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

Sean Milmo

	The number of advanced therapy medicinal products (ATMP) on the market in Europe is, as in the rest of the developed world, fewer than expected despite the large number of academic projects, start-ups, and small- and medium-sized enterprises (SMEs) involved in their development. The low level of commercialization of the advanced medicines covering gene and cell therapies and tissue-engineered products has been attributed to a variety of factors such as the complexity of the technologies, high development costs, low investment returns, and difficulties with manufacturing processes.

	Regulatory issues have also become a major barrier in Europe with the European Union struggling to keep up with the relatively fast changes in technologies and manufacturing and supply-chain procedures. Also, there are still significant inconsistencies between the regulatory objectives of individual countries and, at the EU level, of the European Commission, the EU executive, and the European Medicines Agency (EMA), which is responsible for the marketing authorization of ATMPs.

	These regulatory problems were the main focus of a regulatory affairs conference in London in December 2017 organized by European Biopharmaceutical Enterprises (EBE), part of the research-orientated European Federation of Pharmaceutical Industries and Associations (EFPIA). The meeting took place approximately six weeks after the European Commission and EMA published a joint action plan (1) to “improve the regulatory environment for ATMPs” and two weeks after the issuing of the long-awaited EU guidelines (2) on GMP specific to the products. The lack of GMP rules on ATMPs, a requirement first laid down in a 2007 EU regulation on advanced therapy products (3), has been a big gap in the regulations on the medicines. But the completion of the guidelines has been taking up a lot of resources.

	“We have had to put a tremendous amount of effort into the GMP guidelines,” Ilona Reischl, vice-chair of the EMA’s Committee for Advanced Therapies (CAT) told the meeting. “There is a limited number of people doing this work [on regulations], which poses its own challenges.” She was explaining to the meeting the reasons for delays in the development of a guideline on investigational ATMPs, in which quality matters will figure prominently. The guideline was due to be finalized in the second quarter of 2017 after an external consultation. “In addition to being kept busy with the GMP guideline, we’ve also been very busy with a guideline on genetically modified cells [while] we’ve also had to deal with guidance on the comparability of ATMP products,” she said.

	Under CAT’s workplan for this year, the committee will be discussing with ATMP developers areas in which they want greater regulatory clarity with the aim of publishing a draft investigational guideline for external consultation in the fourth quarter of 2018. The guideline is then scheduled for finalization in the third quarter of 2019-more than two years later than planned. When drawing up regulations, European regulators are being handicapped by a lack of data on the technologies, manufacturing processes, and the supply-chain needs of ATMPs because of the relatively low number that have been successfully marketed.

	“We don’t have many ATMP approved products,” noted Dr Enrica Alteri, head of EMA’s human medicines evaluation division at the EBE conference. “We can learn a lot from them and we have made a lot of progress. But we still have a lot of questions to be answered.”

	Out of 500 clinical trials using ATMP products in 2009–2017, nine have been approved, of which only five are still on the market with three being withdrawn and one suspended, according to Ana Hidalgo-Simon, EMA’s head of specialized scientific disciplines. There are, however, signs of rising development activities in new advanced therapy medicines with an increase in companies seeking scientific advice in the area in 2012–2016. Between a quarter and a third of users of EMA’s PRIME [PRIority MEdicines] support scheme for developers of medicines for unmet medical needs are now involved in ATMP innovations, Hidalgo-Simon highlighted at the EBE conference.

	Difficulties with regulations figured prominently in the first results announced at the conference of a study on the development of ATMPs being carried out by Netherlands’ Utrecht University with an EFPIA grant (4). The study includes a survey of more than 100 ATMP innovators in Europe or 38% of identified advanced therapy medicine developers, two thirds of whom were SMEs.

	“Of the challenges facing the survey respondents, the most mentioned were regulatory ones,” noted Renske ten Ham of Utrecht University’s pharmacoepidemiology and clinical pharmacology division at the EBE conference. Because of their complexities, SMEs have been falling behind in dealing with regulatory and quality issues relating to ATMPs. “Developers who start without in-house regulatory and quality expertise and business goals mostly aren’t able to catch up, especially academic spin-offs and SMEs,” ten Ham said.

Manufacturing and supply-chain challenges

	Many of the regulatory hurdles in the development and lifecycle management of ATMPs stem from the intricacies of creating a robust manufacturing system and supply-chain infrastructure for collecting cells from patients, transferring them for processing, and then administering them for treatment, according to speakers at the conference. The cells can be autologous or collected and returned to the same patient, or they can be allogeneic or coming from donors. The big task is the tailoring of regulations to deal with the scaling up of a procedure for autologous treatments to allogeneic ones for a much larger demand while ensuring that in the transferred substances, there are adequate levels of biological comparability.

	“Current [drug] manufacturing paradigms will need substantial innovation in all aspects-technical, regulatory, and quality-to supply global demand, [in which] a defined control strategy is vital,” explained Christina Basford, leader of the characterization sciences team at the cell and gene therapy group of GlaxoSmithKline (GSK) at the EBE conference. “Close collaboration between all stakeholders is needed to bring these transformational medicines to a wider patient population,” she added.

	Comparability can become a huge challenge when a treatment, usually originating from an academic laboratory attached to a hospital, has to be scaled up with minimum inconsistencies and variabilities to multiple sites while maintaining a decentralized system suitable for personalized medicine. Critical quality attributes (CQAs)-which ensure that biological characteristics are within an appropriate limit to ensure the desired product quality-are the foundation of the control strategy for these ATMPs, Basford noted. But which parameters impact CQAs? Taking into account the controls in place, is testing required for the CQAs? And which raw materials impact CQAs, she asked.

Lack of harmonization in ATMP regulations

	Basford envisaged that the technical and regulatory issues in cell process scale-out would revolve round quality assurance rules in fully automated systems, in-process analytics in hospital-based manufacturing, robust regulatory tracking of continuous process validations, and deviation management of raw material supplies. However, first the lack of harmonization across Europe has to be sorted out. Between regulations at the EU level and at national levels, there are inconsistencies on approvals of quality standards in genetically modified organisms, particularly in clinical trials, and on the activities of specialist advanced therapy hospitals.

	“The absence of harmonization in certain aspects of advanced therapy medicines is an unnecessary hurdle to the development of ATMPs,” said Barbara Feischem, EBE executive director at the conference. “We are hoping we can soon make progress in the whole area of harmonization.”

	Under the treaties governing the operations of the EU, member states are allowed to implement their own regulations in certain public health matters. As a result, a divide has opened up between the policies underpinning EU regulations in areas such as advanced therapies and those in member states. “[There is a] disconnect between European, high level regulations and national [regulatory] hurdles,” said ten Ham. “Local interpretation and execution [of ATMP-related rules] leads to many additional and duplicate information requests, delays, and increased costs. Small companies do not have the resources to address country specific requirements.”

	The EU regulators with the support of the pharmaceutical industry want to achieve a “common understanding” among the member states about the needs of ATMP developers, according to Freischem.

	Greater consistency in national approaches to GMOs is a priority for the European Commission. “GMOs are a national competence, so it is an area in which we cannot tell countries what to do,” explained Rocio Salvador-Roldan, a policy officer at the Commission’s Directorate General for Health And Food Safety during the EBE conference. “We are in a dialogue with member states on a solution which is acceptable to all countries. I am optimistic of reaching a position which would be an improvement on what we have now.”

	The biggest obstacle to greater harmonization between countries on ATMP is what is called the “hospital exemption rule.” This allows member states to exempt from EU regulations advanced therapy medicines that have been developed and produced for individual hospital patients even if a similar treatment from an outside commercial source is available. Critics of the exemption rule led by the pharmaceutical industry claim that it allows hospitals to flout EU regulations on quality and safety standards. It also offers a loophole to drug companies enabling them to sell advanced therapy medicines in hospitals without the centralized EU marketing authorization from EMA.

	“We need stronger guidance from the Commission on hospital exemption, supported by an EU integrated regulatory framework on the issue,” said Freischem. Because most of the hospitals benefiting from the exemption are attached to universities and other research institutes that account for a large proportion of the ATMPs under development, EU regulators will have to tread carefully when sorting out the hospital exemption problem. Otherwise, they might undermine the main source of advanced therapy innovation in Europe.

	1. European Commission and European Medicines Agency, “Action Plan on ATMPs” (Brussels, 20 Oct. 2017).
	2. European Commission, “Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products” (Brussels, 22 Nov. 2017).
	3. European Union, “Regulation on Advanced Therapy Medicinal Products,” Regulation 1394/2007 (Brussels, 13 Nov. 2007).
	4. 


	Vol. 30, No. 1
	February 2018
	Pages: 12–13

	When referring to this article, please cite it as S. Milmo, “Barriers to ATMP Drug Development,” 

Articles

Greater clarity and harmonization in ATMP regulations are needed to promote the development and commercialization of these therapies.

Barriers to ATMP Drug Development

	The European pharmaceutical industry is hoping that 2018 will be a year when a number of regulatory uncertainties will at least start to be resolved. The biggest of these issues are the regulatory reverberations of Brexit, in particular, the impact on the regulatory work of the London-based European Medicines Agency (EMA) having to move, as a result of the United Kingdom’s withdrawal from the European Union, to new offices in Amsterdam.

	There have already been doubts about the speed of implementation of some key pieces of approved EU legislation. Now there could be further delays to the enforcement of new laws because of the possible disruption of the transfer of EMA’s headquarters. In addition, the agency, which handles the centralized approval of new drugs and variations to their authorizations while also coordinating the regulatory activities of the EU’s 28 member states, is also drawing up new guidelines for existing legislation. 

	Brexit is due to take place at the end of March 2019. But its regulatory effects will start to hit companies from early 2018, particularly those based in the UK or with subsidiaries in the country. After Brexit, the UK will become a non-EU state classified as a “third country” in EU legislation with a legal position in relation to Union rules much the same as other countries outside Europe. The country is likely to assume this new legal status only after the end of a transition period of at least two years starting in April 2019. The availability of a transition period is considered by the industry to be particularly important. “[We and other industry] organizations are of the opinion that the agreement of transitional arrangements after March 2019 will be critical in ensuring there is minimal disruption to patients receiving medicines after the UK leaves the EU,” a spokesperson for the European Federation of Pharmaceutical Industries and Associations (EFPIA) told 

	The extent of Brexit’s repercussions on the pharmaceutical and related industries, both in the UK and the remaining EU member states, will depend on the final deal reached in the current UK–EU negotiations on withdrawal and whether a free trade agreement (FTA) is included. A deal is due to be achieved by October 2018 to give the European Parliament and the 27 members states time to approve it. One outcome could be that the UK and its licensing agency, the Medicines and Healthcare products Regulatory Authority (MHRA), will continue to be involved in the EU’s medicine approval and other public health activities in much the same way at present. 

	Under this scenario, Brexit’s public health and economic consequences would be “minimal” for both the EU and the UK, according to a report (1) on the public health implications of Brexit, completed in November 2017 by the London-based Office of Health Economics (OHE), a consultancy partly funded by the pharmaceutical industry.

	Two other scenarios described by OHE would involve the UK introducing a standalone regulatory system within the context of a UK–EU free trade agreement. In the absence of a free trade agreement, trading between the two would be conducted under the rules of the World Trade Organization (WTO). With both outcomes, there would be mutual recognition agreements (MRA) on good manufacturing practice (GMP) and other regulatory inspections but not of batch release processes. 

	In the OHE’s worst-case scenario, the UK–EU negotiations would breakdown without a deal on public health cooperation or MRAs. Trade between the two would be controlled entirely by WTO rules.

	Amidst a lack of legal certitude, UK-based companies and business are having to plan for the possible transfer of market authorizations to legal entities in the EU’s remaining 27 member states or for the application for new authorizations, which would be among a number of additional burdens on EMA before and after Brexit.

	The agency has been given 16 months to complete the move of its headquarters to Amsterdam, which was selected as the new base on 20 Nov. 2017 by the EU member states out of submissions by 19 cities across the Union (2). Pharmaceutical companies are concerned that the 16-month period will put extra pressure on EMA’s activities, which because of Brexit complications, could be disrupted well beyond 2019. 

	“The real work starts now,” said Beata Stepniewska, deputy director general and head of regulatory affairs at Medicines for Europe, representing generic drugs and biosimilars producers. “Looking to the next steps in the process, we hope that the relocation plan will be comprehensive and implemented effectively, which will provide certainty for both EMA staff and for the continuity of the work of the agency,” she told 

	Approximately 200 of EMA’s 900 staff in London have indicated they will not be staying with the agency after the transfer. Some of these staff could have expertise that may turn out to be difficult to replace. Another problem is that the agency’s new offices in Amsterdam will not be ready for full occupation until 2020. In the meantime, some of EMA’s work will have to be done from temporary premises elsewhere in the Dutch city.

	“A major concern is the uncertainty about not having a building that is ready [for full occupation],” Guido Rasi, EMA’s executive director, told a press briefing in London in November 2017 after the selection of Amsterdam for the new headquarters. “The loss of staff will not cause delays in approvals of new medicines but possibly delays in other services,” he continued. “The main challenge is not going to be the physical relocation but [assuring the continuity] of activities for the benefit of all the citizens of Europe.”

Impact on other medicines agencies in Europe

	Among Europe’s medicines agencies, it will not just be EMA and the UK’s MHRA that will be working hard in 2018 to prepare for the post-Brexit regulatory changes. Agencies in the EU’s 27 remaining states and in the three non-EU countries-Norway, Iceland, and Leichtenstein-in the European Economic Area (EEA), which are also in the EU’s pharmaceuticals single market, will be taking on more regulatory, monitoring, and testing responsibilities. This will particularly be the case for regulators outside the UK if the country has to opt for a standalone regulatory status.

	After being headquartered in London since its foundation in 1995, the MHRA had been taking on a disproportionate amount of rapporteur work on the assessment by EMA committees of new medicines under the centralized approval system. Now assessment tasks are being shared out more equally among specialists in the agencies of EU member states. Also, authorizations handled by the MHRA under the decentralized mutual recognition will have to be transferred to national agencies.

	In addition to approximately 1000 licences granted under the EMA-based centralized system, approximately 5800 national market authorizations are held by UK-based legal entities, according to figures from EFPIA. “Where marketing authorizations holders (MAH) are based in the UK, these would need to be transferred or duplicated to an MAH in the EU27/EEA,” warns the OHE in its report (1). “The same applies for MAHs based in the EU27/EEA being transferred or duplicated in the UK.”

Supply chains and post-authorization monitoring

	The UK pharmaceutical, chemical, and biotechnology sectors play a big role in intra-EU pharmaceutical supply chains in the production of starting materials and intermediates through to finished products. These supply chains are starting to be reorganized to reduce the role of UK-based producers with pharmacists in the country already reporting medicines shortages which will inevitably worsen over the next year and into 2019. The UK not only has the EU’s second highest number of GMP and other medicinal manufacturing sites but the third highest number of batch certification sites. Replacement batch release sites in the EU/EEA will have to be set up with qualified personnel. “The impact of no mutual recognition of batch release would be substantial for the EU27/EEA and the UK,” says the OHE (1).

	Alterations are also likely to be needed in the monitoring of the quality, safety, and efficacy of medicines in the post-authorization stages. The UK contains the EU’s highest number of centres for conducting pharmaco-epidemiological studies. Mainly because of the centralized nature of its National Health Service, it also conducts the highest number of post-authorization safety studies (PASS), according to the OHE report (1). 

	Meanwhile, even if there was no Brexit, pharmaceutical companies would have to reorganize some of their activities in 2018 in order to prepare for the implementation of new EU legislation. A major task is ensuring compliance, by March 2019, with part of the 2011 Falsified Medicines Directive (FMD), which requires the serialization or unique identification of each medicine pack, necessitating major changes to packaging lines and distribution channels. 

	“It is a very complex process including regulatory readiness to implement the safety features on packaging,” says Stepniewska. “In view of the huge amount of packages that are affected, a lot of notifications to the competent authorities are expected to be submitted already in 2018, which will create a serious challenge for the pharmaceutical regulatory system, besides Brexit.”

	EMA has indicated that the implementation of the 2014 Clinical Trials Regulation, which includes new rules on the quality of investigational medicinal products, may be delayed further after being put back to the second half of 2019. Similarly, the European Commission, the EU’s Brussels-based executive, may hold back the introduction of a new strategy on Pharmaceuticals in the Environment (PIE). In a year of pre-occupation with Brexit-induced legal uncertainties, these delays may not be unwelcome among both regulators and many pharmaceutical companies.

	1. Office of Health Economics (OHE), “Public Health and Economic Implications of the United Kingdom Exiting the EU and Single Market” (London, November 2017).

	2. Council of the European Union, “European Medicines Agency to be relocated to Amsterdam, Netherlands,” Press Release 20 Nov. 2017.  


	Vol. 30, No. 1
	January 2018
	Pages: 6–8

	When referring to this article, please cite it as S. Milmo, “Pharma Braces Itself for Post-Brexit Regulatory Changes,” 

The repercussions of EMA’s relocation and Brexit will continue to be the dominant regulatory issue throughout 2018.

Pharma Braces Itself for Post-Brexit Regulatory Changes

	The European Commission, the Brussels-based European Union executive, mentioned in a strategy document (1) in 2015 possible changes in the system under which research-based pharmaceutical companies have been able to extend their patents on their new medicines through the granting of five-year supplementary protection certificates (SPCs). Among the alterations to the SPC rules suggested by the commission was one that would provide a waiver for generic and other drug producers to allow them to make, but not market, medicines covered by the extended patents. The commission, however, in October 2017, put forward for public consultation a list of proposed SPC improvements, including a manufacturing waiver. After the consultation ends early next year, the commission has indicated that it would then start work on drawing up firm proposals to include possible amendments to existing EU legislation.

	“The commission has been a little bit slow in doing something about this issue, but now the process for making changes has started,” says Adrian van den Hoven, director general of Medicines for Europe, a lobby group representing generic drug and biosimilar medicine manufacturers. “We are hoping that if everything goes smoothly, the changes will come into force in one and half to two years, with the manufacturing waiver being the priority for us.” The organization wants new rules that will enable large quantities of a drug to be manufactured during its SPC protection period to take advantage of the expiry or non-existence of the protection certificates in non-EU markets. The waiver should also be applicable in the EU itself so that generic-drug or biosimilar producers can launch their products immediately in European markets as soon as the certificates expire.

	“There is a relatively large number of blockbuster drugs, many of them biopharmaceuticals, whose SPCs are expiring in Europe over the next few years,” van der Hoven told 

 “That is an opportunity we want to take full advantage of.” Furthermore, manufacturing waivers would help to make the European generic drugs and biosimilars sector more competitive internationally, attract investment in EU drug manufacturing capacity, and help create thousands of new jobs in the industry, according to Medicines for Europe (2). 

	Manufacturing waivers for bulk production of medicines during the SPC period is, however, being opposed by many drug innovators on the grounds that it is weakening their intellectual property rights. Rather than strengthening the European pharmaceutical sector, it would undermine its R&D capabilities. “[We] believe that the introduction of an SPC manufacturing exemption would be detrimental to medical innovation and Europe’s knowledge-based economy,” a spokesman for the European Federation of Pharmaceutical Industries and Associations (EFPIA), representing the research-based sector, told 

	SPCs were first introduced in Europe in the early 1990s as a means of compensating drug originators for the lengthy testing and clinical trials that their products needed to gain marketing authorizations. Because of stricter regulatory requirements, the 20-year protection period for drugs was effectively being reduced to 10 years or less. By 2015, the number of SPCs issued in Europe had reached 20,000, a figure that the European Commission said showed how important they were to medicine developers.

	Generic-drug and biosimilar producers and small medium-sized enterprise (SME) innovators, particularly small biotech companies, have long complained that the rules on SPCs have restricted the quantities of SPC drugs they can manufacture during the five-year protection period. Bolar exemptions first introduced in the EU legislation (3) in 2001 allow manufacturing of SPC-covered drugs for research or testing purposes to provide data for marketing and other regulatory approvals. But like SPCs themselves, the Bolar exemptions are granted on a national basis by the 28 EU member states, which has led to variations in their scope. Some only apply to development work for national or EU marketing authorizations and others for approvals outside Europe and anywhere in the world.

	The generic-drug and biosimilar producers in Europe are focusing on achieving legislative changes that will enable them to manufacture sufficient quantities of a drug during the SPC period to supply markets that do not have SPC regulations or where the certificate on a medicine has expired. Their major target is the right to stockpile a medicine so that they can immediately launch it on the EU market as soon as its SPC expires. The commission’s eventual proposals for alterations to the SPC system in the EU may fall short of what the generic-drugs and biosimilars sector wants. 

	Impact of the SPC manufacturing waiver and a broadened Bolar exemption

	The proposals (4) listed by the commission for the public consultation include, among three options, one of no change. The other two are the use of non-legislative instruments to improve the implementation of existing rules and the introduction of amendments to existing EU legislation to allow manufacturing waivers for stockpiling purposes. At the same time, as it launched the consultation, the commission published a study (5) by the UK-based consultancy Charles River Associates (CRA) on the economic impact of the SPC manufacturing waiver and a broadening of the Bolar research exemptions. The study, which was funded by the commission, was completed in 2016. 

	The CRA report (5) concludes that the manufacturing waiver would pose minor threats to the innovative sector while boosting sales, investment, and jobs in the generic-drugs and biosimilars segment. Among the main benefits would be more investment in pharmaceutical R&D and in manufacturing, €9.5 billion (US$11 billion) additional net sales for the EU pharmaceutical industry, and the creation of 25,000 direct jobs and 100,000 indirect ones.

	For the EU generic-drug makers and biosimilar producers, the biggest gain would be from an exemption on their manufacturing SPC drugs for export to third, mainly non-European, countries where SPC protection had expired or does not exist. Export generic-drug sales would go up by an additional €7.6 billion while sales of branded medicines are expected to fall by only up to €278 million. The net sales rise would be equivalent to an increase in EU pharmaceutical exports of up to 18%, according to CRA. Biosimilar export sales would increase by nearly €3 billion.

	A significant bonus from the broadening of the Bolar exemption would be the likely benefit to EU-based suppliers of APIs at a time when the vast majority of APIs in the European market are being imported from Asia. The CRA study estimated that sales by third-party European generic-API producers could increase by up to 29%, equivalent to an additional €180 million in annual sales by 2030.

	Disputes from EFPIA and other consultancies

	The combined effects of the SPC export waiver and the extension of the Bolar exemption could result in additional EU API sales of €254 million by the end of the next decade. However, the figures and conclusions of the CRA report are being disputed by other consultancies as well as originator representatives such as EFPIA.

	“The potential negative impact of the adoption of an SPC manufacturing waiver on the R&D-based pharmaceutical industry has been underestimated,” says the EFPIA spokesman. “Recent studies find that the adoption of such a measure would lead to the loss of between 4500–7700 direct jobs in the [research-based] industry with an additional 19,000–32,000 indirect job losses. It would also result into a decrease of between €215–€364 million in R&D investment.”

	Also, the opportunities for exporting European generic drugs to non-European markets prior to an SPC expiry had been exaggerated. Often, SPC extensions in Europe during which generic-drug companies could be entitled to a manufacturing waiver, expire earlier or only a little later than the intellectual property rights for medicines in other non-EU markets, according to EFPIA.

	In a report (6) on the impact of the introduction of SPC exemptions on the biopharmaceuticals sector, Pugatch Consilium, a consultancy in Bicester, England, points out that many non-EU generic-drug and biosimilar markets have erected trade barriers to restrict imports from areas such as Europe. “Why would India and Brazil or other emerging markets favour European generic [-drug] manufacturers as opposed to their own domestic ones?” asked David Torstensson, partner at Pugatch and author of the report (6). “In many cases, they already have a policy framework in place that actively discriminates against foreign competitors,” he continued. “Such localization policies often include price preferences in government tenders; import bans and increased taxation on foreign products; and local affiliation and/or production requirements. As a result, locally-produced generic drugs can take as much as 90% of the local generic-drug market in many emerging markets.”

	EFPIA has urged that in areas where improvements to the SPC system are considered to be necessary, a non-legislative approach should be taken. Without legislation, there would be no manufacturing waiver, which would be a major disappointment to the generic-drugs and biosimilars sector. It will also reinforce the view within the European pharmaceuticals sector that it needs to act together on key issues like patents and patent exemptions.

	“The manufacturing waiver is something which helps the European pharmaceutical industry as a whole,” says van den Hoven. “The research-based sector knows it is a good step for the generic drugs and biosimilars sector. If there was something being considered which was good for them, we would not try to block it.” At the moment, a united front within the industry on matters such as the manufacturing waiver and even other SPC exemptions seems a long way away.

Upgrading the Single Market: More Opportunities for People and Business,

 COM (2015) 550 final (Brussels, 28 Oct. 2015).	

Community Code Relating to Medicinal Products for Human Use,

Public Consultation on Supplementary Protection Certificates (SPCs) and Patent Research Exemptions

		Charles River Associates (CRA), “Assessing the Economic Impacts of Changing Exemption Provisions During Patent and SPC Protection in Europe” (February 2016). 	

		Pugatch Consilium, “To SPC or not to SPC…” (Bicester, England, October 2017).


	Vol. 29, No. 12
	December 2017
	Pages: 8–9

	When referring to this article, please cite it as S. Milmo, “Disputes Over Manufacturing Waiver and Other SPC Exemptions,” 

The European Commission’s effort to relax supplementary protection certificates to help generic-drug makers and biosimilars producers has sparked strong opposition from the research-based pharmaceutical sector.

Disputes Over Manufacturing Waiver and Other SPC Exemptions

	Continuous manufacturing is increasing rapidly in Europe’s pharmaceuticals sector after expanding only slowly for several years. In 2016, Europe had-at 35%-the largest share of world pharmaceuticals output through continuous processes, according to a report by Transparency Market Research (TMR), Albany, New York, on the global continuous manufacturing market, which it forecasts will grow by a compound annual growth rate of 8.8% in 2017–2025 (1).

	TMR expects Europe to retain its leading position as it maintains an above average growth rate, mainly due to the availability of advanced technologies and the greater number of technology providers in the region, led by Siemens AG of Germany. The rise in the introduction of continuous manufacturing technologies, however, has not been accompanied by a similar strong increase in the use of automation, or in particular, the adoption of digitization through the application of sensor-based on-line monitoring. The industry in Europe appears to be holding back from introducing advanced digitalized measuring equipment, data analytics, and advanced automated controls to raise the efficiency of its manufacturing practices. There has, for example, only been cautious use of automated real-time release testing (RTRT) for on-line or in-line measuring and controlling of the quality and specifications of medicine components. 

	“A number of manufacturers have implemented use of instrumentation such as near infrared (NIR) or Raman spectroscopy for gathering information on processes, and in the case of active substance manufacture, for determining reaction end points,” explains an official at Ireland’s Health Products Regulatory Authority (HPRA), Dublin, in an interview with 

. “However, not many have implemented these as fully operating real-time release systems,” he adds.

Regulatory hurdles hinder adoption of new technologies

	Ireland is one of Europe’s major centres for pharmaceuticals production with nine out of 10 of the world’s leading drug companies having operations there. A priority in its current strategy from 2016–2020 is to encourage new technologies such as digitization and the Internet of Things (IoT). Despite initiatives by most regulatory agencies across Europe to encourage pharmaceutical companies to introduce continuous manufacturing and automation technologies, many producers are deterred by the need to obtain regulatory approvals for the installation of digital equipment and systems.

	“The introduction of any in-process sensors as part of the control strategy will need to be appropriately supported and approved prior to implementation,” says a spokesperson for the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). “It is also normal practice for, where relevant, submission-specific manufacturing site inspections to be carried out as part of the review process, [which] would involve both assessors and inspectors.”

	Pharmaceutical companies complain that in Europe, in particular where post-marketing changes or variations to processes are mainly approved at the national level, there are too many inconsistencies in the way authorization decisions on the changes are applied. The Parenteral Drug Association (PDA) announced in July 2017 that a survey of its members on the impact of national-level post-approval changes showed a 97% belief that the regulations on variations were hurting innovation and holding back technological progress (2).

	“It is not so much that the European regulations on variations are prohibitive,” Ursula Busse, a European-based quality regulations specialist and member of the PDA board of directors, told 

. “A lot depends on the way they are implemented.” 

	PDA has been urging that more use be made of the concepts behind the pharmaceutical quality system (PQS) put forward by the Geneva-based International Council for Harmonization (ICH) to be applied throughout a product’s lifecycle along with good manufacturing practice (GMP) requirements. In today’s pharmaceuticals market, post-marketing changes to processes are inevitable, PDA contends, therefore, adherence to PQS principles should be used as a possible means to reduce the need for approval of variations. 

	Another concern for drug companies is that fast advances in technologies, especially in automation and digitization areas, are leading to gaps in existing regulations. “There does not need to be new regulations but rather a reshaping of existing regulations and guidelines,” Busse said. 

	Pharmaceutical companies are worried about the interpretation of regulations by the regulators themselves; the regulations have failed to keep pace with the new technologies, especially those based on the collection of vast quantities of data from automated equipment and sensor systems.

	“Ten years ago, only limited amounts of process control data could be captured, processed, and analyzed,” Peter Behner, leader of the pharma life sciences sector in Europe at the PwC consultancy Strategy&, told 

. “Now huge amounts of it can be stored and analyzed,” he continued. “Furthermore, it can be stored and updated in a permanent, automatic process. This needs to be reflected in guidelines.” Revisions of guidelines can, however, take several years after allowing for multiple drafts and public consultations. As a result, new versions of guidelines could be technologically out of date by the time they are finally published.

	The basic concepts governing regulations and their implementation for quality controls and management in pharmaceutical manufacturing are laid down in three International Council for Harmonization (ICH) guidelines-Q8 and its revisions, Q9, and Q10 (3–5). ICH Q8 covers pharmaceutical development, Q9, quality risk management, and Q10, PQS. A fourth guideline, ICH Q11 (6), gives guidance on the production of drug substances in line with advice in Q8–10. 

	A major disadvantage of the ICH Q8–10 guidelines is that, although accepted by both industry and regulators as still being highly relevant to today’s manufacturing trends, they were drawn up more than five years ago before automation and digitization began to make inroads into life-science sectors such as pharmaceuticals. Also, the guidelines were mainly focused on the creation of quality controls during the development of processes, whereas the introduction of automation systems, particularly in continuous processing, is likely to take place after a product is commercialized. 

	In line with the policy of regulators in Europe and North America to concentrate more attention on controls in the post-authorization period, ICH is currently creating a Q12 guideline (7) to deal with what it calls a “lack of a harmonized approach on technical and regulatory considerations for lifecyle management.” ICH admits that “several gaps exist which limit full realization of intended benefits” of Q8–11, in which the main emphasis has been on the early stages of the lifecycle (7).

	“Generally what is and what is not a variation with digitalization/automation is still a bit of a grey area given the early stage of many of the technologies and their adoption.” said Marcus Ehrhardt, a life-sciences strategy advisor at Strategy&. “We hope that ICH Q12 expert working group will be much more specific in deciding how digitisation can be used in quality control strategies.”

	The expert group, including specialists from governments, regulators, and industry, was due to finalize Q12 in the second quarter of 2017, but now it is not likely to be finalized until the middle of 2018 (8). Meanwhile, professional organizations such as PDA and the International Society for Pharmaceutical Engineering (ISPE) have been putting forward their own guidance on automation. 

	An ISPE group headed by Christoph Herwig, professor of biochemical engineering at the Vienna University of Technology, Austria, published this year proposals (9) for a “holistic” production control strategy that would “address challenges from digitalization and big data management.” It would aim to transform today’s development-based controls system into one that would meet the quality needs of post-authorization commercial manufacturing.

	“Regulatory prerequisites for the [holistic] approach are already in place,” according to the ISPE group (9). The guidelines, however, need to be adapted to take into account current technological trends such as Industry 4.0, the fourth industrial revolution driven by automation, IoT, and cloud computing.

	Although European regulatory agencies, headed by the European Union’s European Medicines Agency (EMA), have been active in promoting innovation, they have fallen behind initiatives in digitization taken by the United States Food and Drug Administration (FDA). Nonetheless, the two agencies are collaborating on automation and digitization matters. In April 2017, they published a report (10) on a five-year joint pilot programme for parallel assessments of applications containing quality-by-design (QbD) elements. The aim of the project, completed in 2016, was to facilitate consistent implementation by the two agencies of QbD concepts in ICH guidelines. The programme included assessment of RTRT methods and prediction models in continuous manufacturing processes and post-approval issues such as change management. The report concluded that on the basis of the parallel assessments in the pilot, “there is solid alignment between both agencies regarding the implementation of multiple ICH Q8, Q9, and Q10 concepts.” As a result, both agencies are “currently exploring potential joint activities with specific focus on continuous manufacturing (and) additional emerging technologies.” 

	“FDA has been more open and progressive about digitization than EMA,” Behner said. “But FDA and EMA are working together and both take into account ICH thinking and guidelines. Ultimately, they will be aiming to achieve the same objectives with digitization.”

		Transparency Market Research, “Pharmaceutical Continuous Manufacturing Market,  Global Industry Analysis, Size, Share, Growth, Trends, and Forecast 2017–2025.” (Albany, NY, October 2017).	

		Parenteral Drug Association (PDA), “Change Regulations Hinder Pharma Innovation According to PDA PAC iAM Survey,” Press Release, 28 July 2017.	

		ICH Q8(R2) Finalized Guideline Pharmaceutical Development, (Geneva, August 2009).	

Development and Management of Drug Substances 

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, Concept Paper 

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, Expert Working Group Work Plan,

		C. Herwig, C. Woelbeling, and T. Zimmer, 

		EMA, “Report from the EMA-FDA QbD pilot programme,” EMA/213746/2017 (London, 19 Apr. 2017).


	Vol. 29, No. 11
	November 2017
	Pages: 8–9

	When referring to this article, please cite it as S. Milmo, “Europe Leads the Way in Continuous Manufacturing,” 

The shift toward continuous manufacturing among European pharmaceutical manufacturers has not been accompanied by a similar strong increase in the use of automation and sensor-based on-line monitoring.


Europe Leads the Way in Continuous Manufacturing

	The European Union is close to finalizing a new strategy on pharmaceuticals in the environment (PIE), which could include proposals for stricter controls on effluents from medicines and active ingredient plants. Its initial focus is likely to be on tackling environmental pollution by pharmaceuticals as a means of curbing antimicrobial resistance (AMR). In the longer term, measures against discharges of antimicrobial manufacturing waste will be followed by steps against emissions from plants making other pharmaceuticals of environmental concern such as endocrine disruptors.

	The European Commission, the Brussels-based EU executive, adopted in June 2017 an action plan (1) on antimicrobial resistance with the objective, according to Vytenis Andriukaitis, health and food safety commissioner, of making “the EU a best practice region worthy of shaping the global agenda on AMR in this increasingly interconnected world.” 

	In a roadmap issued in April 2017 to enable stakeholders to provide feedback on the planned PIE strategy, the Commission acknowledges that pharmaceutical pollution was an “emerging environmental problem” that required initiatives from the Commission, particularly on water contamination by drug substances. So far, the Commission has avoided making any specific proposals on dealing with the issue of discharges of antibiotics waste from plants manufacturing antimicrobial APIs considered by some experts to be a major source of AMR. The Commission, however, has been coming under mounting pressure to take some sort of initiative on waste from the manufacture of antibiotic APIs because of these possible links with antimicrobial resistance.

	In recent years, studies, mostly by academics, have provided mounting evidence that discharges of antibiotics APIs from production plants could be causing the creation of resistant pathogens, which could ultimately be spread around the world. In one of the biggest investigations of AMR, the Review on Antimicrobial Resistance funded by the United Kingdom government and Wellcome Trust and chaired by the economist Jim O’Neill claimed (2) that in discussions of the issue the way antimicrobials were produced “had been too often neglected.” The review, published in 2016, recommended that global bodies, governments, and regulators should set evidence-based, enforceable targets for the maximum levels of discharged antimicrobial APIs in manufacturing waste. It also suggested that pharmaceutical companies should improve the monitoring of their own API manufacturing units and those of third-party suppliers.

	In fact, with the assistance of the Review on Antimicrobial Resistance, the pharmaceutical industry had already been taking action on AMR. In early 2016, 96 pharmaceutical, biotechnology, and diagnostics companies and nine industry associations drew up what was called the Davos Declaration (3) under which the signatories pledged their support for a series of anti-AMR measures, including initiatives to combat environmental pollution by antibiotics. In September 2016, a group of companies within the Geneva-based International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) issued a roadmap laying out a voluntary programme for controlling antibiotic discharges from pharmaceutical plants. The 13 signatories to the document included leading global players such as AstraZeneca, Roche, GlaxoSmithKline, Merck & Co., Novartis, Pfizer, and Sanofi. 

Pollution from manufacturing sites in India and China

	For the European Union, which works mainly through legislation adopted by its 28 member states rather than voluntary schemes, curbing antibiotic discharges is a big challenge. The vast majority of antimicrobial APIs supplied to the European market are manufactured in India and China. Studies have revealed high levels of pollution from antimicrobial APIs at manufacturing sites in both countries. In 2016, a group of German researchers working in Hyderabad in southern India, which is a hub of bulk drug manufacture, detected the antifungal fluconazole at a concentration of 236,950 micrograms per litre, which was more than 20 times greater than therapeutically desired levels in the blood (4).

	“To our knowledge, this is the highest concentration of any drug ever measured in the environment,” said the scientists headed by Christoph Luebbert of Leipzig University Hospital’s infectious diseases and tropical medicine unit. “Our findings confirm those of previous studies that demonstrated a strong association between environmentally stable anti-infective residue pollution and the presence of multi-drug resistant (MDR) bacteria.”

	In the face of such high concentrations of pollution and the likelihood it triggers the creation of large AMR reservoirs, the European Commission is being urged to take a strong line with non-European API suppliers in the fight against antimicrobial resistance.

	“From a moral standpoint, minimizing such discharges fall within the responsibility of Europe, as we are buying and using these drugs,” said Professor Joachim Larsson, a specialist in antimicrobial resistance at Gothenburg University’s Institute of Biomedicine in Sweden. “The responsible way of acting, as buyers and consumers, would be to develop and apply demands and regulations that secures environmentally safe production, regardless if production takes place in Europe or elsewhere,” he explained in a feedback to the proposed PIE strategy (5). He warned about the global threat of inadequate controls on discharges from bulk drug plants. Because of the way that resistant pathogens evolve, theoretically an AMR-polluting incident need happen only “once at one site of our planet, then travelling and globalization takes care of the spread of these bacteria,” he said.

	Many other people participating in the consultation exercise earlier in 2017 on the Commission’s planned PIE strategy also wanted action taken against polluting plants. The vast majority of stakeholders in the consultation, representing industry, non-governmental organizations (NGOs), healthcare providers, and other public and private sector organizations, backed more surveillance and collection of data on discharges and the application of minimum manufacturing standards to prevent pharmaceutical waste causing resistance.

	Even regulators supported tougher controls on emissions. EU legislation should be tightened up with greater transparency and traceability in the manufacturing chain to prevent the environmental consequences of API production, said the Norwegian Medicines Agency in its feedback (6). Norway is a non-EU state but a member of the EU single market. 

	One option being put forward by backers of a more robust European approach is for good manufacturing practice (GMP) standards to be extended to cover control of emissions. This would be fiercely opposed by industry, which wants GMP to remain firmly focused on product quality and safety.

	“GMP is not about environmental standards,” Bengt Mattson, environment and corporate responsibility manager at the Swedish research-based pharmaceutical industry association (LIF), told 

 “If the EU tries to impose environmental standards through GMP, it will risk getting into trade conflicts,” added Mattson, who is also co-chair of a PIE task force backed by the industry’s three main European associations-the European Federation of Pharmaceutical Industries and Associations (EFPIA), Medicines for Europe (previously the European Generics Medicines Association [EGA]), and the Association of European Self-Medication Industry (AESGP) for the European pharmaceutical wholesalers.

	An extension of GMP would also be at odds with the EU’s own system of pollution controls in manufacturing which are applied through plant operating permits. “India and China have their own, similar environmental legislation,” said Mattson. “The difference is in the way it is enforced.”

	An alternative would be for the EU to take a more decentralized approach under which India and Chinese plants would be given “quality marks” for pollution controls. Then individual European governments, national procurement agencies, or healthcare providers would decide for themselves whether to buy from low-ranking suppliers.

	The roadmap signatories within IFPMA are moving towards a system based upon limits on AMR-threatening discharges at individual sites, which with the help of expert advisors, would be set by the industry. The participants in the roadmap scheme will establish in 2018 a common framework of good practice for controlling discharges of antibiotics into the environment in their supply chains.

	By 2020 science-driven, risk-based limits on concentrations of discharges of antibiotics waste will be introduced with good practice methods being applied to reduce the environmental impacts of these emissions. The roadmap group stresses that any system of limits on discharges will need to be funded with the help of higher margins on antibiotics and other antimicrobials.

	“There are enormous price pressures at the moment,” said Mattson. “Some antibiotics are currently as cheap as sticks of candy. This is one reason why some producers have been taking short cuts with their control of emissions. Society has to be prepared to pay for the costs of good quality environmental standards.”

	Low prices are considered to be a factor behind shortages of antibiotics in Europe as a result of poor profitability leading to reductions in production capacity. “This downward price pressure on essential antibiotics has jeopardized their continued availability,” a spokesman for Medicines for Europe told 

. “In most European countries, the price level of antibiotics is close to marginal cost, and sometimes even below that-for example in Denmark and Portugal. As a result of these unsustainable price levels and drastic cost-containment measures, the number of antibiotic manufacturers in Europe has gone down.”

	Medicines for Europe has been urging the EU countries to adopt pricing and procurement policies for antibiotics, which would help boost investment in production capacity in Europe. To be consistent with what is likely to be an EU strategy on PIE aimed at preventing manufacturing discharges causing antimicrobial resistance, such pricing policies will also have to be aimed at generating funds for building state-of-the art waste treatment plants. 

	1. European Commission, A European One Health Action Plan against Antimicrobial Resistance (Brussels, 29 June 2017).

	2. The Review on Antimicrobial Resistance, chaired by Jim O’Neill. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations (London, May 2016). 

	3. Declaration by the Pharmaceutical, Biotechnology and Diagnostics Industries on Combating Antimicrobial Resistance (Davos, 21 Jan. 2016).

	4. C. Lübbert et al., Infection 45, 479–491 (2017).

	5. J. Larsson, European Commission’s Strategic Approach to Pharmaceuticals in the Environment, Feedback reference-F1756 (Brussels, May 2017).

	6. Norwegian Medicines Agency, European Commission’s Strategic Approach to Pharmaceuticals in the Environment, Feedback reference-F1787 (Brussels, May 2017). 


	When referring to this article, please cite it as S. Milmo, “Pharmaceutical Environmental Pollution and Antimicrobial Resistance,”

The European Commission is striving to tackle environmental pollution by pharmaceuticals as a means of curbing antimicrobial resistance.


Pharmaceutical Environmental Pollution and Antimicrobial Resistance

	A report by the European Medicines Agency (EMA) on the international regulation of medicines has pinpointed major deficiencies in the collaboration among regulators in tackling worldwide problems in the management of pharmaceuticals. Regulators are aware of the need for co-ordination within and between regions, which has led to a “myriad of initiatives,” according to the report (1) by EMA, the London-based European Union body responsible for licensing drugs for the whole of the EU market as well as running the EU’s network of national medicines agencies.
	
	“The fundamental question is not if the medicine regulators worldwide need to co-operate but how they can best co-operate in order to achieve the desired results,” says the report, which is one of the first of its kind to provide an overview of the current international regulatory activities in medicines. Because of an inconsistency in how to achieve effective co-operation, the initiatives lack “integration and strategic direction ... often leading to overlap or duplication of activities.” In addition, gaps have opened up in the scope of collaboration so that key issues can be excluded. This fragmentation could become worse amidst signs that economic globalization has peaked, as reflected in the Brexit vote in the United Kingdom’s recent referendum and the outcome of the United States presidential election, although this is a question not covered by the EMA report.

	The study (1), which was conducted in the form of a mapping exercise on international initiatives, was requested by the three-year-old International Coalition of Medicine Regulatory Authorities (ICMRA), a organization representing heads of medicines agencies of which EMA is a leading founder member. Many of the ICMRA members, such as EMA, consider the association to be an important means of resolving the problems of the global control of pharmaceuticals because it can operate strategically by setting worldwide objectives in priority areas relating to the availability, quality, and safety of medicines. “ICMRA is unique due to its high level of membership among heads of agencies, which is necessary to develop and ensure global strategic leadership and co-ordination,” an EMA spokesperson told 

	Among the essential matters that need to be managed more effectively on a global basis are disruptions to supply chains and responses to crises when there is an urgent need for medicines such as vaccines as a result of serious outbreaks of infectious diseases. The report highlights the impact of new, complex technologies such as advances in biotechnology, gene editing, and cell therapies. “Manufacturing phases of a medicine may now be carried out in different countries or even different continents and a medicine may often be distributed in multiple regions,” the report says (1). ICMRA has projects covering generic medicines, GMP, rapid sharing of information between agencies, supply-chain integrity, crisis management, and pharmacovigilance. 
	The pharmaceutical industry sees ICMRA as an opportunity for influencing the international regulation of medicines after its role within the Geneva-based International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was downgraded. After a restructuring of ICH in 2015, the industry found that its ideas on reliability of electronic records and standards for track-and-trace systems for pharmaceuticals had more opportunity of being realized elsewhere. 

	“We discovered that it was better to pursue [these proposals] via ICMRA instead,” said a spokesman for the European Federation of Pharmaceutical Industries and Associations (EFPIA). “The pharmaceutical industry is global and has, therefore, a unique opportunity to identify arising issues early and contribute to the strategic global co-ordination strategy,” he added. 

	In addition to considering the activities of ICMRA itself, EMA looked at initiatives by a range of organizations, some of them operating globally and others regionally such as the EU itself and the Council of Europe’s European Directorate for the Quality of Medicines & Healthcare (EDQM). A total of approximately 20 initiatives were covered by the study. Some organizations, mainly those with a global scope, are well established bodies. These organizations include the World Health Organization (WHO) with its Essential Medicines and Pharmaceutical Policies (EMP) scheme, covering medicines policy, quality assurance, and medicines access throughout the world. 

	The Paris-based Organization for Economic Co-operation and Development (OECD) provides policy analysis and data for developed countries on health policies and draws up standards for R&D and testing processes in pharmaceuticals and biotechnology. Organizations such as ICH, set up in 1990, are more narrowly focused on harmonization and the development of common standards in pharmaceuticals. The Geneva-based Pharmaceutical Inspection Co-operation Scheme (PIC/S) concentrates on creation and maintenance of GMP standards, particularly through the training of inspectors. The International Generic Drug Regulators Programme (IGDRP), launched in 2012, is focused on harmonizing controls of generic medicines to ensure their greater availability across the world. 

	
	The numbers of regional initiatives have been growing steadily. Asia now has the Asia-Pacific Economic Co-operation’s (APEC) projects on harmonization and guidelines in the life-sciences and medical products industries. The Association of Southeast Asian Nations (ASEAN) has its own pharmaceutical products working group dealing with the harmonization of medicines regulation. Africa has the African Medicines Regulatory Harmonization (AMRH) programme. But within the continent, there are a number of sub-regional harmonization initiatives such as those covering East Africa and parts of southern Africa. 

	In the Americas, the Pan-American Network for Drug Regulatory Harmonization (PANDRH) promotes harmonization in drug assessments and approvals. The Ibero-American Medicines Authorities Network (EAMI) is one of the few organizations to forge links between two continents-in this case Latin America and the Iberia area of Europe, comprising Spain and Portugal. It is mainly a forum for exchange of information and developing best practices, such as in the formulation of medicines prepared in pharmacies. 

	
	With most international initiatives, the primary objective is the exchange of information, which is followed by the setting of standards and best practices. The next collaborative stage is usually work sharing. Europe is the only region where a high level of work sharing also coexists with a system of mutual recognition, under which an approval of a drug or medicine improvement by one agency would be recognized by licensing agencies in other regional countries. Many states across the world balk at mutual recognition because of fears about loss of autonomy.

	The thinking behind EMA’s study (1) of international regulatory activities is that a global overview helps to provide the basis for the creation of strategies that should eventually lead to the elimination of overlaps and duplication while also filling gaps in current initiatives. As a result, ICMRA’s approach has been to set priority areas and then use an overview of what is happening in these among regulators internationally to provide a basis for strategies to be drawn up on each one of them by the organization.

	EMA’s task was to use its report (1) to give overviews of three of ICMRA’s current priorities-supply-chain integrity, crisis management, and pharmacovigilance. With 14 different initiatives covering supply chain integrity, EMA found overlaps in the use of databases, track-and-trace schemes, and warning systems. Among the gaps was a lack of mutual awareness among regulators, inability to link systems, and to leverage different projects.

	“Despite multiple track-and-trace initiatives on a national or regional basis that share a common aim, none of them seem to have looked beyond their borders,” the report says. A major problem is that despite international agreement on a global standard for the identification of medicinal products, it is still a long way from being integrated into national or regional databases. So when there are international supply-chain difficulties, regulators cannot be sure they are referring to the same product.

	With the issue of crisis management, there is a lack of common understanding among regulators about what a health crisis means, according to the study. EMA has proposed in the report a definition that a health crisis occurs when routine measures are not considered sufficient after an analysis of an incident’s associated risks. However, among the urgent and co-ordinated actions needed to control a crisis, there is no systematic international mechanism for dealing with shortages of specific medicines caused by manufacturing problems or natural disasters. Nor, the report says, is there a systematic means for the involvement of regulators in helping to tackle outbreaks of infectious diseases, such as Ebola, when there could be an urgent requirement for new medicines or vaccines. 

	Effective pharmacovigilance on an international scale is being held back by similar trends in supply-chain integrity-such as lack of awareness among regulators of other international schemes for reporting adverse reactions to drugs or quality issues. Identification difficulties because of non-compliance with the international standard on naming medicines was another barrier to proper co-ordination, according to the study. 

	The EMA’s report has on the whole been welcomed by European pharmaceutical industry associations. But there has been some skepticism about how much regulators need to be involved in matters like supply-chain disruptions. 

	Medicines for Europe, an association representing generic-medicine manufacturers, warned about the dangers of oversimplifying the matter of medicines availability and shortages. “There are many causes to unavailability, and not all ‘remedies’ will lie in the regulatory arena,” a spokesman for the association told Pharmaceutical Technology Europe. Individual governments, to which regulatory agencies are ultimately accountable, may also decide to take a more direct role themselves in sorting out problems in areas such as supply chain and management of pandemics.

	1. EMA, Connecting the Dots-Towards global knowledge of the international medicine regulatory landscape: mapping of international initiatives (London, October 2016). 

When referring to this article, please cite it as S. Milmo, "Bridging Gaps in the Global Regulatory Framework," Pharmaceutical Technology Europe

Better co-ordination within and between regions is needed to improve the global regulation of medicines, according to the European Medicines Agency.