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

Sean Milmo

	In the aftermath of COVID-19, the European Medicines Agency (EMA) has the task of returning to its level of activities before the onset of the pandemic. But it also faces the longer-term challenge-not directly related to the disease-of restoring all the broad spread of activities of the agency before it had to relocate from London in the United Kingdom in 2019 to Amsterdam in the Netherlands. A move that is required by European Union rules as a result of the UK’s referendum vote in June 2016 in favour of ending the country’s membership of the EU, commonly referred to as Brexit. 

	Due to the upheaval of the relocation, including the loss of some specialist staff, the agency had to suspend some non-core activities. EMA was scheduled to return to pre-Brexit normality in June 2020, but the arrival of COVID-19 has forced it to postpone this deadline.

	Now there is the possibility that some of the suspended activities may have to be abandoned so that EMA can adequately take on new responsibilities. A major reason for this outcome is that the agency would require a larger budget after already receiving extra funds to help pay for the relocation and costs of implementing new legislation.

	“At the end of 2019, the agency was in as good a shape as it could have been following its move,” wrote Christa Wirthumer-Hoche, chair of EMA management board in the foreword to the agency’s annual report, published in June 2020 (1). “However, the board remains concerned about the longer-term prospects of the agency’s full recovery if the on-going constraints cannot be addressed,” she warned.

	Important areas of the agency’s work remained mostly suspended throughout 2019. In June 2019, the agency was able to resume a small number of IT and digitalization activities, which had helped underpin the effectiveness of its medicines’ evaluations and various administrative processes (1).

	Also, in September 2019, some of the working groups within the EU medicines regulation network, which contributed to the EMA’s core activities, were restarted (1). These groups included one focused on good manufacturing and distribution practices, a working party on quality, and a team covering process analytical technology (PAT) (1). Working parties for patients and consumers and healthcare professionals also restarted (1).

	Nonetheless most of the operations, which were suspended or reduced in 2018, remained on hold. This comprised a lot of guideline development work, engagement in international activities, most working party meetings, and the agency’s proactive publication of clinical data.

	The COVID-19 outbreak earlier this year resulted in the full recovery of EMA operations being delayed once again. Instead, priority had to be given to regulatory work on vaccines and treatments for the pandemic even over other non-COVID core activities.

	EMA’s work during the pandemic is geared to giving precedence to dealing with the emergency development and authorization of COVID-19 vaccines and treatments. This is being done, however, without sacrificing standards in its key central role of authorizing and monitoring the marketing of all medicines.

	The agency has established dedicated task forces for meeting the scientific, regulatory, and operational challenges of disease. An EMA business continuity plan (BCP) for COVID-19 aims both to ringfence resources for dealing with the disease while exercising the agency’s core responsibilities for the evaluation and supervision of medicines. 

	The EMA pandemic Task Force (COVID-ETF) helps EU member states and the European Commission (EC) to take quick and coordinated regulatory action on COVID-19 treatments and vaccines. The taskforce, which is accountable to EMA’s Committee for Medicinal Products for Human Use (CHMP), reviews scientific data on potential COVID-19 medicines while also identifying promising candidates. Furthermore, it assists the agency’s pharmacovigilance risk assessment committee on post-marketing safety issues with COVID-19 products.

	The European Medicines Regulatory Network (EMRN), headed by EMA and comprising the medicines licensing authorities of all EU member states and also non-EU members like Norway and Iceland, has also drawn up a BCP ensuring that priority is given by regulators across much of Europe to COVID-19 issues (2). This BCP includes not just the development and authorization of COVID-19 vaccines and treatments but also potential shortages of essential medicines for COVID-19 patients, particularly those in intensive care units (ICUs).

	“The magnitude of this additional work is difficult to quantify at the moment,” said the EMRN BCP, in a joint statement issued by the EC, EMA, and Heads of Medicines Agencies (HMA), representing national authorities (2).

	As a result of pressure on the work time of regulators from COVID-19 matters, pharmaceutical companies are thought to be holding back the application for marketing authorizations of their products or approval of variations of marketing authorizations. “The extent of the impact on the pharmaceutical industry is also unknown, including whether it will result in the reduction or delay of submissions (for authorizations),” the BCP stated (2). 

	One major uncertainty for regulators is how much a reduction in submissions for authorizations of non-COVID-19 drugs will be offset by a rise in applications for approval of COVID-19 medicines. Also, regulators in EMA and national agencies are concerned that once the threat of COVID-19 cases fades there will be a sharp rise in previously delayed submissions from pharmaceutical companies (2).

	Regulators are not only worried about having to grapple with a rush of delayed submissions but also the extra burden of implementing new EU legislation in areas like veterinary medicine, medical devices, and personal data protection. A new veterinary medicines regulation, due to come into effect in January 2022, represents a major overhaul of the agency’s system for authorization of veterinary medicines while strengthening EMA’s action against antimicrobial resistance (1). It is all being done without a staffing increase.

	Under the new medical devices regulation, in which EMA has a role in the approval of products such as drug–device combinations, the agency’s responsibilities have been considerably extended (3).  

	“With the ever increasing pace of innovation and the blurring of the traditional boundaries between medicines and devices, it is inevitable for the agency to assume new responsibilities in the regulation of complex medicines with a medical device component,” said Guido Rasi, EMA’s executive director, in the agency’s latest annual report (1). “The big challenge we face is to ensure we have appropriate expertise and resources to adequately carry out these tasks,” he added.

	A lot of time and resources has also been taken up with the establishment, under the new Clinical Trials Regulation (4), of an EU-wide integrated information system throughout all the member states. “This is one of the most complex and ambitious IT developments ever undertaken by EMA,” said Wirthumer-Hoche in the annual report (1). 

	EMA has been expanding its overall infrastructure and staff expertise in data analytics and artificial intelligence (AI). The agency initiated an in-depth review of its organization last year in what it calls a ‘future proofing’ exercise to strengthen its ability to take on new activities. Four task forces have been set up to deal with key priorities, two of them in digitalization-digital business transformation and data analytics-with the other two covering regulatory science and innovation, and clinical trials and manufacturing strategy. 

	Digitalization will help provide a stronger evidence base for regulatory decision-making. It will also improve productivity when even after a recruitment drive the agency was still suffering staff shortages at the end of last year. Total staff then numbered 775 compared with around 900 in London. Lack of staff with the right expertise remained a concern.

	A joint HMA/EMA Big Data Task Force recommended in December 2019 that the regulatory network set up a platform for access and analysis of healthcare data from across the EU (5). The platform would be called Data Analysis and Real-World Interrogation Network (DARWIN). 

	It would initially focus on the analysis of electronic health records to support regulatory decision-making. One objective would be to complement data from randomized clinical trials with evidence from healthcare practice so that regulators could validate claims by pharmaceutical companies about their products.

	The system would need to be supported by a lot of expertise from external sources and the recruitment of data scientists and specialists in advanced analytics and AI. 

	It would also be expensive, putting further strains on EMA’s finances. With all the other additional burdens on its budget, the agency faces a dilemma about the resumption of activities, which have been put on hold since the move from London. Some may have to be sacrificed by being permanently shelved. 

	Rasi, who is due to retire from his job at the end of 2020, said in his introduction to the agency’s annual report that he hopes that by then EMA can finally “close the chapter on our relocation.” He, or his successor, may find that first some controversial decisions may have to be taken before closure is achieved.

	1. EMA, “Annual Report 2019” (Amsterdam, June 2020).
	2. EC, HMA, and EMA, “European Medicines Regulatory Network COVID-19 Business Continuity Plan” (Brussels, 28 May 2020).
	3. EU, 

Regulation (EU 2017/745) on Medical Devices

Regulation (EU 2014/536) on Clinical Trials on Medicinal Products for Human Use

 (Brussels, 16 April 2014)
	5. HMA and EMA, “Joint Big Data Taskforce Phase II report: Evolving data-driven regulation” (Brussels, January 2020). 


	Vol. 32, No. 7
	July 2020
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “Business on Hold? EMA’s Full Recovery in Question,” 

Articles

EMA is facing a dilemma in trying to restore activities back to normal after relocating and the COVID-19 pandemic.  

Business on Hold? EMA’s Full Recovery in Question

	The European Union has started drawing up a pharmaceutical strategy, which will be closely linked to a new EU industrial strategy and could trigger a shake-up of policies and regulations in the European medicines sector. Broad changes in some parts of the EU’s pharmaceuticals regulations have been on the cards since the European Commission (EC) introduced a regulations improvement programme (REFIT) five years ago to simplify legislation and make it less burdensome for business without compromising policy objectives (1).

	A major driving force behind the pharmaceutical strategy, being drawn up by the EC for consultation due to start by the end of 2020, will be a desire to reverse Europe’s loss of its position as the global leader in the development and production of new medicines. Today almost half of global new drug treatments originate in the United States, according to the European Federation of Pharmaceutical Industries and Associations (EFPIA) in a report in March 2020 backing a new EU industrial and pharmaceutical strategy (2).

	In 2014–2018, only 25% of new drugs emanated from Europe (2). “[This] represents a reversal of the medical innovation landscape [25 years ago],” commented Nathalie Moll, EFPIA director general in the introduction to the document. At the same time, a growing number of new treatments are being approved first in emerging markets, such as China, she pointed out. “Both [strategies] bring the future of Europe’s life-sciences sector into sharp focus and represent a unique opportunity to work together to re-establish Europe’s global leadership in medical innovation,” she added.

	This ambition will require pharmaceutical policies and regulations, which will incentivise new investment in R&D and processing technologies, particularly those based on digitalization and artificial intelligence (AI). Also, the policies and regulations will have to be in line with key objectives of Europe’s industrial strategy, being at the forefront of the global fight against climate change and protection of the environment.

	Europe does currently have a strong position in vaccines R&D and manufacturing, which could be useful in the international competition among medicine producers for leadership in the development of vaccines to combat COVID-19. However, the COVID-19 crisis has also highlighted Europe’s dependence on imported APIs and generic medicines made in China and India. In volume terms around three quarters of Europe’s API requirements come from these two countries (3).

	Partly as a result of plant closures in China and India, there have been shortages of some essential medicines in Europe, such as drugs for treatment of COVID-19 patients in intensive care units (ICUs). Some EU member states have been banning the export of some crucial hospital medicines to other European countries during the COVID-19 crisis. Despite the EU being a free trade area, Union rules give member states the freedom to take virtually whatever measures are necessary to protect public health within their borders. There have been hoarding and stockpiling of COVID treatments by individual countries even though they have had relatively low infection rates of the virus.

	“We have a situation in which countries have more supplies of certain drugs then they have needed while other countries were suffering from shortages of these medicines,” explained Adrian van den Hoven, director general, Medicines for Europe, the main trade association for generic medicines and biosimilars producers and suppliers. “The COVID-19 pandemic has confirmed that the main cause of drug shortages is not problems with production but difficulties of allocation,” he told Pharmaceutical Technology Europe. “This is an issue which ought to be dealt with by the pharmaceutical strategy.”

	COVID-19 prompted some industrial groups to make their own arrangements for sorting out medicines’ shortages. Medicines for Europe, for example, has been acting as an ad hoc coordinator of its members to enable them to divert hospital products to countries where they were most needed, explained van den Hoven. It even brought in management consultants A.T. Kearney to help create a modelling system for forecasting where there would be the strongest demand for specific medicines, he added.

	The EC had to be asked to lift rules on competition and labelling of packaging to make the redirection of medicines legally possible, according to Medicines for Europe. “Current regulations need to be altered so that the EC can organize the allocation of medicines during crises like the COVID-19 pandemic,” said van den Hoven. “The commission is the right body to take on that role.”

	Prior to COVID-19, the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) representing national licensing authorities, had created an HMA/EMA taskforce on medicines availability (4). Its job was to help regulatory authorities ensure continued availability of medicines at times of shortages.

	But the taskforce lacked enough clout to provide fast-track capability during major emergencies. So, in March 2020, the commission created an EU Executive Steering Group to manage shortages during serious events, such as pandemics. The group is chaired by the EC with EMA acting as an official central coordinator.

	The EC has made clear that a key objective of the pharmaceutical strategy is to establish a more streamlined structure for handling big emergencies in the post-COVID-19 period. The new strategy will focus on the “availability, affordability, and security of supply of pharmaceuticals [which] has been highlighted by recent events linked to the coronavirus disease outbreak,” the commission said in a communication issued in March 2020 (5).

	The aim to incorporate lessons learned from the COVID-19 crisis in the pharmaceutical strategy may explain delays in the publication of a roadmap on the strategy, due in March 2020. The pharmaceutical committee of the EC’s health and food safety directorate (DG Sante) was told in March 2020 that it would be given details for the strategy by the end of the year. This may now be put back.

	The plan was that the publication of the roadmap would open the way to detailed discussions on the strategy with the committee, consisting mainly of representatives from EU member states. This would enable the committee to be “an important forum of interaction” on the contents of the document, according to a report on the committee’s March meeting.

	Encouraging investment in API manufacturing

	The issue of shortages is still seen as being closely tied to limitations to Europe’s manufacturing capacity, particularly with APIs. It is acknowledged by industry that there is a need for a regulatory framework that would encourage more investment in the modernization of production processes.

	More could be done to exploit the strengths of European-developed technologies, perhaps through additions to the existing range of regulatory financial and other incentives, extension of intellectual property rights, more protection of technological data, and greater market exclusivity, such as that applied to orphan drugs.

	With APIs, for example, Europe is heavily reliant on Chinese and Indian imports for bulk actives. But in the global marketplace, it is well positioned in the development and manufacture of more advanced APIs, which account for much of Europe’s one-third share of worldwide actives output (2).

	More than three quarters of APIs used in the manufacture of innovative medicines in Europe are sourced in the region with a further 11% coming from the US and only 9% originating from Asia, according to EFPIA figures (6). “European producers can be incentivised to focus on the development and production on APIs for crucial medicines and whose manufacture is complex and difficult,” said van den Hoven.

	The pharmaceutical strategy will also reflect broader key features of the industrial strategy, such as the EU’s quest for international leadership in digitalization and AI and in green technologies. The EC hopes that an acceleration of digitalization across EU industry will help boost the European Green Deal by helping the development of green technologies and lower carbon footprints.

	The current trend in the pharmaceuticals sector is for the expansion of digitalization from manufacturing processes through to clinical trials, pharmacovigilance, and disposal but in a way that ensures that wastewater, for example, can be reused because it is free of pharmaceutical residues.

	Cost-saving increases in regulatory efficiencies through the wider application of IT systems have enabled faster assessments of variations approvals. The high cost of submitting approvals for variations in APIs can be decreased by IT initiatives under which information on active ingredients is stored in the same dossier so that the producer or supplier of the APIs apply for variation approvals rather than individual medicine manufacturers.

	These would be proposals on authorizations, which would involve EMA or national licensing agencies. But a lot of changes put forward by the pharmaceuticals strategy could lead to the EC being given more direct responsibilities in the medicines sector, which may be opposed by member states.

Better Regulation: Delivering Better Results for a Stronger Union

, Communication, 14 Sep. 2016.
	2. EFPIA, “

EU Industrial and Pharmaceutical Strategy: An Opportunity to Drive Europe’s Health and Growth

, Press Release, 9 March 2020.
	3. European Fine Chemicals Group, “

Addressing the Acute and Complex Issue of Medicines Shortages

, Briefing Paper (September 2019).
	4. HMA, 

HMA/EMA Task Force on Availability of Authorized Medicines for Human and Veterinary Use

, Communication, 10 March 2020.
	6. EFPIA, “

EFPIA Statement Following the Call with EU Commissioner Kyriakides


	Vol. 32, No. 6
	June 2020
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “A Strategic Shake Up in Europe’s Medicines Sector,” 

The EU’s pharmaceutical strategy has the potential to shake up the policies and regulations of the region’s medicines sector.

A Strategic Shake Up in Europe’s Medicines Sector

	The European Medicines Agency (EMA) published, at the end of March 2020, the final version of a report on its strategy for regulatory science, which it sees as the basis for meeting the major challenges in medicine during the next five years (1). Three years of the report’s preparation involved several rounds of consultation and two workshops with representatives of stakeholders.

	But, unfortunately, the document was issued at a time when the coronavirus outbreak (COVID-19) had not yet shown itself to be causing the biggest public health crisis in Europe for 100 years. As a result, the report, which covers both human and veterinary medicines, devotes relatively limited space to ways of using regulatory science to deal with pandemics such as COVID-19, particularly the emergency development and mass-scale manufacture of vaccines. 

	Instead, to deal with the outbreak, EMA has implemented its 2018 Health Threat Plan by setting up a COVID-19 EMA Emergency Task Force (ETF), which will assist in the development, authorization, and safety monitoring of therapeutics and vaccines to deal with the pandemic (2). The agency has also been internationally active by co-chairing virtual meetings of the International Coalition of Medicines Regulatory Authorities (ICMRA) on collaboration between regulators on the development of vaccines and the authorization of repurposed drugs for COVID treatments (3).

	EMA also published, with the regulatory science report, an analysis of stakeholder responses during the six-month public consultation to mid-2019 on the last draft of the document (4). The analysis confirmed that prior to COVID-19, pandemics and similar emergencies were not only being given relatively low importance by regulators but also by many stakeholder groups as well, particularly the pharma industry (4). 

	The study on responses also showed that among some stakeholders, even among national regulators, there is scepticism about EMA as the European Union’s central agency for pan-European approval of drug taking on extended roles beyond issues of medicines authorization. This opposition may become significant if EMA’s responsibilities are re-examined post-COVID-19.

	EMA’s consultation analysis, in which the 154 respondents, mostly in human medicines, were split into five clusters of patient/consumer organizations, healthcare professionals, research, public bodies, and the pharma industry, showed a relatively low recognition of the importance of issues linked to emergencies (4). These issues included health threat and preparedness planning, vaccines development and production, and repurposing of existing drugs. Of the regulatory science report’s total of 30 core recommendations, these issues were all ranked among the lowest five in importance (4).

	When respondents were asked to select one of their top three recommendations as delivering “the most significant change in the regulatory system over the next five years,” one on developing a framework for repurposing drugs and another on health threat and preparedness plans received no support (4). A proposed initiative on “innovative approaches to the development and post-authorization monitoring of vaccines” was backed by only four respondents (4).

	The regulatory science report highlighted the challenge of emerging technologies, such as new vaccine technologies and their manufacturing processes. But the main technologies pinpointed by the report were big data, precision medicines, clinical trial design, and even synthetic biology. For regulators, a big dilemma is the acquisition of knowledge about new sciences.

	On plans for the emergency development of vaccines and their large-scale manufacture, EMA suggested working with the EU’s regulatory partners outside Europe to harmonize the regulatory framework for vaccine clinical trials. Dedicated regulatory science advice and evaluation procedures have already been set up in the EU to support the fast development and oversight of new medicines, ranging from pandemic flu to any currently unidentified pathogen or ‘disease X’, the report said (1). The EU has research programmes to promote large-scale clinical research into infectious diseases and to design manufacturing processes to ensure rapid delivery of vaccines and antibodies.

	According to the report, experiences with the Ebola and Zika viruses, as well as the COVID-19 coronavirus, have demonstrated the importance of communications within the EU regulatory network and among stakeholders. To help preparedness, scientific evidence should be defined prior to outbreaks so that resources needed to combat the disease can be identified and ring-fenced (1). Additionally, the report suggested the creation of a platform for the monitoring of vaccine safety and effectiveness in the post-approval phase. It also recommended fostering the development of improved delivery systems based on novel technologies (1).

	The primary goal of the regulatory science strategy was to ensure that regulation can support the development of new medicines and innovative techniques, including manufacturing processes. This goal required even closer collaboration with academics and research centres to ensure an ongoing dialogue between regulators and developers at all R&D stages (1).

	New vaccines are among products requiring new manufacturing processes because of the need for rapid scale-up and fast production to bring them to patients as quickly as possible. These processes may seem to be contrary to the trend towards the development of complex manufacturing systems for the production of personalized advanced therapy medicinal products (ATMPs), which could be made at the point of care. However, there are also similarities. Novel vaccine production processes, particularly those requiring large quantities in response to pandemics, such as COVID-19, need a lot of flexibility and possibly different standards of good manufacturing practice (GMP).

	The report recommended that the creation of novel manufacturing technologies should be enhanced by regulators being trained in their assessment. This would help the identification of potential production problems while strengthening the early interaction between regulators, developers, and other stakeholders on the regulatory requirements for innovative manufacturing technologies.

	The introduction of new manufacturing processes will probably need, for regulatory purposes, the involvement of EMA’s four-year-old Priority Medicines (PRIME) system under which early scientific advice to developers of medicines addressing unmet needs is provided by the agency’s experts.  

	In the regulatory science report, EMA conceded that PRIME is resource intensive, while its purpose is not properly understood by some stakeholders. EMA recommended improved external communication about the scheme and proposed that measures should be taken to shorten PRIME review times. Furthermore, EMA suggested that the system should be reviewed in five years.

	The agency also acknowledged that the involvement of Health Technology Assessment organizations (HTAs) in PRIME is crucial so that the scientific advice takes their requirements into account. In their responses during the consultation, HTAs wanted closer alignment with regulators in areas such as pre-approval scientific advice. Whereas, pharma industry respondents were hostile to HTAs being involved in decision making because it complicates and politicises the licensing process, according to the analysis (4).

	This division of opinion was evident in a range of responses to recommendations in the regulatory science report; although on the whole, the recommendations were welcomed by respondents across the five clusters. Ironically the pharma industry and the research sector, whose representatives made up the majority of respondents, were the most supportive of the research science strategy. Among the organizations that tended to be the most critical and sceptical were public bodies.

	Some HTAs were against EMA extending its role in areas, such as biosimilars uptake and drug shortages, according to the analysis of the responses (4). In addition to medicines authorizations, the agency should concentrate on information sharing and facilitating co-operation between stakeholders, some HTAs claimed. Payers were concerned that EMA’s expanded role in bringing new medicines to market, such as through PRIME, made it a ‘co-developer’, while it should be restricting itself to the demonstration of clinical benefits and assuring a positive benefit/risk balance. Among EU regulators, national competent authorities (NCAs) for medicines licensing had doubts about how the regulatory science strategy would be turned into action and how NCAs would be involved in its implementation.  

	Overall, regulators and institutions questioned the sustainability of the EU’s current regulatory system in areas, such as updating guidance documents and the effective functioning of working parties and committees (4). No doubt some of these differences with stakeholders will be resolved by the imminent finalization of the EU’s regulatory network strategy to 2025 and the publication of the European Commission’s own strategy for pharmaceuticals.

 (Amsterdam, 31 March 2020).
	2. EMA, “

Mandate, Objectives, Rules, and Procedure of the COVID-19 EMA Pandemic Task Force (COVID-ETF)

 (Amsterdam, 31 March 2020).
	3. ICMRA, “ICMRA meeting: COVID-2019 Real-World Evidence and Observational Studies,” 

Analysis and Summaries of Public Consultation Results-EMA Regulatory Science to 2025

	When referring to this article, please cite it as S. Milmo, “Can EMA’s Regulatory Science Strategy Meet Medicine’s Major Challenges?” 

EMA’s strategy for regulatory science has divided opinion amongst various industry bodies.


Can EMA’s Regulatory Science Strategy Meet Medicine’s Major Challenges?

	European medicine regulators have, over the past few decades, been drawing up a series of detailed plans for the emergency development and massâscale production of vaccines, antivirals, and other medicines, as well as diagnostics to combat epidemics or pandemics. Regulatory bodies have been confronted by a range of diseases from outside Europe, such as severe acute respiratory syndrome (SARS) in 2002, H5N1 and H7N9 bird flues in 2003 and 2013, Middle East respiratory syndrome (MERS), and H1N1 swine flu in 2009. Among the most dangerous has been the Ebola virus, which first appeared in 1976 and still has not been completely eradicated (1).

	Most of these infectious diseases have high death rates-from 10% for SARS to 53% for H5N1 flu-but have a relatively low transmission level. Although posing major threats to the health of the region, they have not had a major impact on Europe. 

	However, the novel coronavirus disease, COVID-19, which emerged in China in late December to become a pandemic with over 600,000 cases and close to 30,000 deaths globally by 29 March 2020 (2), has been an entirely different matter. With a high transmission rate and a relatively low death rate, it has changed the whole regulatory process of dealing with sudden pandemics. 

	In Europe, COVID-19 has been a massive challenge to national healthcare services, public health policies, and scientists striving to develop vaccines and medicines to fight the virus as rapidly as possible. The carefully worked out emergency-response plans of the regulators to help bring new vaccines and medicines to the market has been severely tested.

	By late March 2020, Europe had become the global epicentre of the outbreak when growth in infections in China started to slow and cases in the World Health Organization’s (WHO’s) European Region rose to more than 360,000 with over 20,000 deaths (2).

	“There are no vaccines available (for COVID-19), and there is little evidence on the effectiveness of potential therapeutic agents,” the EU’s European Centre for Disease Prevention and Control commented in a bulletin on 12 March 2020 (3). “In addition, there is presumably no pre-existing immunity in the population against the new coronavirus and everyone in the population is assumed to be susceptible.”

	Fortunately, regulators had learned a lot from other, smaller-scale, outbreaks, particularly those of swine flu in 2009 and the 2014–2016 wave of the Ebola virus. The European Medicines Agency (EMA), responsible for the EU’s central medicines authorization process and for coordinating the EU’s medicines licensing network down to national level, performed “lessons to be learned” exercises after the swine flu and Ebola episodes. 

	Swine flu highlighted the importance of providing a scientific platform for quick research into new vaccines and medicines, working closely with partners such as public health agencies, and improved collaboration with international organizations active both inside and outside Europe.

	The regulatory effectiveness of the current response to COVID-19 has been helped by closer relationships built up by medicines agencies in Europe with researchers and drug companies working on new medicines. Regulators now frequently become involved at an early stage in the development of new drugs to speed up time-to-market.

	As a result, many of the companies submitting candidates for anti-COVID-19 vaccines and medicines for approval are already known to regulators, who have often been acquainted with the technologies behind them as well.

	Regulators are having to cope with a growing international dimension to the emergency research into new vaccines and therapeutics, whose ultimate objective is to bring to the market as quickly as possible products with a potential for global application. National agencies are tending to play a limited role amid this drive to globalize anti-COVID-19 vaccines and medicines with availability across Europe being only the first move to a worldwide market.

	CureVac, a German biotech company based at Tuebingen, which is developing a messenger RNA (mRNA) vaccine against COVID-19, is already known to German and EMA regulators because of its progress with work on a rabies vaccine, company officials said in a phone press conference on 17 March 2020 (4). After the COVID-19 outbreak, CureVac’s mRNA technology quickly made it a frontrunner for the development of a global coronavirus vaccine, a role in which it is competing with BioNTech, another German mRNA specialist.

	The attraction of the CureVac and other mRNA technologies is that its production can be scaled up without difficulty to good manufacturing practice (GMP) standards to produce low-cost vaccines that can be relatively easily stored and distributed without the need for refrigeration. Messenger RNA vaccines have the added advantage of being effective in small doses, and they can be modified fairly quickly to counter new strains of a virus.

	With vaccines based on more traditional technologies necessitating refrigeration, European regulators have pointed to the problem of storing and administering investigational products to clinical trial participants who have had to self-isolate. With the early backing of regulators, CureVac’s COVID-19 vaccine seems destined to reach the market quickly. Clinical trials are due to start in the summer 2020 (4). 

	Senior company executives met Ursula van der Leyen, the European Commission’s (EC’s) president, in March 2020. This was followed by the commission offering an €80 million (US$97 million) grant for the building at Tuebingen of a mass production plant for the vaccine (5). Also in March 2020, company executives met in Washington, DC with President Donald Trump and members of his administration. This meeting prompted media reports of an American plan to buy all of CureVac’s COVID-19 vaccine output or even to acquire the whole company, all of which has been strongly denied by CureVac executives. 

	Even for small companies, such as the UK-based start-up vaccine developer and producer Stabilitech, national regulatory approval of their COVID-19 vaccine is regarded as merely a stepping-stone to global distribution. A global goal is especially the case for UK-based companies because the country formally left the EU on 31 January 2020 and, hence, also left the EU’s medicines licensing network.

	Prior to the COVID-19 pandemic, Stabilitech’s technology platform was already known to the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) because of the company’s plans for authorization of a vaccine against the Zika virus (6). The company has developed a formulation technology that enables vaccines to be produced in temperature-resistant capsules, simplifying distribution and administering to patients.

	“Before COVID-19, we have been talking a lot to MHRA about our Zika vaccine, whose technology is similar to that for our COVID-19 vaccine,” Jeff Drew, Stabilitech’s chief scientific officer, told Pharmaceutical Technology Europe. “After clinical trials and completion of arrangements for large-scale GMP production in Europe, we plan to seek MHRA and then EMA approvals.”

	However, similar to a lot of other European companies developing vaccines and COVID-19 therapeutics, Stabilitech is looking to China as a fast-track option for global distribution. It has already established links with the Chinese Academy of Sciences, the country’s leading research institute.

	Another route to global distribution is being provided by WHO, which has been playing a major role in controlling the pandemic. WHO quickly published an updated version of its Emergency Use Listing (EUL) procedure for emergency distribution of unlicensed products two days after the Chinese announced the genome sequence for the COVID-19 virus in early January 2020. The new version simplified the EUL application process for manufacturers after it resulted in no new vaccines or therapeutics being listed in the 2014–2016 Ebola outbreak (7). 

	Unlicensed vaccines, medicines, and in-vitro diagnostic devices on the list can be made available throughout the world. Under the scheme, which is part of the 2005 International Health Regulations backed by all 194 WHO member countries, dossiers on products submitted for listing are thoroughly assessed by an expert committee, with the first endorsements likely to be made in March or April 2020 (7).

	The EUL is seen by WHO as a process running parallel with those operating in individual countries or regional entities, such as the EU, and as a result should not interfere with ongoing clinical trials (7). Additionally, WHO stresses that EUL inclusion is not equivalent to authorization by a medicines licensing agency (7).

	The organization also refers to the EUL scheme covering one or more additional waves of COVID-19. Both itself and other medicines and public health agencies are preparing for COVID-19 to be around for some time.

WHO Recommended Criteria for Declaring end of the Ebola Virus Disease Outbreak

, Technical Information Note, 4 March 2020.
	2. WHO, “

Coronavirus Disease 2019 (COVID-19): Situation Report, 69

Rapid Risk Assessment: Novel Coronavirus Disease 2019 (COVID-19) Pandemic: Increased Transmission in the EU/EEA and the UK-Sixth Update

, 12 March 2020.
	4. CureVac, “Conference Call on Current Developments,” 

Coronavirus: Commission Offers Financing to Innovative Vaccines Company CureVac

, Press Release, 16 March 2020. 
	6. WHO, “

Emergency Use Listing Procedure-Version 9 January 2020


	Vol. 32, No. 4
	April 2020
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “Learning Lessons in Crisis Management,” 

Regulatory emergency planning has been put to the test with the COVID-19 pandemic.


Learning Lessons in Crisis Management

	The European Union medicines licensing network, headed by the European Medicines Agency (EMA) and covering all of its 27 member states, has been falling behind the US Food and Drug Administration (FDA) and Japan’s Pharmaceutical and Medical Devices Agency (PMDA) in the application of Big Data in the authorization of medicines.

	Now a joint Big Data taskforce (BDTF) of EMA and the Heads of Medicines Agencies (HMA), representing national licensing authorities, has completed a twoâphase report on a proposed framework for realizing the potential of Big Data for enhancing public health and innovation (1). It aims to aid decision making not just by regulators but also by stakeholders, such as industry, academia, and healthcare professionals. 

	Although the proposals are mainly focused on raising the efficiencies of authorization and postâmarketing surveillance procedures, they are also aimed at strengthening the development of new medicines and processes, especially with advanced therapy medicinal products (ATMPs). The introduction and implementation of the framework will be a huge task in pulling together the data management activities of EU countries’ healthcare systems, while also establishing links with the Europe-wide data infrastructures of different research communities, especially in life sciences.

	However, the EMA–HMA initiative will be greatly helped by the impetus coming from a programme announced by the European Commission (EC), in February 2020, with the objective of making the EU’s data economy a leading force in the world (2). Through substantial advances in connectivity, processing and storage of data, computing power, and cybersecurity, Europe will be able to make large amounts of quality data available for use and re-use to improve health, well-being, the environment, and public services, according to the EC’s plans (2).

	“[The digital transformation] will be a truly European project-a digital society based on European values and European rules-that can truly inspire the rest of the world,” said the EC in a communication on Europe’s digital future in February 2020 (2). “But the benefits arising from digital technologies do not come without risks and costs. Citizens no longer feel in control over what happens with their personal data.”

	Hence the realization of the EU’s digital strategy will require new legislation, changes to existing regulations, guidelines, and other regulatory actions. This will particularly be necessary in healthcare and regulation of products like medicines, where issues such as standards of data quality, accountability, data management, transparency, and interoperability will be important.

	A key area will be the protection of personal data used in the development and improvement of new and existing medicines and treatments such as gene therapies, which may require access to real-world data (RWD) in patient records. The BDTF’s report is helping to shape the digital future in healthcare by putting forward 10 main recommendations, the implementation of which will become the responsibility of an HMA–EMA Big Data steering group (1).

	The taskforce suggested that the immediate focus should be on preparing the EU’s existing regulatory model for the new data environment. But it warned that the European regulatory network has currently both limited capacity and capability to access and analyse Big Data’s large, mixed, and unstructured data sets. The objective of using Big Data to raise the efficiency of regulatory decision-making “still sit closer to aspiration than reality,” the taskforce said (1). Nonetheless regulators had no alternative but to exploit the growing diversification of data generation.

	The BDTF’s recommendation aimed to tackle what the taskforce saw as the regulatory system’s main weaknesses in dealing with Big Data. These weaknesses ranged from the fragmentation of the European healthcare sector with countries pursuing their own policies in areas such as data generation and distribution. There was a lack of standardization in data management and controls and uniform metrics for gauging data quality (1).

	The General Data Protection Regulation (GDPR), approved by the EU in 2016 to replace the 1995 Data Protection Directive but which started to be implemented only last year (3), is already showing inadequacies in the protection of personal data, especially in respect of the application of artificial intelligence (AI) and machines learning with pharmaceuticals, as well as the use of algorithms in healthcare.

	To sort out many of the issues undermining effective use of data, the EU has had to find a means for dealing with the disparities between the healthcare data provided by its member states. Europe has a richness of healthcare data because in most countries there is universal healthcare coverage but the region lacks the means to take advantage of it, according to BDTF (1).

	Differences in health services, national guidelines, clinical practices, and even terminologies have resulted in the generation of heterogeneous data. Also, there is a shortage of funding at the national and EU levels to promote the creation of data, such as real-world databases, which could be used for regulatory purposes.

	BDTF claimed that in comparison to European countries, the United States, Canada, and Japan had committed ‘significant resources’ to establishing RWD systems to which regulators would have routine access (1). BDTF recommended that to encourage a centralized RWD operation, a European network of databases of ‘known quality and content’ with the highest level of data security should be set up. It would be called the Data Analysis and Real-World Interrogation Network (DARWIN) (1). 

	In addition to worries about data inconsistencies due to differences between national healthcare services, the taskforce was also concerned about poor data quality. BDTF cited a study which found ‘disappointingly low’ numbers of European databases able to meet minimum requirements on content and accessibility (4). BDTF suggested the establishment of a data quality system under which Big Data sources would have to undertake a renewable certification process.

	Operators of Europe’s data infrastructures, particularly those in Open Science sections, have been applying for around five years a standardization system (5). It is called FAIR, for findability, accessibility, interoperability, and reusability, which when bound together should ensure acceptable levels of data quality.

	Although FAIR has now been endorsed by governments not only in Europe but globally, the BDTF considered that it was only a long-term option for creating Big Data standards for the EU regulatory network. An interim report on four pilot assessments of the FAIR-compliance of datasets from research work by Brussels-based Innovative Medicines Initiative (IMI), which is jointly funded by the EU and the European Federation of Pharmaceutical Industries and Associations (EFPIA), found that compliance levels were ‘variable’ (6). Furthermore, the assessment processes themselves were underdeveloped and immature, leaving a lot of scope for improvement.

	Instead the taskforce proposed that for the short-term, EU regulators should use the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) and other repositories, such as Genomic Alliance for Genomic Health (GA4GH), for genomics data and Elixir, a European inter-governmental data-coordination platform for life sciences (1).  

	A major barrier to effective regulatory use of Big Data is the inability of current legislation to give full privacy protection to patient data. Despite its tough controls on personal data, the EU’s GDPR is already considered to be in need of tightening up because of weaknesses particularly in protection of patient data (7). In a review of the legislation issued in November 2019, Germany’s federal and state data protection supervisory authorities concluded that, despite the success of its regulatory concepts, “some uncertainty remains and there are shortcomings when it comes to implementation” (7).

	Because of a lack of clarity in parts of the GDPR, ‘countless’ data protection consultants have been offering customers interpretations of the text, the German authorities complained. These views were echoed in a briefing in on GDPR by GA4GH (8), which claimed that with key issues, such as consent and public interest, the legislation does not “give (enough) flexibility but reinforces a conclusion about the need for clarity.”

	As part of its data strategy, the EC is planning a series of measures, many of them legislative. With so many legislative initiatives in the pipeline, it could be several years before the EU introduces a full regulatory framework that determines how successful medicines regulators will be in using Big Data in their decision making.

	1. HMA–EMA Joint Big Data Taskforce, “

 Communication-COM (2020) 67 final (Brussels, 19 Feb. 2020).
	3. EU, 

The General Data Protection Regulation. Regulation (EU) 2016/679

(Brussels, 23 May 2018).
	4. A. Pacurariu, et al., 

, 8 (9) e023090 (2018).
	5. EC’s Expert Group on FAIR Data, “

(Brussels, 2018).
	6. IMI and FAIRplus, “First phase exemplar IMI projects FAIRified” (Brussels, 2019).
	7. Independent German Federal and State Data Protection Supervisory Authorities, “

Report on Experience Gained in the Implementation of the GDPR

(Berlin, November 2019).
	8. GA4GH, “GDPR Brief: ’At Least One’ Legal Basis for Processing under the GDPR: Clarifying Article 6 (1),” 


	Vol. 32, No. 3
	March 2020
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “Playing Catch Up with Big Data in Europe,” 

EU regulators have accelerated their efforts to use the mass of data emerging from the lifecycles of drugs as an effective basis for both the development and control of medicines.


Playing Catch Up with Big Data in Europe

	The United Kingdom and the European Union were scheduled to start negotiations in February 2020 on a permanent trading relationship in pharmaceuticals and other products after the UK finally departed the EU on 31 January 2020. Since the UK’s referendum vote in June 2016, Brexit has eventually led the way to a year’s transition period for the talks on an EU–UK Free Trade Agreement (FTA).

	Brexit also ended-at least for a while-three and half years of painful uncertainty during which there was a big threat of a ‘no-deal’ scenario on immediate issues, such as financial compensation and the position of around three million EU citizens who reside in Britain. No-deal would have triggered the immediate imposition of customs barriers leading to shortages of medicines both in the UK and the EU.

	For the pharma industry, the FTA aims to be a bold attempt to supply the basis for a collaborative regulatory framework to prevent large regulatory gaps opening up between the UK and European medicines sectors. But few experts believe that a year is long enough to thrash out such a complex arrangement, particularly in a such an intricately regulated sector such as pharmaceuticals. In the summer of 2020, the UK government has the choice of extending the transition by at least another year (1), but it has vowed not to take this opportunity. 

	For the industry, the priority will be that by 1 January 2021, when the transition will have ended and Brexit at last fully completed, there will be sufficient agreement on basic trade rules to ensure a smooth flow of medicines between the UK and the 27 EU member states. The worse-case scenario would be a breakdown in negotiations or a transition that ends without a deal of any sort. The EU–UK trade in pharmaceuticals and other products would then be governed by the rules of the World Trade Organization (WTO), which would seriously disrupt medicines supplies.

	The UK is a major centre of pharmaceuticals production in Europe, representing both a leading exporter and importer of medicines within the region (2). The EU accounts for around half of the country’s pharmaceutical exports and close to three quarters of pharmaceutical imports (3).

	Currently, 45 million patient medicine packs are supplied each month from the UK to EU member states and three European Economic Area (EEA) countries of Norway, Iceland, and Liechtenstein  (4). The EU/EEA in turn exports 37 million packs per month to the UK, according to figures from the European Federation of Pharmaceutical Industries and Associations (EFPIA) in Brussels (4).

	As long as EU regulations continue to apply to the UK during the transition, the stream of medicines, active ingredients, intermediates, and other raw materials between the EU and the UK will continue. Quality testing certificates will be recognized by the EU and vice versa, as will manufacturing and distribution licences. Marketing authorization holders (MAHs) will be able to remain based in the UK to have access to EU markets. In the context of international agreements, including mutual recognition agreements (MRAs) such as those covering good manufacturing practice (GMP) inspections, the UK will be treated as an EU member state.

	The big difference will be that the country will be a taker of EU regulations without any involvement in decisions in the drawing up or approval of new regulations or their amendments. UK regulators are no longer allowed to be rapporteurs or reference states for the co-ordination of approvals and mutual recognitions under the decentralized licensing procedure. In most cases, they will not be able to act as observers at meetings assessing marketing authorization applications. 

	“Decisions taken on marketing authorizations will be applicable in the UK,” a spokesperson for the UK Medicines and Healthcare products Regulatory Agency (MHRA) told Pharmaceutical Technology Europe. “The UK is not permitted to lead work, such as marketing authorization assessments, and is only allowed to attend decision-making committees ‘exceptionally’,” they added.

	UK-based pharma companies have been urged by the UK government or their trade association to use the transition to reorganize their distribution and supply operations in preparation for the full implementation of Brexit at the beginning of next year. EU pharma companies are being advised to take similar steps with regard to their exports into the UK. For many companies, particularly multinationals, decisions on these changes will have been taken last year because of the threat of a no-deal Brexit.

	One key aspect after the transition end is the location of batch testing and the base of a company’s qualified person responsible for quality control, both of which will have to be in an EU member state. Also, the locations of MAHs have to be moved to the EU (5). Preparations will have to be made for the approval, after the implementation period, of variations to centralized and decentralized authorizations if there have been changes to manufacturing and supply operations and to the labelling of products.

	The medicines industry in Europe, led by EFPIA, wants, with the support of the UK pharma sector, to keep pharmaceuticals regulations in the region as closely aligned as possible (4). This may not be achievable because, for the UK government’s ruling Tory party, a fundamental objective of Brexit is the introduction of regulations which diverge from those of the EU.

	The government’s aim with the UK pharma industry is to strengthen its leadership in basic research and product development with the help, if necessary, of the country’s newly acquired legislative freedom. This could be used to boost its biopharma clusters in areas with close links to universities like Oxford, Cambridge, and London, as well as hospital-based centres of excellence with their own manufacturing capacity.

	In EFPIA’s latest study of the performance of the European medicines sector, the UK pharma industry accounted for around 15% of the European industry’s R&D expenditure. It was the second biggest spender behind Germany in the EU (2). The UK is among the top five locations in Europe for clinical trials. Its two main pharmaceutical companies-GlaxoSmithKline and AstraZeneca-have been among the leaders in all European sectors for R&D collaborations between industry and academia.

	To encourage breakthroughs in technologies like gene therapy, the UK government could give hospitals more regulatory opportunities to develop decentralized systems for the manufacture of bedside treatments. This would contrast with the European Commission’s seeking of ways to tighten up controls on hospital-based drugs production (6).

	With the development of new production processes, the MHRA may make use of licensing agreements which after approval would be conditional on improvements in the quality, safety, and efficacy of new manufacturing technologies.

	The UK government, which in December 2019 won a general election by a substantial majority, has promised to replace EU research funds for UK projects with its own money (7).

	In the European pharma sector, the UK is not alone in being a large player able to pursue, if necessary, its own regulatory strategies. Switzerland, which is among the biggest R&D spenders on medicines as well as being a major pharmaceuticals producer and exporter in the region, is not a EU member.

	Between them, the UK and Swiss medicines industries account for around a third of the European pharma industry’s R&D expenditure and around a quarter of total output (2). Some analysts have predicted that the UK will follow the Swiss model of having close ties with the EU in some areas while in others taking advantage of its regulatory flexibility. 

	There has already been one big Anglo-Swiss collaborative initiative in product development. Novartis, which, with Roche, is the big Swiss multinational player in the global market, announced in January 2020 a planned collaboration with NHS England, the English arm of the UK’s state-run National Health Service, for the development of the company’s anti-cholesterol drug inclisiran (8). 

	The UK’s strategy with Brexit is to be less reliant on Europe’s pharma market by becoming a bigger global player. In parallel with the negotiations on the EU–UK FTA, the country is negotiating an FTA with the US to be followed by planned talks on trade deals with other non-EU countries such as China. But it faces a dilemma in reconciling its desire for regulatory divergence with the EU with the growing trends for regulatory convergence in the world’s medicines sector.

	1.  UK Government, “Political Declaration setting out the framework for the future relationship between the European Union and the United Kingdom,” 

, Political Declaration, 19 Oct. 2019.
	2.  EFPIA, “The Pharmaceutical Industry in Figures 2019,” 

(Brussels, 2019)
	3.  Business, Energy, and Industry Strategy Committee, House of Commons, “The Impact of Brexit on the Pharmaceutical Sector,” 

(8 May 2018).
	4.  EFPIA, “Brexit Briefing,” 

(Brussels, 2017).
	5. UK Government, “Technical Information on What the Implementation Period Means for the Life Science Sector,” 

(6 Aug. 2018).
	6.  EC, “European Commission: DG Health and Food Safety and European Medicines Agency Action Plan on ATMPs” (Brussels, November 2018).
	7. UK Conservative and Unionist Party, “Get Brexit Done-Unleash Britain’s Potential,” Conservative and Unionist Party Manifesto (London, December 2019).
	8.  Novartis, “Novartis Announces Intent to Collaborate with NHS England to Tackle Burden of Cardiovascular Disease in the UK,” Press Release, 13 Jan. 2020. 


	Vol. 32, No. 2
	February 2020
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “Brexit: What Happens Next for Pharma?” 

The UK and Europe are entering a transitional period, which will involve negotiations across the board, including those on the pharma regulatory landscape.