc.
Top-down communication of suspicious medicines When a counterfeit medicine is discovered, the authorities and the industry often institute a batch withdrawal. Such withdrawal is then communicated to regulatory bodies, the public, and healthcare professionals.
The information received by healthcare professionals should not only include technical information on the medication, e.g. how to detect it, what to do with the medication, etc.; but also key messages that should be relayed to patients and the public.
Such information can be relayed through professional communication channels. For instance, in France, through the shared patient file (dossier pharmaceutique), pharmacies are inter-connected. When an alert is issued, it is sent to all pharmacies within a very short time.
With such methods, the time needed for pharmacists to receive notification of batch withdrawals is limited and they can properly answer patients’ concerns quite quickly.
Conclusion
Communication plays a major role in the fight against the global threat of counterfeit medicines. Communication programmes educate and empower both healthcare professionals and patients.
Because they are trusted by and available to their patients, healthcare professionals can play a facilitating role in well designed counterfeit medicines communication programmes, as they add their credibility to the message and enable the messages to be delivered rapidly at minimal cost.
Key messages on risk communication on counterfeit medicines
Objectives (including targets) clearly identified
Channel(s) used in line with the target audience
Evaluation is essential to:
determine if objectives are met
improve future communication activities through the lessons learnt
For more information: www.fip.org/counterfeit_medicines
www.whpa.org/counterfeit_campaign.htm
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
References 1. Di Giorgio D, editors. Counterfeit medical products and similar crimes – Risk communication. Rome and Strasbourg: AIFA, Council of Europe, EDQM; 2011.
Author: Luc Besançon, Manager Professional and Scientific Affairs, International Pharmaceutical Federation, 5 Andries Bickerweg, PO Box 84200, NL-2508 AE The Hague, The Netherlands
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.
Abstract:
The International Conference on Harmonisation (ICH) has endorsed a new guideline concerning the development and manufacture of chemical and biotechnological/biological drug substances. The guideline harmonises the scientific and technical principles relating to the development and description of the drug substance manufacturing process to be included within the Common Technical Document (CTD) and submitted to regulatory authorities in the European Union (EU), Japan and USA. This question and answer is intended to provide the reader with a flavour of the background to the guideline and its relevance for biosimilar and generic drug substances.
Submitted: 7 July 2012; Revised: 26 July 2012; Accepted: 27 July 2012; Published online first: 1 August 2012
The need for an International Conference on Harmonisation (ICH) guideline on the development and manufacture of drug substances was endorsed by the ICH Steering Committee in October 2007. This recognised the absence of harmonised guidance for industry and regulatory authorities in this area and the need to consider how principles and concepts described in ICH guidelines Q8 (Pharmaceutical Development), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System) apply to the development of drug substance manufacturing processes.
The ICH Q11 guideline was drafted by an expert working group comprising representatives from regulatory authorities and the pharmaceutical industry in the European Union (EU), Japan and USA. Observers actively contributed to the discussions and included regulators from Canada, China, Singapore and Switzerland, the World Health Organization along with international groups representing biotechnology, generic and self-medication industry sectors.
The ICH Q11 guideline was endorsed by the Steering Committee on 1 May 2012 and was adopted in the EU by the Committee on Human Medicinal Products in May 2012.
This question and answer is intended for those with interest in the development and manufacture of drug substances, those involved in regulatory submissions for marketing authorisations in the EU and quality assessors in competent authorities. It is intended by way of introduction to the guideline. It assumes a general awareness of ICH quality guidelines. Readers should refer to the full text version and other ICH guidelines referred to in this article and available on the ICH website at www.ich.org/products/guidelines/quality/article/quality-guidelines.html
The authors of this article were members of the Q11 expert working group. Direct quotations from the guideline are the agreed position of the expert working group. Any other views or opinions expressed in this article are those of the authors and should not be attributed to the authors’ employers.
What is the purpose of ICH Q11?
The purpose of the guideline is to harmonise the scientific and technical principles relevant to the development and manufacture of drug substances and to provide guidance on the information to be included within the Common Technical Document (CTD) in support of marketing authorisation submissions. The guideline is intended to facilitate the submission of similar information in regulatory submissions within the ICH signatory regions (EU, Japan and USA) and may be helpful to pharmaceutical companies and regulators in other regions.
What is the scope of the guideline?
The guideline is applicable to new chemical drug substances and biotechnological/biological drug substances, as described in ICH Q6A and Q6B, respectively.
It provides guidance on information to be submitted in sections S2.2–S2.6 of the CTD. The guideline will be applicable to biosimilar molecules falling within the scope of Q6B. Although generic chemical substances were not included in the scope of the guideline, the principle of design of robust manufacturing processes through effective development and control, using the approaches described in the guideline, is also relevant for manufacturers of generic chemical substances.
Q11 is not intended as a guide to what to submit in applications during the clinical development of investigational medicinal products but the principles described may be taken into consideration during this time in order to provide information for inclusion in any later marketing authorisation submission.
Q11 does not provide guidance on how to comply with requirements for good manufacturing practice (GMP).
How does Q11 provide guidance for both biotechnological/biological and chemical drug substances?
The approaches to development of manufacturing processes are similar for both biotechnological/biological and chemical substances in respect of the need to define a robust commercial manufacturing process that consistently provides drug substance of defined quality. Both chemical and biotechnological/biological manufacturing processes are required to consistently produce high purity and potent molecular entities with processes designed to minimise and/or remove impurities. However, the limitations in analytical characterisation for biotechnological/biological substances necessitate a control strategy with greater emphasis on process controls as compared to chemical substances.
Q11 provides common principles for both chemical and biotechnological/biological substances but also provides specific guidance, for example, on drug substance starting materials for new chemical substances and what to submit for process validation studies for biotechnological/biological substances.
Does the guideline introduce additional regulatory expectations?
The guideline does not introduce new regulatory expectations. Different approaches may be taken to the development of a manufacturing process for a new drug substance. The ‘traditional’ approach continues to be acceptable. More systematic approaches to development along with quality risk management tools can provide greater understanding of sources of variability in the manufacturing process and flexibility in the application of the controls. Both ‘traditional’ and ‘enhanced’ approaches to development of the manufacturing process are acceptable and a combination of both approaches can also be used in process development.
Does ICH Q11 replace other ICH guidance on drug substances?
Generally applicable guidance concerning process development is given in ICH Q8, Q9 and Q10. ICH Q11 supplements existing ICH guidance and clarifies the application of concepts described in ICH Q8, Q9 and Q10, as relevant to drug substances. It supports approaches to process development in order to better understand and control sources of variability in the drug substance.
Does the concept of ‘design space’ as described in ICH Q8 apply to drug substances?
The definition of design space given in ICH Q8 is applicable for both chemical and biotechnological/biological drug substances. Movement within an approved design space would not require prior regulatory approval.
How should movement within a ‘design space’ be handled for biotech products?
The development and approval of a design space for some biotechnological/biological drug substances can be challenging due to factors including process variability and drug substance complexity, e.g. post-translational modifications. These factors can affect residual risk, e.g. potential for unexpected changes to CQAs (critical quality attributes) based on uncertainties related to scale sensitivity, which remains after approval of the ‘design space’. Depending on the level of residual risk, it may be appropriate for an applicant to provide proposals on how movements within a ‘design space’ will be managed post approval.
These proposals should indicate how process knowledge, control strategy and characterisation methods can be deployed to assess drug substance quality following movement within the approved ‘design space’. This could include proposals for ‘design space’ verification, as well as a risk-based approach to define stratified actions, e.g. routine testing only, addition of characterisation tests.
What guidance is included in ICH Q11 in respect of selection of the starting material for a chemical drug substance?
Harmonisation was reached on the high level considerations for designation of the starting material for a chemical synthesis manufacturing process and on the information to be submitted in the dossier. It is anticipated that multiple chemical transformation steps from precursor structural fragments will be included in the dossier. Steps that require control due to introduction or removal of impurities in the drug substance should be considered in the designation of the starting material for the drug substance. The design of a suitable control strategy and its execution within GMP provide the basis for consistent quality of the drug substance.
Does the definition of CQA stated in ICH Q8 apply to the drug substance?
The definition of CQA as described in ICH Q8 is relevant for both chemical and biotechnological/biological drug substance. A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.
Does Q11 recommend that all drug substance CQA are included in the drug substance specification?
The drug substance specification is only one part of a total control strategy and not all CQAs need to be included in the drug substance specification.
The control strategy should ensure that each drug substance CQA is within the appropriate range, limit, or distribution to assure drug substance quality. Different approaches can be envisaged to the management of specific CQAs, dependent on the knowledge of the relationship between process parameters and the particular CQA. This can include inclusion of a control for that CQA in the drug substance specification with compliance confirmed by testing each batch produced. Alternative approaches may include confirmation of compliance of a CQA using process controls applied upstream from the final drug substance with a control included for the CQA in the drug substance specification that is not tested on every batch. A further situation can be envisaged when a given CQA is controlled by the operating parameters of the process and ensured by process controls without including a control in the drug substance specification.
Can platform manufacturing data be used for biotechnologically-derived substances?
Significant experience gained through the use of a production strategy similar to those used by the same applicant to manufacture other drugs of the same type, i.e. platform manufacturing, is acknowledged in ICH Q11. Where appropriate, such prior knowledge can be used to leverage some development data and support evaluation/validation studies.
Does Q11 provide guidance on the number of batches required in drug substance process validation studies?
There is no ‘magic number’. The number of batches should comply with relevant guidances, e.g. ICH Q7, and can depend on several factors including but not limited to: (1) the complexity of the process being validated; (2) the level of process variability; and (3) the amount of experimental data and/or process knowledge available on the specific process.
To what extent are data generated with small-scale batches relevant to the validation of the commercial process for biotechnologically-derived substances?
The contribution of data from small-scale studies to the overall validation package will depend upon demonstration that the small-scale model is an appropriate representation of the proposed commercial scale. Data should be provided demonstrating that the model is scalable and representative of the proposed commercial process. Successful demonstration of the suitability of the small-scale model can enable manufacturers to propose process validation with reduced dependence on testing of commercial-scale batches.
Does Q11 provide guidance on changing the manufacturing process after approval of a marketing authorisation?
As indicated above, the concept of design space is applicable to drug substances. Following approval, changes within the defined ‘design space’ do not require regulatory approval.
Q11 also recognises that protocols for managing specific changes to the drug substance manufacturing process and intended to be implemented after approval, may be included for agreement with the regulatory authority during the assessment of the marketing authorisation application.
European legislative requirements for post-approval changes to marketing authorisations are applicable.
Further information on the regulation and detailed classification guidance are available on the European Commission website at ec.europa.eu/health/better-regulation-variations-regulations-developments_en.htm
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
Co-author
Kowid Ho, PhD, Unité des produits biologiques et issus des biotechnologies, Agence nationale de sécurité du médicament et des produits de santé, 143–147 Bvd Anatole France, FR-93285 Saint-Denis Cedex, France
Author for correspondence: Keith McDonald, MSc, MRPharmS, Group Manager, Licensing Division, Medicines and Healthcare products Regulatory Agency, 151 Buckingham Palace Road, SW1W 9SZ, London, UK
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: Robin Thorpe, PhD, FRCPath; Meenu Wadhwa, PhD
Abstract:
Biosimilars are firmly established in the EU as copy biologicals with a clear and effective regulatory route for approval. Unfortunately, inconsistency in nomenclature for biosimilars has caused confusion. This problem of terminology has been the subject of a recent publication. The confusion is not just a potential concern for patient safety and efficacy, but also can lead to misconceptions in published reports. Several examples of this have occurred, some of which are discussed below. The definitions provided should be adopted for clarity in the future.
Submitted: 26 June 2012; Revised: 2 July 2012; Accepted: 3 July 2012; Published online first: 3 July 2012
Biosimilars are now firmly established in the EU as copy biologicals with a clear and effective regulatory route for approval, which allows marketing of safe and efficacious biological products.
The comparability studies required for comparing the innovator (reference) product and the potential biosimilar product are crucial for the regulatory process and guarantee the quality and clinical performance of the biosimilar. Clear guidelines have been produced by the Committee for Medicinal Products for Human Use and its working parties, describing the desired criteria including quality, non-clinical and clinical studies needed for biosimilars and requirements for their regulatory approval in the EU [1–5, 20]. The comparability of quality aspects required is significant and some data from such studies have been partially published [6, 7]. To date, 14 marketing authorisations have been approved for biosimilars in the EU and many more are in the pipeline.
Outside the EU, several countries have adopted an identical or similar regulatory approach to the EU for approval of biosimilars, e.g. Australia, Canada, Japan. In addition, the World Health Organization (WHO), with the aim of achieving harmony in regulations and increasing access to safe medicines globally has produced a guideline [8] for evaluation of ‘similar biotherapeutic products’ (effectively biosimilars) which proposes a very similar approach to that described in the EU guidelines [1–3].
Unfortunately, inconsistency in nomenclature used for biosimilars has led to confusion in referring to some products. Thus the terms ‘follow-on biologic’, ‘subsequent entry biologic’, ‘similar biotherapeutic product’, ‘similar biological medicinal product’, ‘biogeneric’, ‘me-too biologic’, ‘non-innovator biologic’ have all been used to describe biosimilars. An even greater problem is that all of these terms have in some cases been used to refer to products which are not biosimilars according to the EU/WHO definitions and have not been evaluated using the comparability approach which is essential if the guidelines are followed. This problem of terminology and its implications has been the subject of a recent publication by Weise et al. [9], and this paper also recommends the use of more precise terminology for biosimilars (and non-biosimilars) to attempt to clarify the confusing situation.
The confusion over terminology is not just a potential concern for patient safety and efficacy, but also can lead to misconceptions which arise from misleading published reports on apparent problems with ‘biosimilars’. Several examples of this have already occurred, some of which are discussed below.
A case of pure red cell aplasia (PRCA) in an end-stage renal disease patient associated with induction of antibodies to administered erythropoietin (EPO) was described in India [10]. The patient had received the EPO product Wepox (Wockhardt Limited, India) which is referred to as a ‘follow-on’ product. In the paper the authors state that ‘in Europe, follow-on EPOs are also referred to as biosimilar EPOs’. However, there is no evidence that this product has been approved using the comparability approach required in the EU for biosimilarity and described in the WHO and other guidelines. This is in fact unlikely as the Indian regulatory process at that time did not include biosimilars (or follow-on products) and approved non-innovator products based on a stand-alone system [11]. Thus the product Wepox which is not a biosimilar and should not be described as such as this clearly misleads the reader by using incorrect terminology.
In some cases, the type of product referred to in studies is unclear. An example of this is a report [12], describing two cases of antibody mediated PRCA in South Korea which developed following treatment with a locally produced EPO (Epokine, CJ Corp, Korea) or a mixture of three such products and an innovator product. The procedure adopted for approval of the locally produced EPOs is not reported, but is unlikely to be via the biosimilar route as the Korean biosimilar guideline was produced only recently. The Korean regulatory process however includes both comparative (biosimilar) and non-comparative procedures, and use of correct terminology in publications would avoid ambiguity and misunderstanding.
Another serious example of misuse of terminology in a publication appeared with the alarming title ‘Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies’ [13].This paper describes loss of response to EPO in a number of patients being treated with what are called biosimilar EPOs in Thailand. These products were produced in Argentina, China, India and South Korea, and 14 different such products were approved for use in Thailand. Laboratory evaluation showed 23 of these patients to be EPO antibody positive, all of whom progressed to PRCA. However, none of these products were really biosimilars as all were approved using the process employed for chemical generics, i.e. no comparison with originator product was conducted. The editor of the journal in which this report appeared seems to have noted a potential problem with terminology for biosimilars as an editor’s note appears in the paper providing an explanation of the term. Unfortunately, this simply states that the term ‘biosimilar’ is applied to subsequent versions of products that have been approved in a given country, and not that the approval process should involve a comparative assessment of the ‘biosimilar’ with the innovator product. This report is particularly misleading as the implication is that biosimilar EPOs are more likely to cause antibody induction and PRCA than innovator products which is not shown in the study as none of the products used were biosimilars in the sense of correct terminology.
It is particularly important that correct terminology for biosimilars is used in reviews highlighting their potential importance. However, this is often not done. For example, in a recent review of the current development of ‘biosimilars’ in India [14], a number of products produced and sometimes approved in India, including filgrastim, epoetins, interferons and a monoclonal antibody are listed as biosimilars even though the limitations described for the above mentioned Indian Wepox/PRCA case also apply to these products. Again, this is a clear misuse of terminology.
Granulocyte colony-stimulating factor (G-CSF) has been widely used clinically and several biosimilar G-CSF products have been approved for marketing. There has been considerable discussion of the pros and cons of biosimilar G-CSFs in the literature. However, in many cases, it is not clear whether products referred to as biosimilars are really biosimilars. For example, in a review of the use of G-CSF for mobilization of stem cells [15], an Argentinean product (Neutromax) is described as a biosimilar although it has not been approved using the biosimilar procedure [16]. This is particularly confusing as the review also discusses ‘real’ biosimilars approved in the EU using the correct regulatory system. This confusion could be easily avoided by only using the term ‘biosimilar’ for products approved using the correct procedure and referring to other subsequent entry products as ‘non-innovator products’.
A glaring example of misleading terminology is evident in a recent publication [17], from Iran describing a comparative study in multiple sclerosis patients receiving Avonex (an innovator beta interferon (IFN) product) and Cinnovex (a locally produced non-innovator beta IFN product). Both products are referred to as ‘biosimilar forms’ of beta IFN and the title refers to ‘biogeneric/biosimilar IFN beta-1a’. Cinnovex is clearly designated a biosimilar in the report, but no reference is made in the text to what the term ‘biogeneric’ as used in the title means. No mention of any comparative quality evaluation between Cinnovex and an originator product is provided and so it is unlikely that it is a true biosimilar.
The above are only a few of many similar examples in the literature. The current situation is very misleading and alarming for healthcare professionals who could be easily misinformed concerning the safety (including the important issue of unwanted immunogenicity [5]) of biosimilars. They may be dissuaded from prescribing biosimilars because of a false concern for patient safety.
It has been shown that the quality of different non-innovator/copy products can vary significantly and even different batches of what appears to be the same product can differ, with implications for both efficacy and safety [10, 18, 19, 20]. It is therefore imperative that clear terminology is used to accurately describe the nature and particularly the regulatory procedure used for particular biologicals.
In order to avoid future problems with terminology for biosimilars and non-biosimilars, it is emphatically proposed that the recommendations expressed in the Weise et al. publication [9], are followed. The definitions provided in the publication for the terms ‘biosimilar’ and ‘non-innovator biologic’ should be adopted in future for accurately referring to the nature of relevant products.
These measures should hopefully lead us out of the confusing and often misleading minefield with terminology for biological products which we are in at present.
For patients
Patient access to biosimilars is an important factor in economic health care. But this requires assurance that biosimilars are safe and efficacious. This is dependent on a clear definition of what is, and is not, a biosimilar. Unfortunately, inconsistency in nomenclature for biosimilars has caused confusion and this problem of terminology has been the subject of a recent publication. The confusion is not just a potential concern for patient safety and efficacy, but also can lead to misconceptions in published reports. The definitions provided here should be adopted for clarity in the future, so that healthcare professionals and patients are clearly aware of the regulatory processes used to approve the products they are using.
Competing interests: None.
Provenance and peer review: Commissioned; internally peer reviewed.
Co-author
Meenu Wadhwa, PhD, Cytokines and Growth Factors Section, Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK
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Author for correspondence:Robin Thorpe, PhD, FRCPath, Head – Biotherapeutics Group, National Institute for Biological Standards and Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
GaBI Journal is an independent and peer reviewed academic journal. GaBI Journal encompasses all aspects of generic and biosimilar medicines development and use, from fundamental research up to clinical application and policies.
