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

Sean Milmo

	European Union regulators are stepping up their efforts to stimulate more research into new drugs, especially those for the treatment of life-threatening conditions and rare diseases. One priority is to help small- to medium-sized enterprises (SMEs) and academics to be more effective in taking newly developed medicines successfully through market authorization to commercial launch. Regulators are, therefore, offering scientific advice so that developers are able to sort out major efficacy, safety, and quality difficulties at an early stage. Nonetheless, there is the issue of how much this support should include advice on the development of manufacturing processes and quality issues covered by chemistry, manufacturing, and controls (CMC).
	
	


	In consultations on two of the most recent initiatives on new drug development, pharmaceutical trade and professional associations have stressed the need for more advice on production processes and CMC. One of the initiatives, launched by the European Medicines Agency (EMA), the London-based agency responsible for the centralized approval of new medicines, has been the introduction of a scientific advisory scheme targeting SMEs and the academia, called PRIority MEdicines (PRIME) (1). EMA’s guidance (2) accompanying the launch of PRIME, however, says little about help with CMC matters or process development.
	
	The other initiative is a streamlining of guidance (3) by the European Commission (EC), the EU’s Brussels-based executive, on the implementation of the EU’s 15-year-old regulation on orphan medicinal products (OMP) in the hope of increasing the numbers of potential OMPs being authorized. But the EC is at the same time proposing to tighten up the EU’s regulation on orphan medicines, which could make the classification of a new treatment as a potential OMP more difficult to obtain, particularly if a key advantage of the product relates to quality issues such as the reliability of its manufacturing process.
	
	EMA has tried to boost new drug research by issuing in February 2016 new guidance (4) on the operation of a 2004 regulation, which allows accelerated assessment of authorization applications for products of “major therapeutic interest.” It also published in March 2016 a new guideline (5) on a 2006 regulation allowing marketing approval of drugs with less than complete data on condition that comprehensive data on the product are provided post authorization.
	
	


	In recent years, a growing number of companies, particularly the SMEs, have been seeking scientific advice from regulators, both at the EU and national levels. From 2011 to 2014, approximately two thirds of SMEs working on new medicines asked for scientific advice from EMA against 40% in the previous four years (i.e., 2007-2010), according to the agency’s latest annual report (6) on SMEs. SMEs have also been taking advantage of financial incentives, such as waiving of assistance and authorization fees and, in some EU countries, tax exemptions. Nonetheless, a lot of SMEs are still failing to gain authorizations for their new medicines. They account, for example, for only 20 percent of new OMP authorizations, which at the start of 2016 totalled 117 (7).
	
	One reason for the failure of SMEs to gain authorization could be inadequate assistance on drug quality matters, particularly manufacturing problems. Among the objections raised by regulators to dossiers for market authorization application by SMEs in 2011-2013, 46% related to quality matters, one percentage point less than deficiencies with clinical efficacy and safety issues (6).
	
	


	The objective of the PRIME project is to strengthen support for the development of medicines for dealing with unmet needs, especially those that offer major therapeutic advantage over existing treatments or benefit patients with no treatment options. The main aim of the project is to help researchers provide the necessary data for an application for a marketing authorization. These data will mostly come from adequately designed clinical trials but will also include information on quality and safety as well as efficacy. Eligibility for assistance from the scheme will require showing adequate non-clinical and exploratory clinical data about a therapeutically innovative medicinal product.
	
	SMEs and academics will be targeted by PRIME advisory teams to help them progress from the stage of having demonstrated a convincing scientific concept to a point in the clinical stage where they can provide proof of the concept. “[This] is often a difficult step for these smaller actors with limited experience in regulatory aspects and medicine development,” says EMA in a response to comments in a public consultation on its PRIME proposals (8). Once the developers have achieved proof of concept, they will be allocated an EMA rapporteur to help them take their products through the clinical stage to application for marketing authorization.
	
	Despite the relatively low profile given to quality problems in the EMA’s documentation on PRIME, the agency insists that SME, academics, and others will be able to seek advice on production processes under the scheme.
	“There is no difference in the procedure and scope for scientific advice provided in the context of PRIME and (other advisory) schemes,” an EMA spokesman told 

. “Companies can ask questions on any aspect of the drug’s development (i.e., on quality, including CMC and manufacturing processes, and non-clinical, clinical efficacy, and safety issues).”
	
	Representatives of pharmaceutical companies and R&D specialists point out that what matters the most is not so much the availability of advice on processes but the importance attached to manufacturing standards by the regulators.
	
	In comments on a consultation document on the PRIME scheme, the International Society for Pharmaceutical Engineering (ISPE) pointed out that a study on the US Breakthrough Therapy scheme operated by the US Food and Drug Administration (FDA), which is similar to PRIME, showed the need for close interaction with regulators on CMC issues (9). This interaction was a necessity for larger companies as well as SMEs. “For exciting new therapies, companies not fitting the definition of SMEs may not have the previous experience of regulatory requirements for these new therapies,” said ISPE (9). “[They] would welcome regulatory advice to ensure the CMC programme is optimized alongside the proposed clinical programme.”
	
	Also in comments on the consultation document (9), the European Federation of Pharmaceutical Industries and Associations (EFPIA), representing R&D-orientated companies, argued that PRIME would meet its objectives more successfully if its scientific advice covered both clinical development milestones and topics relating to production processes and CMC.
	
	“We are confident that with PRIME, the advice will include CMC matters, were this to be requested by companies,” Paer Tellner, EFPIA’s regulatory affairs director told 

. “In fact, CMC could be very important, as not all CMC documentation might be available [when trying to achieve] earlier access to patients to innovative medicines.”
	
	


	In the encouraging of research into unmet needs, the rules on development of OMPs overlap with those of PRIME, whose system can be used in R&D on orphan treatments for rare diseases. The EU feels that more could be done to close the gap between the number of estimated rare diseases at 5000-8000 and the number of authorized medicinal treatments, which amount to 1.5-2.5% of the conditions (7). Hence, the European Commission’s decision to issue new guidance on the designation of OMP status and granting of marketing authorizations to clear up uncertainties that may be acting as barriers to research.
	
	By 2015, more than 1500 potential new drugs had been granted OMP status by EMA, which enabled developers to claim fee reductions and to gain 10-year market exclusivity in the event of a successful application for market authorization. However, as with the PRIME scheme, the issue of manufacturing standards has aroused controversy in the OMP sector.
	
	Shortages of existing OMPs have become a fairly regular occurrence, often because of poor manufacturing standards of market authorization holders. Yet under the EC’s guidance, manufacturers with more reliable and efficient production processes will not be able to claim OMP status for alternatives to the products with scarcity problems because of the market exclusivity rule. Instead, they will only be granted an OMP designation for their replacements if they can provide evidence that shortages are causing patients harm.
	
	On the other hand, the EC is planning to allow medicines to be made in hospital pharmacies for the assessment of products for OMP designation. This provision is despite the production units of hospital pharmacies being exempt from having to meet GMP standards.
	
	The European Commission is also proposing that vaccines being developed to combat outbreaks of communicable diseases such as Ebola can be given an OMP status to speed up their development. Stakeholders, however, have been pointing out the dangers of going ahead with this plan without taking into account the ability of the potential OMP marketing authorization holders to make large quantities of vaccines at GMP standards in the event of an Ebola-type outbreak. Manufacturing capabilities seem likely to gain much more prominence when regulators are considering incentives to encourage more R&D into new medicines.


	1. EMA, “Launch of PRIME-Paving the Way for Promising Medicines for Patients,” Press Release, 7 March 2016.
	2. EMA, Enhanced Early Dialogue to Facilitate Accelerated Assessment of PRIority MEdicines (London, February 2016).
	3. European Commission, Application of Articles 3, 5, and 7 of Regulation (EC) No 141/2000 on Orphan Medicinal Products-Consultation Document  (Brussels, 16 Nov. 2015).
	4. EMA, 

Guideline on the Scientific Application and the Practical Arrangements Necessary to Implement The Procedure For Accelerated Assessment Pursuant to Article 14(9) of Regulation (EC) No. 726/2004

Guideline on the Scientific Application and the Practical Arrangements Necessary To Implement Commission Regulation (EC) No 507/2006 on the Conditional Marketing Authorisation for Medicinal Products for Human Use Falling Within the Scope of Regulation (EC) No 726/2004

  (London, 25 Feb. 2016).
	6. EMA, Annual Report from SME Office-2014 (London, 3 Feb. 2015).
	7. European Commission, “Orphan Medicinal Products-Major Developments,” Press Release, 29 Jan. 2016.
	8. EMA, Outcome of the Public Consultation on the Reflection Paper on PRIME (London, 7 March 2016).  
	9. EMA, Overview of the Comments Received on ‘Reflection Paper On A Proposal To Enhance Early Dialogue To Facilitate Accelerated Assessment of Priority Medicines (PRIME)’ (London, 7 March 2016).

 When referring to this article, please cite it as S. Milmo, "EU on a Mission to Boost R&D," 

Articles

In a move to encourage drug development, EU regulators are offering scientific advice to companies on major efficacy, safety, and quality issues at an early stage.

EU on a Mission to Boost R&D

	The European Union’s medicines licensing agencies have committed themselves in a strategy document in December 2015 (1) to ease the regulatory burden on the pharmaceutical industry by being more efficient in their control of pharmaceuticals throughout product lifecycles. This pledge has been raising the hope of the generic medicines industry. One of the generic medicines industry’s priorities is the reduction of the costs and administrative difficulties that occur when complying with variations regulations for keeping authorization dossiers up to date.

	Problems with variations rules were a major topic at an annual regulatory and scientific regulatory affairs conference in London in January 2016, which was organized by the European Generic and Biosimilar medicines Association (EGA). Approximately a third of the 200 participants were regulators with most of the remainder from the industry.

	As the EU’s pharmaceuticals regulations have been tightened up in recent years, the submissions on variations to regulatory agencies--comprising the London-based European Medicines Agency at the center and a network of national agencies in the EU’s 28 member states--have increased substantially. As a result, variations have been taking up a rising proportion of the pharmaceutical industry’s regulatory costs.


	Pharmaceutical producers and importers are required to provide regulators with even more information about changes to their medicines, such as modifications to manufacturing processes, improvements or extensions to formulations, and even minor additions such as alterations to names and addresses. The industry is seeing many of the variations requirements as being the imposition of an unfair weight of responsibility on their shoulders.

	The current regulatory requirements are laid down by an EU legislation (2) approved in 2008, which came into force in August 2013. The aim was to provide clearer rules by dividing the variations into four main categories. Two of these are type IA, which have “minimal or no impact at all” on the quality, safety, or efficacy of medicines and type II, which can have a “significant impact.” An “extension” category covers changes to an active substance or the strength, pharmaceutical form, and route of administration of a medicine. Type IB variations are changes that are neither minor, major, nor an extension.

	Although the legislation’s main objective was to simplify rules on the notification and approval of variations, a series of guidelines have had to be issued to clarify their application. At the same time, new EU pharmacovigilance legislation (3) was introduced, which brought in additional requirements for information of variations in the quality, safety, and efficacy of medicines after their launch on the market. This new legislation also had to be clarified by guidelines, the latest of which was issued in the form of a questions and answers document (4) in January 2016.

	“Guidance covering matters that should be clearly described in legislation has increased the regulatory work load of the industry,” Susana Pereira, a principal regulatory affairs officer at Teva Pharmaceutical Industries, told the conference (5). An increasing proportion of variations are now related to details about the production, origin, and composition of APIs. This follows the migration of API manufacture out of Europe and North America to China and India, which has considerably complicated the supply chains for active substances, mainly used in generic medicines. At the same time, rules on good manufacturing practice (GMP) have been made stricter and broader while GMP inspections of API facilities have become more rigorous. A lot of additional variations information is being generated by the more stringent application of GMP.


	The average number of variations per marketing authorization per year had increased by 45% in the five years leading up to 2014 (5), the equivalent to one additional variation per authorization. Variations in APIs are a major factor behind this increase. Up to 60% of quality variations submitted by marketing authorization holders (MAHs) are now related to API changes, said Pereira (5). New interpretation of regulatory data requirements had led to rises of up to 300% in the variations related to the API supply chain, with a high proportion relating to GMP matters, she added (5).

	With the addition of stricter GMP rules and the new requirements under the pharmacovigilance legislation, “variations have become a mechanism to implement new legal obligations,” Pereira claimed. The result was rises in regulatory costs covering the maintenance of a product’s lifecycle to a level that is higher than the authorization costs for the marketing of the medicine. “This imbalance can lead to the withdrawal of a medicine from the market, particularly if the cost of maintenance is higher than the product’s profit,” she warned (5). Instead of taking a drug off the market, a company may delay process improvements or hold back other changes that would reduce the medicine’s cost.

	Companies are also choosing carefully the regulatory authorities to which they are submitting variations, particularly because of differences in the fees they charge. These costs can range from zero to up to $1544 (€1400) for type IA variations; up to $1654 (€1500) for type IB; and up to $19,852 (€18,000) for type II, Pereira said. “The current system doesn’t create incentives for [national licensing authorities] to implement cost-effective mechanisms,” she added.

	Other speakers pointed out how certain aspects of API manufacture were increasing the requirements for variations information, often as a result of the interpretation of regulations made in guidelines. Marieke van Dalen, global regulatory specialist at Aspen Oss B.V., a Dutch API producer, said that a recent trend was a requirement for information on starting and even pre-starting materials, even including the names and addresses of the suppliers. This information was passed to the MAH before being added to the authorization dossier. Some authorities also wanted information on the analytical methods used in the validation of the starting materials and their intermediates.

	Joseph Bondin, executive director, quality operations, at the generic-drug producer Actavis, gave examples of how much information had to be provided when an outsourced API manufacture introduced intermediates from new producers with new testing sites. In one example, details of as many as 12 additional players in the API supply chain had to be submitted because of changes in the suppliers of intermediates. As a result of new regulatory interpretations of the information requirements on API intermediates, he warned that there could be a two- to three-fold increase in the total number of variations, which in 2015 averaged just under three variations per marketing authorization per year (6).

	“This increase seems contradictory to several EU policies,” he said. “[These policies include] have effective and fit regulatory systems that foster supply-chain resilience to prevent temporary supply disruptions.” In addition, it would seem to refute the value of the systems adopted by pharmaceutical companies themselves to validate the quality of intermediates, even though these could be based on quality guidelines proposed by the International Conference on Harmonization (ICH).


	In a regulatory efficiency report (7) published in September 2015, the EGA recommended a series of specific improvements to the EU regulatory system on variations. These recommendations include reliance on the new database system of Identification of Medical Products (IDMP) to make the API supply chain more transparent. It proposed that API information should be limited to details about the final API manufacturer. Information on other involved sites, such as intermediate producers, would be managed through the drug manufacturers quality systems and regulators’ GMP inspections.

	Much greater use, as a source of required variations data, could be made of the central European inventory of information on medicines and active substances, which is being set up under the EU’s pharmacovigilance legislation. Under article 57 of the law, companies have to provide up-to-date post-marketing information on their products relating to quality, safety, and efficacy (3).

	Regulators at the conference reiterated their commitment to making regulatory compliance easier and less costly for the pharmaceutical industry, particularly for the generic-drug sector. Noel Wathion, the EMA’s deputy executive director, stressed that the article 57 database and the implementation of IDMP would be used to improve the cost-effectiveness of regulations for generic and biosimilar medicines within the EU’s regulatory network. The regulators, however, were unable to make pledges about specific measures, particularly on the vexed issue of variations. This issue seems likely to remain a matter of grievance among generic-drug companies for some time.


	1. European Medicines Agency (EMA) and Heads of Medicines Agencies (HMA), 

EU Medicines Agencies Network Strategy to 2020: Working Together to Improve Health

 (London, Dec. 17, 2015).
	2. EC Regulation No. 1234/2008 

The examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products

 (Brussels, Nov. 24, 2008).
	3. EC Regulation No. 1235/2010, 

Amending as regards pharmacovigilance of 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 

Practical questions and answers to support the implementation of the variations guidelines in the centralised procedure

, EMA/427505/2013 (London, Jan. 18, 2016).
	5. S.Pereira, “Challenges of the Current Variations System,” presentation at the EGA Regulatory and Scientific Affairs Conference (London, Jan. 28-29, 2016).  
	6. J.Bondin, “Management of the Active Substance Regulatory Dossier,” presentation at the EGA Regulatory and Scientific Affairs Conference (London, Jan. 28-29, 2016).
	7. European Generic and Biosimilar medicines Association (EGA), 

An Efficient Regulatory System for Patient Access to New Generic Medicines


	When referring to this article, please cite it as S. Milmo, "Tackling Regulatory Challenges of EU’s Variations Framework," 

The EU is striving to reduce the costs and administrative burden facing pharmaceutical manufacturers when complying with variations regulations for keeping authorization dossiers up to date.

Tackling Regulatory Challenges of EU’s Variations Framework

	The European Union’s network of medicines regulating authorities is, for the first time, following a common strategy for at least the next five years in an effort to achieve more consistency and efficiency in the control of pharmaceuticals in Europe. The adoption of the strategy, outlined in a document (1) entitled

 to 2020 and published in December 2015, has been welcomed by Europe’s pharmaceutical industry. But there are divisions within the industry about what should be the strategy’s priorities.

	The strategy has been drawn up by the European Medicines Agency (EMA), responsible for regulating medicines for EU-wide marketing, and by the heads of medicines agencies (HMA), which run the decentralized part of the system for the licensing of drugs for single or groups of national markets. The initiative will mean that EMA, which assesses mostly new medicines and biologics, and the licensing authorities of the EU’s 28 member countries as well the three non-EU states of Norway, Iceland, and Liechtenstein, will work much more closely together in the regulation of pharmaceuticals. This strategy will have an impact not just on the control of medicines within Europe, but also globally. The region’s regulatory network will effectively become a single entity representing a population of 500 million, the third largest in the world after China and India.

	One key objective of the new strategy is that Europe should have much more clout in the global pharmaceuticals sector at a time when the worldwide harmonization of regulations on the quality, safety, and efficacy of medicines is accelerating. In addition, Europe will be in a stronger position to deal with the growing complexities of the global pharmaceutical supply chain, particularly in the monitoring of manufacturing standards of imported products. Approximately 80% of APIs used in medicines authorized in Europe are now manufactured outside the EU, mostly in India and China, while a significant proportion of medicines on the EU market have been partially or fully manufactured outside the EU, according to the strategy document. One of the 16 main objectives behind the strategy to make better use of the EU’s regulatory network is to ensure that the supply chain of imported pharmaceuticals is properly managed.


	Another major goal behind the five-year strategy is to provide patients with easier access to new and existing medicines, particularly to innovative treatments for unmet needs and rare diseases. Achieving medicines access requires more regulatory resources to be directed at encouraging the development of innovative medicines for the EU market, which will contribute to a vibrant life-science sector in Europe. Nonetheless, representatives of the pharmaceutical industry who are not involved in the development of original, patent-protected products have been complaining that the strategy document puts too much emphasis on innovative medicines without paying enough attention to problems of access to existing treatments. In the 28-page document, there is only a limited reference to the need for regulatory support for a broad range of generics and biosimilars.

	“Innovation and scientific progress, being a key pillar of the pharmaceutical industry, shall be supported as much as possible,” said the European Generic and Biosimilar medicines Association (EGA) in comments (2) on the final draft of the document in 2015. “However, access of the majority of the population to essential, first-line quality treatment should not be neglected, but rather, given equal consideration as one of the regulators’ strategic objectives for 2020,” the association added. “Currently more than half of the European population is treated with generic and biosimilar medicines.”

	On the other hand, the research-based part of the industry reckons that the strategy does not focus strongly enough on innovation, especially on the need to harness broad support for the development of novel medicines. “Regular initiatives are needed to ensure leverage of knowledge of evolving science between industry, academia, and regulators,” said the European Federation of Pharmaceutical Industries and Associations (EFPIA) in its comments (2) on the strategy. EFPIA explained that the industry is willing to contribute to this pooling of knowledge while also being able to help in the setting of strategic priorities in the innovation process.


	Individual member states, most of them fiercely protective of the independence of their medicines regulatory authorities, will be balancing any concerns about the increased centralization inherent in the strategy with the benefits they will gain from it. For authorities in the smaller countries, some of the most important advantages of the strengthening of the network will be greater assistance with the vetting of GMP standards  on imported APIs. They will also gain from the expanded capabilities of the network in GMP and other inspections of the production facilities of exporters of pharmaceuticals to Europe.

	EMA and HMA are hoping that the network’s efforts to tackle more effectively the causes of medicine shortages and lack of availability of both new and existing pharmaceuticals, particularly as a result of disruptions to the international supply chains, will be a major driving force behind increased collaboration outside Europe. “All regulators worldwide are facing increasing economic constraints, in the context of which international collaboration can provide opportunities to create synergies, avoid duplication, and facilitate work and information sharing,” the document says (1).

	Problems in supply chains can be minimized, the document claims, with the help of sharing of information on manufacturing standards so that the same standards can be applied irrespective of production location. The integrity of these data, however, can be undermined by poor training, inadequate attention to accuracy, and occasionally, possible falsification. “The integrity of the data in the studies used to support market authorization is fundamental to trust and confidence in the products themselves,” says EMA and HMA (1).

Another challenge highlighted in the network strategy is the need to deal with supply-chain problems that, often in the wake of severe disruptions of manufacturing processes, lead to a reliance on a few manufacturers to make one or more essential medicines. A similar dilemma could be posed by outbreaks of infectious diseases requiring the rapid development of vaccines and capacity for their production. The network’s regulators have to be better prepared to deal with such public health emergencies. “Over the next five years, a priority will be to ensure that the network continues to be able to respond to public health emergencies, whether novel infectious diseases or other threats, by facilitating the early introduction of appropriate new treatments or preventative measures,” the document explains (1).

	In tackling sudden outbreaks of dangerous infectious diseases and also the growing incidence of antimicrobial resistance, the strategy calls for closer links between human and veterinary medicine in a “One Health” approach covering both humans and animals. Approximately 75% of new diseases affecting humans over the past decade have been caused by pathogens originating from animals or products of animal origin, according to the document (1).

	Nonetheless, the need for interdisciplinary collaboration will have to extend beyond human and veterinary medicine. All regulatory authorities in the network will have to ensure that they have the necessary expertise available for dealing with scientific advances that could apply to all medicines, particularly the new ones. There has to be “a clear identification of any gaps in scientific and regulatory expertise [in the network] based on current and future needs,” says the document. If necessary, authorities will have to make more use of others in the network with more expertise. “A more optimal organization of the available expertise across the network should be considered avoiding duplication of work and facilitating enrichment of the expertise through more collaborative working,” it adds.

While striving for greater use of scientific excellence, the network will also aim to reduce the regulatory burden on the pharmaceutical industry and other stakeholders through increased administrative efficiency and cost effectiveness. In reaching this objective, a major role will be played by improvements in the network’s IT services, some of which will be coming from the gradual convergence of national IT systems into an EU IT structure.

	The strategy document acknowledges, however, that one dilemma for the network is how to ease the regulatory pressures on industry without hampering moves to higher levels of scientific excellence among regulators. “Initiatives to reduce the administrative burden should go hand in hand with initiatives to further strengthen the output, and in particular, the scientific quality, of regulatory processes during the life span of medicines,” the document stresses. This is only one of a number of major dilemmas facing the network as it endeavours to fulfil its strategic objectives over the next five years.

EU Medicines Agencies Network Strategy to 2020

: Working Together to Improve Health (London, 17 Dec. 2015).

	2. EMA, Overview of comments received on 


	When referring to this article, please cite it as S. Milmo, "Macro Matters," 

The EU’s key objectives include improving medicines access, tackling drug shortages, and increasing administrative efficiency in its regulatory framework.

EMA Outlines Network Strategy for Next Five Years

	The worldwide role of the World Health Organization (WHO) looks likely to be revitalized in a way that could lead to changes in the loose network of agencies and non-state organizations in global health governance. WHO may, as a result, be exerting far more influence than at present on international organizations involved in setting international standards and regulations, such as those for GMPs.


	The Geneva-based United Nations body, which was founded in 1948, has been heavily criticized in a number of respected studies (1, 2) on the 2013-15 Ebola outbreak in West Africa for its slow and initially inadequate response to the crisis. There have even been calls for the replacement of the agency by a number of separate bodies with different public health responsibilities. The most favored option, however, is a strengthening of the organization so that it can be given a much bigger role in the protection of health.

	“This is a defining moment for the health of the global community,” said a report (1) issued in July 2015 by a panel of outside independent experts commissioned by WHO to assess its response to the Ebola outbreak. “WHO must re-establish its pre-eminence as the guardian of global public health, which will require significant changes throughout WHO,” it added.

	Another independent group of 19 international experts convened by the London School of Hygiene and Tropical Medicine (LSHTM) and the Harvard Global Health Institute concluded in a report (2) on the outbreak issued in November 2015 that WHO had shown a failure of leadership. Nonetheless, it decided that the crisis should be followed by a radical improvement in the running of the global health system but with the focus on WHO.

	“WHO is an essential hub in the global system for health security,” the report (2) says. It is uniquely placed to carry out core functions because of its near-universal state membership, governance structure, and deep relationship with health ministries across the world. The organization has lost so much trust and authority, however, that it will have to undertake fundamental reforms within a tight time line before being able to assume a leadership role, the report says. There are signs of a response among at least the larger and richer UN member states to calls for a more powerful WHO.


	The recent G7 summit in Germany of the world’s leading nations backed moves to strengthen WHO in its central role in international health security. “We must draw lessons from [the Ebola] crisis,” said the G7 communiqué (3). The meeting acknowledged the need for action on the funding of WHO. It backed the World Bank’s initiative, in close co-operation with WHO, to organize the funding of a Pandemic Emergency Facility (PEF).

	The World Bank has warned that the costs of the next pandemic could be far greater than the Ebola outbreak, which infected more than 28,000 people and claimed more than 11,000 lives. A Spanish-flu-like pandemic, like that in the 1920s, would kill more than 33 million people in 250 days, according to the Bank (4).

	The G7’s response could mean that some progress will soon be made in resolving the financial problems of the WHO. Currently, only 25% (5) of WHO’s funds come from the member states with the remainder being provided by voluntary contributions. The Bill & Melinda Gates Foundation is WHO’s biggest funder, bigger than any of the member states.


	A revived WHO could mean changes in the balance of responsibilities between the UN organization and the myriad of agencies and bodies involved in creating international health norms and standards. One of these organizations could be the Geneva-based International Council for Harmonization (ICH), which currently has global leadership in the creation of harmonized guidelines and standards for drug development and registration.

	ICH, founded jointly in 1990 by the regulatory agencies of Europe, the United States, and Japan as well as the international research-based pharmaceutical industry, is seeking an even broader role after becoming a wholly independent Swiss-registered legal entity in early 2016. Regulators will be given more control of the organization, which will have a broader membership including, for example, regulatory agencies from emerging economies such as China and India. Harmonization of GMP standards is one of ICH’s main responsibilities. WHO, which will continue to have an observer status at ICH, also draws up GMP standards, but usually in line with those at ICH.

International Coalition of Medicines Regulatory Agencies


	At the same time as a reformed ICH dominated by regulators becomes active, the International Coalition of Medicines Regulatory Authorities (ICMRA) is due to become fully operational. The idea behind it is to provide strategy and direction to regulators in the belief that they must act globally as well as domestically.

	“To date, there has not been co-ordinated, consistent, and strategic global regulatory leadership, and ICMRA endeavours to fill that gap,” the organization said in a fact sheet (6) when its launch was announced in 2014. At present, ICMRA has 19 members, eight of whom are from Europe, including the European Union’s European Medicines Agency, with the remainder being national agencies. Other members include the regulatory authorities of China, Brazil, and Nigeria. WHO has an observer status.

	GMP is already one of ICMRA’s major areas of activity, with a working group headed by the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). “This project continues to make progress in developing a framework to allow greater mutual reliance on other regulators’ inspection outcomes and assist in better utilization of inspection resources by global regulators,” Mark Birse, group manager of MHRA’s Inspection, Enforcement & Standards Division, told Pharmaceutical Technology.

	Management of emergency health crises is currently for ICMRA a priority area in which the know-how of its members and advances made by them in research science can be of vital assistance. “Supporting innovation and regulatory science underpins ICMRA,” said John Lynch, compliance director at Ireland’s Health Products Regulatory Agency (HPRA). “While ICMRA is not a research organization, by creating better global regulatory responses to emerging crises such as Ebola, it can support the quicker access and availability of vaccines or treatment of these diseases,” he said in an interview with Pharmaceutical Technology.

	The HPRA, which is a member of ICMRA’s management committee, has recently helped to set up Research Science Ireland, a network embracing academia, the pharmaceutical and medical devices industries, the HPRA, and other government agencies. ICMRA has yet to sort out fully its relationship with the new ICH and, in particular, with WHO. In August 2014, after WHO officially categorized the Ebola outbreak as a public health emergency of international concern, ICMRA pledged to co-operate with WHO on fast access to investigational treatments for patients most in need.

	Since the outbreak was brought under control, WHO has been quick to react to pleas for it to establish an R&D scheme on vaccines, diagnostic tests, and other relevant medicinal products for combating potentially dangerous pathogens. The scheme would cover the preclinical and early clinical stages of drug development. The new products would then be ready to go through emergency clinical trials in the event of a pandemic before full-scale manufacture.


	The Ebola virus, which causes an haemorrhagic, often-fatal, fever, was first discovered in 1976 (7). WHO, however, brought together technical experts to discuss possible vaccines for the disease only recently, in September 2014, when two advanced vaccines for accelerated development were identified. The panel set up by the London School of Hygiene and Tropical Medicine and the Harvard Global Health Institute has recommended the earmarking of large-scale manufacturing facilities for the rapid production of vaccines and diagnostic tests. WHO has responded to these suggestions by inviting submissions of ideas to improve R&D readiness for potentially threatening infectious diseases.

	The initiative would specifically include propositions for “flexible development and production platform technologies” for vaccines, therapeutics, and diagnostics against 5-10 priority diseases, as defined by WHO. The vetting of suitable production facilities is likely to be similar to that applied in WHO’s existing prequalification program under which plants and laboratories have to go through an evaluation and inspection process before taking part in UN drug procurement schemes. One drawback for potential participants in the R&D readiness project is that WHO will not be providing direct financial support for any proposal. Instead, it intends to hold a dedicated workshop in 2016. Some experts, however, fear that WHO’s responses to the Ebola crisis will not extend much further than initiatives in R&D preparedness because of a lack of political will to conduct a shake-up of the organization.

	“The issue is whether even after fundamental changes in the agency, the member states will trust it enough to give it much more authority,” said Charles Clift, senior consulting fellow, Center on Global Health Security, Royal Institute of International Affairs (Chatham House), London, in an interview with Pharmaceutical Technology. “There could now be a prolonged period of uncertainty about the future role of WHO, which could extend to other agencies and organizations in global health governance,” he added.

Final Report of the Ebola Interim Assessment Panel

 (Geneva, July 2015).
	2. S. Moon et al., 

, online http://dx.doi.org/10.1016/S0140-6736(15) 00946-0 (Nov. 22, 2015).
	3. G7 Summit, “Leaders’ Declaration-Think Ahead. Act Together,” G7 Germany (Schloss Elmau, June 2015).
	4. World Bank, Pandemic Emergency Facility-Frequently Asked Questions (Washington DC, September 2015).
	5. Center on Global Health Security, Royal Institute of International Affairs (Chatham House), 

What is the World Health Organization for?

 (London, May 2014).
	6. ICMRA, Fact Sheet (September 2014).
	7. WHO, “Ebola Virus Disease,” Updated Fact Sheet 103 (Geneva, August 2015). 

:
	When referring to this article, please cite it as S. Milmo, "A Call for Radical Reformation of the World Health Organization," 

Leading nations are backing moves to strengthen WHO’s central role in international health security following the Ebola crisis, which sparked criticisms on the organization’s ability to address a pandemic outbreak.

A Call for Radical Reformation of the World Health Organization

	A consultation period on GMP guidelines (1) in the European Union, specifically for advanced therapy medicinal products (ATMPs), comprising gene- and cell-therapy products and tissue-engineered treatments, was due to be completed in November 2015. The guidelines, which will be drawn up by the European Commission, however, are taking a long time to complete. They are a requirement of an EU regulation on ATMPs (2) which was approved in 2007.

	The objective behind the guidelines is to bring together in a single document GMP standards from a variety of sources, mainly other pieces of EU legislation. But even when the first dedicated GMP guidelines for ATMPs are finalized, probably in 2016, they are likely to have to be constantly revised. 

	Compliance with GMP standards has been a major challenge for ATMP developers in Europe. In fact, these difficulties could be a prime reason why, up until 2014, only four medicines under the ATMP regulation had been given marketing authorization in the EU’s centralized medicines licensing procedure. Just how GMP problems for advanced medicines are sorted out in Europe could be a key influence over the future of personalized medicines and other new pharmaceutical technologies in the region.


	At the core of the difficulties with GMP is the R&D structure in the advanced medicines sector. Much of the development work on ATMPs is carried out by academic scientists and clinicians attached to hospitals of universities and other research institutes. They lack the regulatory expertise and resources to establish and operate GMP-compliant manufacturing processes. In particular, they often do not have adequate systems in place for evaluating the quality of starting and raw materials, which is a vital necessity in the production of advanced, usually biological, medicines.

	Academics seeking to arrange preclinical and clinical trials for their innovations are so concerned about the complexities of compliance with GMP that they try to avoid having them classified as ATMPs by the regulatory authorities, according to AGORA, an EU-funded research project on solutions to GMP problems in the sector (3).

Lack of harmonization in applying GMP standards


	The difficulties with GMP are aggravated by the lack of harmonization in the way GMP standards are applied by the EU’s member states. “Research [has] found substantial heterogeneity in the regulatory practice across member states, which is leading to confusion and uncertainty and is creating a severe barrier to the development and delivery of [ATMP] medicines,” said AGORA in a progress report to the European Commission on its project (3). “[This is] weakening the position of the EU academics and industry to collaborate and compete globally in this expanding field.”

	Advanced medicines may need the adoption of a different strategy to manufacturing standards within the sector. The consultation document (1) itself does not call for any radical changes in GMP, but stakeholders in their comments on the document may take a different view.


	Senior members of the European Medicines Agency, which is responsible for the EU’s centralized approval procedure, have hinted that different concepts of manufacturing quality may need to be applied to advanced medicines. “ATMPs are complex pharmaceuticals, for which traditional approaches may not be possible,” Paula Salmikangas, chair of the EMA’s committee for advanced therapies (CAT), told an European Directorate for the Quality of Medicines & Healthcare (EDQM) workshop on Paving the Way for the Future-Biologicals at Strasbourg, France, in 2014 (4).

	Because ATMPs are in the front line of scientific discovery, new standards become outdated. By the time the standards are implemented, the products for which they have been drawn up have been superceded by a new technology. “Manipulation of cells and use of recombinant nucleic acids may bear unknown risks, which may not be solvable through standardization or quality control,” Salmikangas added.

	A major problem area with advanced medicines is the quality assessment of starting and raw materials, which often comprise high-risk raw materials. The availability of these in high-quality grades was limited because they were mainly sold “for research use only” and were accompanied by little product documentation from the suppliers, according to Salmikangas. Raw-material suppliers claim that their products are “GMP compliant,” but many ATMP developers are sceptical about the value of such claims.

	Delegates at a symposium in April 2013 on gene and cell therapy raw materials at Strasbourg, France, jointly organized by EMA and EDQM, complained about the lack of a definition of GMP compliance. The meeting also acknowledged that the term “GMP grade” meant different things to different groups, according to an EDQM report on the conference (5).

Adapting GMP implementation based on risk


	Some research organizations are calling for a relaxing of GMP rules at the early stages of ATMP development, for example, in first-in-man (FiM) studies. “The level of application [of GMP requirements] should be appropriate to the ultimate risk associated with their use (e.g., the number of patients in a Phase I/FiM study can vary and so does the risk),” says the cell therapy unit of the government-funded Catapult UK, which runs a network of late-stage R&D centres in the country, in comments (6) on a European Commission review last year of the ATMP regulation (7).

	This view is consistent with a growing support in the R&D sector in Europe for a phased approach to the application of GMP standards, as detailed by the Parenteral Drug Association (PDA) in a 2012 technical report (8). This proposed that standards should become more stringent as new drugs move from the discovery stage through to Phase III clinical trials and market launch. It is also in line with the emphasis placed by the European Commission’s consultative document on the need for a risk-based approach with the application of GMP for ATMPs.

	The document (1) is mainly focused on conditions of GMP compliance that would be applied in the marketing authorization of advanced medicines, as well as those required in the manufacture of ATMPs for clinical trials. It, however, acknowledges that with investigational or experimental ATMPs, which are often developed in an academic or hospital setting operating under different quality systems to those for conventional drugs, “additional flexibility is warranted, in particular for early phases of clinical trials” (1). The document also says that under a risk-based approach, the ATMP manufacturer has a responsibility “to put in place additional measures-beyond those suggested in the [EU’s] GMP guidelines-if that is necessary to address the specific risk of the product” (1).


	The two-year AGORA project has been testing schemes for giving personnel in academic R&D facilities more expertise in basic GMP standards. “[Our own data] has consistently shown that GMP manufacturing knowledge remains a barrier for academic triallists aiming to perform the full cycle from preclinical investigations to early and subsequent late-stage clinical trials,” it says (3). As a result, it has been designing training course packages aimed at specific target groups, such as cell biology scientists who know about ATMPs but need to learn GMP skills.

	The project, whose participants are mainly academics from the United Kingdom, German, and Dutch universities, has attempted to extend the scope of its exploratory training courses by working together with other researchers in biologicals and with industrial partners with GMP experience. It has had a close co-operation with Pharmacell BV, Maastricht, Netherland, a contract manufacturer of cell therapy and regenerative medicine products, which has two GMP plants, one of which was first certified in 2006.

	The AGORA team has spoken out against proposals to reduce the product quality requirements for ATMPs in academic development on the grounds this would lead to the “creation of a two-tier ATMP development process, which would substantially undermine the delivery of safe and effective ATMPs across the EU.” A major issue to be sorted out in the discussions following the issuing of the consultative document is how the flexibility proposed by the document in the application of GMP standards in ATMP manufacturing can be made consistent with the maintenance of existing GMP rules.

	National regulatory agencies, which are responsible for the enforcement of GMP standards in clinical trials of ATMPs, tend to apply them in ways they think fit for individual medicines. “Concerns about GMP [with ATMPs] are handled on a case-by-case basis,” says a spokesperson for the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK, which is a leading European country in advanced medicines development. In the many years in which the agency had been in discussions with ATMP developers, its message had been that GMP is about applying “an appropriate quality standard” for consistent manufacture in the “wide range of situations under which ATMPs are developed,” the spokesman told 

	Clearly, a great deal of adaptability is required with GMP in the early-stage development of ATMPs. Just how this can be balanced against the need for greater consistency in the implementation of GMP with advanced medicines in the later clinical trial phases and the post-marketing period could be a matter of debate for some time.

Consultative Document: Good Manufacturing Practice for Advanced Therapy Products

 (Brussels, July 2015).
	2. European Union, 

Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products

Progress Report: Advanced Therapy Medicinal Product Good Manufacturing Practice, Open Access Research Alliance

 (London, 2015).
	4. P. Salmikangas, “Advanced Therapies and the RCG Working Party-Preliminary Aspects,” presentation at workshop on 50 Years of EDQM Leadership in the Quality of Medicines (Strasbourg, October 2014).
	5. EDQM, 

Symposium Report: Raw Materials for the Production of Cell-based and Gene Therapy Products

 (Strasbourg, 2013).
	6. Cell Therapy Catapult UK, 

EC Review of the ATMP Regulation-Cell Therapy Catapult Responses

 (London, 2014).
	7. European Commission, 

Report to European Parliament and the Council: Regulation (EC) No. 1394/2007 on Advanced Therapy Medicinal Products, COM 2014/188

 (Brussels, March 2014).
	8. Parenteral Drug Association (PDA), 

Technical Report No. 56: Application of Phase-Appropriate Quality Systems and CGMP for the Development of Therapeutic Protein Drug Substance


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

	This article was originally published in the December 2005 issue of 

 When referring to this article, please cite it as S. Milmo, “GMP Challenges for Advanced Therapy Medicinal Products,” 

Finalizing GMP requirements and quality standards for the development,
manufacture, and clinical testing of ATMPs in the EU is proving to be a complex task.

GMP Challenges for Advanced Therapy Medicinal Products

	The European Union has embarked on an ambitious programme to streamline the collection and use of data on new and licensed medicines and their substances, including excipients, throughout the EU. The scheme aims to ensure that the European Medicines Agency (EMA), the EU central organization for authorizing medicines throughout Europe, and the licensing authorities of the EU’s 28 member states will use the same IT system, based on a single data standard. The objectives behind the programme are to improve the efficiency of regulatory processes, raise cost effectiveness, achieve interoperability for the sharing of knowledge, and enhance collaboration through promoting open access to data repositories.

	The vision behind the scheme with details of its projects and their benefits was outlined in a document (1) on an EU telematics strategy and implementation roadmap for 2015–2017, published in August 2015 by the EMA and Heads of Medicines Agencies (HMA) of the member states. The strategy, however, is already running into problems, mainly stemming from the complexity of the standards being applied to achieve data uniformity and from variations in degrees of enthusiasm among the members states for the scheme.

	Most licensing agencies, called national competent authorities (NCAs), are keenly supportive of the plan, but many of them want to give precedence to pursuing their own IT initiatives. A few are already refusing to participate in some existing collaborative IT projects.


	In addition, the pharmaceutical industry is unhappy that it has had minimal involvement in the creation of the strategy while it is being offered, so far, limited participation in its operation (1). The industry will not be engaged directly in the EU telematics governance structure, which will be headed by a management board representing EMA and HMA. Nonetheless, the strategy document recognizes the “significant impact” of the pharmaceutical industry, and is, therefore, allowing for its participation in project working groups.

	The main European pharmaceutical trade associations are, nonetheless, expecting to be more of an active partner in the achievement of improvements to and the operation of the telematics strategy. “There has been one meeting (so far this year) between the EU telematics management board and industry representatives,” said Remco Munnik, chair of the telematics working group of the European Generic and Biosimilar Medicines Association (EGA), in an interview with 

	“However, the question of the frequency and the scope of the industry’s strategic contribution still remains open and a meeting once a year may not be sufficient to achieve real progress on this,” he continued. “An efficient telematics structure, supporting the EU regulatory network in its regulatory activities, is crucial for the future. As an industry, we would like to be an active partner, not only operationally but also strategically by being involved in setting objectives that can be achieved.”

	The industry is already participating in an EU task force on the implementation of the International Organization for Standardization’s (ISO) Identification of Medicinal Products (IDMP), which is a key working group in realization of the telematics strategy. The five standards of the ISO, which comprise the IDMP, are at the core of the EU strategy. IDMP provides the basis for the scheme’s aim of consistency, uniformity, and single repositories where data on products and substances can be reused throughout a medicine’s lifecycle. It also has the potential to be the cornerstone of an internationally harmonious data system, particularly since the US Food and Drug Administration (FDA) is also planning to implement IDMP.

	In the longer term, EMA expects that IDMP will provide the EU with a pathway to the operation of a Global Ingredient Archival System (GiNAS), a common substance identifier that uses a consistent definition of substances throughout the world. The National Centre of Advancing Translational Sciences (NCATS), part of the US National Institutes of Health (NIH), is currently developing the GiNAS.

	The introduction of IDMP is proving to be a massive challenge not only for EMA and the rest of the EU’s regulatory network of NCA, but also for the pharmaceutical industry. The EU is taking on a pioneering role because it will be the first globally to implement the IDMP standards. The job is enormous, especially with substances, mainly because of the amount of existing data that has to be collated and, if necessary, changed to comply with IDMP. The aim is that the IDMP standardization of definitions of product and substance concepts will substantially improve the identification and exchange of information on medicines, not just within the EU but also internationally.


	In the telematics strategy document (1), July 2016 is given as the deadline for the start of the implementation of IDMP because it is the date set in the EU pharmacovigilance legislation for compliance with the standards. However, even when the document was being published, the European Commission, the EU executive responsible for the EU telematics strategy, was being pressed to adjust the deadline so that regulators and the industry would have more time to switch to IDMP.

	Although there has been no official announcement, the industry and software vendors understand that the Commission has agreed that the IDMP will be introduced in phases with the first step being the issuing in July 2016 of the EU IDMP implementation guide. Also, the terms and controlled vocabularies used with existing pharmacovigilance data will by then be aligned with IDMP requirements. The submission of pharmacovigilance data to IDMP standards will now start to be mandatory in late 2017, according to the Commission.

	“An important reason for the phased-wise approach is the fact that the ISO standards are not yet final and will probably only become final at the end of 2015 or early 2016,” says Munnik. “[The] industry welcomes this approach. We should rather take time and do this properly, instead of rushing and resubmitting the data due to the short preparatory phase.”

	“This IDMP data are available within industry, but might not be in one place or structured,” he added. “In order to align this data in a company, multiple departments and databases will have to start sharing the same data. This is especially a challenge for generic companies with large portfolios and multiple manufacturing sites and partners.”

	With substances, which include excipients as well as active ingredients, the difficulty is that the data required by IDMP, such as the characterization of chemical properties, are not kept by the pharmaceutical manufacturers but by external sources such as the contract manufacturers. “There could be huge gaps in availability as well as quality between the data held and controlled by the pharmaceutical companies themselves and that held by external sources,” Niels Henriksen, a consultant at the Danish IT service provider NNIT A/S, told 

 “The data required by IDMP, sometimes derived from work in the early development phase of a drug, will be lying around somewhere in a document. The difficulty will be finding it.”

	The main vehicles for the introduction of the IDMP-at least at the EU level-will be single data repositories, the biggest of which will be that of the Periodic Safety Update Reports (PSUR) set up under the EU’s current pharmacovigilance legislation. This legislation requires marketing authorization holders (MAHs) to provide updates on the safety profiles of the more than 500,000 medicines on the EU market. Another repository is EudraGMDP on Good Manufacturing and Distribution Practice, giving details on all GMP certificates and statements of GMP non-compliance.


	An important stage in the implementation of the EU telematics strategy will be when all application dossiers will have to be IDMP-compliant and submitted in an electronic Common Technical Document (eCTD). This requirement has been scheduled to be mandatory by 2018 for all application dossiers within the EU’s centralized and decentralized licensing procedures. This deadline, however, may have to be rescheduled following the postponement of the start of the IDMP implementation. A lot of the barriers facing the realization of the EU telematics strategy at the member state level are derived from differences in priorities between EMA and the NCAs. EMA is required mainly to implement EU legislation on medicines regulation while the NCAs have a range of obligations including meeting EU requirements and also carrying out national policies.

	“In many cases,” the EU telematics strategy document (1) acknowledges, “the NCAs have a variety of obligations outside the pharmaceutical regulatory domain.” These obligations will be dictated by public health needs, legislative mandates, and economic conditions. As a result, a lot of NCAs will be giving greater importance to their own IT projects and objectives.

	The Netherlands Medicines Evaluation Board (MEB), for example, is considering the option of working with groups of other NCAs on data projects. “We are currently reconsidering our own IT strategy and infrastructure, and keeping an open eye on EU developments,” says Stan van Belkum, MEB deputy director. “Wherever and whenever, the MEB will work with colleague member states of similar size and adapt EU solutions if proven functionally advantageous.”

	The agency also wants to concentrate on improving its own IT services, particularly those aimed at helping the industry and some of which provide different services to those at the EU level. “Since 2007, the MEB has a fully operational workflow and document management system dedicated to all MEB business processes in both national and EU procedures,” says van Belkum. “On top of that, we provide marketing authorization holders online access to information about the status of their application procedures. For the coming years, the MEB’s IT strategy aims to extend this portal with additional functionality and to make part of the information in that portal publicly available-for example, assessment reports, product information and relevant patient information.”

	Within the EU’s medicines regulatory network, full data integration and uniformity may not be accomplished for many years, but for the industry, the priority will be to advance the introduction of IDMP as far as possible not just for the sake of reducing regulatory costs but also for its business opportunities.

EU Telematics Strategy and Implementation Roadmap 2015-2017, 

 When referring to this article, please cite it as S. Milmo, “EU’s New Telematics Strategy for the Regulation of Medicines,” 

The scheme aims to ensure that EMA and licensing authorities of EU member states will use the same IT system, based on a single data standard.