The following chapter is an excerpt taken from Fundamentals of EU Regulatory Affairs, Seventh Edition.
- Introduce the problem of falsified medicines
- Define falsified and counterfeit medicines
- Define active substances and excipients
- Explain the aims and scope of the Falsified Medicines Directive (FMD) Directive 2011/62/EU)
- Identify requirements for different stakeholders in the medicines supply chain arising from the FMD
- Discuss challenges in implementing FMD requirements
- Identify relevant existing EU initiatives
- Provide a list of third countries
- Outline expected timelines for implementation of the FMD
- Evaluate potential developments in detecting and managing falsified diagnostics
Directives, Regulations and Guidelines Covered in this Chapter
- Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products
- Commission Implementing Regulation (EU) No 699/2014 of 24 June 2014 on the design of the common logo to identify persons offering medicinal products for sale at a distance to the public and the technical, electronic and cryptographic requirements for verification of its authenticity
- Commission Delegated Regulation (EU) No 1252/2014 of 28 May 2014 supplementing Directive 2001/83/EC of the European Parliament and of the Council with regard to principles and guidelines of good manufacturing practice for active substances for medicinal products for human use
Falsified medicines, as defined by the European Medicines Agency (EMA), “are fake medicines that pass themselves off as real, authorised medicines.” Such medicines pose a significant public health risk as they may lack active ingredients, contain dangerous contents, contain incorrect doses, or be inappropriately labelled.1 According to the World Health Organization (WHO), “Spurious/Falsely-Labelled/Falsified/Counterfeit (SFFC)” medicines comprise up to 1% of market value in the developed world, with the global figure rising to 10%2,3 of a pharmaceuticals market worth, more than $300 billion USD per year.4 Remarkably, efforts to estimate the global market value for fake medicines are as high as $75 billion (US).5
Pioneering attempts to address this important global health issue, the European Parliament and Council of the European Union adopted the Falsified Medicines Directive (FMD), Directive 2011/62/EU6 and delegated acts and regulations.7,8 Adoption of the FMD has been described as the single largest change in the pharmaceutical industry in the last 40 years,9 and resulted from recognition of the issue’s significance.10 (Figure 8-1). This chapter provides a comprehensive overview of this significant policy, outlines anticipated requirements and means of execution, and discusses implications for multiple stakeholders involved in healthcare delivery.
Defining Falsified Medicines
Understanding the meaning of “falsified medicines” is critical to understanding the FMD’s scope. The terms “counterfeit” and “falsified” medicine often are confused and applied incorrectly; counterfeit medicines “do not comply with intellectual-property rights or infringe trademark law,” whereas falsified medicines are “fake medicines designed to mimic real medicines.”11 This difference and the need for explicit definitions is emphasised by the European Medicines Agency (EMA).12 The FMD defines falsified medicinal products as:
“Any medicinal product with a false representation of: (a) its identity, including its packaging and labelling, its name or its composition as regards any of the ingredients including excipients and the strength of those ingredients; (b) its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorisation holder; or (c) its history, including the records and documents relating to the distribution channels used.”
Note:,the definition “does not include unintentional quality defects and is without prejudice to infringements of intellectual property rights.” Confusingly, although the two terms clearly are distinct, SFFC medicines often are referred to collectively as “counterfeits,” and those producing falsified medicines may be termed “counterfeiters” (e.g., WHO).13,14
Greater nomenclature clarity and consistency would be useful. Within WHO Member States, there is little consensus in defining counterfeit and falsified drugs,15 creating considerable difficulty in global discussions. The EU has attempted to standardise the terminology, and the authors recommend the definitions used herein (Table 8-1) be adopted worldwide to facilitate standardisation in both discussion and policy.
SFFC medicines are not a new concept; however, the advent of the Internet and e-pharmacies has augmented their threat. SFFC medicines’ appearance in international commerce was mentioned first in 1985 at the WHO Conference of Experts on Rational Drug Use in Nairobi, Kenya.16,17 Increasing international trade and the increase in online pharmaceutical sales has facilitated entry of SFFC medicines into the complex supply chain,18 eventually leading WHO to establish the International Medical Products Anti-Counterfeiting Taskforce (IMPACT) in 2006.19 More than 50% of medicines purchased online from illegal sites, which do not reveal their physical addresses, have been found to be SFFC medicines.20 However, SFFC medicines also may reach patients via the legal supply chain (Figure 8-2).
SFFC medicines often are perceived as a problem largely affecting less economically developed countries and high-cost drugs (e.g., the 1985 WHO Conference Report suggested only high-cost drugs were affected). However, the problem actually affects high- and low-cost products, including branded and generic drugs in more and less economically developed countries (Table 8-2). For example, falsified vials of the relatively high-cost breast cancer drug Herceptin were confirmed in Germany and suspected in Finland, Austria and Sweden, following their theft in Italy. In France in 2013, 1.2 million doses of the common drug aspirin were seized.
To attempt to address the problem of falsified medicines, the EU adopted the FMD in 2011.
Falsified Medicines Directive
Aims and Scope
The FMD amended Directive 2001/83/EC on the Community code related to medicinal products for human use22 and aims to tighten medicinal product distribution chain control and protect consumers from falsified medicines. FMD addresses problems arising from the medicines supply chain’s increasing complexity, with the Internet being one of the biggest threats. Controls and checks throughout the supply chain are to be strengthened, including active substances (sometimes also called active pharmaceutical ingredients (APIs)) sourced from non-EU countries and the point at which patients receive medication from a pharmacist or delivery via the internet.
Similar to other recently introduced legislation in the EU, such as ATMP Regulation (Regulation (EC) No 1394/2007), one of the FMD’s central aims is harmonisation of falsified medicines regulation across the EU. Delegated acts ensure each Member State implements them uniformly, ensuring consistency throughout the EU. The directive also emphasises falsified medicines are a global problem, and in the interests of global health, cooperation with international bodies is essential with regard to falsified medicines.
The FMD introduces new requirements for various stakeholders in medical supply chains, who can be broadly categorised as manufacturers, brokers, wholesalers and retailers. These requirements are outlined in Table 8-3. Introducing safety features—mandatory tamper-evident seals and unique pack identification—on packaging will provide assurance of medicines’ authenticity. The FMD substantially changes the European framework for the supply of medicines, and also will include businesses traditionally not directly regulated: medicinal product brokers, who do not handle products physically. Further, it provides definitions for active substances and excipients (Table 8-4), and introduces Good Manufacturing Practice (GMP) guidelines for active substances.
Not all medicines will be subject to the FMD’s rules. The directive states prescription medicines must bear the safety features mentioned above, whereas those not subject to prescription shall be exempt from the requirements. There are exceptions: if risk assessment excludes them, prescription medicines will not require safety features and, conversely, nonprescription medicines deemed particularly vulnerable to falsification will require the features. Risk assessment to determine exceptions should include considerations of price, sales volume, previous cases of falsification in the EU or third countries, implications of falsification for public health and severity of the condition to be treated. Any excepted medicines must be listed in a delegated act.
Perhaps the most significant regulation imposed in the FMD is the requirement for new safety features for medicinal product packaging to: verify whether the packaging has been tampered with (‘tamper-evidence’), and verify the product’s authenticity and identify an individual product pack (‘unique identifier’). In a concept paper released for public consultation in 2011,23 the European Commission outlined expected requirements for these features. For tamper-evidence, the technical specification choice is left to the manufacturer and specific guidance is not given. However, for the unique identifier, specific technical guidance is provided: the only way to uniquely identify a pack is to label it with a randomised serialisation number affixed to the package by a carrier holding the number. This carrier most likely will be a 2-D barcode, although radio-frequency identification also has been proposed. The serialisation number then is checked against its entry in the repositories system, which verifies its authenticity.
For this system to be successful, a reliable verification system must be in place. Since randomised numbers could be reproduced easily, the serialisation number must be ‘checked in’ to a repositories system and after its final use, removed or ‘checked out’ of the system (Figure 8-3). Such a system would have various benefits, for example, allowing recall of medicines, safety messaging, notification of expired or suspicious medicine and information on previously dispensed medicine, all based on information stored in the serial number and/or verification system.
In addition to those covered in Table 8-3 and made explicit in FMD, the introduction of unique product identifiers may elicit new stakeholders in the medicinal product supply chain: those who establish and maintain the verification systems and repositories. Several organisations are beginning to address unique identifier requirements, and some existed prior to the FMD’s publication (Table 8-5). Such organisations will need to comply with several requirements specified in the FMD; notably, safeguards protecting personal and commercially sensitive information should be in place and the FMD applies without prejudice to Directive 95/46/EC on protecting individuals with regard to processing personal data and the free movement of such data.24
Under the FMD, countries outside the EU are obliged to provide written confirmation active substances exported from their country adhere to Good Manufacturing Practice (GMP) standards equivalent to those in the EU. Third countries can be added to a ‘white-list’ if the country’s “regulatory framework applicable to active substances exported to the Union and the respective control and enforcement activities ensure a level of protection of public health equivalent to the [EU].”25 So far, Australia, Switzerland, Japan, the US, Brazil and Israel have been added to the list, and other countries are at various stages in the process (Table 8-6). In particular, the assessment will take into account:
- GMP rules in the country
- regularity of GMP compliance inspections
- effectiveness of GMP enforcement
- regularity and rapidity of provision of information regarding noncompliant active substance production26
With this legislation, the EU aims to protect its Member States, but also supports recognising equivalent scientifically based standards worldwide, helping protect the public better and provide a greater level of protection on a wider international scale.
GMP for Active Substances
Commission delegated Regulation (EU) No 1252/2014 supplements Directive 2001/83/EC of the European Parliament and the Council with regard to principles and guidelines of GMP for active substances for medicinal products for human use.27 Continuing with one of the FMD’s central aims, the regulation strives to promote use of harmonised standards at a global level; therefore, developing guidelines aligning with those established by the International Conference on Harmonisation (ICH).
Broadly summarising the regulation:
- Personnel and equipment in the manufacturing area’s vicinity must be sanitary.
- To prevent cross-contamination when producing active substances harmful to human health, those substances should be manufactured only in separate areas; for active substances with potential to be harmful to human health due to potency, toxicity or infectiveness, risk assessment must be undertaken to evaluate the potential need for separate production areas.
- Detailed written records of production processes must be kept, and any changes affecting the active substance’s quality should be communicated to manufacturers using the active substance.
- Procedures must be in place allowing product recall and investigation of concerns over active substance quality.
- If the manufacture of any part of an active substance is entrusted to another party, responsibilities of the other party in terms of GMP quality compliance must be clarified in writing.
- GMP must be applied to the repackaging and relabeling process.
Timeline for Implementation
The FMD was published in the Official Journal of the European Union (OJ) 1 July 2011. This mandated all Member States to transpose legislation into national law by the end of January 2013 with full compliance mandated within three years of the publication of FMD delegated acts in the OJ.28 Delegated acts were expected in mid-2015; however, they have not yet been published, and the delay between publication of the FMD and the delegated acts been criticised.29,30
Safety features introduced require substantial medicinal product packaging manufacturing process adaptations. As such, the FMD stated the timeline for implementing provisions relevant to safety features must be sufficiently long to allow manufacturers to adapt their manufacturing processes effectively. Some Member States already have authentication or verification systems in place and will be given additional time to adapt to the harmonised EU system. Several EU initiatives have emerged or exist already with relevance to various FMD components, including the unique identifier and, more generally, combatting illegal drug sales via the Internet.
Implications and Challenges
Addressing falsified medicines ultimately requires global cooperation. The FMD recognises the need for concerted international effort against falsified medicines, in particular regarding Internet sales. As such, Member States and the European Commission are encouraging cooperation and supporting ongoing international efforts on falsified medicines. In line with this, and “to promote the use of harmonized standards at a global level,” delegated regulation regarding GMP for active substances31 adopted guidelines in agreement with those established by ICH. If other worldwide regulatory bodies act similarly and standardise terminology as suggested above, the battle against falsified medicines will be greatly accelerated and facilitated.
Despite these positive steps, many perceive FMD implementation as a challenge. Costs for affected actors in the medical product supply chain likely will be considerable, particularly regarding new safety feature requirements and accompanying systems; some have expressed concerns these costs will make some medicines unaffordable and could impact parallel trade negatively, particularly given they often are repackaged.32 Complex information transfer required for FMD compliance will necessitate substantial changes to current system infrastructures, and ensuring these changes are harmonised throughout the EU will be essential to successful implementation.
This chapter has discussed implications for multiple stakeholders in the medicinal product supply chain affected by the FMD. However, ultimately, the most important stakeholder affected by the directive is the patient, and issues with costs of implementation likely will be outweighed by patient benefits. Beyond the clear benefits of reducing the prevalence of falsified medicines, there is considerable scope for wider reaching impact. In particular, adoption of unique identifiers and verification/repository systems could allow other health-related issues to be addressed: data generated could be used to measure and characterise patient behaviour with regard to medicine, aid communication between pharmacy and patient and allow development of tools to communicate with and support patients directly (Figure 8-3).
Although other legislation aims to combat trade of falsified medicines worldwide (e.g., the Drug Quality and Security Act, H.R. 3204 in the US), with the FMD, the EU is leading an ambitious attempt to develop a harmonised approach to tracking and labelling safe medicines and ensuring falsified medicines do not reach patients by authentication at the dispensing point. The FMD applies directly to the EU; however, by promoting standardisation more broadly, patients throughout the world may benefit. While inevitably introducing costs and challenges to the medicinal product supply chain, this historic regulation is an essential step toward a world free of falsified medicines, and should be perceived as such.
Ultimately, the problem of falsified medicines is a major risk to patient safety, damaging public trust in healthcare and the pharmaceutical industry—reducing revenue available to reinvest in R&D efforts to address unmet medical needs. While investment in requisite manufacturing and distribution infrastructure, particularly in primary and secondary care pharmacies, initially may be burdensome, generation of primary benefits—reduction in falsified medicines and reimbursement fraud and tighter control of active pharmaceutical ingredients—likely will be swift. Secondary benefits including reduced dispensing errors, opportunity for patient engagement, providing information about medicines and supporting optimal adherence, electronic informed consent, real-time pharmacovigilance and business intelligence are tractable and impactful.
Preventing falsified medicines and realising the FMD’s secondary benefits are not just legal requirements; they are healthcare professionals’ responsibilities at all stages of the lifecycle33 to safeguard patient safety and improve patient outcomes.
Potential Developments in Detection and Management of Falsified Medicines and Devices
The FMD’s primary purpose is to identify and deter falsified medicines in today’s pharmacopeia, dominated by small molecules (high volume, low cost) and mAb biologics (high cost, low(er) volume). However, a snapshot of contemporary basic science and clinical trial landscapes clearly indicates the future pharmacopeia is more complex, moving away from allogeneic small molecules to complex autologous therapeutics and combinational strategies, utilising therapeutics and devices34 (Figure 8-5). Consequently, guidance and regulation pertaining to falsified medicines and devices must adapt.
Scope of Combination Therapies
Combination therapies may be applied in a variety of approaches, including a small molecule being co-administered with a biologic; for example, anti-TNFs and Methotrexate. At the core of stratified and personalised medicine approaches is use of companion diagnostics to identify patients with a disease-specific genetic marker, which indicates a high likelihood of efficacy arising from application of a specific therapeutic. Finally, and more futuristically, combinational approaches include de-cellularised xeno-derived and/or cadaveric scaffolds to which human cells are engrafted in tissue engineered approaches; and gene modified autologous immunotherapies. All permutations of combinational therapies have major implications for effective implementation of the the FMD.
Companion diagnostics, applied with a (biological) therapeutic, are increasingly common feature of medical practice and biopharmaceutical company clinical trial pipelines. Presently, only the therapeutic component of the treatment will be protected against SFFC by FMD-mandated safety features. However, there is an incentive to falsify the companion diagnostic—which can command a high reimbursement level akin to some high-cost small molecules—both to generate direct revenue from the counterfeit diagnostic, but also potentially by generating a deliberate false positive to stimulate sales of legitimate and/or counterfeit therapeutics. Therefore, while discussions pertaining to potential legislation to identify and control falsified devices are on-going among international regulators, positive synergies between the FMD and the forthcoming EU Falsified Device Directive (EU FDD) should not be overlooked, nor should potential complexity in their parallel implementation and enforcement.
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Brindley DA, Rakhi R, Fuerstenau-Sharp M, Kantoff P, Hollander G, Smith JA, et al. “The Potential Application of Real-Time Release Testing for the Biomanufature of Autologous Cell-Based Immunotherpies.” BioProcess Int. 2014;13(4(s));34–43.
The authors wish to express their sincere thanks to the following organisations that have contributed to the CASMI Translational Stem Cell Consortium (CTSCC) as funding and events partners, without whom the consortium and the benefits it will bring to stem cell translation would be constrained: GE Healthcare, CCRM, Sartorius Stedim Biotech (formerly TAP Biosystems), Lonza, CIRM, SENS Research Foundation, UK Cell Therapy Catapult, NIH Centre for Regenerative Medicine, NYSCF, ThermoFisher Scientific, Eisai, Medipost (US), Medipost (Korea), Celgene, Roche and Oxford Biomedica. D.A.Brindley gratefully acknowledges personal funding from the Oxford Musculoskeletal NIHR BRU, the Said Foundation and the SENS Research Foundation. J.A. Smith gratefully acknowledges support from the CTSCC. The authors also acknowledge the invaluable support of Paul Thomas, Peter Fox, Adrian Hitchen and Gavin Hanks at Aegate Ltd.
This chapter’s represents the authors’ individual opinions and may not necessarily represent the viewpoints of their employers. DA Brindley gratefully acknowledges support from the SENS Research Foundation (Mountain View, CA). Brindley is a stockholder in Translation Ventures Ltd. (Charlbury, Oxfordshire, UK), providing cell therapy biomanufacturing, regulatory, and financial advice to clients in the cell therapy sector. He is subject to the CFA Institute’s codes, standards and guidelines and, as such, must stress this chapter is provided for academic interest only and must not be construed in any way as an investment recommendation. Additionally, at time of publication, Brindley and the organisations with which he is affiliated, may or may not have agreed and/or pending funding commitments from the organizations named herein. B. Naughton and Brindley are consultants for Aegate Ltd. Naughton also is a registered UK pharmacist and, therefore, complies with GPHC codes, standards and guidelines and stresses this publication is provided for academic interest only. Rob Horne has undertaken speaker engagements with honoraria from the following companies: Abbvie, Amgen, Biogen Idec, Gilead Sciences, GlaxoSmithKline, Janssen, MSD, Pfizer, Roche and Shire Pharmaceuticals. He is founder and shareholder of a UCL-business, Spoonful of Sugar, providing consultancy on medication-related behaviours to healthcare policy makers, providers and industry. Graham Smith and Mark De Simone are employees of Aegate Ltd.