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

Sean Milmo

	The new year looks likely to be one in which the European Union’s medicines regulatory system makes a determined effort to ensure that advances in science and technology result in more innovative medicines being made available to patients in Europe. However, it is also likely to be a year in which regulators will be under even greater pressure to deal more effectively with chronic problems of medicines shortages and quality deficiencies in imported APIs.

	It is also projected that 2020 will see the European Medicines Agency (EMA), responsible for the approval of medicines for marketing in the whole of the EU and for the coordination of the drugs licensing network covering the union’s 27 member states, strive to return to a level of normality after two years of disruption. Efforts to regain normality come after the agency’s relocation of its headquarters in 2017 from London to Amsterdam in the Netherlands after the United Kingdom voted to leave the EU in the 2016 referendum. 

	EMA only formally took over its new headquarters in Amsterdam in January (2020) after initially being accommodated in interim offices in the Dutch city. With the relocation leading to lower staffing levels, the agency has had to considerably curb its activities. It is also trying to cope with a squeeze on its budget at a time of increasing costs.

	A major objective in 2020 for EMA will be to return operations to a pre-Brexit level. But with staff numbers being substantially reduced and constraints on its budget that seems to be a difficult task. Instead the agency could end up becoming a slimmer operation focussed on its core priorities of monitoring and evaluating the quality, safety, and efficacy of drugs during their development and throughout their life cycles.

	The whole EU regulatory network headed by EMA is answerable to the DG Sante, the health directorate of the European Commission (EC), the Brussels-based EU executive, within which the advisory pharmaceutical committee is exercising a growing influence.

	The committee, comprising officials of the commission, EMA, and EU member states, recommended in November 2019 that priority be given to the completion of on-going projects (1). These included action plans on pharmaceuticals in the environment (PIE), improvements in the regulatory environment for advanced therapy medicinal products (ATMPs), antimicrobial resistance (AMR), support for drugs repurposing, and on improving quality of APIs. But the commission itself has just changed its top management with a new president, Germany’s Ursula von der Leyen, and a new agenda, which will generate changes of focus in the pharmaceuticals area. 

	In healthcare, the new commission has set a number of priorities, such as affordability of medicines and patients’ access to innovative drugs, combatting medicines shortages, encouraging through legislation digitalization in health services, and ensuring the effective oversights of the global supply chain in medicines. In addition, the new commission has launched a European Green Deal to take measures to combat climate change, cut pollution, and help companies develop clean products and technologies (2).

	The regulatory agendas of Europe’s medicines agencies at the EU and national levels will be dictated to some extent this year by the commission’s priorities. Among the most important regulatory tasks this year for the EU’s network of medicines licensing agencies will be the finalizing of a strategy covering regulatory science. 

	A draft EMA strategy on regulatory science to 2025 (3) was the subject of a consultation with a range of stakeholders during 2019, including industry, researchers, healthcare professionals, and patients’ representatives. Regulatory science is seen as a vital platform to fulfilling the mission of the EU medicines licensing network in translating science and innovation into more effective medicines and ensuring that patients have access to them.

	“In the pharmaceutical landscape R&D is evolving rapidly, and we, as regulators, must keep pace with it and must be prepared for the future challenges it will present to us,” said Guido Rasi, EMA executive director, at a stakeholders workshop in Amsterdam on the agency’s regulatory science draft strategy in November 2019 (4). 

	The workshop was held to help in the finalization of the strategy early this year, particularly in sorting out the different priorities put forward by the various clusters of stakeholders taking part in the consultation exercise. The industry representatives in the consultation wanted priority to be given, for example, to novel manufacturing technologies and greater exploitation of digitalization technologies.

	The final version of the strategy will be used as a basis for a five-year strategy for the EU’s medicines regulation network (EMRN). This document is due to be drafted by June for publication in October after going through a stakeholder consultation.

	EMA and the Heads of Medicines Agencies (HMA) representing the national authorities already have a joint task force on big data identifying how digitalized data sets can be used to develop new and improved medicines (5). This work should provide key components of regulations on digitalization in the medicines sector. But EU regulators face a daunting job in the regulation of areas like data quality and standards for data analytics. 

	One important consideration is the need for the regulators themselves to have access to skills and training so that they can effectively evaluate the quality of large data sets and the analytics performed on them.

	With the EU wanting to be a global leader in using regulation to encourage medicines innovation, it also wishes, through the European Green Deal, to be a pace setter in imposing safeguards on PIE. As a result, PIE tops the list of the current priorities of the commission’s pharmaceutical committee.

	Other major objectives, which will be determining regulatory agendas in 2020-and probably much of the rest of the new decade-will be the assurance of secure, efficient, and clean supply chains extending from starting materials, APIs to finished medicinal products.

	In 2019, a big threat to these supply chains within Europe was a no-deal Brexit. Under this scenario, the UK-a leading medicines exporter and importer-would be relegated to the status of a third country under EU legislation without the protection even of a free trade agreement (FTA). Both the EU and the UK had to prepare provisional emergency measures to prevent serious medicine shortages due to the sudden introduction of customs checks and quality controls.

	However, after the Brexit-supporting ruling Tory party won a UK general election in December 2019 by a substantial majority soon after clinching a withdrawal agreement, the country looks certain to finally leave the EU at the end of January 2020 with trade in medicines and other products remaining relatively intact. Its departure will be accompanied by a transition period of at least a year during which an EU–UK FTA would at least start to be negotiated with the relationship between the two sides staying substantially the same as if the UK were still an EU member.

	But the danger of a no-deal scenario will not have been lifted completely. Despite warnings by trade experts that a full FTA will need longer than a year to negotiate, the UK government has indicated that if a trade agreement is not reached by the end of December 2020 it will leave without one, even though there would be an option for extending the transition period to continue negotiations.   

	The UK could be aiming for a short framework trade agreement with the EU in which regulatory standards, such as those on pharmaceuticals, could be thrashed out over several years. During this time, there would still be a considerable risk of EU–UK trade disruptions and hence medicines scarcities.

	Even without the effects of the Brexit dispute, availability of medicines will still remain a major issue in Europe. In recent years, supply chains have been suffering from chronic shortages, particularly stemming from quality issues with APIs, most of which are imported from China and India. 

	Quality problems worsened with the discovery of nitrosamine impurities, first in late 2018 in Asian-produced APIs for sartan blood pressure medicines and then last year for the diabetes treatment pioglitazone and the ulcer treatment ranitidine. EMA had to ask all relevant pharmaceutical companies to check raw materials and processes in their supply chain for risk of production of nitrosamine impurities, which are classified as probable carcinogens. 

	Results of an EMA investigation into the episode with ‘lessons to be learned’ are due to be revealed in mid-2020, opening the way to a further tightening up of EU rules generally on checking the quality of imported APIs. Also, this will coincide with a decision by the EMA on the future scope of its operation in the light of a 20% reduction in staffing after its relocation and budgetary restraints.

	By the end of the year, not only the rules on imported APIs will likely have changed, but the future of the agency mainly responsible for imposing said rules will have changed as well.

	1. Pharmaceutical Committee, Health, Safety, Food Directorate-General, EC, “Work Method and Main Priorities” (Brussels, November 2019).
	2. EC, “Communication: The European Green Deal” (Brussels, 11 Dec. 2019)
	3. EMA, “Draft European Regulatory Science to 2025 Strategy” (Brussels, December 2018).
	4. Guido Rasi, EMA executive director, “Delivering the Strategy,” presentation at Stakeholders Workshop on EMA Regulatory Science (Amsterdam, November 2019).
	5. HMA and EMA Joint Big Data Task Force, “Summary Report” (Amsterdam, 13 Feb. 2019).


	Vol. 32, No. 1
	January 2020
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “European Regulators Strive to Make Up for Lost Ground,” 

Articles

In 2020, European regulators are expected to start to be even more active in encouraging drugs innovations rather than hindering them through legal restrictions.


European Regulators Strive to Make Up for Lost Ground

	Digitalization is spreading rapidly throughout Europe’s healthcare and pharmaceutical sectors. But the pace of the change is leaving regulators struggling to keep up. Vast amounts of data from the development and production of medicines and patient treatments and outcomes are being collected, processed, and analyzed for creating algorithms for application in artificial intelligence (AI) such as machine learning.

	However, few pieces of legislation in Europe, even at the national level, specifically tackle the problems emerging from the digitalization transformation in healthcare, such as quality of data and lack of standards.

	Regulatory issues with digitalization are mainly focused on three, often overlapping, areas. First, there is AI itself, which is an umbrella term used to cover technologies enabling machines to perform tasks such as recognition of specific images and patterns in datasets.

	Algorithms, the step-by-step instructions given to AI equipment to process data or conduct tests, pose regulatory challenges because they can be ‘trained’ to draw up their own instructions or make their own decisions. In pharmaceuticals and related European sectors, the use of AI, and other digitalization tools, is mainly confined to applications at the points of patient care. It has yet to penetrate deeply into medicine production and even drugs R&D. But this is expected to change over the next decade, mainly because of the growth in personalized medicine, which will lead to an overlap between drug manufacturing and point-of-care treatments in, for example, hospitals.

	A survey in 2017 of executives in life sciences, including pharma, by Camelot AG, a German-based management consultancy, found digitalization was having zero impact on manufacturing and only five percent impact on drug development and clinical trials (1). However, by 2020 the executives expected the impact on manufacturing to increase to 21% and on R&D to 11%, while by the early 2030s it would have risen to 35% and 29%, respectively.

	During the next decade, regulations of AI will be playing a much bigger role in European pharma than it is now, with the biggest factor being the use of regulations to gain the trust of patients in the new digital technologies.

	A report on AI, by the London-based thinktank Future Advocacy in conjunction with Wellcome Trust, a charitable foundation, predicted in 2018 that the biggest influence on social, political, and ethical aspects of AI centred on consent, fairness, and rights (2). Matters on rights also need to be considered when developing regulatory oversights of AI, the report said. Aspects of care being increasingly delivered autonomously by AI raised questions such as “do people have a right to know how much AI is used in their care?” Or “do people have a right not to have AI involved in their care at all?”, the report asked.

	The European Union’s General Data Protection Regulation (GDPR), introduced in 2018 to replace the 1995 Data Protection Directive (3), enables individuals to have more control over their personal data in all sectors, including healthcare, even when it is exported outside Europe. 

	The legislation obliges controllers of personal data to take “appropriate technical and organizational measures” to implement the data protection principles. This and other provisions in GDPR have raised fears in the pharmaceutical industry, among others, that the regulation could stifle innovation.

	One controversial protection in the legislation is the ‘right to explanation’, which entitles citizens to “fair and transparent processing” of their personal data as well as “meaningful information about the logic” used in automated decision-making systems (3). Lawyers and law academics believe, however, that because of the way the ‘right to explanation’ is written into the regulation it is not legally binding.

	In a report published in November 2019 on AI policy, Digital Europe, a Brussels-based trade association representing digital technology producers, recommended that AI regulation should be drawn up to meet specific needs (4). It suggests that policy makers should endeavour to use current regulatory and legislative frameworks as much as possible, with, if necessary, additional guidelines to make them more effective.

	In the application of good manufacturing practice (GMP) in a digitalization age, regulators in Europe are relying on Annex 11 of the EU’s GMP guide, which covers computerized systems (5). At the core of the annex is the application of risk management throughout the lifecycle of the computerized system taking into account patient safety, data integrity, and product quality. “As part of a risk management system, decisions on the extent of validation and data integrity controls should be based on a justified and documented risk assessment of the computerized system,” the annex specified. Operators of plants using AI are as a result being considered to have the same capability to assess risks with AI as with other traditional computerized systems. 

	The Geneva-based Pharmaceutical Inspection Co-operation Scheme (PIC/S), whose members are regulatory authorities in the GMP field and whose GMP guide is virtually identical to the EU’s, has conceded that Annex 11 has become ‘outdated’.  

	One glaring gap in regulatory controls on AI is the lack of an internationally agreed definition of AI. A committee of the House of Lords of the UK parliament complained in a report on AI last year (2018) about participants in its hearing of evidence providing ‘dozens of different definitions’ (6). 

	The Paris-based Organization for Economic Co-operation and Development (OECD), representing the world’s rich nations and which was responsible for drawing up an international version of the principles of good laboratory practice (GLP) in the 1990s, announced in February 2019 that it is working on a set of AI guidelines that would include an answer to the question, “What is an AI system?”

	The OECD’s committee on digital economy policy has made recommendations identifying a number of principles on responsible AI stewardship. These include fairness, transparency, explainability, robustness, safety, and accountability. 

	The Geneva-based International Organization for Standardization (ISO) and the International Electrotechnical Commission (IEC) do provide standards related to AI. But in healthcare, these mainly apply to medical devices or the hardware component of drug-device combinations (DDC).

	A joint big data taskforce of the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) complained in a summary report issued in February 2019 about the lack of standards, particularly on data quality (7). The taskforce had been split up into six subgroups covering genomics and other ‘omics’, such as proteomics, clinical trials, adverse drug reactions, and other aspects of healthcare data. “Almost without exception, each of the subgroups raised the need for standardization as a key prerequisite” to drive data digitalization forward, the report said. Data standardization is needed to “define and, where possible, improve data quality and progress to actions to promote data sharing, access, and enable robust big data processing and analysis.”

	Many datasets in Europe, outside of those for clinical trials, are not standardized because they have evolved over many years when different technologies have been applied to them. Nor were the data generated to support regulatory decisionâmaking and hence the need to comply with strict quality guidelines.

	Even with relatively new areas of science such as genomics on which data on almost 250 million genomes is available and relatively well structured, accessibility to the data is restricted because of lack of standardization, according to the report. Much of it is siloed by disease, institution, and country, generated with different methodologies, analyzed by non-standard software and often stored in incompatible file formats.

	Regulators must have “the capability and capacity to analyze, interpret, and profit from the data generated,” the summary report said (7). “In this way, we will improve our decision making and enhance our (evidence-based) standards.”

	One barrier could be a lack of specialized expertise among regulators in data science. This sort of knowledge is needed to enable “informed and critical assessment of regulatory applications in future” of innovative products and processes, according to the report (7).

	The knowledge gaps may be so large that a system for linking up experts with regulators may be necessary to ensure that the capacity of the regulatory system to make appropriate assessments is maintained. Standardization of data will be a major challenge, which from the regulatory perspective will require prioritization of what issues need to be tackled first.

	1. Camelot Management Consultants AG, “Digitalization: Blessing or Curse for Compliance?” (Mannheim, 2017).
	2. Future Advocacy and Wellcome Trust, “Ethical, social and political challenges of artificial intelligence in health” (London, April 2018).
	3. EU, “Regulation 2016/679 on the Protection of Natural Persons with Regard to the Processing of Personal Data and of the Free Movement of Such Data,” General Data Protection Regulation, (Brussels, 27 April 2016).
	4. Digital Europe, “Recommendations on Artificial Intelligence Policy,” (Brussels, 13 November 2019).
	5. EC, 

Rules Governing Medicinal Products in the European Union: Good Manufacturing Practice, Annex 11 Computerized Systems

 (Brussels, 2011).
	6. House of Lords, “AI in the UK: Ready, Willing and Able?” Select Committee on Artificial Intelligence, Report on Sessions 2017–2019 (London, 16 April 2018).
	7. HMA and EMA, “HMA-EMA Joint Big Data Taskforce-Summary Report” (Brussels, 13 February 2019). 


	Vol. 31, No. 12
	December 2019
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “The Challenges for Regulators in the Digital Age,” 

Regulators are facing huge challenges on how to deal with the digitalization transformation occurring in the healthcare and pharmaceutical sectors.


The Challenges for Regulators in the Digital Age

	The European Medicines Agency (EMA) and the European Union’s national licensing authorities have taken the unusual step of requesting that pharma companies investigate the production processes for all medicines containing chemically synthesized active substances for the possible presence of nitrosamines, which are classified as probable human carcinogens (1). Many pharma companies, therefore, face a massive task of completing risk evaluations of their production processes and suppliers, including producers of starting materials, by March 2020. 

	The EU measures follow an EMA recommendation in January 2019 that companies making sartan blood pressure medicines-also known as angiotensin II receptor blockers-reassess their production processes to avoid the creation of nitrosamine impurities (2). This action was preceded by the discovery in mid-2018 that Zhejiang Huahai, a Chinese drug manufacturer, was making a sartan medicine, valsartan, which contained nitrosamine impurities (2). Soon afterwards, nitrosamines-mainly N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA)-were detected in four other sartan medicines (2).

	The impurities were found to be formed in certain conditions during the production of sartans containing a specific ring structure-known as a tetrazole ring-and when particular solvents, reagents, and other raw materials were used. Also, some sartans could contain impurities because their manufacturers had inadvertently used contaminated equipment or reagents.

	After its review of sartans, completed in January 2019, EMA set a two to three-year transition period for marketing-authorization holders (MAHs) with nitrosamines in their sartan medicines to make changes in their processes during which they would have to adhere to strict limits on the levels of the impurities. After the two years, MAHs would be required to demonstrate that their sartan products had no quantifiable levels of nitrosamines before they could be marketed in the EU.

	Furthermore, the agency warned that there was a potential for nitrosamines to be present in APIs of other non-sartan medicines. Then, in April 2019, EMA revealed that both itself and national authorities were requesting ‘as a precaution’ that companies using certain reagents to manufacture the diabetes medicine pioglitazone test their products and check their processes to rule out the presence of NDMA (2). 

	The request followed the detection of low levels of NDMA in a few batches of pioglitazone made by Hetero Labs in India (2). The levels were within strict safe limits previously set for sartans by guidelines of the Geneva-based International Council for Harmonization (ICH).

	In September 2019, EMA announced it is to start a review of prescription and over-the-counter versions of ranitidine, a histamine-2 blocker for the treatment of excess acid in the stomach causing conditions like heartburn and ulcers. This notice came after tests showed that some ranitidine products contained NDMA.

	At the same time, the agency disclosed that its Committee for Medicinal Products for Human Use (CHMP) would be providing guidance on avoiding the presence of nitrosamines in human medicines containing chemically synthesized active substances (3). “It is of paramount importance that we learn from our experience with sartans and take a proactive approach for other classes of medicines,” said Guido Rasi, EMA’s executive director (3).

	Initially CHMP will be basing its guidance on an investigation of processes for making chemically synthesized medicines and their active ingredients. But in a two-part procedure, CHMP will also be considering whether its study should be extended to other forms of medicines, especially biopharmaceuticals (3). CHMP’s examination will cover the whole value chain from starting materials through to finished products.

	The task will be almost unprecedented in its scale for the EU medicine authorities, who will have to rely on MAHs collecting information throughout their chains. This will be made more difficult by the practice among a lot of MAHs of relying on the contracting out of production at each stage of the chain.

	“There were very few cases in the past where carcinogenic impurities or contaminations were found in authorized medicines,” an EMA spokesperson told 

. “However, these [cases] were very specific to one product or a manufacturing issue.”

	The EU actions on sartans, pioglitazone, and ranitidine are being performed under a 2001 EU directive and its subsequent amendments on a quality and safety code for pharmaceuticals for transposition into member states’ legislation (4). These actions are mainly being done under the directive’s article 31 as well as 107 on urgent procedures under which the supply of specific medicines may be prohibited (4).

	However, the 2001 directive and its amendments are related to the quality, safety, and efficacy of individual drugs or groups of types of medicines (4). The articles within the directive also allow EU regulatory authorities to impose mandatory requirements on companies.

	The review of ranitidine medicines, for example, will be performed by CHMP under article 31 of the directive. The review’s conclusion will be passed to the European Commission for the possible creation of binding decisions applicable in all EU member states. 

	The broad sweep of EMA’s CHMP guidance being drawn up on the prevention of nitrosamine impurities has had to be made under different legislation-a 2004 regulation laying down EU procedures for the authorization and supervision of medicines (5). The guidance is being prepared under article 5 (3) of the regulation, which allows CHMP to provide an opinion on any scientific matter concerning medicines evaluation. But it is unclear whether the opinion can be used as a basis for binding regulatory measures.

	EMA sent out a notice to companies on 19 September 2019 requesting that, as a result of the article 31 review of sartans, pioglitazone, and ranitidine, pharma companies evaluate the risk of nitrosamine presence in chemically synthesized medicines (1). Under the 2001 directive, the notice pointed out that MAHs are responsible for the quality, safety, and efficacy of their products, including the quality of the APIs, excipients, and raw materials (1). 

	API manufacturers and others in the supply chain are obliged to make the information necessary for risk evaluations available to MAHs and for taking responsibility for the quality of the finished product and its active substance, as per the notice. This requirement may cause problems for manufacturers of products with active substance master files (ASMFs) and certification suitability to the monographs of the 

(CEPs) because these contain information not available to MAHs (1). But the notice implies that it may suffice for MAHs to ensure that “robust risk evaluations have been appropriately carried out by the ASMF or CEP holder.”

	In the notice, EMA provides more information-since its sartans review in January 2019-about potential sources of nitrosamine impurities about which, until mid-2018, there was not much awareness among many pharmaceuticals manufacturers (1). The use of sodium or other nitrites in the presence of secondary or tertiary amines is a major cause of nitrosamine formation, the notice specified. Secondary amines can be present in reagents and solvents as impurities or degradants of reagents, solvents, and APIs. Amide solvents, for example, can degrade to secondary amines. Tertiary amines are also common functional groups in APIs and their precursors.

	There have been cases where sodium nitrite has been used as a reagent in one step and then carried over into subsequent steps, where, despite extensive purification, it has reacted against an amine to generate a nitrosamine impurity, according to the notice.

	Recycled solvents, reagents, and catalysts may pose a risk of nitrosamine formation due to the presence of amines in waste streams. Third parties, to which recovery of materials, such as solvents and reagents, are frequently outsourced, can use non-dedicated equipment potentially leading to cross-contamination. Starting materials contaminated with impurities like nitrites are another source of nitrosamines, the notice warned.

	“In view of the large number of authorized products (to be evaluated), MAHs are requested to prioritize products following a risk-based approach,” the EMA spokesperson told 

. “For the purposes of this prioritization, MAHs may consider factors such as the maximum daily dose taken, duration of treatment, therapeutic indication, and number of patients treated.”

	“MAHs and manufacturers should test a representative number of samples of the relevant starting material, intermediate, API, or finished product, with the number of batches/samples tested (being) scientifically justified,” the spokesperson added.

	Companies with nitrosamine problems in their production processes and supply chains will have six months to complete a risk evaluation. Then a maximum of three years to perform a confirmatory test on an identified risk of nitrosamine presence. Finally, if they have to change a production process, they will have to gain authorization of a variation. It could all be a long procedure.

	1. EMA, “Information on Nitrosamines for Marketing Authorization Holders,” Notice-EMA/189643/2019 (Amsterdam, 19 Sept. 2019).
	2. EC, “Angiotensin-II-Receptor Antagonists (Sartans) Containing a Tetrazole Group,” Review (final decision), EMA 248364/2019 Rev. 1 (Amsterdam, 1 February 2019).
	3. EMA, “EMA to Provide Guidance on Avoiding Nitrosamines in Human Medicines,” Press Release (Amsterdam, 13 Sept. 2019).
	4. EU, 

Directive 2001/83 on the Community Code Relating to Medicinal Products for Human Use 

Regulation No. 726/2004 Laying Down Community Procedures for the Authorization and Supervision of Medicinal Products for Human and Veterinary Use 


	Vol. 31, No. 11
	November 2019
	Pages: 9–11

	When referring to this article, please cite it as S. Milmo, “Investigating NDMA Impurities at EMA’s Request,” 

Companies are facing a huge undertaking to be able to complete risk evaluations of all medicines containing chemically synthesized APIs by March 2020.


Investigating NDMA Impurities at EMA’s Request

	The new Brussels-based European Commission, which is due to take over in November 2019, will be playing the powerful role in the European Union of putting forward legislation, which must be approved by the parliament and the council of ministers representing the governments of member states, soon to be reduced to 27 with the departure of the United Kingdom. 

	The commission will also have a key role in drawing up EU-wide strategies not just in the economic sphere but also the social field, including health. Environmental issues, such as climate change, are being considered at the EU level from an economic and social policy standpoint. The Finnish government has pledged to promote wellbeing during its current six-month presidency of the council of the EU on the grounds that wellbeing is an EU responsibility and is at the core of its raison d’être (1).

Getting more active in healthcare affairs

	Authorization of pharmaceuticals is no longer just a matter of ensuring an open, barrier-free market in medicines but is also an instrument of social policy covering areas such as the right to effective healthcare. In fact, certain EU political and social groups believe that social policy should now be given top legal priority so that in the judgments of the European Court of Justice (ECJ) it would be given prominence over purely economic factors (2).

	Ursula von der Leyen, a German politician, who has been appointed by EU leaders to be the president-elect of the new commission, has already indicated that she wants the body to be more active in healthcare affairs than its predecessors (3). This could result in stricter controls on pharmaceuticals but could also encourage more innovations in medicines and their production processes. Her healthcare focus was confirmed by her decision to move all responsibilities for pharmaceutical-related activities to the commission’s health directorate-DG Health and Food Safety. 

	The directorate will, for example, take over implementation of regulations for medical devices, including drug–device combinations (DDCs), from the commission’s industry and internal market directorate DG Grow (4). Responsibilities for pharmaceutical-related biotechnology and the food supply chain will also be transferred from DG Grow to the health directorate (4). The accountability to the commission of the European Medicines Agency (EMA) will be centralized more clearly within DG Health (4). As a result of all these changes, the commission’s duties for the instigation and implementation of pharmaceutical regulations, as well as enacting medicines-linked public health policies, will be concentrated within a single directorate.  

	The appointments of von der Leyen and her designations of 26 commissioners still have to be approved by the European Parliament. But it is unlikely that the membership of the new commission or the agenda put forward by its president-elect will be radically changed.

	Among the first initiatives on medicines legislation by the new commission could be sorting out difficulties with the authorization of DDCs under a new medical device regulation (MDR), which is due to come into force in 2020 (5). “I want you to focus on the effective implementation of the [MDR] to protect patients and ensure it addresses new and emerging challenges,” von der Leyen told Kyriakides in a letter (5).

	The MDR may need to be modified to clarify the role of pharmaceutical agencies in the authorization of DDCs, particularly with respect to quality standards. Medicines authorities have the job of assessing the quality and safety of the drug in the DDC, while certification organizations, called notified bodies (NBs), judge the quality and safety of the device component (6). 

	In the current text of the MDR or its guidelines there is a blurring of the responsibilities of medicines agencies and NBs in assessing the interaction between the drug and device in a DDC, particularly with single non-reusable integral products such as pre-filled syringes or autoinjectors (7). Pharmaceutical companies have also been complaining about a lack of clarity in what information they are required to give NBs and vice versa.

	Another worry is that an insufficient number of NBs will have been designated by the EU to conduct MDR assessments when the new regulation, which replaces a 1993 piece of EU legislation, is due to be implemented in May 2020 (8). Certification organizations have to meet tougher criteria to be chosen as NBs under the MDR, which has aroused fears that many will fail the selection process. Only about half the required number could be in operation by the end of this year, according to MedTech Europe, the medical devices trade association (8).

	Once chosen, NBs will find that the MDR assessment of products will take longer than under previous legislation because the scope and number of quality, safety, and performance requirements has been increased. Re-certification of an existing product could take up to nine months and even longer in cases of new products (8).  

	The pharmaceutical and medical device sectors are warning that after MDR is scheduled to come into force in 2020 large numbers of products may have to be taken off the market while the launch of many new ones will have to be postponed because they will be non-compliant (8). This will be at a time when a growing proportion of medicines are being introduced as DDCs because of their greater convenience and effectiveness.  

	Among the other tasks set by von der Leyen for the health directorate is greater use of Big Data and digitalization to promote health data exchange and research on preventive strategies as well (5). Also, ways should be explored to ensure that Europe has sufficient supplies of affordable medicines to meet its needs. “The pharmaceutical industry (should be supported) to ensure it remains an innovator and world leader,” said von der Leyen.

	Another assignment for the directorate is the putting forward of a ‘Europe’s Beating Cancer Plan’ to help member states improve cancer prevention and care (5). This should propose actions to strengthen the EU’s approach at every key stage of the disease-prevention, diagnosis, treatment, life as a cancer survivor, and palliative care. 

	Perhaps under the new commission, DG Health’s top priority will be the fight against antimicrobial resistance (AMR) through the full implementation of the European One Health Action Plan against AMR covering human, animal, and environmental health (5). “Many of today’s epidemics are linked to the rise or return of highly infectious diseases,” said von der Leyen.

	The importance given by the new commission to the enforcement of the EU’s One Health Action Plan is strongly supported by the pharmaceutical industry. “Tackling one of the great public health challenges of our time requires collaboration,” Nathalie Moll, director general of the European Federation of Pharmaceutical Industries and Associations (EFPIA), said in a blog in September 2019 in response to von der Leyen’s call for action (9).

	“The One Health approach demands collaboration between the human, animal, environment, and food sectors to address this complex shared problem,” Moll continued. “That’s why, together with 16 organizations active in human and animal health, we have called for AMR to be at the forefront of EU inter-institutional discussions.”

	Health campaigners want the One Health Action Plan to be broadened in scope. “This plan lacks concrete targets, so we call on the EU to set targets which are measurable and ambitious,” an 18-strong alliance of healthcare non-governmental organizations (NGOs) and patient groups declared in a statement in April 2019 (10).

	Some NGOs have been urging pharmaceutical manufacturers to do more to curb AMR by eliminating it from wastewater discharges from their antibiotics plants. In fact, leading producers of antibiotics are already taking steps to curb antibiotics discharges from their plants. In a survey of international research-based and generic antibiotic manufacturers, the Amsterdam-based Access to Medicine Foundation revealed that 15 out of 18 research-based companies had some form of environmental risk-management strategy aiming to minimize the impact of antibiotic discharges (11). Six of these companies-GSK, Johnson & Johnson, Novartis, Pfizer, Roche, and Sanofi-were the best performers, applying their environmental risk-management strategies not only to their own manufacturing sites but also those operated by third-party manufacturers of APIs and drug products. 

	The foundation is using data from its surveys to develop a benchmark on anti-AMR actions by pharmaceutical companies to help governments in drawing up procurement policies for medicines. However, even the best performing producers have been reluctant to disclose details of their activities with antibiotic discharges, in particular the metrics they use to put limits on discharges and whether these have been exceeded. 

	AMR is probably the area in healthcare where the new commission has the opportunity to achieve the most success because of the amount of backing throughout industry for action. But it will be a tough job.

,” accessed 30 September 2019.
	2. ETUC, “Protocol on the relation between economic freedoms and fundamental social rights in the light of social progress” (Brussels, 18 March 2018).
	3. U. von der Leyen, “A Union that strives for more. My agenda for Europe,” 

(Brussels, September 2019).
	4. EC, “European Commission 2019–2014-Allocation of portfolios and supporting services” (Brussels, 10 September 2019).
	5. EC, “Ursula von der Leyen, President-elect European Commission: Mission letter Stella Kyriakides, Commissioner-designate for Health” (Brussels, 10 September 2019).
	6. EMA, “Medical devices” (Amsterdam, June 2019).
	7. EBE and EFPIA, “An Industry Perspective on Article 117 of the EU Medical Devices Regulation and Impact on how Medicines are Assessed,” Reflection Paper (Brussels, 12 July 2018).
	8. MedTech Europe, “Industry Perspective on the Implementation Status of MDR/IVDR” (Brussels, 14 June 2019).
	9. EFPIA, “EFPIA is Ready to Answer EU’s Call for Action on Antimicrobial Resistance,” Blog (Brussels, 19 September 2019).
	10. EU4Health, “Joint position: Europe, let’s do more for health!” (Brussels, April 2019).
	11. AMR Benchmark, “B Manufacturing and Production,” Research Areas, 


	Vol. 31, No. 10
	October 2019
	Pages: 8–10

	When referring to this article, please cite it as S. Milmo, “Out with the Old and In with the New European Commission,” 

A new European Commission is likely, with the support of a new European Parliament, to give a higher profile to healthcare and pharmaceutical matters during its five years in office. 

Out with the Old and In with the New European Commission

	The European Union’s medicines regulatory network, headed by the European Medicines Agency (EMA), is currently seeking ways to improve how it ensures that scientific innovations and new technologies lead to new medicines, particularly for patients with unmet needs. The agency is at present finalizing a report-EMA Regulatory Science to 2025-on the regulatory impact of emerging scientific and technological innovations (1). A six-month public consultation on the document, published in December 2018, was completed in June 2018.

	Additionally, the agency is investigating ideas for raising the effectiveness of its three-year-old Priority Medicines (PRIME) scheme, which was developed to expedite the progression of new medicines for patients whose diseases cannot be treated or need better options for pharmaceutical treatments. Ideas were put forward at a joint EMA and US Food and Drug Administration (FDA) workshop, which was held in London during November 2018, for PRIME and FDA’s similar Breakthrough Therapy programme (2). EMA published a report on the workshop in July 2019 (3).

	In fact, the objectives of PRIME and the aims behind EMA Regulatory Science to 2025 are closely linked. This is especially the case with the regulatory report’s number one goal of providing a basis for the integration of science and technology in medicines development. Among the core recommendations of the regulatory science report is increased investment in PRIME, shortening the time between scientific advice, clinical trials, and marketing authorization, and collaboration with stakeholders to ensure efficient post-approval oversight of medicines.

	The main features of PRIME are an accelerated evaluation of a medicine’s development through close interaction between the sponsor and regulator, and support of a multi-discipline review team (4).

	In 2018, the first products developed under PRIME-two chimeric antigen receptor (CAR) T-cell immunotherapies for blood cancer treatment-were approved by EMA (5). PRIME’s main contribution to these successes was to identify at an early stage the data needed by the regulator for authorization. “Through PRIME, we offer early and enhanced dialogue to enable the generation of better data and more robust evidence on a medicine’s benefits and risks,” said Guido Rasi, EMA’s executive director (5).   

	By the end of 2018, the agency had accepted 48 applications for medicines development support, equivalent to approximately a fifth of the total of applications, which predominantly consisted of small and medium-sized enterprises. Of the medicines admitted to the scheme, 42% were advanced therapy medicinal products (ATMPs), mainly gene and cell therapies. 

	Encouraging development of ATMPs is a key aim of PRIME. An EMA report on the first two years of PRIME, issued in May 2018 (6), concluded that the scheme had been a success. Nonetheless in its implementation, regulators and sponsors of the medicines have been facing stiff challenges. These challenges mainly stem from the necessity of conducting evaluations, both of products and processes, and making risk/benefit analyses in less time than for the development of normal medicines.

	The agency’s choice of ideas from the joint workshop for further investigation has been mainly dictated by the need to address these challenges, among the biggest of which is drawing up specifications and control strategies, and other quality assurance tools, on the basis of only relatively few batches compared to normal.

	EMA’s main preferred solution to scarcity of some evidence in PRIME projects appears to be to make greater use of regulatory actions through the lifecycle of new medicines so that knowledge gaps before authorizations can be filled by post-authorization decisions.

	“We will often not understand the full clinical value of (new, life-changing) drugs at the time of approval,” Tomas Salmonson, who retired as chair of the EMA’s committee for medicinal products for human use (CHMP) in September 2018, said in an interview for EMA’s latest annual report (5). “Ensuring that we obtain answers to relevant questions from all stakeholders in the post-approval space is an increasing responsibility for the regulator,” he added.

	The lifecycle approach will mean more use of concurrent validation, which is done simultaneously with a medicine’s commercialization. Usually it is performed only in exceptional circumstances and when the benefit-risk ratio is strongly in favour of the patient. As a result, some authorization applicants will be allowed to defer submission of process validation data until the postâapproval stage.

	With control strategies, there will be more room for flexibility so that control parameters can be revised in the light of knowledge gained after commercialization. In this respect, biological molecules may have to be treated differently from small molecules, which have the advantage of back-up data from animal studies. Data for biological molecules may have to come from a combination of preâclinical data and prior knowledge derived from a company’s internal information, as well as external sources such as scientific and technical publications.

	There could also be more use of post-approval change management protocols (PACMPs), in which submission of post-authorization data is linked to specific pre-arranged postâapproval product and/or process changes. It is a stepâwise approach that allows an early evaluation to be followed by a later, separate evaluation of the data produced, based on an agreed strategy. 

	“Such a stepwise approach is expected to lead to faster and more predictable implementation of changes post-approval, since the (marketing authorization holder) will have obtained agreement from the regulatory authorities about the proposed strategy and tests to verify the effect of the change on product quality,” stated the EMA’s report (3).

	With PRIME products and ATMPs in general, there may have to be changes in regulators’ attitudes to timelines for PACMPs. With drugs under normal development, these timelines are quite flexible, whereas with priority and advanced medicines they may have to be made more time specific. There may have to be more guidance on the application of PACMPs with ATMPs, according to EMA (3).

	The agency’s committee for advanced therapies (CAT) issued a question and answer guide on the use of out-of-specification batches of authorized cell/tissue-based advanced treatments in April 2019 (7). Forthcoming regulatory changes look likely to result in alterations to current practices but also standards and even legislation.

	GMP guidelines may have to be modified to help inspectors deal with the issue of sites supplying both clinical trial investigational medicinal products (IMPs) but also commercial medicines. Increasingly hospitals, acting as centres of excellence for the development of ATMPs and other similar innovative drugs, are manufacturing small quantities of medicines for clinical and commercial use.

	Matt Popkin, UK-based director chemistry, manufacturing, and controls strategy, product development, at GlaxoSmithKline (GSK) told the workshop that in accelerated access scenarios there was only limited time to develop long-term supply chain and complete commercial GMPâcertified activities, according to the EMA report. 

	Instead, Popkin suggested alternative good manufacturing practice (GMP) tools may be appropriate for manufacturing facilities that are only supplying limited numbers of products to a small number of critically ill patients for a limited period (3).

	Similar GMP rules for sites supplying clinical IMPs should be applied to those serving early stage commercial segments. Allowing commercial supply from clinical manufacturing facilities would enable patients to have accelerated access to medicines early in their commercial lifecycle, according to Popkin.

	EMA listed in its workshop report, for further consideration, possible guidance on requirements for the use of IMP manufacturing sites for early commercial supply of innovative medicines (3). The agency also suggested using comparability as the basis for accepting clinical trial data from products manufactured in facilities not compliant with GMP. Furthermore, EMA indicated that the requirement for GMP certification could be waived for use of material from master or working cell banks in third countries, which are not compliant with GMP.

	Difficulties with assessing the comparability of biological materials can also hold up accelerated product development. How, for example, could the comparability of materials from healthy donors and patients be validated when there may be significant differences between the two, asked the report. 

	Demonstration of comparability was particularly important at different development phases of the manufacturing process. If an adequate risk assessment was to be performed on comparability, more knowledge of the impact, for example, of manufacturing changes on ATMPs was needed. 

	“Most of the currently available knowledge is present in registration dossiers and not publicly available,” as stated in the EMA report (3). “It would be of great benefit if this information was published.”

	There is a big gap in scientific knowledge about the differences between healthy donor and patient materials in relevant manufacturing processes, according to the EMA report. “It would be useful if all existing experience would be published,” EMA said (5). “That would be a good resource to assess new comparability cases.”

	Greater international collaboration, like that between EMA and FDA, could help to solve problems such as lack of accessible data. Agencies can cooperate to pool knowledge. They may even be able to distribute joint guidance on issues such as validation, control strategies, and specifications for innovative new medicines. 

	One key area for international collaboration in the future will be the use of regulatory science to use big data and artificial intelligence to create models for validation and other quality controls. Global cooperation will be necessary to gain the most regulatory benefits out of digitalization.

	1. EMA, “EMA Regulatory Science to 2025-Strategic Reflection” (London, December 2018).
	2. EMA, “Stakeholder Workshop on Support to Quality Development in Early Access Approaches, Such as PRIME and Breakthrough Therapies” (London, 26 November 2018). 
	3. EMA, “Meeting Report: Workshop with stakeholders on Support to Quality Development in Early Access Approaches” (London, 26 November 2018). 
	4. EMA, “PRIME: priority medicines” 

[accessed 22 August 2019].
	5. EMA, “Annual Report 2018” (Amsterdam, May 2019).
	6. EMA, “PRIME: a Two-Year Overview” (London, May 2018).
	7. EMA, “Questions and Answers on the Use of Out-of-Specification Batches of Authorized Cell/Tissue-Based Advanced Therapy Medicinal Products” (Amsterdam, 24 April 2019). 


	Vol. 31, No. 9
	September 2019
	Pages: 8–9

	When referring to this article, please cite it as S. Milmo, “EMA’s Regulatory Impact: Not Yet in its PRIME,” 

EMA is seeking ways to improve the effectiveness of its PRIME scheme, so that scientific innovations and new technologies more readily lead to novel medicines.


EMA’s Regulatory Impact: Not Yet in its PRIME

	The European Medicines Agency (EMA) and Heads of Medicines Agencies (HMA) representing the regulatory agencies of European Union member states-or national competent authorities (NCAs)-issued in early July two guidance documents (1,2). The documents address the detection and notification of shortages (1) and good practice in public communications on medicines availability (2).

	But the EU and its member states still have a long way to go before they can sort out what the pharmaceutical industry considers to be key issues at the core of the medicines scarcities, such as low prices and delays in deciding public sector reimbursement levels.

	Dealing with deficiencies in medicines availability was highlighted as an important objective at a meeting of EU leaders in Romania in May 2019 on the future of the Union (3). In a five-year strategy document drawn up in 2015 by the EU medicines agencies network comprising the EMA and NCAs, the issue was already being classified as “an area of great concern.” 

	The EU is likely to introduce new regulations to replace the 15–20-year-old rules governing shortages reporting and prevention, in which great importance is attached to free movement of medicines and competition. Now, precedence is being given to the interests of healthcare professionals and patients in combating scarcities. The EU and national governments are under pressure to take action because levels of insufficient supplies are worsening rather than improving (4).

	In a survey of medicines scarcities in European hospitals performed in 2018 by the Brussels-based European Association of Hospital Pharmacists (EAHP), 92% of hospital pharmacists reported that shortages were a problem in their pharmacy, particularly in terms of delivering the best care to patients. This compared to 86% making a similar claim in 2014 (4).

	“Such reports are alarming and demonstrate the urgent need to draft and implement corrective policies at all decision-making and professional levels across Europe,” said the EAHP in a position paper issued in June 2019 (4). “Multi-stakeholder action is urgently needed since only joint efforts can help diminish the impact of medicines shortages on patients.” 

	A major objective behind the two new guidance documents, drawn up by an EU task force on medicines availability mainly comprising the chairs and representatives of the EMA and NCAs, has been to encourage collaboration by harmonizing the process of prevention and management of shortages already being operated by the majority of EU states.  

	A key feature of the guidance on detection and notification is the inclusion of a definition of a shortage (1). It is stated in the document: “An essential element to a harmonized approach for reporting and managing shortages is the use of a harmonized definition of a shortage. The lack of a common definition has meant that the detection and coordination of the management of shortages in the [European] Union has been inconsistent.”

	Three years ago, a group of experts at the Geneva-based World Health Organization (WHO) trying to work out a suitable definition of a started with a selection of 56 definitions, which was whittled down to two, one covering the supply side and other the demand side (5).

	The EU task force opted for a definition focused on demand (1), which reads: “A shortage of a medicinal product for human or veterinary use occurs when supply does not meet demand at a national level.”

	In the WHO definition on the demand side a ‘shortage’ occurs when demand exceeds supply (5). But in its definition on the supply side (5), a ‘shortage’ takes place when the supply of medicines identified as being essential by a health system is considered to be “insufficient to meet public health and patient needs.” With the EU definition, the emphasis is on the demand of healthcare professionals and patients (1). 

	The new EU definition will replace or at least take precedence over a variety of different national definitions in the EU. Some of these definitions are based on length of time of the drugs unavailability. Norway, although not an EU member complies with EU rules as it is part of the European Economic Area, considers that unavailability for at least two weeks constitutes a shortage. In Belgium, it is an ‘uninterrupted period of four consecutive days’. 

	In France, a shortage occurs when a community or hospital pharmacy has been unable to make a drug available within 72 hours. But France also applies other definitions of shortages, like when a manufacturer is unable to produce a medicine or a distribution problem prevents the supply of a drug even though sufficient amounts of it have been manufactured.

	The guidance places much of the onus for notifying shortages to the EMA or NCAs. MAHs should report not just current shortages but also impending or anticipated scarcities, which are expected to affect one or more EU states.

	Shortages or potential ones to be reported would include those stemming from regulatory issues, such as defects revealed by good manufacturing practice (GMP) or good distribution practice (GDP) inspections, batch failures, and medicine recalls.

	A proposed template in the guidance contains details such as risk assessments of the impact of shortages and suggested mitigation plans for dealing with the unavailability of products (1). The impact assessment would give information on potential alternative medicines. The report should also include estimates of current stocks in the supply chain and how much inventory will be available at the end of the shortage.

	The guidance expects MAHs to continuously monitor the supply and demand positions of their products with the help of regular communication with supply chain operators, such as contract manufacturers and wholesalers. In addition, they should watch out for signals of potential shortages from pharmacies, retailers, healthcare professionals, and patient groups.

	Monitoring of contract manufacturers is considered important by the guidance because they may be producing drugs for a number of MAHs so that a production problem would impact more than one medicine. MAHs should be particularly vigilant with medicines that have no or only limited alternatives and with whom supply interruptions could threaten public health, according to the guidance (1). It warns that with these products NCAs may require MAHs to develop shortage prevention plans.

	Although under existing EU legislation MAHs are required to notify impending shortages-such as those possibly caused by the withdrawal of products for commercial reasons-two months before the anticipated interruption in supplies, the guidance stresses that both current and expected shortages should be reported as early as possible (1): “Early shortage notification allows for better management of the shortage by the competent authority and stakeholders.” 

	Since it was set up in 2016, much of the work of the task force so far has been directed at improving communications about shortages to healthcare professionals, patients, and the general public, which has culminated in the completion of the guidance on the subject.

	Now with the publication of the guidance on detection and notification, the task force should be able to focus more on dealing with the shortages themselves and their avoidance. By the end of 2019, the task force is due to develop metrics for measuring the severity of shortages. It is also working on ways of encouraging best practices among stakeholders on the prevention of shortages.

	The effectiveness of the task force will be tested by Brexit in which it has been given a central role in coordinating actions between member states, EMA, and the European Commission, the EU’s Brussels-based executive. 

	The long-delayed departure of the United Kingdom from the EU, which now seems likely to take place before the end of the year, possibly without a withdrawal agreement between the two parties, could cause serious drug shortages because the UK is one of Europe’s leading medicines producers. The EU’s newly emerging strategy of tackling shortages through collaboration and close supply chain cooperation will be on trial in the immediate post-Brexit period.

	The introduction in February 2019 of an EU regulation on pharmaceutical packaging (6), which should help streamline medicines supply chains from the production plant to the pharmacy dispensing point, has highlighted the difficulties of gaining a uniform response to efficiency-raising initiatives.

	The regulation, part of the Falsified Medicines Directive (FMD), requires the identification of individual medicine packs through the use of 2D barcodes whose data can be verified by a pharmacist with a scanner at a dispensing point connected to a central data bank. 

	A dual objective behind the regulation is to combat medicines counterfeiting and to considerably improve the tracking and tracing of individual drugs through the distribution chain so that at times of shortages spare stocks can be quickly located. Yet, according to figures issued in July 2019 (7), 40% of manufacturers as well as one quarter of other supply chain actors such as pharmacies, hospitals, and wholesalers have not yet connected to the pack verification system. 

	The figures were published by the Belgian-based European Medicines Verification Organization, a joint industry and pharmacists body, which runs the pack checking scheme. It has urged NCAs to starting enforcing compliance with the regulation.

	The troubles with the implementation of the FMD regulations indicate that resolution of Europe’s medicines supplies difficulties is going to be a slow-moving process and will need a lot of commitment by individual companies and organizations.

Guidance on Detection and Notification of Shortages of Medicinal Products for Marketing Authorization Holders (MAHs) in the Union (EEA)

(Brussels, 1 July 2019).
	2. EMA and HMA, 

Good Practice Guidance for Communication to the Public on Medicines’ Availability Issues 

(Brussels, 4 July 2019).
	3. EC, “Preparing for a More United, Stronger, More Democratic Union in an Increasingly Uncertain World” (Brussels, May 2019).
	4. European Association of Hospital Pharmacists (EAHP), “EAHP Position Paper on Medicines Shortages” (Brussels, June 2019).
	5. WHO, “Meeting Report: Technical Definitions of Shortages and Stockouts of Medicines and Vaccines” (Geneva, October 2016).
	6. EU, 

Delegated Regulation 2016/161 Laying Down Detailed Rules for the Safety Features Appearing on the Packaging of Medicinal Products for Human Use 

(Brussels, 2 October 2015).
	7. EMVO, “EMVO Stakeholders’ Consideration on Enforcement and Inspections Under the Falsified Medicines Directive 2011/61/EU (FMD) and its Delegated Regulation EU 2016/161 (DR)” (Brussels, 10 July 2019). 


	Vol. 31, No. 8
	July 2019
	Pages: 10–11

	When referring to this article, please cite it as S. Milmo, “One Small Step for Man, One Giant Leap for Pharma Regulators,” 

European Union regulators have taken a significant step towards resolving some of the major supply-chain difficulties behind medicine shortages.
