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

Sean Milmo

	The European pharmaceutical sector and its packaging suppliers could be destined for a shake-out because of the inability of small companies to comply with new rules on packaging safety features aimed at combating counterfeiting. The European Commission, the European Union’s executive, published its last draft (1) of the rules in August 2015, and they are likely to become EU law by the end of 2015 or in early 2016. Pharmaceutical producers and their packaging contractors will then have three years to comply with the new regulation or be forced to take their products off the EU market.

	Packaging experts believe that three years may not give many companies enough time to complete the process of re-engineering their packaging lines to meet the new obligations required by the EU’s Falsified Medicines Directive (FMD) (2). At the core of the rules is a requirement for the serialization or unique identification of each medicine pack, which will necessitate major changes to most packaging lines.

	“Companies, especially the smaller packaging companies specializing in pharmaceuticals, could disappear or be bought up by larger companies,” says Bart Vansteenkiste, EU life sciences sector manager, at Domino Printing Sciences plc, Cambridge, England, in an interview with 

“A lot of companies have left compliance with the new regulations very late. Already suppliers of packaging hardware and software are reporting full order books and longer lead times.”

	3C Integrity Consulting, a UK-based specialist in FMD packaging requirements, has compared the threat to the industry to the extinction of the dinosaurs. A big difference will be that the big creatures, namely the large multinational pharmaceutical players, will survive because they have prepared themselves well in advance for the impending changes. Instead, it will be the smaller and usually more versatile ones that will become extinct.


	“For any remaining pharma companies that have doubts about whether or not they should progress their FMD readiness program, any suggestion that they should further delay [the preparation] would certainly be considered a courageous decision,” the consultancy said in a bulletin issued after the publication of the final draft of the rules in what is called a *Delegated Act (3). 3C Integrity advises companies yet to start preparing for the new regulations, to find out immediately what needs to be done to ensure compliance, both in-house and along their supply chain. “Simply-get started,” 3C Integrity said in the bulletin. “ If you are not in that position, then things may be getting uncomfortable soon.”

	In a survey (4) by Domino in June 2015 of small to large research-based pharmaceutical manufacturers, medicine-device makers, generic-drug producers, and packaging contractors, 65% had started a program of upgrading their packaging lines. “Most of these companies have installed a pilot line to determine what changes they need to make to their existing packaging lines,” explains Vansteenkiste. “The remaining 35% have either just started looking into what they need to do or are doing nothing.”

	What has been stopping companies even budgeting for a re-engineering of their packaging lines has been a lack of detail about certain aspects of the FMD serialization system, even though the main features of it have been clear since the approval of the directive in 2011. Knowledge of the basic requirements has enabled the pharmaceutical majors to press ahead with their own re-engineering schemes so that many of their packaging lines have been producing packaging with unique identification of individual packs for several years. “[There is] nothing in this [final] draft Delegated Act that we have not had visibility of before,” says 3C Integrity. “The key features have indeed been set in stone since the publication of the directive itself in 2011.”


	However, among SMEs in particular, there are concerns about the expense of FMD compliance. “The Delegated Act is really only about how and precisely when [the directive should be implemented],” says Warwick Smith, director general of the British Generic Manufacturers Association (BGMA). “None of our members has raised concerns about the necessary changes, though everyone has noted that it will be a very costly exercise.”

	The European Generic and Biosimilar Medicines Association (EGA) informed 

 that it has estimated that upgrading packaging lines for FMD compliance could cost generic-drug manufacturers a total of approximately €1 billion ($1.1 billion). The EGA is alerting generic-drug companies to the dangers of delaying preparations for the compliance deadline but also warning that the squeeze on margins due to the extra cost could lead to products being taken off the market.

	“We are encouraging members to start with the implementation since the number of suppliers of this type of equipment for the packaging lines is limited,” says Maarten Van Baelen, EGA’s market access director. “We are very concerned about the number of medicinal products that will be withdrawn from the market because they will no longer be profitable.”

	Domino calculates that the average upgrading cost per packaging line is approximately €125,000. But with the addition of aggregation or the essential matching of serialization codes with data on batch-carrying pallets and shipped cases, this cost increases to €250,000, according to Vansteenkiste. With the compliance deadline getting nearer, companies are, nonetheless, faced with a Catch-22 dilemma of equipment and software prices going up as delayed purchasing decision leads to demand outstripping supply.


	The Delegated Act lays down rules on the harmonized structure and content of the unique identifier. It also requires each pack to have an anti-tampering device, but its specification is left to the manufacturer. It stipulates details of an “end-to-end” system for the verification of the authenticity of each pack’s safety features. This system will operate through a centralized data base or repositories network, into which the unique identifier data of each medicine pack will be fed from the packaging unit and then verified by the pharmacist at the dispensing point. The network is to be managed by industry stakeholders under the supervision of the relevant authorities of each of the EU’s 28 member states.

	The unique identifier will consist of a product code, serial number, national reimbursement number (if necessary), batch number, and expiry date. It must be encoded in a GS1 Data Matrix ECC200 2D barcode. In addition to being machine readable, all the data, except the batch number and expiry date, must also be human readable.

	The serial number must comprise “a numeric or alphanumeric sequence of a maximum of 20 characters, generated by a deterministic or a non-deterministic randomization algorithm.” The randomization requirement is outside GS1 specifications for barcodes used in the supply chains of multiple sectors.

	An important stipulation in the Delegated Act is that the only 2D barcode allowed on the packs is the one “carrying the unique identifier for the purpose of their identification and verification of their authenticity.” This limitation may necessitate that companies redesign their packaging to remove other barcodes, such as those related to inventory and price.

	The Delegated Act also lists medicines exempted from the serialization requirement. These medicines include homeopathic products, advanced therapy medicines containing tissues or cells, intravenous solution additives, allergic diseases tests, and allergen extracts.


	For compliance, pharmaceutical companies will need higher-performing code-printing equipment. With inkjet printing, which currently accounts for approximately 70% of printed codes on medicine packs, more durable and light-resistant ink will have to be used to meet a requirement of machine readability for up to five years, according to Vansteenkiste.

	Another challenge is aligning the printing process with an adjacent machine-vision system with technologies for optical character recognition (OCR) to check the content of the text and for optical character verification (OCV) to assess quality. As indicated in the Delegated Act, these should ensure that the barcodes meet the joint standards on printed security information of the International Organization for Standardization (ISO) and the International Electrotechnical Commission (IEC).

	The Domino survey (4) found that with nearly half of respondents, the biggest worry was the task of integrating the serialization hardware into current systems. “There are unlikely to be any shortages of coding and vision equipment because it is not difficult to increase their manufacture,” says Vansteenkiste. “But integrating all the new hardware and software into each packaging line could pose big problems. With software, the main issue is manpower. As the deadline approaches, there could be shortages of the right expertise.”

	Companies are also looking beyond FMD to compliance with other possible legislative initiatives in the future both inside and outside Europe. They are willing to pay extra for a packaging operation that is able to respond positively to future developments in serialization and the management of all the data that comes from it. They can, at least, expect that as serialization become more widespread across the world, the cost of the hardware and software needed for its up-to-date application will be much less expensive than it is today.

*The concept of the Delegated Act (DA) was introduced by the EU’s 2007 Lisbon Treaty to enable the European Commission to draw up regulations on non-essential, mainly technical, matters relating to new legislation. The European Parliament and the Council of Ministers-the EU’s two legislative arms-would lay down the objectives, scope, and duration of the DA. Once the DA has been finalized by the Commission, usually after lengthy consultations, it becomes law as long as the Parliament and Council raise no objections to its content.


	1. EC Delegated Regulation supplementing Directive 2201/83/EC, Detailed rules for the safety features appearing on the packaging of medicinal products (Brussels, August 2015).
	2. EC Directive 2011/62/EU amending Directive 2001/83/EC, The prevention of the entry into the legal supply chain of falsified medicinal products (Brussels, June 2011).
	3. 3C Integrity Consulting, “

EU-FMD: Draft Delegated Act publicly released by ED for comments

,” accessed 11 Sept. 2015.
	4. Domino Printing Sciences, “

Domino survey uncovers marked differences in serialization readiness

 When referring to this article, please cite it as S. Milmo, “Serialization Shake Out,” 

Articles

The complexity of new packaging regulations laid out in the Falsified Medicines Directive could threaten the existence of smaller pharma and packaging companies.

Serialization Shake Out

	The European network of medicines regulatory agencies, co-ordinated by the European Medicines Agency (EMA), announced in March 2015 its strategy until 2020 (1), with one of the priorities being its contribution to greater worldwide collaboration on inspections of pharmaceutical production sites. A key part of the network’s agenda in achieving this objective would be to reach an agreement with FDA on co-operation on inspections of drug manufacturing sites to assess compliance with good manufacturing practice (GMP).

	The European Union and FDA have been striving unsuccessfully for nearly 20 years to reach a long-term deal on GMP inspections that would avoid duplication and help to reduce the overall costs of monitoring the growing number of Asian plants producing finished drugs and APIs for the European and US markets. An EU–FDA deal would be considered a major breakthrough in the struggle to achieve international collaboration in GMP inspections. FDA and the EU, through its network of national licensing authorities headed by EMA, are by far the most active in conducting GMP inspections, not only in their own territories, but throughout the world.

	Another view, however, is that bilateral agreements, even as big as the one between the EU and FDA, are no longer the main driving force behind the global advancement of GMP inspection standards. Instead, a much greater influence is now being exerted by two Geneva-based international bodies-the International Conference on Harmonization (ICH), which draws up worldwide standards on GMP, and the Pharmaceutical Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), which has been developing standards for inspections to ascertain GMP compliance. Soon, the newly founded International Coalition of Medicines Regulatory Authorities (ICMRA), which is headquartered in Canada, will become a third international body involved in the setting of global GMP standards.

	Efforts to create uniform, worldwide standards on GMP inspections have increasingly been driven by multilateral agreements thrashed out within a few key international organizations. Nonetheless, the lengthy endeavours by the EU and US to reach a long-term bilateral deal on GMP inspections has been helping to clarify key issues that need to be resolved during negotiations on agreements aimed at making more efficient use of the stretched resources of regulatory agencies.


	EMA and FDA are hoping that by early 2016, a final framework for a mutual reliance agreement on inspections and its implementation will have been completed. This deal on a final framework will have been around 20 years after EU and US authorities started discussing plans for a mutual recognition agreement (MRA) that would embrace pharmaceuticals and several other sectors.

	In 1998, an US­–EU MRA was reached covering pharmaceuticals, medical devices, and four other sectors, including telecoms equipment and electrical appliances (2). The procedure was that after the drawing up of individual MRAs for each sector, there would be a transition period to see if they worked so that they could become permanent arrangements. The mutual recognition was not of standards but of inspection, testing, and certification requirements relating, in the case of pharmaceuticals, to GMP in production plants. It quickly became clear early in the three-year transition for the pharmaceuticals MRA that it would be impractical and politically unsustainable. In fact, it had been virtually abandoned before the transition period ended in 2001.

	The main problem was the differences in regulatory structures. While FDA is a long-established single central authority with GMP inspections responsibilities, the EU, at the time, had medicines authorities in 21 member states with the task of carrying out inspections. EMA, the EU’s central medicines agency founded only in 1995, had not yet fully taken over its current role in ensuring uniform GMP standards and inspection processes.

	The EU had successful MRAs on GMP inspections with a number of countries-one of first being with Health Canada, the Canadian pharmaceuticals licensing authority, which was finalized in 1998 (3). Nonetheless, after the collapse of the pharmaceuticals MRA with the US, the European Commission decided that, in future, MRAs would be negotiated “only in cases where there is a clear equivalence of respective rules and a real prospect of making them operate almost automatically” (4).

	After a lull of a few years, EMA and FDA continued their efforts to find common ground on inspections. They were helped by the development of much closer ties between the two organizations as a result of joint activities in a number of areas, such as orphan and pediatric medicines, scientific advice, quality-by-design (QbD) assessments, and pharmacovigilance.

	Instead, after six years of joint pilot inspection programs covering both finished products and APIs, an alternative to MRAs had begun to emerge in the form of a mutual reliance deal. EMA, EU member states, and FDA decided in 2014 to start to work on a mutual reliance initiative (MRI) (5).


	“In general, MRAs on GMP allow EU authorities to rely on GMP inspections performed by other regulators, the waiving of batch testing of products on entry into the EU, and information sharing on inspection-related information and quality defects,” explains an EMA spokesperson. “In the context of the MRI, the term ‘mutual reliance’ means that the EU, member state authorities, and FDA would rely upon each other’s data and information from GMP inspections to the extent possible,” she continues. “Because of the differing legal systems and other factors, from time to time, the US and EU might take different actions on an application, facility, or products, based on the same inspectional findings.”

	The main emphasis has shifted to information sharing to enable inspection resources to be focused on high-risk inspection sites. One idea to come out of the pilot joint inspection programs was for a master file of manufacturing sites for inspection, including those in third countries. From this master file, EMA created its central EudraGMDP database (6) providing information on GMP and good-distribution-practice (GDP) certificates. A major objective of the database is to help the co-ordination of inspections in third countries among national medicines authorities and to facilitate the sharing of information on the outcomes of inspections.


	Now that organizations such as PIC/S are encouraging more information sharing among inspectorates across the world, the EU–US mutual reliance deal might focus on specific areas of GMP inspections that are raising new concerns. One of these areas is the matter of data integrity, which has been growing in importance because of the massive rise in the technological capacity to gather large quantities of data. However, this increase has not been commensurate with measures by companies to ensure the generation of accurate data or to improve their ability to process data efficiently.

	After a recent inspection of the Czech API manufacturer VUAB Pharma, FDA heavily criticized the company for failing to “prevent unauthorized access or change to data and to provide controls preventing data omissions” (7). The United Kingdom Medicines and Healthcare products Regulatory Authority (MHRA) has this year updated its guidance on data integrity (8), which it says has become a “hot topic” after a number of data failures led to withdrawals of drug supplies across multiple markets (9).

	Another issue is how much the MRI will take into account moves by FDA to use quality metrics as an indicator of quality management efficiencies so that it can plan risk-based inspections more effectively. The agency recently published guidance on quality metrics (10) to gauge how well quality systems on medicinal products and API sites are being maintained.

	Because, at least in EU–US trade relations, the idea of MRAs in the pharmaceuticals sector is being replaced by that of mutual reliance, medicine and API producers will be watching closely the extent to which their inspection fees are being reduced, particularly in the US in the context of the Generic Drug User Fee Amendments (GDUFA).

	The European Fine Chemicals Group (EFCG), representing mainly API but also generic-drug manufacturers and which has been pressing for a EU–US MRA in pharmaceuticals, criticized in 2014 the mutual reliance concept, saying it was only a “half-way house” to a mutual recognition agreement (11).

	“The difference may be just for legal reasons,” says Guy Villax, chief executive of the Portuguese pharmaceutical company Hovione FarmaCiencia SA and an EFCG board member. “At the end of the day, what is important is how much a mutual reliance deal will bring down inspection costs so that the inspection fees can be reduced, particularly for GDUFA purposes.”

	Costs will also be an important consideration for EU and US regulators. The more successful the MRI is in the raising inspections efficiencies, the more they can concentrate on improving GMP levels in the most worrying sites and also start investigating sites that have never been inspected before.


	1. HMA & EMA, “EU Medicines Agencies Network Strategy to 2020,” Consultation Draft EMA/MB/151414/2015 (London, March 2015).
	2. European Commission, COM (1998) 180 Final, 

An Agreement on Mutual Recognition in relation to Conformity Assessments between the European Community and the United States of America 

(Brussels, March 1998).
	3. European Community and Canada, CE/CA/en 3, 

Agreement on Mutual Recognition between European Community and Canada

 (Brussels, October 1998).
	4. European Commission, “Priorities for bilateral/regional trade-related activities in the field of MRAs for industrial products and related technical dialogue,” SEC (2004) 1072 (Brussels, August 2004).
	5. Howard Sklamberg, “Ensuring Pharmaceutical Quality Through International Engagement,” FDA Voice, May 2014.
	6. 

Data Integrity, Definitions and Guidance for Industry

Good Manufacturing Practice (GMP) data integrity: a new look at an old topic, part 1

Request for Quality Metrics-Guidance for Industry Draft 

(Washington, July 2015).
	11. G.M. Baccalini, “Global Business Developments,” presentation at EFCG press conference, CPhI, Paris, October 2014.

	About the Author
	Sean Milmo is a freelance writer based in Essex, UK, 

When referring to this article, please cite it as S. Milmo, "Collaborating on GMP Inspections," 

EU and US regulators are striving to work together on improving GMP inspection efficiencies and avoiding duplication of efforts.

Collaborating on GMP Inspections

	In Europe, the regulation of medical devices has traditionally been completely separate from pharmaceuticals. But in recent years, pressure has been mounting for a more integrated approach to the control of medical devices, particularly 

 diagnostic (IVD) tests, so that medicines regulators would be much more involved in their approval. Medicines regulators have tended to avoid participating in the assessment of devices, even though at the national level, they work within agencies that are ultimately responsible for authorization of the devices. Nonetheless, health technology assessment (HTA) bodies, which decide on which and often by how much pharmaceuticals and healthcare products should be reimbursed, have started investigating combinations of individual medicines and IVD tests for detecting patients most responsive to them. These HTA evaluations, however, are not comprehensive because they do not cover the design, materials, and manufacturing process that may affect the accuracy and reliability of the IVD equipment.

	The impetus behind moves for the combined examination of pharmaceuticals and devices, particularly companion diagnostics specifically intended to select patients for targeted therapy, has come from the trend towards personalized medicines in Europe. Another driver has been the development of electronic digitalized technologies enabling diagnostics and health monitoring to be conducted outside laboratories at points of care (POC) and, increasingly, by lay people with the use of electronic wearable devices, during exercising and other every-day activities.

	As a result, the question of whether companion diagnostics and other medical devices that help provide more effective pharmaceutical treatments need to be regulated in ways similar to that for medicines has become a key issue among politicians, regulators, professionals, and healthcare sectors in Europe. Should medicines licensing authorities control devices, particularly with regard to design and manufacturing standards?


	The European Union’s two legislative arms-the European Parliament and the Council of Ministers representing the EU’s 28 member states-are currently in the later stages of approving a new legislation that attempts to resolve some of these issues. Two new proposed regulations (1, 2), one on medical devices and other IVDs, have been drawn up by the European Commission, the Brussels-based EU executive, to replace existing rules (3–5), the first of which was introduced in 1990.

	The objective of the regulations is primarily to achieve greater harmonization and consistency in the way the assessment and certification rules are applied. Initially, the commission aimed to make only a series of incremental improvements. But then a number of scandals took place, which forced the commission to put forward more radical measures.

	In the medical devices market, a French company was found to have distributed breast implants made with industrial rather than medical-grade silicone, while across Europe, there was a widespread deterioration in the quality of metal-on-metal hip implants (6). One of the most disturbing occurrences was with IVDs, where an officially approved HIV test providing a high level of false negative results was able to stay on the market for several years (7).


	The main aim of the two new regulations is to raise standards of assessment and monitoring along the regulatory chain. The nationally designated organizations-called notified bodies-responsible for evaluating and certifying medical and IVD devices are being given powers to make unannounced audits of sites of manufacturers and their subcontractors to check, in particular, whether they are complying with quality management systems. The notifying bodies, which mainly comprise certification services companies or research institutes, will themselves be subject to much stricter accreditation requirements, which a lot of the existing ones may not be able to meet.

	These notifying bodies will be scrutinized more closely by the national agencies, many of them also medicine licensing authorities, to which they are accountable. They will be subject to joint assessments by teams from other member states. Their workload will rise considerably. With IVD devices, the vast majority of products will be switched from a classification needing only self-certification by their manufacturers to one in which they will have to be assessed by a notified body. Similar to medical devices, submissions for approvals of IVD tests will have to be supported by much more clinical evidence than before. In addition, this clinical information will have to regularly updated with data from post-marketing surveillance.


	A central Medical Device Coordination Group (MDCG), consisting of experts in medical and IVD devices, will be set up to help in the assessment of high-risk and companion diagnostic products. The evaluation of some high-risk devices is considered to be so complex that it will be carried out at the national level by specially designated notified bodies.

	The MDCG will also be involved in drawing up quality standards or common technical specifications (CTS) for companion diagnostic devices. A network of high-calibre laboratories, known as reference laboratories, will be allocated the task of verifying that devices comply with CTS.

	When assessing companion diagnostic devices, notified bodies will have to consult with national medicines authorities or the European Medicines Agency (EMA) “regarding the suitability of the device in relation to the medicinal product concerned,” according to the Commission’s draft law (1). The new IVD regulation, however, does not lay down to what extent the notified body has to take account of the opinion of EMA or national agency, except that it must be included in the documentation for the product.


	This centralization of the evaluation process is worrying the medical and IVD devices industry. “We don’t need a centralized component in the assessment procedure,” said Oliver Sude, legal counsel to the European Confederation of Pharmaceutical Entrepreneurs (EUCOPE), an association representing SMEs making pharmaceuticals and medical devices. “The present decentralized system is on the whole working relatively well,” he told 

	Members of the European Parliament (MEPs) are, however, opposed to EMA and/or the national medicines agencies being consulted on the evaluation of the performance of companion diagnostics on the grounds they have neither “the necessary competence or mandate” (7). This is in line with the opposition of the industry to medicines regulators being consulted during the approval process of a companion diagnostic. The European Diagnostic Manufacturers Association (EDMA) has suggested a system in reverse, in which the medicines agencies would consult the notified bodies when approving drugs with companion diagnostic tests.

	“At the time of approval of a medicinal product that relies on a companion diagnostic, it is to be expected that the medicines agency would want to have an assurance that the companion diagnostic used performs as required,” EDMA says in a position paper (8) on the new IVD regulation. EMA has been assisting in the development of companion diagnostics by issuing draft guidance on the detecting of genomic biomarkers in patients for anticancer drug treatments, while also creating a system for consultation with innovators in the areas. However, while the agency has approved anticancer medicines with the licensed indication based on the selection of patients with certain pharmacogenetic biomarkers, none of the authorizations has referred to the use of a specific companion diagnostic device.


	A growing number of HTAs in Europe have been investigating medicines, particularly anticancer ones, with companion diagnostics in the hope that they would be able to recommend the combination of a drug with a specific IVD test. This approach is seen as a way of reducing treatment costs at a time when healthcare funds are being squeezed. But few have been able to make specific recommendations mainly due to the scarcity of evidence showing that one IVD test works better than another in combination with an individual drug.

	The National Institute for Health and Clinical Evidence (NICE), the UK’s main HTA, has published approximately 15 studies of pharmaceuticals with companion diagnostics. The vast majority of these publications, however, are appraisals rather than guidance documents with specific recommendations.

	In a paper (9) published in 2014 on the assessment of companion diagnostics, a team of NICE researchers described the difficulties they encountered when trying to evaluate tests for epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutations prior to anticancer drug treatments. It cited one test with 99% sensitivity and 69% specificity estimates while other tests had sensitivity and specificity estimates ranging from 61% to 84%, respectively.

	“A wide variety of different test methods and strategies were being applied across the laboratories (in England) providing EGFR-TK mutation tests services,” the researchers said in the paper published in the 

 (9). “During the assessment (of the tests), it became clear that for several of the test strategies, there was very limited evidence on which to determine clinical and cost effectiveness,” they added.

	With pharmaceutical companies investing more in the co-development of medicines and companion diagnostic devices with their medicines, they will be hoping that medicines authorities in Europe will be able to make “one drug, one test” approvals, or even that HTAs will even be able to make similar recommendations. “Part of the problem is that regulations often lag behind technological progress,” Benjamin Roussel, activity leader at Yole Developpement, Lyons, France, a market research consultancy specializing in the IVD sector, told 

 “With IVD devices, the European regulations could take a long time to catch up,” he added.

	Regulating companion diagnostics within the same legislative framework as pharmaceuticals could be a strong platform for sustained market growth in IVD devices. Nevertheless, the creation of such a regulatory structure seems unlikely to happen in the near future.


	1.   EC proposed regulation 2012/0266, 

 (Brussels, September 2012).
	2.   EC proposed regulation 2012/0267, 

(Brussels, September 2012).
	3.   EC Directive 1990/385/EEC, 

(Brussels, June 1990).
	4.   EC Directive 1993/42/EEC, 

 (Brussels, June 1993).
	5.   EC Directive 1998/79/EC, 

 (Brussels, October 1998).
	6.   UK House of Commons, Science and Technology Committee, “Regulation of medical implants in the EU and UK,” Fifth Report of Session 2012–13, 17 October 2012.
	7.   European Parliament, “Text tabled of amendments with explanatory statement on proposed regulation on 

 diagnostic medical devices,” AT-0327/2013 (Brussels, October 2013).
	8.   European Diagnostic Manufacturers Association (EDMA), “A Need for Separate Legislation,” 

, accessed 15 July 2015.
	9.   S.K. Byron et al., 


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

When referring to this article, please cite it as S. Milmo, "Regulation of Medical Devices," 

The trend towards personalized medicines in Europe requires a more integrated framework that regulates the approval of devices and diagnostics.

Regulation of Medical Devices and Companion Diagnostics

	The European Medicines Agency is approving a growing number of advanced therapy medicinal products (ATMP) despite claims that their commercialization is being hampered by increasingly complex regulatory and standards requirements. The creation of ATMPs by a 2007 European Union regulation (1), backed by a specialist committee for advanced therapies (CAT) within EMA, aimed to boost development of medicines derived from progress in cellular and molecular biology.


	Initially, the regulation seemed to have little impact on the number of advanced medicines on the market after the start of its implementation in early 2009. By mid-2013, there were only four marketing authorizations from 10 applications in the three ATMP categories of gene therapy, somatic cell therapy, and tissue engineering.

	Over the past few years, however, there have been signs of a surge in ATMP development. The number of medicine applications recommended by CAT to be classified as advanced therapies rose by 26% in 2014 (2). In late 2014, EMA recommended for EU approval the first advanced therapy medicine containing stem cells. It is also the first drug for the treatment of moderate to severe limbal stem cell deficiency (LSCD), a rare eye condition due to physical or chemical burns to the eyes that can result in blindness.


	At the same time, the quality, safety, and efficacy rules under existing and proposed EMA guidelines on ATMPs have been becoming more complex. One reason is that expanding knowledge about the new therapies has raised new concerns, particularly relating to issues regarding the quality of starting materials and drug substances. The regulators have gradually become more aware of the biological variability and intricacy of ATMPs. This tightening of standards seems to be deterring big pharmaceutical companies rather than small- and medium-sized enterprises (SMEs) from developing advanced therapy products.

	In a 2014 report (3) on the application of the 2007 regulation, the European Commission, the Brussels-based EU executive, found that the majority of ATMP research was being done by small companies and entities. Approximately 70% of sponsors of ATMP clinical trials were SMEs or not-for-profit organizations, while large pharmaceutical companies accounted for less than 2%.

	The report concluded that because there are “still many unknowns” with advanced therapies, “it is important to put in place adequate controls to prevent detrimental consequences for public health” (3). Nonetheless, it is also acknowledged that “too burdensome requirements” could have adverse consequences for public health because they could prevent the marketing of valid treatments for unmet medical needs.


	One onerous requirement is the amount of data needed on starting materials, such as the source and history of cells, and their detailed characterization. In addition, a complete description, including source, characteristics, and testing details, of all materials used during the manufacture of products is needed. Some developers of ATMP products complain about the regulators making demands for data that existing analytical technologies cannot yet provide. There have also been complaints about EMA wanting unnecessary high levels of purity in cell-therapy treatments, especially those comprising mixtures of undifferentiated cells.

	Another matter of contention has been EMA’s insistence that marketing authorization applicants for tissue-engineered products must demonstrate through pharmacokinetics the longevity or persistence of their medicines. “From the point of view of our members, pharmacokinetics does not include longevity, but resorption, distribution, and excretion of a drug,” Matthias Wilken, head of European drug regulatory affairs at the German Pharmaceutical Industry Association (BPI), told 

. “The requirement to demonstrate longevity might lead to extensive clinical studies that would be an undue burden to pharmaceutical entrepreneurs,” he explained.

	Also in some cases with ATMPs, the regulators are seen as taking too much of a “generic” approach to advanced technologies and not making a strong enough distinction with conventional pharmaceuticals. “The assessors and members of EMA scientific committees often come from the field of conventional medicinal products,” said Wilken. “Initially, there was a lack of understanding of the peculiarities of ATMPs. But this [understanding] is getting better, as is shown, for example, by the fact that EMA, along with the Commission, is currently working on tailoring GMP requirements for ATMPs.”


	The big regulatory differences between ATMPs and chemical-based pharmaceuticals is the greater emphasis needed with biological products on quality issues, mainly because with many of them, there are gaps in knowledge about ways of managing their risks. However, EMA has acknowledged the limitations of applying uniform rules to ATMPs by adopting a risk-based approach that allows the products to be assessed on a case-by-case basis.

	The distinct approach needed for ATMPs has been highlighted by the latest EMA guidance (4) on advanced therapies, which covers the quality, preclinical, and clinical aspects of gene therapy. The draft guideline (4) on gene therapy was issued in May 2015 for a period of public consultation ending in August. It replaces a guidance note (5) published in the early phase of gene-therapy development in 2001.

	Since the 2007 ATMP regulation was implemented, EMA has had to deal with three applications for gene-therapy authorizations, only one of which has so far been successful. “[From a quality perspective], there were no major changes or inconsistencies in the 2001 guideline that required an immediate revision,” an EMA spokesman informed 

. “However, some updates were necessary, for example, to reflect novel methodologies for testing and characterization, and also to ensure cross references to new legislation and guidelines that were developed separately.”


	Also, the format of the sections on quality and manufacturing aspects in the revised guideline has been changed to follow that in the harmonized Common Technical Document (CTD) for marketing authorization application dossiers, according to EMA. “This is expected to be helpful for the small developers of gene-therapy products when compiling their dossiers,” said the EMA spokesman. As a result, 40% of the 42-page draft guideline covers quality matters, 30% non-clinical issues, many of which relate to assessing risks linked to quality management, and only 10–15% to clinical development.

	A lot of the obligations in the guideline requirements relate to the quality of the components in the vectors or delivery systems of the products. Details of the quality of all starting materials and their sources have to be provided, including virus seed as well as mammalian and bacterial cell banks. All raw materials used during manufacture have to be tested and characterized.


	Partly due to the detailed EU quality and safety requirements for advanced therapies, companies developing ATMPs are critical of an exemption to EU rules granted to hospitals involved in R&D and the manufacture of the products. Hospital-based research and production in the sector are increasing rather than contracting in Europe. This trend is mainly because some EU states are using these hospitals as ATMS development centers at the core of national regenerative medicine programs.

	The United Kingdom, which is seeking global leadership in the sector has, for example, a network of cell therapy centers of excellence based in leading hospitals. “The establishment [of these centers] is essential if we are to build a concentrated critical mass of knowledge, skills, and therapeutic know-how,” according to a UK government-commissioned report on regenerative medicine (6).

	Under the 2007 EU regulation on ATMPs, member states are allowed to give hospitals exemption from the legislation as long as the hospital’s advanced therapies are being provided on a “non-routine basis” to its own individual patients. Some organizations are calling for the “non-routine” provision, which is open to different interpretations, to be extended to cover products only when a fully validated, EU-approved advanced therapy alternative cannot be used.

	“While the hospital exemption rule allows the early development and delivery of ATMPs that meet an otherwise unmet clinical need in a patient, the exemption should only be used to deliver a product if there is no licensed alternative, with proven efficacy and safety, available,” says Michael Werner, executive director of the US-based Alliance for Regenerative Medicines, a global advocacy group representing stakeholders in the ATMP sector.

	Its European arm has been among the leading critics of criteria applied for the exemption, particularly those relating to manufacturing standards. Sceptics about the potential of exempted hospital-based development systems contend that they encourage the avoidance of the strict EU data requirements because the hospitals have to adhere only to national quality and safety standards, although these standards should be consistent with those at the EU level.

	Even the European Commission in its report (3) on the impact of the ATMP regulations concedes that the exemption can enable hospital-based centres to have lower development costs than commercial ATMP organizations because of the advantages of being subject to less rigorous standards. A major objective behind the EU’s ATMP regulation was the introduction of harmonized standards across Europe. The way the hospital exemption is operating shows that there is still some distance to go before full harmonization is achieved.

Regulation on advanced therapy medicinal products 

 (London, April 2015).
	3. European Commission, 

Report in accordance with Article 25 of EC 1394/2007 on advanced therapy medicinal products

Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products–draft 

 Note for guidance on the quality, preclinical and clinical aspects of gene therapy medicinal products

 (London, April 2001).
	6. UK Department of Health, “Building on our own potential: a UK pathway for regenerative medicine,” Report of Regenerative Medicine Expert Group, March 24, 2015 (London).

 When referring to this article, please cite it as S. Milmo, "Unravelling the Complexity of EU's ATMP Regulatory Framework," 

The European Union has a challenging task ahead as it strives to harmonize regulations on advanced therapy medicinal products.

Unravelling the Complexity of EU’s ATMP Regulatory Framework

	The European Union’s system for post-authorization variations has been given a major shake-up in recent years with the help of close consultation with the pharmaceutical industry. Companies in some pharmaceutical sectors are still trying to adjust to the novel rules and procedures covering changes ranging from small packaging modifications to alterations of manufacturing processes. The legislation on the new system, as amended in 2012, came fully into effect in August 2013 (1).

	“The feedback from our members is that they still need time to adapt to the recent changes,” says Miriam Gargesi, healthcare biotechnology director at the European Association for Bioindustries (EuropaBio), Brussels, in an interview with 

 “The [new] EU system for dealing with applications for post-authorization approvals is very complex and still in an implementation phase.”

	Other segments, however, particularly for generic medicines, are pressing for yet more simplification and streamlining to speed up the regulatory process for variations not just for the sake of greater efficiencies but also to reduce costs.

Implications for generic medicines manufacturers

	For generic medicines manufacturers and suppliers, the regulatory costs of variations have become a major burden as the numbers of post-marketing notifications and authorizations have increased rapidly during the past few years, according to a survey of its members by the European Generic and Biosimilars Medicines Association (EGA).

	The number of variations per marketing authorization each year has gone up by approximately 45% during the past five years, Beata Stepniewska, EGA’s deputy director-general and head of regulatory affairs, informs 

 EGA also claims that the survey shows a big rise in fees paid by companies to agencies for regulatory work on variations. “Based on data gathered on an average of more than 16,500 marketing authorizations each year over a four-year timeframe, the variation fees per marketing authorization per year appear to have increased by 45%,” adds Stepniewska.

	Most generic-drug companies use the EU’s decentralized procedure (DCP) operated by national regulatory agencies for variations submission. But there also appears to have been a steep rise in variations applications through the centralized procedure run by the European Medicines Agency (EMA). From April 2014 to March 2015, the numbers of pre-submission queries being handled by the agency rose from an average of 150 per month in the first three months to approximately 200 in the last quarter, according to EMA figures (2). Despite the increase in queries, the agency has been able to maintain a relatively quick response time with 90% of the 2200 queries during the year receiving replies within five days.

	Much of the provisions of the new system are laid down in the EU’s Regulation 1234/2008 (3), which was soon amended by Regulation 712/2012 (1), mainly to clarify the process of variation approvals by single national agencies. Also the EU’s pharmacovigilance legislation, as contained in directive 2010/84 (4) and which started to be implemented in 2012, is relevant to the variations system through its article 57 (4) on the creation of a database of details of market authorizations. This database can provide a source of information of minor alterations to marketing authorizations.

	The objective of the 2008 regulation (2), which replaced two previous ones on variations approved in 2003, was to establish “a simpler, clearer, and more flexible legal framework while guaranteeing the same level of public health protection,” according to its preamble. It splits variations into four main categories. Applications are to be detailed in the guidelines that will be regularly updated, particularly as a result of scientific and technical advances.

	A type IA variation is one that has a “minimal or no impact at all” on the quality, safety, or efficacy of medicines, while type II, which is the highest variation level, may have a “significant impact.” An “extension” involves a change to an active substance or to the strength, pharmaceutical form, and route of administration of a medicine. Type IB variations are those that are neither minor or major or an extension.

	To ease the administrative work on changes, the regulation introduced a system of grouping, in a single submission, of similar or linked variations held by the same marketing authorization holder. Variation relating to a manufacturing process improvement, for example, can be put into a single grouping. To avoid duplication in the regulatory work on variations covering several marketing authorizations, a worksharing scheme was also established under the regulation to enable one national agency or EMA to assess similar changes to different medicines on behalf of other national authorities.

	Regulatory agencies claim that on the whole the new groupings and worksharing schemes have made the variations assessment procedure faster and more efficient. “[They] increase efficiency by avoiding the complexity of running parallel-related procedures and by ensuring consistency in the assessment of the same changes across products,” explains an EMA official. They also help to streamline some specific processes, such as that for evaluating changes to active substance master files (ASMF). “Worksharing of ASMF assessments reduces the frequent updating of ASMFs and [as a result] the regulatory burden on national authorities, ASMF holders, and marketing authorization holders,” the official says.

Additional workload, more delays, and higher costs

	On the contrary, pharmaceutical companies complain that the grouping and worksharing arrangements can lead to more delays than previously in the processing of variations, while at the same time pushing up costs. “In practice, the system does not appear to have been drastically simplified,” says Stepniewska. She cited, as an example, the need for details of individual variations within a grouping, whereas previously, combinations of multiple minor changes could be filed as a type II variation. “There is no reduction in the administrative workload,” she continues. “Some companies also report an additional workload associated with the need for a regulatory authority’s confirmation that a proposed grouping is acceptable.”

	National agencies are sometimes not accepting variations in groupings because they would take too long to assess due to their number and complexity, according to the European Federation of Pharmaceutical Industries and Associations (EFPIA). The association estimates that with worksharing, the CMDh (the co-ordination group running the DCP mutual recognition procedure) can take as long as four weeks to allocate the assessment task to an individual member state. “This adds a significant delay to variation processing timelines, which does not encourage the use of the work-sharing scheme by marketing authorization holders,” says an EFPIA spokesman.

	In a guideline on worksharing (5), the CMDh outlines processes that could take as long as 150 days with the inclusion of a “clock-off” period to allow for the supply of supplementary information by the marketing authorization holder and its assessment. National agencies are generally having difficulties meeting the time limits on the completion of assessments as stipulated in the EU’s variations legislation. “Less than one out of five variation procedures for type IB and II currently starts on time,” says Stepniewska.

	EGA and other pharmaceutical industry associations want to speed up the way variations to APIs are handled by eliminating the need for similar API variations to be evaluated separately by different agencies. “Our member companies report that they are dedicating a growing part of their marketing authorization maintenance activity to API-related changes,” Stepniewska explains. “It is certainly not desirable to continue having multiple non-synchronized, uncoordinated procedures where, in effect, the regulatory information to be assessed is identical.”

	The solution could be for API producers to be given the responsibility of dealing with the regulatory aspects of changes to their products. “[There could be] a certification-based procedure for all APIs to facilitate and speed up the submission and maintenance of API regulatory information through a direct relationship between regulatory authorities and API manufacturers,” Stepniewska says.

	Another concern is the amount of information from GMP certificates being required by some agencies for variations assessments. “There should be a way to exclude routine GMP-compliance activities from the variation process,” says the EFPIA spokesperson. “One suggestion is to have a centralized database in the EU for all licence holders to give the complete GMP status of API suppliers so that this [information] could be accessible to all EU national authorities and the EMA.”

	Despite the introduction of the new variations system, their assessment is still being dogged by different approaches by national agencies. “There have been improvements since the implementation of the amended regulation,” says the EFPIA spokesperson. “But there are still some differences in approvals for type IB and II categories across national authorities.” There are even differences between agencies in the classification of variations indicating that there is still work to be done in even removing basic regulatory inconsistencies in the EU’s variations procedure.

Amendments to Regulation 1234/2008 on the examination of variations 

	2. A. Ganan and I. Gravanis, “Procedure Management of Variations,” presentation at EMA meeting: Industry Stakeholder Platform on the Operation of the Centralized Procedure (London, April 24 2015).

Examination of variations to the terms of marketing authorizations 

Pharmacovigilance directive on medicinal products for human use 

CMDh/297/2013/Rev, February 2015 (London, February 2015).

 When referring to this article, please cite it as S. Milmo, “EU’s New Post-Authorization Variations Framework Comes Under Scrutiny,” 

The pharmaceutical industry wants to speed up the variations process by eliminating redundant assessment by different national agencies in the European Union.

EU’s New Post-Authorization Variations Framework Comes Under Scrutiny

	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,” 

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.