Sean Milmo is a freelance writer based in Essex, UK.

Sean Milmo

	The European Medicines Agency’s (EMA’s) role as one of the world’s leading regulators, which has been a major force in the drive to harmonize medicines regulations across the globe, could be seriously weakened as a result of the need to relocate its current London headquarters to Amsterdam. EMA, which is responsible for centralized approval of medicines in the European Union (EU), has been a big influence in areas such as the standardizing global rules on good manufacturing practice, medicines identification, the introduction of biosimilars and post-marketing pharmacovigilance.

	Within Europe itself, as a result of its job as co-ordinator of the activities of approximately 30 national medicines licensing authorities in the region, EMA has done much to establish uniform approaches to the authorization of medicines and to keep pharmaceutical regulation in line with advances in science.

	But now it is being threatened with such a large reduction in staff due to the relocation of its headquarters in 2019 that it will have to concentrate mainly on high-level priorities such as the assessment and safety monitoring of medicines. With some of its international activities in bodies like the International Council for Harmonization of Technical Requirements for Pharmaceuticals (ICH) and the International Coalition of Medicines Regulatory Authorities (ICMRA), it may only be able to act mainly as an observer.

	EMA has stressed that the cutbacks or suspensions of its activities will only be temporary (1), lasting until 30 June 2019, soon after Brexit is scheduled to take place on 29 March 2019. It also points out that cutbacks will mainly result in slowdowns of specific operations while suspensions will mean they will be completely halted for a period. But it has itself admitted that there could be longer-term effects on the agency’s operations (1).

	After the United Kingdom voted in June 2016 to leave the EU, making necessary EMA’s relocation to an EU member state, the agency estimated that with an attractive location like Amsterdam it would lose initially approximately 20% of its 900 employees (2). However, in August 2018, it revealed that the staff exodus was likely to be around 30% (3).

	This was despite the choice of Amsterdam as the site for EMA’s new headquarters. Among 19 competing bids from EU countries, the Dutch city was the favoured choice among the agency’s employees (2). A winning bid by most of the other cities would have resulted in even more drastic staff losses (4).

	The agency has been operating out of London since its foundation in the early 1990s, since then it has built up a staff with considerable expertise. The most qualified of these employees who are leaving the agency will be difficult to replace in the short to medium-term.

	Before it started to lose employees who did not want to relocate, EMA’s 900 staff in London included a number of temporary and part-time workers, giving it a total of full time equivalents (FTE) of approximately 700, according to agency figures (4).

	A 30% reduction, as forecasted by the agency which had been hoping for a retention rate of at least around 80%, would lower the staff total, including temporary and part-time employees, to approximately 600 (4), with the FTE total probably dropping below 500.

	For carrying out its highest priority-category 1-activities, mainly the assessment and monitoring of the safety of medicines, EMA estimates it requires 462 FTEs. With medium priority category 2 operations, such as combating antimicrobial resistance (AMR), collaboration with health technology assessment bodies which decide on reimbursement entitlements at the national level, and dealing with medicine shortages, it needs 140 FTEs. For the lowest category 1 activities, covering governance and support activities, audits and participation and organization of meetings, 110 FTEs are required (4).

	In addition to its own staff, the agency relies on medical and other scientific experts provided by EU and other European agencies, particularly in the assessment of new drug applications.

	For much of its existence in London, EMA has depended a lot on experts in the UK’s Medicines and Healthcare products Regulatory Agency (MHRA). It has accounted for around 15–20% of the more burdensome rapporteur and co-rapporteur work on new drug assessments.

	Since the Brexit referendum result, EMA has been sharply reducing contributions by the MHRA. This year, the UK agency has been given only two (co)-rapporteur contracts by EMA compared with an annual average of 22 before the referendum (5). Instead, work previously allocated to the UK agency has been spread around other EU national authorities. Also, the post-marketing responsibilities of a total of 370 human and veterinary medicines for which the MHRA had been (co)-rapporteur are being moved to other agencies (5). So, Brexit has not only increased the individual workloads of EMA staff but that of national agencies as well.

	EMA’s surveys of its own staff before the selection of Amsterdam as the relocation site showed that at its new Dutch headquarters it would retain the necessary 462 FTEs for category 1 work but hang onto only 102 for category 2 and 11 for category 3 work (4). But these should be jobs which will be easier to fill than those for high priority category 1 positions.

	The remaining top four favourite cities bidding for selection as the relocation site would also retain sufficient category 1 staff, according to EMA figures (4). These would have included Milan, which in the selection process attracted the same number of votes as Amsterdam but lost out in the equivalent of a toss of the coin to decide the winning city.

	With the remaining 15 contestants, staff retention rates ranged from 72% to as low as 26%, so that with the majority of bidders employees losses would have been so high the agency would not have been able to carry out its core public health responsibilities (4). 

	EMA’s latest report on its Brexit preparedness issued in October 2018 reveals that it is having to make further cutbacks and suspensions in its operations six months before its move to Amsterdam, extending into areas of medium, category 2 priorities (1). These priorities include international activities, guidelines development, working party activities, stakeholder interaction, and clinical data publication.

	International level collaboration will be further scaled back until the end of June 2019 with the exception of responses to productârelated requests, supply chain issues-such as medicine shortages-and the EUMed4all scheme, under which EMA does product assessments for developing countries (1).

	Involvement in other international activities will be decided on a case-by-case basis with the agency taking, if necessary, only a reactive or observer role, especially in areas like harmonization of global medicine regulations.

	Guideline development will be restricted to subjects relating to urgent public health needs, Brexit requirements, and the implementation of new or revised legislation. Work on guidelines will continue on, for example, revised or new annexes in the EU GMP guide on sterile products and medicine imports and quality requirements for drug device combinations (DDCs) (1).

	Within the ICH’s operations, EMA will continue to act as topic lead or rapporteur with four guidelines, including one on electronic standards for regulatory information transfers. It will also continue to be involved in the preparation of the Q12 guideline on pharmaceuticals lifecycle management because of its ‘particular interest’. However, with the remaining ICH’s ongoing guidelines, EMA will switch to an observer role (1).

	Meetings of the agency’s non-product related working parties, except those involved in priority guidelines development, will be suspended from 1 October 2018, to end of June 2019. The frequency of meetings of certain expert groups, such as the GMDP Inspectors Working Group, may be decreased or reduced to virtual meetings.

	EMA has warned that there will be further cutbacks and suspensions in its activities from 1 January 2019 lasting until the end of June 2019 (1). These could be more severe than expected if the relocation runs into major problems. From early January 2019, EMA staff will start moving into temporary offices in Amsterdam to await the completion, scheduled for November 2019, of its eventual headquarters in a custom-designed new building.

	“This is not an optimal solution,” Guido Rasi, EMA’s executive director, complained at a press conference in the Netherlands early last year (2). The temporary offices will only have half the space in the current London headquarters and will require the use of external meeting facilities.

	Members of the European parliament have been so concerned about complications with the relocation that the Dutch authorities are now legally obliged to submit quarterly reports to the parliament and EU member states on the new building’s progress.

	Once the agency’s full range of activities are resumed in mid-2019, it will still need time to make up for lost ground. It estimated last year that even with a staff retention level of over 65% it would take two to three years to fully recover. If retention rates slipped to 50–64%, full recovery could be delayed by up to five years and to 30–49% by up to 10 years (4).

	1. EMA, “EMA Brexit Preparedness Business Continuity Plan-Phase 3 Implementation Plan,” EMA/701082/2018 (London, 9 October 2018).
	2. EMA, “Statement by Executive Director Guido Rasi in The Hague,” Press Release, 29 January 2018.
	3. EMA, “Brexit Preparedness: EMA to Further Temporarily Scale Back and Suspend Activities,” Press Release, 1 August 2018.
	4. EMA, “EMA Business Continuity Planning and Impact of Staff Retention Scenarios from EMA Staff Survey,” (London, 26 September 2017).
	5. EMA, Cut-off Days for UK Rapporteurship Appointments for Pre- and Post-authorization Procedures for Centrally Authorized Products (London, 9 October 2018).

Vol. 30, No. 12
	December 2018
	Pages: 8–9

	When referring to this article, please cite it as S. Milmo, “Relocating EMA: A Far From Ideal Situation," 

Articles

EMA’s relocation to Amsterdam and resulting staff losses could severely weaken the agency’s role as a leading medicines regulator.

Relocating EMA: A Far from Ideal Situation

	The European Union has been overhauling its rules on 

diagnostics (IVD), particularly companion diagnostics, to bring them more into line with internationally agreed standards. But despite the changes, it is still retaining a regulatory system that keeps the approval of IVDs separate from those for pharmaceuticals. The authorization of medicines and diagnostics will continue to be done along different regulatory pathways even though the use of companion diagnostics (CDx) is considered to be crucial to the performance of the drug.

	The splitting of regulatory responsibilities could hamper prospects for the co-development of a medicine and its CDx and cause the drug and the diagnostic to reach the market at different times. Co-development, particularly of drugs with assays for pharmacogenomic biomarkers necessary for patient selection, will be an important component of the shift to precision or personalized medicines. The division of responsibilities could also maintain gaps in controls, in the pre-analytical phases of biomarker testing, on the quality of specimens, particularly during their storage and transportation, and in the monitoring of the reproducibility of tests. 

	Legislation on IVDs (1) was approved, simultaneously with a regulation on medical devices, by the European Parliament in April 2017. The regulation on diagnostics (1) will come into full force in 2022 and the one on medical devices (2) in 2020. Both replace existing legislation, parts of which date back to the early 1990s. The new rules are more consistent with those developed at the international level for medical devices including IVDs, in particular, with the guidance from the Global Harmonization Task Force (GHTF) and the International Medical Devices Regulators Forum (IMDRF). However, unlike in countries and regions outside Europe, the EU has decided that even new technologies, such as pharmacogenomics testing, whose regulatory requirements are increasingly overlapping with those of pharmaceuticals, should not be brought under the ultimate control of regulators responsible for licensing medicines.

	The United States Food and Drug Administration (FDA), for example, has had responsibility for the approval of medical devices since 1975. The EU’s European Medicines Agency (EMA), which runs Europe’s centralized procedure of marketing authorizations of medicines, has responsibility only for pharmaceuticals. Within the EU’s 28 member states, only a minority of national medicines agencies also have responsibility for controls of medical devices and diagnostic products.

	“Diagnostics are gaining considerable importance in the effective treatment of patients, especially in oncology, but also other conditions,” Peter Keeling, chief executive of the Irish consultancy Diaceutics, told 

. “It makes sense that the control of diagnostics should be brought under the control of single regulatory bodies. It helps to harmonize standards and benefit/risk assessments.”

	One major similarity between the European and US diagnostics sectors is the high proportion of diagnoses carried out with laboratory developed tests (LDTs), which are exempt from the regulations on IVDs. Many of these are administered in the laboratories of hospitals and other healthcare institutes specializing in oncology, cardiology, neurosciences, and other conditions requiring detailed diagnoses.

	“In Europe, approximately 50–60% of testing-and only a little bit less in the US-are still conducted through LDTs, with the remainder of the market comprising commercial 

 kits,” said Keeling. “These in-house laboratories have demonstrated their excellence in finding evidence, especially in genetics. We don’t want to thwart this innovation.”

	The EU’s new IVD legislation states that health institutes, including hospitals, should continue to have the freedom “of manufacturing, modifying, and using devices in-house” outside the regulation, although they may still be subject to national quality rules. The legislation also retains much of its existing regulatory system under which IVD manufacturers are able to self-certify the quality and safety of their diagnostic kits. The higher-risk tests have to be certified by organizations, called notified bodies (NB), which specialize in assessing whether diagnostic products or other medical devices comply with EU standards laid down by the European standards agency.

	A big change under the new legislation is that the majority of IVDs, including CDx products, will be certified by NBs, which themselves will be subject to close scrutiny by the national competent authorities within the member states responsible for medical and diagnostic devices. The NBs will also be required to audit and inspect at minimum regular intervals the sites of IVD manufacturers. 

	Another major alteration is that, for the first time, a definition of a CDx is included in the text of the IVD legislation, which is similar to that used by FDA in the US. A CDx is defined in the new regulation as a device that is “essential for the safe and effective use” of its corresponding medicine (1). The CDx is used to identify, before or during treatment, patients most likely to benefit from the medicine or those likely to be at increased risk of a serious adverse effect from the drug. As a result of the division of regulatory responsibilities, the NB’s main task is to assess the technical quality and performance of the CDx. Both the NB and the medical agency, either EMA or the national authorities, have to assess, in the light of evidence from clinical trials, whether the CDx has sufficient sensitivity and specificity to be safe and effective.

	Under the new legislation, the NB is required to consult EMA or, if necessary, a national medicines licensing agency on its scientific opinion before issuing an EU compliance certificate for a CDx product. EMA or the national agency has to provide an opinion within 60 days. But EMA, under the legislation, does not have the power to veto the NB’s assessment. The NB only has to give “due consideration” to EMA’s or other agency’s opinion. EMA, however, will have the option of deciding, in the light of an NB assessment contrary to its own scientific opinion on a CDx product, that the medicine has a negative benefit/risk balance and cannot be given a marketing authorization. In the five-year transition period between the approval of the IVD regulation and its full implementation, EMA will have plenty of opportunity to lay down requirements in guidelines. These could limit the freedom of NBs to certify CDx products, which do not sufficiently take into account the essential role of CDx technologies in ensuring the effectiveness of its corresponding drug.

	Under the legislation, the European Commission in its role as the EU executive is allowed to stipulate common standards in areas where no harmonized standards exist. As an agency of the commission, EMA will have a key role to play in drawing up guidelines on the operation of the regulation.

	In an analysis of the new IVD regulation, a group of experts at the German Federal Institute for Drugs and Medical Devices (BfArM), one of the minority of national agencies with combined responsibilities, suggested that EMA should impose requirements on NBs for individual CDx products. The group included Harald Enzmann, head of European and international affairs at the agency, who is also vice chair of EMA’s key committee for medicinal products for human use (CHMP). “The EMA could define in their initial assessment of a new medicine, the minimum requirements for the performance of the CDx,” the study said (3). 

	In a concept paper (4) issued in July 2017, for a planned guideline on the use of predictive biomarkers in the light of the IVD regulation, EMA admitted that a system under which medicines and IVDs are developed independently “may not be ideal as there remain gaps in evidence and validation.” It stressed that it was crucial that any CDx used to select patients for treatment is “sufficiently quality assured.” 

	“[The guideline] will address some technical performance requirements used for predictive biomarker assays depending on the stage of development and how the biomarker status may affect patients’ eligibility to participate in a clinical study,” an EMA spokesman told 

. “It is anticipated that feedback on the concept paper received by medical device stakeholders will be used to address various aspects related to the expected quality standards of companion diagnostics,” he added.

	EMA is among a number of specialist bodies that will be providing guidance and possibly standards on the implementation of the legislation. Under the new regulation, a Medical Device Co-ordination Group (MDCG), comprising experts in medicine devices including IVDs, is being set up to ensure its uniform implementation.

	The commission will also have its own expert advisory panel. There will also be a network of EU reference laboratories that, when necessary, will use their specialist staff and equipment to verify the performance of CDx products and other higher risk IVDs. The role of the MDCG could turn out to be highly important because it will be able to press for amendments to the legislation to make it work more effectively, particularly on quality and reproducibility issues.

Concept Paper on Predictive Biomarker-Based Assay Development in the Context of Drug Development and Lifecycle,

 EMA/CHMP/800914/2016 (London, July 2017). 


	Volume 29, Number 9
	September 2017
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “Regulation of Companion Diagnostics,” 

EMA recognizes that a regulatory framework, under which medicines and diagnostics are developed and approved independently, may not be ideal.

Regulation of Companion Diagnostics

	The European Medicines Agency has decided that it needs to give more help to small and medium enterprises (SMEs) in developing new medicines, 11 years after the agency first launched a scientific advice project to assist them in bringing innovative drugs to market. The scheme has been a relative success. At the end of 2016, a total of 1810 SMEs were registered with the agency’s SME Office, a 12% rise on the number in 2015 and an increase of more than 10-fold compared to 2006, the first year EMA was legally obliged to provide scientific assistance to SMEs (1).

	Manufacturing inadequacies raise quality issues

	There is, however, still a high proportion of failures among SMEs in Europe in the development of new medicines. Many do not even reach the stage of making marketing authorization applications. A high proportion of those that do have their applications rejected were because of manufacturing inadequacies that have raised quality issues with their products.

	EMA is now trying to tackle some of the causes of the deficiencies behind these failures by launching a new action plan to help SMEs become more efficient drivers of pharmaceutical innovation. Yet it is unclear how the plan will help small companies deal with challenges in the collection of data on the development of manufacturing processes. One key strategy behind the plan is to run EMA’s assistance programme for SMEs in parallel with a newly introduced framework of collaboration with academia so that universities and research institutes, which are the source of many start-ups, also understand more about the regulatory requirements behind the approval of new medicines.

	In 2016, EMA handled 174 requests (1) for assistance from SMEs on both regulatory and administrative aspects of pharmaceutical legislation, the highest ever figure. It is not surprising that increasing numbers of small companies are looking for help because so many lack the adequate resources. Forty-one percent were categorized as being micro in size with staff of 10 or less and annual turnover at or below €2 million. Only 25% were classified as being medium sized with staff of 250 or less and turnover at or below €50 million. Half were owned by individual entrepreneurs. Only 7% benefitted with funding by venture capital and other private investment and 5% from funds by business angels.

	In the 11 years from late 2005, when the European Union’s SME legislation on development assistance came into effect, 107 marketing authorization applications by SMEs for human medicinal products had been made to EMA, according to the SME Office’s 2016 annual report (1). Of these, 59 received positive outcomes and 48 negative ones. A study of marketing applications from 2011-2015 showed that among SME submissions for human medicines, 88% of files had major clinical objections and 73% had major quality issues.

	Many SMEs appear to have difficulties developing innovative medicines that have the potential to deal with the unmet needs of patients, particularly those with rare conditions. One of the problems facing small companies is the requirement for reliable data on manufacturing processes. In 2016, EMA introduced a new scheme called PRIME (PRIority MEdicines) to give early and proactive support to those developing medicines that target, in addition to uncommon diseases, conditions such as Alzheimer’s disease and other dementias.

	“PRIME aims to foster better planning of medicine development,” Guido Rasi, EMA’s executive director, noted in the agency’s latest annual report issued in May 2017 (2). “This will help companies to generate the high-quality data we need to assess the quality, safety, and efficacy of medicines.”

	EMA has stressed that the scheme is designed to help those companies able to “collect robust data and submit high-quality marketing authorization applications” (2). Of the 84 applications for PRIME assistance received in 2016, half were from SMEs. Altogether, 15 medicines were granted help, of which 10 were advanced therapies. “As the programme is intended for the most promising medicines, only a relatively small number have been accepted in the scheme so far,” the agency says (2).

	In the EMA’s action plan for SMEs (3), issued in May 2017, the development of treatments for unmet needs has been pinpointed as an area where small companies require more support. This means, according to the agency, encouraging SMEs to make more effective use of PRIME by improving the quality of their marketing authorization applications.

	The plan identifies a total of 16 actions for implementation in 2017-2020. One aim is to have more initiatives specifically tailored to deal with SME requirements. “SME-friendly” written advice will, for example, be published on the introduction of the data standards in the Identification of Medicinal Products (IDMP) drawn up by the Geneva-based International Organization for Standardization (ISO).

	One key objective is to bring SMEs into closer touch with major players in the development of new pharmaceuticals such as research institutes, biotech incubators, innovation clusters, and private and public investors. This objective will be achieved both by increased awareness among SMEs about these sources of knowledge and support in innovation activities, but also by the regulators themselves doing more to make these players aware of the requirements of small companies. One way is to increase the profile of the scientific advice programmes of EMA and also those of national medicines agencies.

	EMA wants also to strengthen the ties between its Innovation Task Force (ITF) and SMEs. The ITF is a multidisciplinary group of scientific, regulatory, and legal experts that provides a platform for early dialogue with companies developing emerging innovative therapies and technologies. Almost half of the ITF’s 41 meetings in 2016 were with SME drug developers.

	The ITF aims to aid SMEs-and the agency’s own staff and committee members-by proactively identifying scientific, legal, and regulatory issues of emerging therapies and technologies. The taskforce can act as a bridge between SMEs and academia because it also provides a platform for discussions with academics and researchers on similar scientific and regulatory matters arising from new technologies.

	In its framework on collaboration between the agency and academia, published in March 2017, EMA noted that “although academic contribution has been intrinsic to the European Medicines Agency’s work since its creation, gaps remain and new challenges keep emerging” (4). In a way, the problems with academia are similar to those with SMEs. There is a lack of awareness of the work of the European medicines regulatory network and of the need for regulatory support to ensure that academic research achievements are translated into novel medicines.

	At the same time--as with SMEs-a divide has opened up between universities and research institutes and regulators. Many SMEs in the pharmaceutical and other sectors tend to be wary of regulations, with a wish for reductions in regulatory costs and burdens. This might conflict with the EMA’s objectives of improving marketing authorization applications through the provision of “robust data.”

	SMEs are also under pressure to deliver data that not only satisfies the requirements of regulatory agencies. Other bodies and groups, such as Europe’s health technology assessment (HTA) organizations, that help fix the prices of new medicines and the level of reimbursement at the national level, healthcare professionals, and patients associations are also being given a role in the shaping of scientific advice to drug developers.

	EMA and the European Network for Health Technology Assessment (EUnetHTA), representing HTAs, announced in July 2017 that they are setting up a joint platform to provide medicine developers with simultaneous, coordinated advice to facilitate uniformity in data requirements. “Our work with EUnetHTA aims to align our respective requirements as much as possible so that developers can generate one set of data that allows the assessment of both the benefits and risks of a medicine and its added value,” said Rasi (5).

	EMA is testing a scheme under which more information would be supplied to healthcare professionals on the quality data from the manufacturing process on which regulators have based comparability assessments for the authorisation of biosimilars. Also, SMEs, together with larger drug companies, are concerned that the introduction of the IDMP standard for pharmaceutical data, including that relating to manufacturing processes, will make data collection for authorization applications more difficult.

	EMA’s desire to make greater use of real-world data covering the whole lifespan of a drug from its manufacture through to its consumption by patients on the market will result in demands for even more data from medicine producers. The agency sees real- world data as part of Big Data or the application of very large data sets of far greater volume and variety than traditional data sets. “These data have the ability to significantly contribute to the way the benefit-risk balance of medicines is assessed over their entire life cycle,” says the agency (2). An important aim behind the EMA’s building of closer relations with SMEs is this ambition to ensure that regulatory decisions are based on high quality and in-depth evidence.

EMA Action Plan for Small and Medium-Sized Enterprises

,
	EMA/337458/2017 (London, May 2017).
	4. EMA, 

Framework of Collaboration Between the European Medicines Agency and Academia

, EMA/125511/2017 (London, March 2017).
	5. EMA, “EMA and EUnetHTA step up interaction to align data requirements,” Press Release, 4 July 2017.

Volume 29, Number 8
	July 2017
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “EMA Increases Support for SMEs," 

EMA recognizes the need to provide more assistance and guidance to SMEs developing new medicines and applying for marketing authorizations.


EMA Increases Support for SMEs

	The size of the European biosimilars market is accelerating rapidly as government-funded healthcare services increase their support for these medicines in an effort to reduce costs. Sales of biosimilars in Europe has tripled in the past five years (1). In 2015-2016, they soared by approximately 50%, according to figures from QuintilesIMS, the US-based international healthcare services company that has been carrying out studies on the European biosimilars market for the European Commission, the European Union executive (1).

	By March 2017, 26 EU-approved biosimilars were available in the European market, 10 years after the European Medicines Agency (EMA), the EU’s centralized licensing body, authorized its first biosimilar. In 2016, Europe accounted for 87% of global sales of biosimilars, underlying its world leadership in the development of the medicines, particularly in the regulatory procedures for establishing comparability between biosimilars and the original products. The biosimilars sector in Europe, which is still in its infancy, has now reached a stage where more information about these regulatory procedures needs to be provided to stakeholders, particularly healthcare professionals, if the strong momentum behind biosimilar sales is to be maintained.

	Physicians are not greatly concerned anymore about the safety of biosimilars. In the 10 years since they have been on the European market, the EU’s pharmacovigilance monitoring system has not identified any marked differences in the types of adverse effects between biosimilars and their originals. But prescribers are concerned about the challenges of convincing patients about security of treatments by biosimilars for new therapeutic areas such as autoimmune diseases, oncology, and especially chronic conditions.

	This necessity for greater transparency is being centred on the way the quality attributes of the manufactured biosimilars are compared with those of the original or reference product. Manufacturers are required to establish that their biosimilars have sufficient levels of similarity in order to be authorized. 

	These attributes mainly comprise physicochemical and functional properties such as molecular structure, protein modifications, and biological activity. Because the drugs are biological, there are inevitable differences. But for a drug to be “highly” similar so that it can be licensed as a biosimilar, these differences must not result in inferior levels of safety and efficacy to the reference product.

	With biologicals in which the active substance is a protein, the biosimilar and reference product must contain the same protein (i.e., amino acid sequence) and the same three-dimensional structure or folding of the protein. In the finished medicine, certain differences, such as excipients used in formulations and in the administration device, are allowed because they have no effect on safety and efficacy.

	Quality assessments have become such an essential part of the process for approving biosimilars that in most cases once a biosimilar has proved itself to be highly similar on a quality basis to regulators, investigation of clinical studies to establish safety and efficacy has not been required. “By demonstrating biosimilarity [at the quality level], a biosimilar can rely on the safety and efficacy experience gained with the reference medicine,” says an EU guide to biosimilars for healthcare professionals published jointly in May 2017 by EMA and the European Commission (2). “This avoids unnecessary repetition of clinical trials already carried out with the reference medicine,” it adds. 

	With quality having such a key position in biosimilars’ authorization, healthcare professional organizations have been urging EMA to increase the transparency of the comparability exercise applied to quality data to show high similarity between biosimilars and their reference products. “Given the role of healthcare professionals on the front line of patient care, it is vital that they have access to reliable information on these medicines: what they are and how they are developed, approved, and monitored,” says Professor Guido Rasi, EMA’s executive director.

	When selecting biosimilars for patients, prescribers have tended to rely on the basic details in its summary of product characteristics (SmPC), which focuses on safety and efficacy information. A much more suitable communications vehicle on the quality aspects of biosimilars would be a group of documents known as the European Public Assessment Report (EPAR). In addition to the SmPC information, EPAR documents contain assessment reports on the scientific evaluation of the medicine at the time of approval and on major changes, such as the addition of new indications. Crucially, it integrates the whole comparability exercise covering the quality, safety, and efficacy of the biosimilars. By extending EPAR to give more information on quality aspects, EMA could deal, for example, with concerns about lack of appropriate data when prescribers switch patients from one biosimilar to another. 

	In a joint position paper (3) on biosimilars switching issued in March 2017, the European Federation of Pharmaceutical Industries & Associations (EFPIA), European Biopharmaceutical Enterprises (EBE), and International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) complained about the lack of comparability data between biosimilars for prescribers. “This type of data may not be available to stakeholders when evaluating a switch between two biosimilars of the same reference product,” the three organizations said (3).

	Now EMA has revealed it is testing a scheme for giving more technical information on quality comparability data in the EPAR of an unidentified biosimilar that the agency has recently approved. “This initiative is part of the agency’s efforts to ensure that healthcare professionals have access to reference information on the science and regulation underpinning the use of biosimilars and thereby increase healthcare professionals’ and patients’ confidence in the approval process for biosimilars,” an EMA spokesperson told 

	“Once the EPAR for the medicine has been published later this year, EMA will conduct a small survey among relevant healthcare professionals to find out whether this additional information is considered helpful.”

	At the same time, EMA is making moves to raise the efficiency of analytical methods for the collection and assessment of quality data. In February 2017, it launched a scientific advice pilot project to help biosimilar developers assess existing data. The agency will advise developers on the studies they should conduct on the quality, analytical, and functional data that they already have available. EMA’s scientific advisors usually do not make suggestions on the assessment of existing data. The agency plans to run the pilot until it has undertaken six scientific advice requests, with a maximum of one scientific advice request being accepted per month. 

	EMA is also considering ways of gaining greater value from the statistics generated by quality assessments in the development of drugs, particularly biosimilars. Conclusions or inferences could be reached from data rather than using the statistics merely in a descriptive manner to make measurements or to detect patterns.
	The agency issued in March 2017 a reflection paper (4) on statistical methodology in comparative quality assessment to investigate to what extent the implementation of inferential statistical methods can facilitate comparative evaluations of quality data. The paper highlighted some current difficulties with quality assessments in biosimilars development with some experts being sceptical about what could be achieved with the help of statistics. 

	“From related discussions between [biosimilar] developers and regulators, it became evident that there is no common understanding what kind of statistical data analyses approaches would be considered suitable, if any, for comparison tasks involving quality attributes data,” EMA said in the paper. Furthermore, the effects of quality differences on safety and efficacy can be difficult to measure. “The impact of differences at the quality level on clinical outcome--efficacy/safety/immunogenicity--is often hard to predict or quantify,” the paper said.

	Some of the concerns about quality data stem from the limitations of data sources when biosimilars have been produced in small commercial batch quantities over a relatively short period. “At first sight, it might seem straightforward to apply inferential statistical methods for comparing data from quality attributes,” the paper continues. “But often severe limitations exist regarding practical applicability, given the specific circumstances relating to sampling and data collection. Hence, the question of whether the desired conclusion of similarity of products could indeed be inferred from often limited information from sample data remains difficult to answer on many occasions.”

	Meanwhile, physicians in some parts of Europe are coming under growing pressure to prescribe more biosimilars as governments step up their efforts to drive down medicine prices by introducing tendering schemes for mass supplies of biologicals, including both originals and biosimilars. They are also offering incentives for doctors to prescribe lower-cost biosimilars through “gain sharing” projects under which at least some of the money saved is channeled into local healthcare budgets.
	Nonetheless, the biosimilars market in areas of Europe remains fragmented. Levels of prescribing are high in Scandinavia but relatively low in Western European countries such as France and Spain and, despite recent rises in the availability of certain biosimilars, in Eastern Europe (5). 

	There are also huge contrasts in individual countries. In Italy, for example, uptake of biosimilars has reached close to 75% in the north but is as low as 10% in the south (6). Caution among healthcare professionals has been a major factor behind these differences. It remains an open question as to how much greater transparency and reliability in information on quality will help to change their attitude to biosimilars. 

	1. P. Troein, R.Logendra, Stephen Deitch, QuintilesIMS, “Market development in Europe and Globally-A perspective on biologicals and biosimilars,” presentation at Medicines for Europe’s Biosimilar Medicines Conference ( London, March 2017). 
	2. EMA and European Commission

, Biosimilars in the EU-Information Guide for Healthcare Professionals

 (London, May 2017). 
	3. EBE, EFPIA, IFPMA, 

Considerations for Physicians on Switching Decisions Regarding Biosimilars

Reflection Paper on Statistical Methodology for the Comparative Assessment of Quality Attributes in Drug Development

, EMA/CHMP/138502/2017 (London, March 2017).
	5. IMS Institute for Healthcare Informatics, 

Delivering on the Potential of Biosimilar Medicines

 (Parsippany, New Jersey, March 2016).
	6. M. Uda, Italian Biosimlars Group, “The New Italian Procurement Law on Off-Patent Biological Medicines,” presentation at Medicines for Europe’s Biosimilar Medicines Conference (London, March 2017).

	When referring to this article, please cite it as S. Milmo, “A Question of Quality,” 

Greater transparency and reliability of information are needed in the quality assessments of biosimilars.

A Question of Quality

	A big worry for the European pharmaceutical industry about Brexit is the impact it will have-at least temporarily-on the efficiency of the operations of the European Medicines Agency (EMA). As a result of the United Kingdom’s departure from the European Union following a referendum on the issue of its membership in June 2016, EMA is having to move its headquarters from London to a location, yet to be decided, in one of the 27 remaining EU member states. EMA, which has been based in London since its foundation in 1995, runs the EU’s centralized system for the approval of new medicines and its pharmacovigilance system, as well as coordinating the European Union’s regulatory network of national competence authorities (NCA) responsible for licensing and regulating drugs in each member state.

	There have been hopes that the effects of the agency’s move would be minimized by the transfer taking place over a phased transition period of a few years in line with a gradual withdrawal by the UK from the EU starting in March 2019. This approach would enable the UK to continue to assist in the agency’s operations to help avoid delays in approvals of medicines and licence variations, as well as in the publication of key documents such as guidelines. However, it is now possible that the relocation may have to take place relatively quickly. The agency revealed in late April 2017 that it is starting to draw up contingency plans for a complete break between the EU and the UK in March 2019.

	“Although negotiations on the terms of the UK’s departure have not yet officially commenced and one cannot prejudge their outcome, work will now start on the basis of the scenario that foresees that the UK will no longer participate in the work of EMA and the European medicines regulatory system as of 30 March 2019,” the agency said in a press release (1).

	The UK and the EU are due to start negotiations in June 2017 on a withdrawal deal, which is increasingly expected to amount to what is dubbed as a “hard Brexit” without an agreement on trade and regulatory issues, covering matters such as an extended timetable for EMA’s transfer to a new location.

	“We don’t want any disruption of EMA’s operation leading to delays causing the build-up of a backlog of work,” says a spokesman for the Brussels-based European Federation of Pharmaceutical Industries and Associations (EFPIA). “It is essential that we have regulatory continuity across Europe,” he told 

	EFPIA published in April 2017 an open letter (2) signed by heads of R&D in 19 multinational drug companies expressing anxieties about the “stark and alarming reality that [EMA’s] fundamental activities would undoubtedly be impeded were the operations of the agency to be disrupted as a result of the United Kingdom’s exit from the EU.” It added that “in the event of obstruction or failure, Europe possesses no backup option.”

	A disorderly departure by EMA is of particular concern to UK pharmaceutical manufacturers, which include leading international drug companies GlaxoSmithKline (GSK) and AstraZeneca. The country needs a smooth transition to what is likely to be a stand-alone medicines regulatory system operating separately from the EU’s regulatory network.

	“Moving an agency like EMA is a huge task,” Virginia Acha, executive research director at the Association of the British Pharmaceutical Industry, told 

 “We have made clear that we would like the EMA and all 28 national competent authorities to work closely to ensure that we avoid delays to the important work of regulating and ensuring supply of medicines for patients across the EU.” 

	A big challenge for EMA is filling the post-Brexit gap being left by the loss of the expertise of the UK’s drugs regulator-Medicines and Healthcare products Regulatory Agency (MHRA). Its experts have been contributing 30–40% of assessments of new medicines and other items, according to an MHRA official. EMA says that in 2016, the agency acted as a rapporteur for 14% and co-rapporteur for 16% of the products approved by EMA’s Committee for Medicinal Products for Human Use (CHMP). Now EMA has started work on sharing out contributions from experts in national agencies much more evenly. “The expertise available across the network is impressive and [Brexit] is an opportunity to streamline the way we work, increase our capacity, and work even more efficiently,” said EMA’s Executive Director Guido Rasi (1). 

	The agency started discussions in April 2017 on changes to the system for evaluating and monitoring medicines. The changes will be based on the principles of “ensuring business continuity; maintaining the same high standards of the scientific assessment; continuing compliance with legal timelines; and ensuring knowledge retention, either by building on existing knowledge, or through knowledge transfer,” an EMA spokesperson told 

	A number of EU member states are already preparing to increase their capacity for assessment and monitoring work so what has been done by 28 member states will be able to be carried out as efficiently by 27. Furthermore, the work will be carried out by more mixed teams of experts from different EU countries rather than, as previously, by teams from single states.

	“EMA has found an effective response to the challenge [of Brexit],” the spokesperson said. “We have put in place multinational assessment teams. Traditionally, the assessment of medicines was carried out by teams from individual member states. This shows that science works best without borders.

	“This multilateral approach benefits the EU system as a whole but it also benefits the individual member states as it raises standards and increases participation,”
	she continued. “This approach will become even more crucial as EMA faces a loss
	of expertise through Brexit. Increasing skills across Europe and promoting participation in EMA’s activities will allow us to keep our complex machinery
	working and delivering for patients in the EU.”

	EMA claims that the EU regulatory network, the largest of its kind in the world,
	is strong and flexible enough to adapt to changes such as Brexit without putting at risk the quality of its work. “Using a timely and inter-connected process, it brings together the best experts from across the EU to do the right job at the right time with the right people,” the spokesperson said. “EMA and the patients in Europe cannot afford that this well-oiled machinery starts to stutter.”

	In its efforts to maintain continuity, the agency also faces the challenge of keeping as many of its 890 staff as possible, particularly employees who provide expertise and experience. “We have seen a decrease in the number of [job] applications received by the agency,” the spokesperson said. “We are looking at this closely to understand if it could have any implication for the agency’s work and to keep possible disruptions to a minimum.”

	The choice of a new location for EMA, a decision that is due to taken by the
	governments of the 27 EU member states in 2017, is seen as being crucial to the need to attract adequately qualified staff as not all existing employees are expected to stay with the agency. More than 20 countries are reported to have expressed
	an interest in hosting the new EMA headquarters with the favourites being
	countries that have relatively large domestic pharmaceutical industries, such as France, Germany, Italy, Spain, Ireland, and Denmark.

	Among the essential requirements for the location listed by the R&D heads in their open letter are a capability to accommodate approximately 36,000 visits of experts annually, excellent transport links, and an adequate number of hotel rooms. Also, there must be “sufficient and decent housing and access to international schools for staff with children,” they say.

	Another cloud hanging over the transfer of EMA’s headquarters is a lease agreement that commits it to paying rent on its offices in London until 2039. With business rates and services charges, the total debt could be approximately €400 million. A European Parliament report on the agency’s finances published in April (3) reveals that the total payable rent for the period from 2017 until 2039 amounts to €347.6 million because of the absence of a break clause in the rental agreement signed in 2011 when “the potential exit of the UK from the Union was not foreseeable.”

	The report expresses concern about the “risk of budgetary volatility faced by the agency” as a result of the need to move its offices. It suggests that “in the spirit of sound financial management,” EMA should be authorized to maintain a budgetary reverse to cover unforeseen costs due to the transfer.

	Some EU politicians are arguing that the UK should pay the outstanding rental and the costs of the move of offices because it voted to leave the Union rather than being made subject to an involuntary exit. This issue should be a matter to be sorted out in the withdrawal negotiations. But with the agreement having to be finalized by March 2019, there may not be time to resolve issues relating to the costs associated with the EMA’s new location.

	1. European Medicines Agency, “EMA and Heads of National Competent Authorities Discuss Consequences of Brexit-Key Principles and Working Methodology Established,” Press release, EMA/271635/2017 (London, 28 Apr. 2017).

	2. EFPIA, Open Letter from the Pharmaceutical Industry Heads of Research and EFPIA on the Relocation of the European Medicines Agency  (Brussels, 24 Apr. 2017).

	3. European Parliament, Decision on Discharge of the European Medicines Agency Budget for the Financial Year 2015, 2016/21/2169–DEC (Brussels, 27 Apr. 2017). 

The impact of Brexit on the European drug approval regulatory framework presents challenges for EMA.

EMA Faces Brexit Challenges

	The European Union is aiming to play a big role in the creation of a global uniform system for medicines identification by establishing across Europe a project under which pharmaceutical data would be captured once and then used to underpin a product’s whole lifecycle. The pioneering scheme would be based on a five-year-old package of data standards on the Identification of Medicinal Products (IDMP) drawn up by the Geneva-based International Organization for Standardization (ISO). However, a growing proportion of the European pharmaceutical industry have been losing enthusiasm for the project because of its complexity, which has been causing numerous problems with its implementation. 

	“The leading multinational pharma companies are taking IDMP seriously and are taking steps to be ready when it legally has to be implemented,” said Paul Attridge, senior director R&D Europe of the Veeva Vault data management platform of San Francisco-based Veeva Systems Inc. “But a lot of medium-sized and smaller companies are holding back,” he told 

	The European Commission, the EU’s Brussels-based executive, and the European Medicines Agency (EMA), the EU’s central medicines authority, which at present is headquartered in London, are having to step up their efforts to persuade doubting pharmaceutical companies of the benefits of the scheme. Medium and smaller pharma companies have become even more sceptical in the wake of postponements of key stages in the introduction of IDMP in the EU. Much of the blame for these disruptions has been put on failures by ISO to meet timelines for the publication of implementation guides for IDMP standards.

	Companies are reluctant to spend money now on making their data systems IDMP-compliant when EMA may have to yet again put back the mandatory enforcements of the standards. In 2016, EMA postponed the full implementation of IDMP by two years. 

	A big worry among companies, however, is the impact of Brexit on the operations of the agency because of the need for it to move its headquarters out of the United Kingdom following the country’s vote in favour of leaving the EU in a referendum held in June 2016. The UK’s departure from the Union is not due to take place until the spring of 2019, while the relocation of EMA to one of the EU’s remaining 27 member-states may be deferred beyond that date. There are still fears that during preparations for its exit, work in the agency on IDMP will be slowed down, particularly if specialist staff start to leave.

	“Companies are not investing in IDMP themselves because of the constant delays in its implementation and now concerns about the impact of Brexit,” Christine Hirt, managing consultant at Extedo GmbH, regulatory information management specialists at Ottobrunn, Germany, told 

 Another factor is a distrust of standards, particularly among the smaller companies. Such distrust tends to become stronger the more complex the standards are and the more effort and preparation are required to comply with them. 

	A major reason for IDMP’s complexity is the breadth and depth of the scope of its five standards with an emphasis on a high degree of “granularity” or detailed information on the main stages of a product’s lifecycle. The standard on substances (ISO 11238) covers both active and non-active substances, their general characteristics, and also specific details on manufacturing, purity, and grade (1). The one (ISO 11239) focusing mainly on dose forms includes units of presentation, routes of administration, and packaging (2). It identifies, for example, injection solution, injection suspension, and infusion solution. Another standard (ISO 11240) relates to the usage of units of measurement with requirements for reference code systems and vocabularies for units (3). 

	IDMP distinguishes between products as medicines and pharmaceuticals by having two separate standards for each. The one (ISO 11616) on pharmaceuticals brings together identifiers such as active substance, strength of units, and administrable dose forms (4). The standard (ISO 11615) on medicinal products focuses mainly on regulation information during the entire lifecycle-such as that on development, authorization, post-marketing, and approval renewal or withdrawal from the market (5).

	The first versions of the standards were published by ISO in 2012 to serve the needs of pharmacovigilance schemes, in particular the necessity that authorized drugs found to have previously unknown side effects can be accurately identified with their manufacturing details such as production sites and batch numbers. The primary purpose of IDMP was to create a basis for healthcare providers and professionals to be alerted across Europe immediately after the reporting of an adverse reaction to a drug. Over time, it would also allow data banks on these reactions to be built up for in-depth analysis so that actions can be taken to prevent side effects. However, it soon became clear that IDMP also had the potential to be applied to many more areas of pharmaceuticals and healthcare than pharmacovigilance. 

	An EMA list of other applications for IDMP include batch recalls, in addition to those triggered by pharmacovigilance, inspections including those related to good manufacturing practice (GMP), drug shortages, regulatory activities such as approval of variations like process changes, e-prescriptions, and initiatives under the EU’s Falsified Medicines Directive (FMD), such as the identification of individual product packs.

	A drawback of IDMP’s broad scope is that it makes the necessity for continuous correction of glitches and deficiencies more likely. This problem became clear at an early stage when ISO specialists discovered defects when working on implementation guides for the standards. When EU experts started looking closely at the standards, they found important omissions, such as proper coverage of differences in packaging and pack sizes. All these flaws-some minor and others major-were a primary reason for delays in the implementation stages. 

	For EMA, the key application of IDMP will be the obligation for pharmaceutical companies under article 57 (6) of its amended 2004 medicines authorization legislation to submit information to the agency on authorized medicines and keep this information up-to-date. Currently, article 57 data are based on an EMA format, Extended EudraVigilance Medicinal Product Dictionary (XEVMPD), that ultimately will be replaced and considerably expanded by IDMP. It is an example of a process under which large amounts of data are captured at one source and then reused for several other applications, such as pharmacovigilance and variations approvals.

	For EMA, IDMP is viewed as a master data management system with master data being defined as any information that is considered to play a key role in the core operation of a business. IDMP will be realized through the agency’s SPOR master data programme covering the four domains of substances, products, organizations, and referentials (SPOR). Data on substances will be on the ingredients making up the medicinal product while data on products will cover their marketing and medicinal information. 

	Organization data will be about organizations that develop, own, and manufacture the products, which, with pharmaceutical manufacturers, will be their company names, their addresses, plants, distribution centres, and their regulatory agencies. Referentials data list terms and controlled vocabularies (CVs) used to describe attributes of products such as dosage forms, country codes, package codes, and weight codes.

	Each SPOR domain is being operated through management services projects that will be key enablers in a phased implementation of IDMP, especially in the maintenance of timelines. By mid-2017, the referentials and organizations management services (RMS and OMS) should start the process for testing their data systems with external users who will then have the chance to correct deficiencies. This will provide a basis for the later testing of the products and substances management services (PMS and SMS). The whole of SPOR should go live for testing as an integrated system by mid-2018, leading to IDMP becoming mandatory for pharmaceutical and other companies a year later.

	EMA’s IDMP operation should extend beyond just the agency being a repository for vast quantities of data. It also must provide the means for the analysis of data, especially data relating to adverse drug reactions.

	“The analytics capability is crucial to the whole realization of the IDMP scheme because without it, EMA will not be able to work out where else adverse reactions may take place and where they may be able to take preventive action,” explained Attridge. “Otherwise pharmaceutical companies will not be very happy about establishing IDMP-compliant systems at quite high costs when the agency is not able to make proper use of it.”

	“For companies, IDMP can be a transformational programme, which will provide them with their own master data management system to break down information siloes and ensure that important information is accessible,” he continued. Ultimately, the success of IDMP in Europe and elsewhere will depend not only on its improvement of regulatory efficiencies but also of the IT operations of pharmaceutical companies.

		International Organization for Standardization, 

ISO 11238. Health informatics-Identification of medicinal products-Data elements and structures for the unique identification and exchange of regulated information on substances 

ISO 11239. Health informatics-Identification of medicinal products-Data elements and structures for the unique identification and exchange of regulated information on pharmaceutical dose forms, units of presentation, routes of administration, and packaging

ISO 11240. Health informatics-Identification of medicinal products-Data elements and structures for the unique identification and exchange of units of measurement

ISO 11616. Health informatics-Identification of medicinal products-Data elements and structures for the unique identification and exchange of regulated pharmaceutical product information

		International Organization for Standardization,

 ISO 11615.Health informatics-Identification of medicinal products-Data elements and structures for the unique identification and exchange of regulated medicinal product information

Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency


	Vol. 29, No. 5
	May 2017
	Pages: 6–8

When referring to this article, please cite it as S. Milmo, “The Complexity of IDMP,” 

Many pharmaceutical companies are sceptical about IDMP despite the business benefits and its contribution to patient safety.