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

Sean Milmo

	In late 2015, the Geneva-based International Conference on Harmonization (ICH) will begin to restructure itself in what could trigger radical changes in the way pharmaceutical regulations are harmonized throughout the world. It may be a confusing process, with different representative bodies closely linked to ICH vying to be the main driving force behind endeavours to make the regulation of medicines more responsive to conditions in the global pharmaceuticals marketplace.
	
	


	ICH is considered to have done a good job since it was founded in 1990 by an alliance of regulatory agencies and the international research-based pharmaceutical industry in Europe, the United States, and Japan. “It has been a great success in terms of fulfilling its main objective of developing and implementing harmonized guidelines and standards for drug development and registration,” says Paer Tellner, regulatory affairs director at the European Federation of Pharmaceutical Industries and Associations (EFPIA).
	
	In line with its mission to reduce drug-development costs by eliminating duplication and cutting the time lag between discovery and market launch, ICH had, by 2003, drawn up guidelines on nearly 60 topics. By then, its main achievement had been the drawing up of the common technical document (CTD), a standard form for applications for drug marketing authorizations.

	During the past 10 years, ICH has concentrated a lot of its efforts in gaining more international consistency in key areas such as standards of good manufacturing practice (GMP), particularly in the production of APIs. Other priorities have been rules on good clinical practice and standards for biopharmaceuticals and advanced therapies. Nonetheless, in the era of globalization and rapidly growing emerging economies such as those of China and India, ICH’s legitimacy has been undermined by the fact it is run by a partnership of six organizations-the regulatory agencies and pharmaceutical industry associations of the European Union, the US, and Japan.
	
	


	ICH is being reorganized so that it has a structure that enables new members to join the organization, particularly the regulatory agencies of China and India, where the vast majority of APIs on the world market is produced. These reforms, however, are taking place when a new alliance of regulators is being established. Some of its members will also be ICH members or regular participants in its meetings.

	The International Coalition of Medicines Regulatory Authorities (ICMRA) is being set up in response to the increased complexity of global pharmaceutical supply chains and of new medicinal products, according to a fact sheet issued by the new group (1). “Regulators must act globally and domestically, and collaboratively,” the fact sheet says. The future  relationship between the ICH and ICMRA, whose objectives and structure will be finalized by 2016, is at the moment uncertain. The International Pharmaceutical Regulators Forum (IPRF), formed in June 2013, already acts as an offshoot of the ICH by providing a regulators-only facility for discussions on the margins of ICH meetings. Its membership is open to all regulatory authorities, not just ICH participants.

	“The IPRF is a technical platform for regulators, [while] ICMRA is discussing high-level/strategic issues amongst heads of agencies,” explains a spokesperson for Swissmedic, the Swiss medicines agency that runs the IPRF secretariat and is itself a member of both organizations. In addition, ICMRA’s position with the 35-year-old International Conference of Drug Regulatory Authorities (ICDRA), which has more than 100 members including ICMRA members, needs to be sorted out. ICDRA, which is run by the World Health Organization (WHO), also determines priorities for the international and national regulation of medicines.

	ICMRA will also have to clarify its relations with a growing number of organizations, which, besides ICH, set standards in the pharmaceutical and related areas. These organizations include the International Organization for Standardization (ISO); the Council for International Organization of Medical Sciences (CIOMS), which covers mainly biomedical products; Health Level Seven International (HL7), dealing with electronic health information; and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S).
	
	


	A key objective behind the ICH reform is to strengthen its leadership in the drawing up of global pharmaceutical standards by enlarging its membership. This move would not only give it more clout on the global stage but also broaden its access to scientific and technical expertise. The need to extend the range of participants in its meetings was acknowledged
	10 years ago when five groups of regional agencies, undertaking their own regional harmonization initiatives (RHIs), were invited in 2005 to take part in ICH’s global co-operation group (GCG), a subcommittee of its steering committee. Two years later, this invitation was extended to representatives of drug regulatory authorities (DRAs) from non-ICH regions. Since then, representatives from RHIs and DRAs have been participating in the meetings of the ICH steering committee itself, although without voting rights. In 2014, the Swiss and Canadian regulatory agencies-Heath Canada and Swissmedic-were made full members of the committee to which they had previously, with WHO, been observers. Other changes have been improvements to the transparency of the ICH. Agendas and minutes of the steering committee meetings are published on the organization’s website together with the work plans of the expert working groups.

	A key agreement has been an enhanced role for regulators in the development of guidelines by dividing the process into two distinct parts. The technical content of guidelines is the responsibility of industry and regulator scientific experts, but their adoption is the responsibility of the regulators. Regulators, therefore, have the right to sign off guidelines without the agreement of industry representatives.

	The ICH reforms will enter their final phase in 2015 when the organization is due to become an independent legal entity. Currently, it effectively has no separate legal status as the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) hosts its secretariat at its Geneva headquarters and signs contracts on its behalf as an ICH trustee.
	As an international association, under Swiss law, ICH will have much more flexibility over choice of membership, funding, and structure. The move will underline how much the regulators will be the dominant force within the new ICH, although the aim will be to reach decisions as much as possible by consensus. Once the ICH becomes a legal entity, changes to its structure can go ahead. Its steering committee will be replaced by a management committee, which will be responsible primarily for administrative and financial matters. The organization will ultimately be controlled by an assembly, which will approve guidelines and amendments to statutes. It will consist initially of the existing permanent members, but will be enlarged later by the inclusion of current non-ICH DRAs and RHIs.


	These new full members will have to first meet eligibility criteria. For regulatory bodies, they will have to have attended at least three ICH meetings during the past two years and be able to make commitments for all their members. Industry associations will have to be global in scope and membership, have made similar regular attendance at ICH meetings, and must be affected by ICH guidelines.

	Among the regulators, the leading candidates to be first of the non-permanent members of the assembly are the DRAs of Brazil, Korea, Russia, Singapore, South Africa, and China. The RHIs would be those operated within the Asia-Pacific Economic Co-operation, Association of Southeast Asian Nations, East African Community, South African Development Community, and the Middle East Gulf Co-operation Council.

	The permanent regulatory members of the ICH, as well as some its regulatory participants, are already members of ICMRA’s interim management committee. These members include the DRAs of China and Brazil, as well as some individual medicines agencies in the EU, such as those of Ireland, Italy, Netherlands, and Germany.

	The new association seems to be positioning itself as a co-ordinator of the developers of international standards, including the ICH. Among its priorities are “the need to align the agendas of international initiatives enablers with regulators’ evolving needs” and “improved integration of all different international regulatory initiatives,” Peter Bachmann, an official at Germany’s medicines agency, stated at a London medicines conference (2). The reformed ICH will be a major focus of ICMRA’s attention. For the first time, ICH may be answerable to a single global regulators’ organization that will be able to influence both its agenda and strategy.

International Coalition of Medicines Regulatory Authorities (ICMRA)-Fact Sheet

,” accessed April 15, 2015.
	2. P. Bachman, “Opportunities and challenges of globalization,” presentation at EGA Regulatory and Scientific Affairs Conference (London, February 2015).

 When referring to this article, please cite it as S. Milmo, “ICH Prepares for Major Reform,” 

Articles

The restructuring of the International Conference on Harmonization, which is expected to begin in late 2015, could have a significant impact on the way pharmaceutical regulations are harmonized worldwide.

ICH Prepares for Major Reform

	Regulators are helping to drive a surge in the development of innovative medicines and their manufacturing processes in Europe by giving advice and encouragement to companies, particularly the small and medium-sized enterprises (SMEs). The support has been especially effective in helping to achieve a big increase in the development of medicines for treating rare diseases. Nonetheless, companies, patients groups, and
	healthcare professionals believe that regulatory agencies could do more to assist small innovators, especially in the creation of new production processes. Regulators, as well as drug producers themselves, are also being criticized for not doing enough to tackle the relatively high rate of shortages of medicines for rare diseases, often caused by manufacturing disruptions.
	
	SMEs are now making more use of the various initiatives that the European Medicines Agency (EMA) has introduced to help them develop new medicines. In the four years leading up to 2014, 64% of SMEs working on new medicines requested scientific advice from EMA on their drug development compared with 40% in the previous four years, according to the agency’s annual SME report (1). This rise was accompanied by a jump in the proportion of successful applications by SMEs for marketing authorizations, from 49% in 2007-2010 to 62% in 2011–2014.

	At the same time, involvement of drug developers and drug producers in the process for orphan medicine approvals, many of them developed by SMEs, is growing rapidly. The number of applications for orphan product designation rose 63% in 2014 to 327 applications compared with 2013, according to figures from the EMA’s committee for orphan medicinal products (COMP) (2). This figure was more than three times higher than 10 years ago. Allocations of orphan medicine designations went up 18% to 160, while those actually gaining marketing authorizations rose 71% to 12 (2).
	
	


	There is also a rising number of leading edge innovations categorized as advanced therapy medicinal products (ATMPs), made from tissues, genes, or cells, which may offer ground-breaking new treatment opportunities for many conditions. EMA’s committee for advanced therapies (CAT) has issued more than 100 recommendations for the classification of innovative medicines as ATMPs (3). Of new medicines under development for the treatment of rare diseases or that are categorized as ATMPs, micro-, small-, or medium-sized companies account for half, according to EMA (1). Yet, while SMEs are becoming major drivers behind medicine innovation in Europe, they are still struggling to gain authorizations, at least at the level of centralized approvals. The number of orphan medicine approvals has actually been decreasing as a proportion of designations. On the basis of COMP’s statistics, the proportion of approvals to designations was 5.6% in the five years prior to 2014 compared with 9.2% in the previous five years (2).
	
	“The development of orphan medicinal products remains a risky undertaking for those investing in the research, development, and commercialization of these treatments,” says Miriam Gargesi, director of healthcare biotechnology at the European Association of Bio-Industries (EuropaBio), Brussels. “Due to the rarity of the diseases, there is often only partial knowledge of the mechanisms of the diseases, scarce medical expertise, and recruitment for clinical trials is a challenge.”
	
	


	In addition to EMA, national agencies in Europe are running advisory services to assist companies in the development of new medicines and processes. Large companies and SMEs are being encouraged by their national authorities to contact them as early as possible in the development of medicines to ensure that their manufacturing processes will not create regulatory obstacles, which could be expensive to overcome.
	
	The United Kingdom’s Medicine and Healthcare Products Regulatory Agency (MHRA) in London has published a series of case studies describing the assistance it has been giving to companies in the process development and preclinical stage of medicine innovation. For example, the agency has been advising OxSonics, Oxford, England, a spin-off from Oxford University, on the quality assessment and controls of particles for use in a technology for the enhanced delivery of anti-cancer drugs deep into solid tumors. Within the university itself, the MHRA has also been helping the Jenner Institute and the university’s clinical biomanufacturing facility in the development and production of a new malaria vaccine through the bio-engineering of a viral vector.

	The agency has also been giving guidance to companies in the design of new sites and plants, sometimes even prior to an investment decision. One of these investments has been a £120 million ($184 million) plant at Macclesfield, northeast England, in which AstraZeneca is making a sterile implant for treating cancer, involving multiple aseptic stages.

	“It was essential that we had a good understanding of the regulatory expectations very early on in the process to understand the impact on the design, cost, and time lines in proposing the business case for the Macclesfield location,” explains John Parker, AstraZeneca’s UK quality director.
	
	


	Much of the advice being offered by EMA and national agencies is focused on helping companies, particularly SMEs, to prepare their medicines properly for clinical trials where most new products fail. But for a large proportion of producers, quality issues, often linked to the manufacturing process, are a major issue.

	In dossiers for marketing authorization applications by SMEs in 2011–2013, 46% of major objections by regulators were related to quality issues compared with 47% that were because of clinical efficacy and safety matters, according to an EMA investigation, the results of which are published in its SME annual report (1). Of applications for biologics, 51% of objections were on quality topics while for chemical entities, it was 41%.

	Among the most frequent problem areas was the quality documentation related to manufacturing process validation, said the EMA report (1). Other issues included control and/or characterization data of the active substance or the finished product, stability, compatibility, and shelf life data and pharmaceutical development.

	A joint study (4) published by the Deerfield Institute, the research arm of the Deerfield investment organization, and EuropaBio, found that SMEs welcomed regulatory scientific advice because it provided “opportunities to get input on manufacturing processes, [which was] particularly important for complex products that involve newer technologies, such as genetic engineering.” The companies, however, complained about a lack of flexibility among the agencies, particularly EMA, according to the report which was based on interviews with companies, regulators, and reimbursement authorities.

	EMA, for example, wanted specific rather than open questions, making it difficult for companies to work out what would be the right questions. Compared with the advice from local agencies, “the EMA process can be lengthy, formal, and cumbersome,” the report said. Apart from informal exchanges in pre-submission meetings, “there are not enough opportunities for discussion with EMA reviewers,” the report added.
	
	


	SMEs and larger companies have been criticized for not doing enough to ensure the reliability of their production processes once they start making commercial quantities of their medicines. This is especially the case with treatments for rare diseases, for which there have been a disproportionate level of shortages caused often by manufacturing failures. A group of European healthcare NGOs, led by EURORDIS, a rare diseases patients group, has argued that the incidence of drug scarcities has become so serious that supply shortage risk assessment plans should be provided by manufacturers before their medicines are granted marketing authorizations.
	
	“The current risk management plans submitted by marketing authorization applicants do not contain information on risks related to manufacturing issues or shortages as this is not legally required,” explains Francois Houyez, EURORDIS’ health policy advisor. “Applicants could submit information on these aspects on a voluntary basis, but to make it mandatory would require legal changes.”

	Some companies argue that the solution to shortages could be more thorough GMP inspections. “We question whether more inspections would help and regulators don’t seem to think so either,” says Houyez. “Thinking that more inspections would reduce the risks of shortages, even with an army of inspectors worldwide, is not the way forward.”

	EMA believes that the industry should be more pro-active in the assessment and management of the risks of shortages not only at the production stage but throughout the supply chain. Industry associations have a role to play in the promotion of information sharing and the development and sharing of the methodologies for risk assessments, Brendan Cruddy, EMA’s head of manufacturing and compliance, told a rare diseases conference in Berlin in 2014 (5). “Industry, don’t compete. Collaborate,” said Carla Hollak, a professor in metabolic diseases at Amsterdam University’s Academic Medical Centre, at the same meeting. The development of innovative medicines and production processes is becoming dependent not only on guidance from the regulators at an early stage, but the industry also needs to work more closely together to ensure the efficiencies of their supply chains.

, EMA/699351/2014 (London, Feb. 3, 2015).
	2. EMA’s Committee for Orphan Medicinal Products (COMP), 

Report on the Review of Applications for Orphan Designation

, EMA/COMP/737192/2014 (London, Dec. 12, 2014).
	3. EMA, “EMA releases revised guidance on advanced-therapy classification for public consultation,” Press Release, June 6, 2014.
	4. Deerfield Institute-EuropaBio Survey, “Regulatory and HTA scientific advice for small and medium enterprises,” March 2015.
	5. B. Cruddy, “EMA initiatives on product shortages due to manufacturing/GMP and quality issues,”  presentation at European Conference on Rare Diseases & Orphan Products (Berlin, May 2014).

 When referring to this article, please cite it as S. Milmo, “The Role of Regulatory Advice in Drug Development,” 

Drug developers understand the importance of early communication with regulators, but is EMA providing enough flexibility and support to companies?

The Role of Regulatory Advice in Drug Development

	The European Union’s decentralized procedure (DCP) for drug approval is regarded outside Europe as an effective system for cross-border collaboration in the authorization of medicines, such that it is being used as a model for a number of new global initiatives in the harmonization of pharmaceutical regulatory standards. Yet within the EU, both industry and regulators now acknowledge that deficiencies with the procedure need to be tackled before they start to undermine its benefits. 

	“The DCP has been a very successful procedure,” Stella Koukaki, managing partner and scientific affairs director at PharOS Ltd., a Greek-based developer of generic medicines, told the annual regulatory and scientific affairs conference of the European Generic Medicines Association (EGA) in London in January 2015 (1). “But it is time to take the DCP to the next stage [of its evolution] so that it is able to face a very challenging environment,” she added.
	
	


	
	The EGA used the meeting as a platform to reveal publicly, for the first time, a series of its own proposals for making the procedure more efficient. Generic and hybrid medicines now account for more than 90% of the activities of the DCP, which is currently used by the 28 member states of the EU and three non-EU European countries--Norway, Iceland, Liechtenstein. A key objective of the EGA is to make the handling of information on the manufacturing processes for generic drugs quicker and less cumbersome. Some of the regulators from the 60 national and regional medicines authorities from 27 countries attending the conference also outlined their suggestions for improving the DCP, although their ideas were not so radical as the EGA’s.
	
	“It’s time to ask ourselves whether we are efficient enough,” said Xavier De Cuyper, chief executive of the Belgian Federal Agency for Medicines and Health Products (FAMHP), speaking on behalf of the management board of the Heads of Medicines Agencies (HMA) in Europe. “We can do better, especially in the way we interact with other medicines agencies both inside and outside Europe,” he said. 
	
	De Cuyper was referring in particular to the operations of the European Medicines Regulatory Network (EMRN), which includes 44 national competent authorities in medicines control in the 31 countries involved in the DCP. It also embraces the EU’s centralized procedure (CP) for pharmaceuticals approval run by the European Medicines Agency (EMA). “I am convinced that if we continually set higher standards, we can improve how our network currently operates,” De Cuyper continued.
	
	The DCP was introduced 10 years ago to streamline a system of multistate mutual recognition under which an authorization of a medicine in one state could be automatically accepted by other EU states. It was drawn up to help companies wanting to market the same drug in only a limited number of states rather than in all EU countries for which the centralized procedure had been devised.
	
	Under the decentralized procedure, a marketing application for an individual medicine is assessed by a reference member state (RMS). This evaluation is submitted to the other countries, called concerned member states (CMSs), where the applicant wants to market its drug. Disagreements about the RMS evaluation among CMSs are normally resolved by the Co-ordination Group for Mutual Recognition and Decentralized Procedures-human (CMDh) that is responsible for the smooth running of the DCP.
	
	


	
	The DCP is seen to have been operating so well that it is influencing the ways new international initiatives, such as the International Coalition of Medicines Regulatory Authorities (ICMRA) and the International Generic Drug Regulators Pilot (IGDRP), are being organized. With the IGDRP, which aims to provide a foundation for faster authorization across the world on safe, effective, and high-quality generic-drug products, a pilot information sharing system is based on that used in the DCP. As part of the pilot, details of assessments of products carried out by RMS countries are, with the agreement of the companies applying for authorization, being sent to the states participating in the IGDRP.
	
	The pilot, which was due to be completed in 2014, is likely to be extended for another two years to 2016 with the assessment of generic medicines under the EU’s centralized procedure also being included in the information sharing component of the project. EMA agreed in January 2015 to share its CP assessments in real time with regulatory agencies in the IGDRP.
	
	“We should be proud of what we are doing in Europe in the regulation of medicines,” commented Peter Bachmann, CMDh chair and head of the European and international affairs co-ordination group of the German Federal Institute for Drugs and Medical Devices (BfArM) at the EGA conference (2). “One of Europe’s strengths is the existence of a (cross-border) legal framework. Also, after years of experience, we trust each other.”
	
	“People inside Europe are thinking the CP and DCP are still not working as well as they should be,” Bachmann added. “It is always more difficult [to appreciate how well they’re working] when you are inside the box.”
	
	

Prerequisites for a successful authorization procedure


	
	In the eyes of the EGA, the shortcomings of the DCP now need urgent attention to ensure that it operates efficiently and reliably for generic-medicine producers. From the industry’s viewpoint, there were two important prerequisites for a successful authorization procedure. 
	
	“One absolute need is flexibility and we need a lot of it,” said Caroline Kleinjan, chair of the EGA’s regulatory and scientific committee and head of the European regulatory competence centre of Sandoz, part of Novartis (3). “Our association has many different types of companies with difference needs--small and big ones and companies developing medicines for licensing.”
	
	“Another big need is speed,” Kleinjan continued. “Timelines need to be as short as possible and as transparent and predictable as possible.” Among the flaws pinpointed by the EGA in the current DCP are delays in the granting of marketing authorizations (MA) and approvals of process and other post-authorization variations. Some applications for marketing authorizations can take more than three years to be accepted so that the MA is often too late to be used, according to the association. These lengthy hold-ups are frequently caused by duplication of examinations of dossiers and CMS prevarications when evaluating RMS assessments. 
	
	


	
	The EGA has suggested the creation of four DCP types that will help to deal with the present needs of generic medicine producers. They would assist companies wanting to take quick advantages of new manufacturing processes and to respond rapidly to changes in market conditions within groups of countries, according to Kleinjan.
	
	A major change should be the introduction of what the EGA called a “backbone” decentralized procedure, with similar characteristics to the CP, with one application undergoing a core assessment and approval by a rapporteur and co-rapporteur, with the approval being confirmed by the CMDh. The holder of this marketing authorization would be able to choose in which state it wanted further approvals “in any number and at any point of time within five years,” Kleinjan told the meeting.
	
	A “basket” DCP, another EGA proposal, would also comprise one application containing all potential strengths, supply arrangements, and pack sizes. “The MAH would be able to choose the desired elements in each of the involved member states,” Kleinjan said.
	
	Another suggested change would be the introduction of a “mini” DCP that would be applied to a minority of states when the majority of countries have approved a product. It would provide “almost immediate access” to these other states.
	
	Finally, the EGA has put forward the idea of a DCP under which several applications for a medicine could be assessed under a work-sharing arrangement by different RMSs to make better use of assessment resources in agencies.
	
	“What we want to do with these proposals is start a dialogue with regulators,” Kleinjan later told 
	

. “The response at the meeting from regulators was very promising--much more so than we expected. One national agency has said it will hold a special meeting to discuss them while another has already come up with its own alternative proposals.”
	
	In addition, the association is pressing for a simplification of data requirements in application dossiers, such as, for example, details of GMP certification being dealt with separately. The mandatory inclusion of some GMP information in dossiers is seen as being a barrier to the fast approval of post-authorization variations. 
	
	Reorganization of the DCP, however, will not be easy. Even if eventually the regulators and industry reach agreement on a modified, more efficiency procedure, it is likely to require amendments to existing EU legislation that will have to be approved by the European Parliament and EU governments. It could, therefore, be a lengthy process.
	
	


	1.   S. Koukaki, “10 years’ Experience with the DCP--Does DCP Need Refreshing,” presentation at the 14th EGA Regulatory and Scientific Affairs Conference (London, 2015).
	2. P.Bachmann, “Opportunities  and Challenges of Globalization,”presentation at the 14th EGA Regulatory and Scientific Affairs Conference (London, 2015).
	3. C.Kleinjan, “’Dream DCP’--The EGA’s Proposal for Improvements,” presentation at the 14th EGA Regulatory and Scientific Affairs Conference (London, 2015). 

Proposals to make the decentralized procedure more efficient were discussed at the January 2015 EGA conference.

Europe Strives for a More Efficient Generic-Drug Approval Framework

	The European Medicines Agency (EMA) has reached a key stage in the lengthy process of creating a regulatory framework for the development and marketing of biosimilars in Europe. In December 2014, guidelines on quality standards for biosimilars with proteins as an active substance came into effect (1), while guidance on clinical and non-clinical issues with the products was being finalized. A revised overarching guideline (2) on the basic principles governing the approval of biosimilars is due to be implemented in April 2015. It includes a provision that authorization of a biosimilar in the European Union (EU) can be based on comparisons with certain clinical and 

 non-clinical studies on a non-EU originator or reference product.

	
	The first overarching guideline (3) on principles of biosimilars approval was issued in 2005, four years after the legal basis for the marketing of biosimilars was established by an EU directive (4). The laying of the legal foundations for the control of biosimilars over the past 14 years has given the EU global leadership in the regulation on the products, of which it had approved 19, including the first two monoclonal-antibody biosimilars, by late 2014.
	
	


	Nonetheless, there are a number of regulatory issues with biosimilars that parts of the pharmaceutical industry believe still need to be sorted out by EMA. The biggest of these issues is the matter of labeling, on which there are differences of opinion between the original innovators and the biosimilar developers. The current position on labeling by EMA is based on a 2012 guideline (5) covering generic medicines, hybrids, and biosimilars. This guideline states that, as with generic drugs, the biosimilar’s summary of product characteristics (SmPC) has to be derived from those of the reference product.
	
	“The general principle is that the SmPC for a biosimilar medicine has to be consistent with the reference medicinal product for the common information applicable to the biosimilar product,” explains an EMA spokesperson. “In other words, the information from the reference medicinal product’s SmPC that applies to the biosimilar should be included in the SmPC of the biosimilar.”
	The SmPC also refers to detailed information being available on EMA’s website, where comprehensive and transparent information on biosimilars is presented in European Public Assessment Reports (EPAR). The agency acknowledges that the “topic has generated a lot of interest with stakeholders.” There has been speculation that because of the level of controversy on the subject, EMA will have to issue some extra guidance on the subject. Despite drawing up a series of guidelines on biosimilars, EMA has yet to draft one specifically on the labeling of the products.

	Critics of EMA’s policy on the issue, led by the European Biopharmaceutical Enterprises (EBE) and the European Association of Bio-industries (EuropaBio), claim that it is too close to that on the labeling of generic medicines. They claim that it does not highlight sufficiently the inherent differences between biosimilars and their reference products because being biological, they cannot be identical as small-molecule generic drugs are with their originals. Instead, a biosimilar has to demonstrate similarity to the reference product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise.
	
	Opponents of EMA’s position argue that biosimilars’ labeling should focus more than other medicines’ labeling on the quality characteristics-pharmacochemical and biological properties-as determined by the manufacturing process. Under the EU’s step-wise approach to biosimilars, these characteristics and any differences between them and the reference product dictate the scope of clinical and non-clinical trials necessary to establish safety and efficacy comparability. Information on quality is important because it will fulfill the whole purpose of labeling by enabling both physicians and patients to make informed decisions about the safe and effective use of biosimilars.

	“The inclusion of the preclinical and clinical data [only] on the biosimilar is misleading because the assessment of biosimilarity is primarily based on extensive analytical comparisons [on quality] which may not be included in the SmPC,” says the EBE in a recent paper (6) in
	

. “Since the SmPC does not usually contain analytical data, it would also be important to explain the inclusion of relevant analytical data to prescribers.”

	With EuropaBio, EBE calls for a labeling approach that combines information on both the biosimilar and the reference product to achieve “full and transparent disclosure” of all data generated by the two medicines. “A lot of stakeholders at EU level have agreed that physician perception and patient acceptance impact biosimilars uptake,” says Miriam Gargesi, EuropaBio’s healthcare director. “We believe that a new and transparent labeling regime for biosimilars will contribute to facilitating physicians’ and patients’ understanding and acceptance of these products.”
	
	


	“It is important for physicians and other healthcare professionals, as well as patients, to understand how the biosimilarity exercise was built up and which additional data were generated to show that previously proven safety and efficacy of the reference product also apply to the biosimilar,” Gargesi continues. “For this reason, and since the development of each distinct biosimilar requires generating specific preclinical and clinical data, we believe that a specific label should better reflect the outcomes of these data. The label must provide the information needed for prescribers to understand the technical and scientific context under which the product was approved to ensure its safe and effective use.”

	The scientific principles underlying the comparability exercise required for changes in the manufacturing process of a biological medicinal product and for development of a biosimilar medicinal product are much the same. However, the data requirements for the biosimilar are higher, because of the potential impact of quality differences on safety and efficacy, Gargesi points out.

	On the other hand, the European Generic Medicines Association (EGA) argues that any deviations in the labeling between information on a biosimilar and its reference product would be highly confusing to physicians and patients. “[The deviations] would increase the ongoing misunderstanding and misinterpretation of the biosimilarity concept,” says Adrian van den Hoven, EGA director general. “They would not reflect the totality of evidence of the biosimilar being comparable to a reference product with regard to quality, safety, and efficacy. They would mislead the healthcare professionals and the patients on the data requirements for approvals of biosimilar medicines,” he adds. “They may lead to potential medication errors. Physicians may withhold biosimilar medicines from patients in need.”


	The disagreements over labeling in the EU reflect controversies over the regulation of the global biosimilars sector, which has prompted arguments over the quality, safety, and efficacy controls of the products. The International Federation of Pharmaceutical Manufacturers & Association (IFPMA), the Geneva-based organization representing the research-based drugs industry, has claimed that in addition to biosimilars, there are “non-comparable biotherapeutic products” on the world market, which have not undergone complete comparability exercises on quality, safety, and efficacy.

	With biosimilars, most national regulatory authorities (NRAs) are approving them in a way consistent with the guidance of the World Health Organization (WHO) on similar biotherapeutic products (SBPs), which is consistent with the EMA guidelines. But some are still not conducting comparability studies in line with the WHO guidance. With non-comparables, the scope of their quality as well as safety data is unknown, while their data may also not include any side-by-side assessments showing similarity to the reference products, says IFPMA.

	“Some NRAs are still in the process of adapting their regulatory frameworks for biotherapeutic products,” the organization continues in a policy statement (7). “As a result there are some countries where intended ‘copy’ (or non-comparable) biotechnology products have been licensed under regulatory pathways that are not appropriate for biotherapeutic medicines.”

	With so many doubts about the quality, safety, and efficacy of biosimilars and what are now being called “biosimilar-type” products on the world market, EMA is under pressure to exert even tighter standards on biosimilars being marketed in Europe. One way of doing this is seen to be, at least by the R&D sector, the introduction of a fully transparent labeling system.

Guidance on similar biological medicinal products containing biotechnology-derived proteins as active substance:quality issues

 (revision 1) EMA/CHMP/BWP/247713/2012  (London, June 2014).
	2. EMA, Guidance on similar biological medicinal products (revision 1) CHMP/437/04 (London, October 2014).
	3. EMA, 

Guideline on similar biological medicinal products

, CHMP/437/04 (London, October 2005).
	4. EU Directive  2001/83/EC, 

Community code relating to medicinal products for human use 

QRD general principles regarding the SmPC information  for a generic/hybrid/biosimilar product

, EMA/627621/2011 (London, May 2012).
	6. K. Watson et al., 

 (4) (2014), accessed Jan. 15, 2015.
	7. International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), Policy Statement: Non-comparable Biotherapeutic Products (Geneva, July 2014).


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

: When referring to this article, please cite it as S. Milmo, “Labeling of Biosimilars,” 

EMA is under pressure to exert even tighter standards on biosimilars being marketed in Europe.

Labeling of Biosimilars

	The year 2015 will be a testing time in the area of pharmaceuticals and related products such as medical devices for the new European Commission, which took over in November under the presidency of former Luxembourg prime minister, Jean-Claude Juncker. The performance of the Commission will be closely scrutinized during the year by the pharmaceutical industry, healthcare non-governmental organizations (NGOs), and members of the European Parliament (MEPs).

	The industry will be watching carefully to ensure that the Commission, in the first of its five-year term, adheres to its declared objective of helping to create a more innovative and internationally competitive European pharmaceutical sector, while improving the efficiency of the European Union internal market in medicines. In particular, it will be hoping that the Commission will make progress in resolving the key issue of how much improved health, with the help of pharmaceuticals and other treatments, can help to stimulate economic growth at a time when many EU economies are struggling to bolster job creation and industrial output. NGOs, organizations representing healthcare professionals and MEPs will, on the other hand, be attentive to the Commission’s pledge to give priority in pharmaceutical matters to public health.

	Controversy about the incoming Commission’s strategy with pharmaceuticals and to a lesser extent, medical devices, has been raging since Juncker proposed in the summer that Elzbieta Bienkowska, the Polish new Commissioner for the directorate-general (DG) or department for the internal market, industry, entrepreneurship, and small and medium-sized enterprises (SMEs), would have responsibility for all pharmaceutical issues including the operations of the European Medicines Agency (EMA), the EU’s London-based central licensing agency for medicines. This meant that Vytenis Andriukaitis, the Lithuanian new Commissioner for DG health and food safety, would, unlike his predecessor, not be in charge of pharmaceutical regulations, including the marketing authorization of medicines.

	The proposals immediately met fierce opposition from the healthcare community, many politicians, and even health ministers in the EU’s 28 member states on the grounds that the interests of manufacturers were being put before those of patients. The prestigious United Kingdom medical publication, 

 (BMJ), claimed that the change, if it went ahead, would represent a “victory for profits over public health” (1).

	Faced with the possibility that the European Parliament might not approve the new Commission, Juncker backed down, acknowledging to MEPs that “medicines are not goods like any other.” While returning the responsibility for pharmaceutical regulation back to the DG where it had resided since 2009, Juncker decided to keep medical devices under the charge of Commissioner Bienkowska. He also stipulated that policies on pharmaceuticals and medical technologies such as devices would be drawn up jointly by Commissioners Bienkowska and Andriukaitis. This move has triggered criticism that within the new Commission no one has been allocated clear leadership on pharmaceutical matters.

Orphan drugs, advanced therapies, and personalized medicines

	Meanwhile, the organizations representing various sections of the pharmaceutical industry are hoping that after the dust from the fight over the allocation of responsibilities has settled, the Commission will be effective in taking action on key issues. This is particularly the case with innovations in areas like orphan medicines, advanced therapy medicinal products (ATMP), and personalized medicines, with which the Commission is seen as having an influential role to play in Europe.

	The European Confederation of Pharmaceutical Entrepreneurs (EUCOPE), which mainly represents SMEs, wants the Commission to do more to harmonize the ways orphan medicines are assessed for use in the healthcare services of EU countries. “Despite the benefits of [the EU orphan medicine regulation], major inequalities in patient access to them still subsists between the member states,” Oliver Sude, EUCOPE’s legal counsel for EU affairs told 

	“The availability of harmonized value assessment of orphan medicines based on a common definitions [of aspects like quality, safety, and efficacy] will be very useful for SMEs who don’t have the resources to fund large regulatory affairs departments,” he continued. “It is something that the previous Commission started tackling and despite the restructuring of the new one, we expect it to be able to carry on with this work.”

	The European Association of Bio-industries (EuropaBio), a major trade association for biotech companies, wants the new Commission to give precedence to raising awareness of the benefits of personalized medicines and to help SMEs navigate their way through the regulations on the products. “Personalized medicines are not only dealing with unmet health needs but also is a field that stimulates investment in innovation, develops high-level skills, and has a positive impact on academia and second- and tertiary-care institutions,” said Miriam Gargesi, EuropaBio’s healthcare director.

	Pharmaceutical companies hope to benefit from the Commission’s continued work on the EU Better Regulation program, although it seems to be giving precedence initially to the effectiveness of regulations on the environment and waste.

	EU-based producers of generic medicines want a relaxation of the regulation on supplementary protection certificates (SPCs) extending the lifetime of patents on original drugs by up to five years. They want to be able to export during the SPC period to third countries where no patent or protection certificate is in place. “Introducing an export exception in the SPC regulation will allow the European generic and biosimilar medicine industries to produce more high quality medicines in Europe for export to the rest of the world,” Adrian van den Hoven, director-general of the European Generic Medicines Association (EGA), told 

“An SPC export exception would insource dozens of thousands of high-technology jobs, R&D, manufacturing science, and know-how, while stimulating the global competitiveness of the European generic and biosimilar medicines industries.”

	EGA wants the Commission to use its system of setting annual economic targets, including, if necessary, healthcare indicators, to bolster sales of generic drugs. The system, called the European Semester, aims to help the EU meet its Europe 2020 targets for economic growth and recovery. One Europe 2020 target is to raise industry’s share of EU gross domestic products (GDP) from a current 16% to 20% by the end of the decade.

	“We support the inclusion of clearer EU Semester recommendations on uptake of generic and biosimilar medicines in relation to the 17 member state reports [under the Semester system] that include healthcare reform measures,” said van den Hoven. “Our data show that uptake measures [for generics] that stimulate more competition in pharmaceutical markets provide much higher overall savings and better health outcomes for patients than short-term cost containment measures.“

	EGA has been advocating to EU officials initiatives that both improve healthcare systems and make the European generic-drug industry globally competitive. “We have been clear from the beginning that we want coherence in the EU’s pharmaceutical policy,” van den Hoven said. “Commissioners Bienkowska and Andriukaitis have all the policy tools in hand-health policy, pharmaceutical policy, industrial policy-to deliver over the next five years.”

	European Federation of Pharmaceutical Industries and Associations (EFPIA), representing research-based companies, has stressed to policy makers the importance of healthcare to a thriving economy. “The economic crisis in Europe at times has led to sometimes drastic steps to be taken on healthcare that have not only affected patients, but have also raised questions about how we see healthcare as a driver of Europe’s future prosperity,” explained Richard Bergstroem, EFPIA director general, to 

 “Health should be seen as a key enabler of a productive economy in Europe,” he added. “Additionally, the pharmaceutical industry adds value to the EU not only in terms of health, but also through exports and economic activity, such as employment of skilled people.”

	Like most other European trade associations in pharmaceuticals and related products, EFPIA is optimistic about the new Commission, particularly about its objective of overcoming what Juncker calls “silo mentalities” through greater collaboration and collegiality in the Commission itself. “His efforts to support coordination across the Commission is a positive step,” said Bergstroem. “His programme offers a compelling vision for the future and a renewed call for partnership between EU institutions and member states.”

	An achievement for the new Commission this year will be to convince at least some of the leading sceptics in the healthcare community that a strong pharmaceuticals sector will not only help boost the health of Europe’s population but also help revive Europe’s ailing economy.

The European Commission and pharmaceutical policy


	Sean Milmo is a freelance writer based in Essex, UK, seanmilmo@btconnect.com.

When referring to this article, please cite as S. Milmo, “Great Expectations from New European Commission,” 

The European Commission’s new structure has sparked controversy about its allocation of responsibilities and the impact on the development and approval of new medicines.

Great Expectations from New European Commission

Incidents of drug shortages in Europe have been increasing over the past few years with few signs of an overall reduction in scarcities across the region. Most of the initiatives to deal with the issue at the production stage are being taken by the manufacturers themselves. The European Medicines Agency (EMA) and the variety of national competent authorities (NCAs), such as licensing bodies and government ministries responsible for drugs supplies at the national level, seem content to leave it to manufacturers to put forward proposals for dealing with disruption of output at their production plants.

EMA believes that the industry’s risk management tends to “to be very reactive rather than proactive.” An agency official told

, “Sustained pressure is needed to bring about a change in a manufacturer’s approach to quality risk management and supply chain security.” The agency’s policy has been to encourage “the pharmaceutical industry to develop its own solutions to address the prevention of drug shortages caused by manufacturing and quality issues,” the official added.

Nevertheless, medicine manufacturers want more action on the issue from the European Union and the governments of the 28 member states. They reckon the problem has to be resolved through a broader approach embracing manufacturers, distributors, healthcare professionals, and even the patients themselves.


A number of industry groups have been drawing up or are close to finalizing proposals for dealing with shortages stemming from manufacturing disruptions. Patient associations and management consultancies have also been making recommendations.

The Drug Shortages Prevention Plan of the International Society for Pharmaceutical Engineering (ISPE) was discussed at a meeting in early October 2014, attended by EMA representatives, national regulatory authorities, and representatives of the industry and ISPE itself, even before it was officially published. Its recommendations focus on the need for manufacturers to improve their quality systems, use metrics to identify and mitigate risks, foster a corporate quality culture, and improve communication with the authorities on potential shortages.

“We believe that the industry needs to adopt the proposals in the ISPE plan,” John Berridge, ISPE advisor, told   

. “We would like EMA and NCAs to help us make manufacturers aware of the proposals by, for example, putting details of them on their websites and by joining us in training programmes.”

The Parenteral Drug Association (PDA) is planning to publish a technical report on the prevention and management of drug shortages. Among its suggestions will be the adoption of concepts on the control of drug shortage risks based on the criticality of the product and an overall product risk evaluation.

The European Federation of Pharmaceutical Industries Associations (EPIA), the European Generic Medicines Associations (EGA) along with two other pharmaceutical associations for wholesalers and biopharmaceuticals producers have been working on an improved process for communications on shortages. This process would relate to the way manufacturers inform regulatory agencies of “meaningful interruptions of supply” (1).

EURORDIS, a rare disease patients group, together with other patients organizations and professional associations, including those representing community and hospital pharmacists, have drawn up a set of proposals, in the form of a Common Position, on medicines shortages (2). These proposals include a requirement on drug approval applicants to provide supply shortage risk assessment plans to regulatory agencies before gaining marketing authorization. Manufacturer and/or marketing authorization holders (MAH) would have to inform the regulatory agencies as soon as a shortage becomes possible. If a shortage occurs, a calendar of production until the expected end of the shortage would have to be provided.


Although there is broad agreement in the pharmaceutical sector that the problem of shortages has been worsening in recent years, groups differ in their judgement of the prevalence and severity of the problem, depending on their position in the supply chain. The European Association of Hospital Pharmacists (EAHP) told 

 that 87% of 600 hospital pharmacists it surveyed considered it to be a problem, particularly with oncology drugs and antibiotics. There is, however, a lack of consistent and in-depth data on shortages mainly because it is collected by national agencies, if at all, and there is no Europe agreement on the definition of a “shortage.” Some NCAs have turned down a request from EMA for the drawing-up of catalogues of drug shortages in their countries because what was meant by the term was unclear, especially since the term can have different connotations in different languages.

“We cannot agree on a definition of shortages,” says Marten Forrest, spokesperson for the Swedish Medical Products Agency (MPA), explaining why his agency had not created a shortages list. “For example, there is the question of what sort of supply difficulties can be referred to as a ‘shortage’ and whether these difficulties are global, European, or national,” he continues. “It is difficult to draw up a list of medicines shortages without a definition.”

This lack of clarity about what are shortages can lead to gaps in the reporting of them or of manufacturing disruptions that could cause shortages. “Not all manufacturers are notifying us about problems they are having which are or could cause shortages,” said Forrest. “One of the important signals of existing shortages is phone calls or email messages from pharmacists asking for more information about a shortage of a particular medicine we don’t know about.”


The industry now wants much more research into the causes of shortages, particularly into incidents linking them with manufacturing difficulties. “We don’t know what are the amount of shortages arising from manufacturing problems,” says Berridge. Some governments see the influence of   globalization on patterns of pharmaceutical manufacturing as being a major cause of shortages. “The globalization of the pharmaceutical industry means that medicines are often manufactured in just a few sites worldwide,” explains a spokesman for the UK Department of Health, which is   responsible for drug supplies in the country. “Production schedules have to be planned months in advance and this along with the move to ‘just-in-time’ manufacture to reduce the cost of stockholdings means that there is little flexibility in the system when problems do arise,” she adds.

In a recent report on medicines shortages in Europe, birgli AG, a Swiss-based management consultancy linked government-initiated price-curbs on medicines and legislative support for parallel trading to reductions in manufacturing sites and the use of ‘just-in-time’ supply chains.

“Before shortages can be reduced, the underlying reasons and root causes of shortages should be well understood,” explained Julie Marechal-Jamil, EGA’s senior manager quality and regulatory affairs, in an interview with

. For quality and manufacturing-related issues to be tackled properly in relation to shortages, a combination of measures had to be taken, Marechal-Jamil added. In addition to the initiation of shortage-prevention plans at the corporate level, she said there had to be a harmonized definition of drug shortage, a harmonized shortages reporting process with identical trigger points, triaging procedures and timelines, as well as an improved flow of information along the supply chains.

One key issue yet to be resolved and upon which there are divergent views even among the regulators is the relation between GMP rules and supply disruptions caused by weaknesses in quality control systems, which could lead ultimately to medicine shortages. “Quality defects are usually caused by some kind of GMP failure but not always,” says the EMA official.

  However, a different view is taken by some national agencies that believe they can deal with production deficiencies causing supply disruptions without reference to GMP rules. “The obligation to ensure the continuous supply of medicines so that the needs of patients in the UK are met is a condition of a manufacturer’s licence [so] this is not a GMP matter,” says a spokesperson for the Medicines and Healthcare products Regulatory Agency (MHRA), the country’s licensing authority, which deals with possible manufacturing deficiencies related to shortages. “MHRA routinely inspects manufacturers for compliance with the conditions of their licence and with EU guidance on GMP,” he continues. “To date there has been no occasion where MHRA has needed to take action against a manufacturer in relation to this obligation (in respect of its licence conditions).”

Nonetheless, ISPE reckons there is a close enough connection between GMP standards and those underpinning systems preventing supply disruption and procedures for reporting potential shortages to the authorities. “Since the EU’s revised GMP guidance will say that manufacturers must notify competent authorities about impending interruptions in supplies due to quality issues, GMP inspectors would seem to be in a position to ask for details about what steps are being taken in manufacturing plants to avoid disruptions,” says Berridge “[They will also be able to ask] for details of the company’s procedure for making notifications of disruptions to the authorities.” The issue of medicines shortages in Europe will clearly require a lot of dialogue between the industry and regulators before significant progress is made in resolving it. More communication between the industry regulators is required to resolve the problem.


1. 	Birgitte Holst, Novo Nordisk A/S, “Communications Principles in cases of Q and Manufacturing driven supply disruptions,” presentation at the PDA Drug Shortage Workshop (Washington DC, September 2014).
  2. 	EURORDIS and six other organisations, “

Common position between patients’, consumers’ and healthcare professionals’ organizations involved in the activities of the European Medicines Agency on supply shortage of medicines


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

Resolving the problem will require more communication between the industry and regulatory bodies.