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

Sean Milmo

	The issue of data integrity in pharmaceuticals is now becoming a hot topic among regulators and the industry, particularly in Europe and North America. The number of cases of poor data being submitted to inspectors and auditors of good manufacturing practice and other manufacturing standards has been increasing rapidly. This problem is happening in particular among API producers in India and China. As a result, products have been banned from the European market because their manufacturers have failed to maintain adequate levels of data integrity. The amount of lapses, however, has also been rising among manufacturers of APIs and finished medicines in Europe itself.

	“[We and our] international regulatory partners are continuing to see significant data integrity failures at manufacturers, laboratories, and clinical research organizations,” a spokesman for the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) told 

	“In MHRA’s experience, some of these companies have attempted to adopt the available regulatory guidance, but failed to do so effectively,” he continued. “This is often due to a failure to understand data lifecycle risks and the influence of organizational behaviour on the implementation of procedural and technical elements of data governance.”

	Other factors behind breaches of data standards include intensifying competition, shorter delivery times, the need to cut costs, and inadequate training. Stricter regulations are also putting greater pressure on manufacturers to provide satisfactory data, particularly through electronic means.

	European national medicines agencies have been considering banning the use of APIs produced by an Indian manufacturer after an inspection in June 2016 found a lack of quality assurance oversight on GMP-relevant data in its enterprise resource planning (ERP) computer systems (1). The inspection was carried out by the European Council’s European Directorate for the Quality of Medicines (EDQM), responsible for the 

	The scope of data integrity--generally defined as the extent to which data are complete, consistent, and accurate, throughout the data’s lifecycle--has been broadened to include other criteria of data quality, such as ALCOA and ALCOA+. ALCOA stands for data that are attributable, legible, contemporaneous, original, and accurate, while ALCOA+ adds the qualities of being complete, consistent, enduring, and available.

	The degree of concern about the quality of data related to GMP and other manufacturing and related standards has been reflected in the number of new guidelines on data integrity being issued by the world’s leading regulatory bodies. So far in 2016, new or proposed guidelines have been published by the United States Food and Drug Administration (FDA) (2), World Health Organization (WHO) (3), and the European Medicines Agency (EMA) (4). In addition, the Geneva-based Pharmaceutical Inspection Co-operation Scheme (PIC/S), representing health authorities and GMP inspectorates, issued draft guidance in August 2016 (5). Among European national agencies, the MHRA was among the first to publish guidance in 2015 (6), while a number of pharmaceutical industry groups and consultancies have been drawing up suggested voluntary codes of best practices in data integrity.

	The objective behind the regulators’ guidelines has been to describe in detail what levels of data integrity are expected from pharmaceutical manufacturers and suppliers to ensure adequate product quality. The guidelines, however, also show an awareness that a crucial factor behind the achievement of data integrity in today’s global pharmaceutical market is the presence of a quality culture embracing both management and employees.

	“Organizational behaviour is key to the successful implementation of data governance measures,” said the MHRA spokesman. This was a view echoed by EMA, which sees difficulties with data stemming from the way it is controlled. “In most cases, the underlying problems arise from weaknesses in the way the control of data is assessed and managed,” an EMA spokesperson told 

	Consequently, with some of the guidelines, the regulators have been straying into new territory by trying to influence corporate cultural strategies and policies. They point out that senior management must show commitment to data reliability by leading by example. Business targets on data quality should be set, which are consistent with a manufacturer’s process capabilities. Employees should not only be empowered to provide accurate data but to report to management breaches of data quality by other personnel.

	In its guidance on good data and record management practices (3), published in May 2016, the WHO’s expert committee on specifications for pharmaceutical preparations emphasized the importance of a quality culture. The guidance was only finalized after extensive consultation with national GMP and other quality performance inspectors.

	Robust data integrity begins at the top. “Leadership is essential to establish and maintain a company-wide commitment to data reliability as an essential element of the quality system,” the document says (3). Staff must also be given responsibilities by being unrestrained in their provision of data. “An essential element of the quality culture is the transparent and open reporting of deviations, errors, omissions, and aberrant results at all levels of the organization, irrespective of hierarchy,” the guidance says (3). “Senior management should actively discourage any management practices that might reasonably be expected to inhibit the active and complete reporting of such issues, for example, hierarchical constraints, and blame cultures.”

	The PIC/S guidance (5) provides advice to GMP and other inspectors, primarily those working for the organization’s 49 member authorities in Europe, North America, and Asia Pacific, as well as Argentina and South Africa. It has been drawn up in draft form for review early next year mainly to ensure a document was issued relatively quickly in response to the deep interest in data integrity in pharmaceuticals across the world.

	The PIC/S data integrity working group decided to “make the initial draft of convergent guidance available to PIC/S participating authorities as a soon as possible to ensure a consistent approach to regulatory expectations,” explained David Churchward of the MHRA and Matthew Davis of Australia’s Therapeutic Good Administration (TGA), the group’s co-chairs.

	The 14 authorities making up the group identified out-of-date practices and technologies as a major cause of data integrity failures. “Examples include an increasing use of IT in manufacture and analysis, and the challenges of remote supervision of sites in a global supply chain,” Churchward and Davis told Pharmaceutical Technology Europe. “The guidance addresses the interpretation of existing GMP norms in the context of current technology, and discusses the key elements of effective data controls throughout the data lifecycle,” they added.

	The guidance acknowledges the positive influence of quality cultures within companies but concedes the difficulties of making inspection citations based on observations of organizational behaviour. Nonetheless, inspectors can use behaviour as an indicator of risks for further investigation.

	Companies should draw up a code of values and ethics that reflects management’s philosophy on quality and provides an environment of trust, where all individuals are responsible and accountable for ensuring patient safety and product quality. “The company’s general ethics and integrity standards need to be established and known to each employee and these expectations should be communicated frequently and consistently,” the guidance says (5). Management should aim to create a quality culture in which “personnel are encouraged to freely communicate failures and mistakes, including potential data reliability issues, [with an] organizational reporting structure permitting the information flow between personnel at all levels,” the document adds.

	Regulators seem to agree that in the long term, the content of guidelines on data integrity will have to be changed for the sake of harmonizing standards for data quality across the world, with PIC/S perhaps becoming a hub for sorting out differences of approaches to the issue. “EMA intends to work with PIC/S to publish more permanent international guidance,” said the agency’s spokesperson.

	PIC/S believes that through the 14 authorities participating in its data integrity group, including FDA and nine EU agencies, and the rest of its membership, it has the structure for taking account of a broad range of views. “In the future, it is foreseen that harmonized inspectorate-focused guidance will be available through the PIC/S network,” said Chapman and Davis.

	WHO views its guidance (3) as being of “an evolutionary, illustrative nature and will, therefore, be subject to periodic review based upon experience with its implementation and usefulness, as well as the feedback provided by the stakeholders, including national regulatory authorities (NRAs).”

	One major barrier to effective application of guidelines in an area such as data integrity is the regional and national cultural variations that generate different viewpoints on what is, for example, efficient leadership. “Depending on culture, an organization’s control measures may be: ‘open’ (where hierarchy can be challenged by subordinates, and full reporting of a systemic or individual failure is a business expectation) or ‘closed’ (where reporting failure or challenging a hierarchy is culturally more difficult),” PIC/S says in its guidance.

	Good data governance in ‘open’ cultures may be facilitated by employee empowerment to identify and report issues. “In ‘closed’ cultures, a greater emphasis on oversight and secondary review may be required to achieve an equivalent level of control due to the social barrier of communicating undesirable information,” the document (5) explains. The task of reconciling these differences has hardly yet begun. It will require input from a much wider spectrum of agencies than at present.

	1. EMA, Eudra GMP, “Statement of Non-Compliance with GMP,” Report No: DE_SH/NCS/API/01/2016 (London, June 2016).
	2. FDA, Draft Guidance for Industry: Data Integrity and Compliance with CGMP (Washington, April 2016).
	3. World Health Organization, Guidance on Good Data and Record Management Practices, WHO Expert Committee for Pharmaceutical Preparations--Annex 5, Fifteenth Report (Geneva, May 2016).
	4. EMA, Questions and Answers on Good Manufacturing Practice--Data Integrity (London, August, 2016). 
	5. Pharmaceutical Inspection Co-operation Scheme (PIC/S). Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (Geneva, 10 Aug. 2016).
	6. MHRA, GMP Data Integrity Definitions and Guidance for 
	Industry (London, March 2015).

	When referring to this article, please cite it as S. Milmo, "Tackling Breaches in Data Integrity,"

Articles

Robust data integrity begins with both management and employees embracing a quality culture and successful implementation of data governance measures.

Tackling Breaches in Data Integrity

	The European Union introduced a guideline (1) in August 2016 on the monitoring of the safety of biological medicines on the market amidst industry worries about the ability of regulators to deal with quality deficiencies due to manufacturing variations in biopharmaceuticals. Manufacturing standards can have a bigger impact on the post-marketing safety and efficacy of biological medicines than those of chemically synthesized pharmaceuticals with which different producers can achieve a uniform quality.

	“[With biologicals], the manufacturing process--including choice of cell line, raw or starting materials, fermentation and purification process, final formulation--is as much a determinant of the product’s quality as the active substance,” states the guideline (1). “Minor changes in any manufacturing step can affect the product quality and subsequently its safety and efficacy.” As a result, the guideline, published by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA), constantly highlights the need to find the “root cause” of a suspected adverse drug reaction (ADRs) by tracing the product back not only to its manufacturer but also to its batch and the individual medicines within it.

	The guideline applies to reference biological medicines, biosimilars, and related biological products such as interferon and faction VIII. Traceability is the vital tool for discovering what could be responsible for the lapse in quality during the manufacturing that has impacted the safety and efficacy of the medicine on the market. It has become even more important in the wake of a rise of approximately 50% in the reporting of suspected ADRs in Europe, a large proportion of them relating to biologicals.

	In 2014, biologicals accounted for 42% of 181,000 side-effect reports on centrally approved medicines in the EU or 27% of all suspected adverse reaction reports. Yet, the pharmaceutical industry has been protesting about the weaknesses of the traceability system operated by the European regulatory network, headed by EMA and the regulatory authorities of 28 EU member states represented by the HMA.

	Dissatisfaction with the standards of traceability, especially tracking medicines back to the batch and product stages of their manufacture, was evident in the industry’s comments during a public consultation on the last draft of the guideline (2) before the issue of its final version. Comments (3) made during the consultation were published with the guideline.

	The European Federation of Pharmaceutical Industries and Associations (EFPIA), Europe’s main trade association for research-based drug companies, and its sister biotechnology organization, European Biopharmaceutical Enterprises (EBE), welcomed the guideline’s emphasis on the importance of batch traceability. “But overall, [it] does not appear to acknowledge the sheer practical challenges of obtaining batch numbers when a suspected ADR is reported for any product and especially biological medicinal products where the reporter may not even be aware of the batch number,” the two organizations said (3), referring to medicines such as insulin, which had been on the market for decades, but also more recent products.

	The current pharmacovigilance legislation

	Marketing authorization holders have had a low response rate to repeated requests to the ADR reporter, usually a healthcare professional, for batch data. This has often been due to hospital supply difficulties resulting in substitution so that the prescribers did not know that the patient had been dispensed a biosimilar rather than the original brand, according to EFPIA and EBE. Because of differences in member state regulations on issues such as substitution and hospital prescribing, EFPIA and EBE doubted whether the EU’s present pharmacovigilance legislation on post-marketing surveillance of medicines could provide an adequate traceability system, especially for biologicals.

	“Until there is a consistent system in place across the EU that reliably tracks batch numbers of medicines dispensed to patients and follows this throughout the entire treatment pathway, it is unrealistic to expect such information to be collected via current routine pharmacovigilance activities,” the two organizations said (3).

	The EU’s current pharmacovigilance (PV) legislation (4) was approved in 2012 with EMA being made responsible not just for monitoring centrally approved medicines but coordinating the whole PV system in the EU and the three non-EU states of Norway, Iceland, and Liechtenstein. EMA also maintains various central databases storing information on ADRs both in Europe and worldwide.

	Member states of the EU have been criticized for delaying the transposing of the PV legislation into their national laws with some holding back the transfer to 2014. In addition, the publication of PV guidelines on a range of aspects of the legislation has been slowed down.

	The European Association for Bioindustries (EuropaBio) has, for example, urged that the biologicals guideline should only come into effect with other relevant guidelines whose revision has yet to be finalized, particularly dealing with risk management of known and potential safety issues. In addition to the issue of manufacturing variability and traceability, the guideline pinpoints other major challenges with pharmacovigilance of biologicals, such as immunogenicity and stability of the medicines during distribution. Nonetheless, EMA and HMA have made few significant changes in the guidelines following the comments during the public consultation, despite the increased burden on the industry in dealing with the big rise in ADR reports.

	In the final version of the guideline, the need for MAHs to give details of numbers/codes of batches and their geographical distribution in safety update reports, particularly after changes to manufacturing processes, has been deleted. But it does refer to batch information as being “required data” when MAHs assess new ADRs needing further investigation. The guideline also mentions the necessity to obtain information on batch numbers when MAHs submit or update risk management plans particularly in cases of batch-specific matters.

	The importance of healthcare professionals and patients giving batch and product data when reporting ADRs is stressed even more strongly in the guideline’s final version. EMA and HMA are hoping that the increased transparency of the PV system will encourage the two groups to become more active in post-authorization surveillance.

	The guideline suggests that information on the manufacturing process for biologicals and its variability should be communicated to not just healthcare professionals but to patients as well. Medicines for Europe, formerly the European Generic and Biosimilar Medicines Association (EGA), said that regulatory authorities should consider as an “essential step” the continuous training of professionals on the new PV rules on recording of ADRs and related product information.

	The European industry as a whole has been calling for more consistency in the application of pharmacovigilance by the EU’s member states. More uniformity has been particularly important in areas where there seems to be a clash between the PV responsibilities of MAHs to find the “roots causes” of ADRs and the freedom for countries to take their own initiatives in post-marketing surveillance.

	“It is important to have a clear separation between activities falling under member state responsibilities and expectations of the marketing authorization holder in terms of traceability,” an EFPIA spokesman told 

. He points out that the guideline stresses that different products with the same international non-proprietary name (INN) should be “readily distinguished so safety issues can be traced to a product, batch, location, or patient.”

	Yet member states will be able to exempt hospitals and other healthcare facilities from certain safety features under an EU pharmaceutical packaging regulation (5) due to come into effect in early 2019. The regulation, which is part of the EU’s Falsified Medicines Directive (FMD) to combat counterfeiting of pharmaceuticals, stipulates that individual medicines should have a 2D matrix serialization barcode containing a “unique identifier,” consisting of a product code, serial and batch numbers, and expiry date. The packaging safety features scheme will be an ‘end-to-end’ system under which the serialization and other data on each pack can be verified by a pharmacist with a scanner at the dispensing point.

	The regulation is seen by both regulators and industry as a possible effective means of tackling traceability problems with biologicals. “[Yet] member states can exempt healthcare institutions--including hospitals and in- and out-patient clinics--from the obligation to verify safety features on the packaging, including the unique identifier,” says the EFPIA spokesman. “It needs to be understood that the traceability will depend upon the way each member state implements the (regulation).”

	Due to manufacturing variability between a growing number of biosimilars and their reference products and increases in changes of manufacturing processes, an effective PV system covering biologicals throughout their lifecycle will become even more vital. A high level of efficient traceability will be a crucial part of that.

	1. EMA and Heads of Medicines Agencies (HMA), Guideline 
	on good pharmacovigilance practices (GVP)--Product- or 
	Population-Specific Considerations II: Biological medicinal products, EMA/168402/2014 (London, Aug. 4, 2016). 
	2. EMA and Heads of Medicines Agencies (HMA), Track-change version following public consultation of Guideline 
	on good pharmacovigilance practices (GVP)--Product- or 
	Population-Specific Considerations II: Biological medicinal products. EMA/168402/2014 (London, Aug. 4, 2016). 
	3. EMA, Comments received from public consultation on 
	good pharmacovigilance practices, GVP--EMA/168402/2014 
	(London, Mar. 3, 2016). 
	4. European Union, Implementing Regulation 520/2012. 
	The performance of pharmacovigilance activities provided 
	for in Regulation 726/2004 and Directive 2001/83/EC (Brussels, June 19, 2012).
	5. European Commission, Delegated Regulation 2016/161, 
	supplementing Directive 2001/83/EC, Detailed rules for 
	the safety features appearing on the packaging of medicinal products for human use (Brussels, Oct. 2, 2015).

	When referring to this article, please cite it as S. Milmo, "Pharmacovigilance of Biologics Under Scrutiny,” 

Regulators are tightening up on post-marketing monitoring of biological medicines to detect deficiencies caused by manufacturing problems, particularly those stemming from post-authorization changes in the manufacturing process.

Pharmacovigilance of Biologics Under Scrutiny

	The European Union’s two main legislative arms--the European Parliament and the Council, representing EU governments--have finally reached a compromise on two closely related regulations (1, 2) on medical devices and 
	

 diagnostic (IVD) products. The deal was made four years after the two pieces of legislation were first drafted. But it still leaves a number of key issues unresolved. This is particularly the case with products combining devices and pharmaceuticals, in which the dividing line between a device and a drug is becoming increasingly blurred.

	For years, some trade, professional, and patient groups have been calling for high-risk combination devices, such as implanted products, to be assessed and authorized by a central body such as the European Medicines Agency. But the exact responsibility of the EMA in the authorizing of more sophisticated devices is still unclear in the new regulations. Also with combination products, differences in the application of production quality standards will remain. While the pharmaceuticals in the products will be subject to good manufacturing practice (GMP) standards, the manufacturing of a device will be covered by the standards of the Geneva-based International Organization for Standardization (ISO). 

	The new regulations, which replace three existing items of EU legislation covering devices and 

 diagnostics, aim to introduce greater consistency and uniformity in the way the two groups of products are assessed and approved across the EU at a time when the numbers of them on the European market have been rising strongly.

	The EU’s medical devices industry now comprises approximately 25,000 companies, most of them small- and medium-sized enterprises (SMEs) and employing 575,000 people, according to figures from the European Commission (3).

	Total annual sales currently amount to approximately €100 billion ($115 billion), with much of the increase in value terms coming from the upper end of the market where combination and other innovative technologies are being introduced (3). Some leading pharmaceutical companies are now targeting this section of the market because of its potential for growth and for the development of new treatments.

	Although it is becoming a new frontier of medical science, its regulation in Europe will remain relatively fragmented despite the two new pieces of legislation (1, 2). The control of medical devices and IVDs will still be carried out, once the new rules start to be enforced early in the next decade, at different levels with individual EU countries continuing to have the scope to pursue their own policies on product approvals.

	The key organizations in ensuring that the main objectives of the new regulations--to raise standards of assessment and monitoring along the regulatory chain--are achieved will be around 80 notified bodies (NBs). Mainly consisting of certification services companies and research institutes, these NBs are designated nationally to evaluate and certify medical and IVD devices.

	Under the new regulations, NBs are being given more powers, such as, for example, to make unannounced audits of manufacturers and their sub-contractors sites to check in particular whether they are complying with quality management systems (1, 2). The NBs will continue to have room in which to forge their own strategies for ensuring that device manufacturers are complying with the rules.

	In shaping the two new regulations, the legislators have tried to reach a balance between the need for greater patient safety and product quality with the requirement for continued flexibility in the enforcement of rules in order not to stifle innovation. The legislators seem to be aware of the future technological trends that are likely to require authorization and a monitoring system similar to that currently applying to pharmaceuticals in Europe. This system operates on a centralized level through the EMA and on a decentralized basis through mutual recognition of decisions by national medicines agencies. As a result, NBs will be more closely scrutinized by the national agencies, many of them responsible for the controlling of both medicines and devices and to which the NBs are accountable.

	When assessing devices, NBs will have to consult, if necessary, specialists at the EU level although they will not be obliged to comply with their opinion. A Medical Device Co-ordination Group (MDCG), composed of experts in medical devices and IVD products, will be set up under the two regulations. It will be able to establish subgroups to provide “in-depth” technical expertise with the support of specialist laboratories. The MDCG will effectively be at the core of a pre-market assessment system that the European Parliament has been demanding.

	The European Commission itself will also, under the new legislation, be appointing expert panels and laboratories to advise the Commission, the MDCG, manufacturers, and NBs. “The expert panels should fulfil the tasks of providing an opinion on the clinical evaluation in the case of high-risk implantable devices,” says the approved text of the medical devices regulation (1, 2). It is, however, uncertain from the text of the two regulations what contribution EMA will make to this expert advice. Currently, under the existing regulations (4-6),

	EMA is the main central source of specialist advice on combination devices. Its know-how on devices has been expanding considerably as a result of a growing number of marketing applications for combination devices in which pharmaceutical treatment is the principal function so that they have to be authorized by the agency.

	Other centralizing measures to be introduced by the regulations, similar to those already being applied in the pharmaceutical sector, include a central database of quality, safety, and performance details of each device on the EU market. Its clinical-trial data will be linked closely to that available centrally on pharmaceutical clinical trials.

	In addition to manufacturers having to conform to quality- and risk-management systems, they will also have to apply post-market surveillance systems as well. An EU-wide unique device identification (UDI) scheme covering each device will be created to boost the effectiveness of post-market surveillance and improve monitoring of device deficiencies by medical agencies. However, critics of the new legislation wanting more centralization of controls on medical devices claim it does not go far enough, particularly with the responsibilities being given to expert groups (1, 2).

	The European Consumer Organization (BEUC) said in a statement (7) that “clinical experts should be in charge (of pre-market assessment), not non-experts who merely check if the device works.” Because of the degree of uncertainties in the legislation, “consumers will still be guinea pigs,” BEUC added.

	Healthcare providers and health insurance groups, which in Europe are primarily state funded or supported, have been expressing concerns about the lack of strict central controls on devices at a time of rising healthcare costs.

	“[We’ve] always asked for a centralized approval procedure at the European Union level for high-risk medical devices, similar to that of the United States Food and Drug Administration (FDA) or what is currently in place for pharmaceuticals in the EU,” said Menno Aarnout, executive director, International Association of Mutual Benefit Societies (AIM), Brussels, in an interview with Pharmaceutical Technology Europe. “These expert panels are only a small step in that direction,” she explained. “After seeking advice from the panels, the notified bodies don’t have to follow that advice. They should only give ‘due consideration’ to the views expressed by the panels. This is not enough for us.”

	The major challenge facing medical-device regulators in future is differentiating between combination devices that are primarily devices and those that are basically medicines. This means distinguishing clearly between devices in which the pharmaceutical is an integral part or is supporting the device’s function and those in which the application of medicine is the principal function and must be authorized as a pharmaceutical.

	The emergence of new technologies is likely to make this task increasingly difficult, especially the drawing up of quality, safety, and performance standards to go with them. 

	Among the latest of these new technologies is bioelectronics, the importance of which has been highlighted by the recent announcement of the creation of a United Kingdom-headquartered joint venture in the relatively new sector by GlaxoSmithKline (GSK) and Google’s Alphabet life-sciences unit (8).

	Devices controlling electrical signals in the human body have been used in the management of heart conditions and Parkinson’s disease. The new bioelectronics, being pioneered by companies such as GSK, use miniaturized devices that connect to specific groups of neurons or their nerve fibres. They can then modulate electrical signalling patterns so that targeted organs suffering from chronic diseases are restored to health. Some of the devices could both diagnose and treat diseases.

	Although GSK has been involved in research into bioelectronics for the past year, it concedes that the regulatory status of its bioelectronics devices is still uncertain. “It’s too early to say what the regulatory position is and we haven’t yet even started to go through the regulatory process yet,” a spokesperson at GSK told Pharmaceutical Technology Europe. The drugmaker does not expect to launch its first bioelectronics product before seven years. 
	Many of the standards and criteria to be applied by the two regulations, such as those in quality management and pre-market assessment, will be drawn up by the EC in its position as the EU executive. Once the European

	Parliament and the Council have formally adopted the new legislation by early 2017, the medical devices regulation will come into effect in 2020 and that for IDV in 2022. The European Commission will need that time to ensure it gets the standards and criteria right.

	1. Council of the European Union, Proposal of the European Parliament and the Council on Medical Devices, Document 10617/16 (Brussels, 27 June 2016). 
	2. Council of the European Union, Proposal for a Regulation of the European Parliament and of the Council on In Vitro 
	Diagnostic Medical Devices, Document 10618/16 (Brussels, 
	27 June 2016).
	3. European Commission, 

The Importance of the Medical Devices Sector

, accessed 23 Aug. 2016. 
	4. European Union, Directive Concerning Medical Devices, 93/42/EEC (Brussels, 12 July 1993).
	5. European Union, Directive on the Approximation of the Laws of the Member States Relating to Active Implantable Medical Devices, 90/385/EEC (Brussels, 20 June 1990).
	6. European Union, Directive on In Vitro Diagnostic Medical Devices, 97/79/EC (Brussels, 7 Dec. 1998). 
	7. European Consumer Organization, 

.
	medical_devices_factsheet.pdf, accessed 23 Aug. 2016.
	8. GlaxoSmithKline, “GSK and Verily to Establish Galvani Bioelectronics--A New Company Dedicated to the Development of Bioelectronic Medicines,” Press Release, 1 Aug. 2016. 

	When referring to this article, please cite it as S. Milmo, “New Regulations for Combination Products,” 

The new regulations aim to introduce greater consistency and uniformity in the assessment and approval of medical devices and in-vitro diagnostics across the European Union.

New Regulations for Combination Products

	On 24 June 2016, it was announced that the United Kingdom had voted to leave the European Union. The result of an in-or-out referendum on the country’s EU membership has shaken the UK pharmaceutical industry, which had come out overwhelmingly in favour of remaining in the EU. However, it has also caused tremors of concern among the EU’s 27 other member states about its impact on the Union’s system for medicines regulation and on the long-term future of its pharmaceuticals industry. 

	Opinion polls had predicted a narrow majority in favour of remaining in the EU. But instead, by 16 to 17 million, the country opted for what has been dubbed Brexit. The decision is a setback for the EU’s ambition to build up a closely knit European regulatory network binding together the centralized medicines authorized procedure run by the London-based European Medicines Agency (EMA) and the decentralized systems operated through mutually recognized national approvals.
	
	A five-year Network Strategy (1) published at the end of 2015 outlined a series of measures that would make the EU effectively a single regulatory entity covering a population of 500 million, the third largest in the world after China and India. It is also a reversal of plans for pan-European medicines regulation to underpin the successful development of new medicines in the region through scientific advisory services provided by licensing agencies, particularly to academia, start-ups, and small and medium-sized enterprises (SMEs).

	Once the UK leaves the EU, a large proportion of Europe’s leading research-based pharmaceutical companies will be based outside the Union. GlaxoSmithKline (GSK) and AstraZeneca both have their headquarters in the country, while Novartis and Roche are in Switzerland, a non-EU state. Both countries make up approximately a third of Europe’s pharmaceutical exports and a sizeable amount of the region’s R&D expenditure. 

	The UK’s pharmaceutical sector accounts for approximately 25% of the country’s spending on R&D. Due to its considerable knowledge of new medicines, the UK medicines authority-the Medicines and Healthcare products Regulatory Agency (MHRA)-has a pool of experts who are more involved in helping to assess applications for marketing authorizations at the EMA level than those from most other EU national agencies. 

	The UK pharmaceutical industry now faces a period of uncertainty as it endeavours to establish a new position in both the European and global medicines markets. Much depends on the outcome of the negotiations on a withdrawal agreement between the UK and the EU. These negotiations will start, probably in early 2017, after the UK has officially notified the EU Council, representing EU governments, of its intention to leave under Article 50 of the 2007 Lisbon Treaty, which allows member states to pull out of the Union. 
	
	Once Article 50 has been invoked, the Brexit negotiations have to be completed within two years unless the 27 member states agree unanimously to extend the period. Because the UK is the first country to make use of Article 50, the EU will be entering unchartered territory. It is unclear, for example, whether a departing country can start negotiating, before withdrawal, its own free-trade deals not only with the EU itself but also with non-EU countries. 

	Under the present rules, no EU countries can reach trade deals with other member states nor with non-EU countries with which trade by individual EU states is covered by EU-negotiated free-trade agreements. Officially, the UK ceases to be an EU member only when an exit agreement has been approved by the EU Council, representing the governments of member states, and the European Parliament. As a result, regulatory authorities, trade associations, and other organizations have been stressing that nothing will change until the UK is formally no longer a member. Even with a Brexit deal, there will still be many unresolved issues, which has prompted some projections that the complete departure could take several years.

	“It’s now up to the UK government to decide how to act upon the outcome of the referendum,” said EMA in a statement (2). 

	“EMA would like to underline that its procedures and work streams are not affected by the outcome of the referendum.” 
	For the MHRA, it is also business as usual. “MHRA continues to play a full, active role in European regulatory procedures,” an agency spokesman told 
	Pharmaceutical Technology Europe.
	“We continue to contribute significantly in both the centralized and decentralized regulatory procedures.”

	One certainty is that EMA, after starting its existence in London 21 years ago, will have to be transferred to an EU country. How and where the agency, now with a staff of 890, will be relocated is unlikely to be decided until a Brexit agreement has been reached. Plans to make London the home of the pharmaceuticals division of the Unified Patent Court, an EU institution for settling EU-wide intellectual property disputes, will also have to be abandoned. The division, due to come into operation next year, will have to be set up in another EU city, probably after a delay.
	
	The relocation of EMA will be a blow to the UK strategy of becoming a global centre for the development of new medicines and pharmaceutical production processes, particularly of advanced therapies. The UK pharmaceutical industry has benefited from moves by EMA to expand its scientific advisory activities to stimulate more research into new drugs and processes, especially those for the treatment of life-threatening conditions and rare diseases. The MHRA also operates its own scientific guidance schemes, which have links with the EMA’s advisory services. 

	The country’s pharmaceutical trade associations, led by the Association of the British Pharmaceutical Industry (ABPI), representing the research-based sector, and individual drug companies such as GSK, AstraZeneca, and Pfizer are, for example, involved in Medicines Manufacturing Industry Partnership (MMIP), a UK public-private body, which encourages research into new processes in areas like advanced therapies. It liaises closely with the MHRA, which acts as a channel of communication of information on MMIP’s work to EMA. The UK agency has a leadership role in EMA in dealing with the regulatory implications of new manufacturing processes. 

	The UK government’s objective in the Brexit negotiations is likely to be an agreement that allows the country access to the EU’s single market without tariff and above all non-tariff barriers. This approach is called the Norway option because Norway, with the two other non-EU states of Iceland and Liechtenstein, is a part of the single market and, consequently, an EMA member.

	The attraction of the EU single market is that it is one of the world’s most advanced free-trade areas with tariffs not only being eliminated but also non-tariff barriers through the harmonization of national health, safety, and environmental regulations and standards. Remaining in the single market has the support of the vast majority of the more than 500 pharmaceutical companies in the UK and also the rest of the European pharmaceuticals sector because it would cause the least disruption and be the least costly.

	But it has major drawbacks because the conditions of single market membership would be contrary to two key issues that swung the referendum vote in favour of Brexit--control of immigration and national sovereignty. Non-EU states in the single market have to accept a basic EU principle of free movement of people across borders and comply with EU regulations in whose approval they would not be able to participate. They also have to contribute to the EU budget.

	Another option for the UK is a relationship such as that between the EU and Switzerland, which enjoys the equivalent of open access to the single market through a series of mutual recognition agreements and deals on information exchange in areas such as GMP inspections. But such a deal could take years to negotiate.

	It could also take many years to thrash out the less appealing alternative of a UK-EU free-trade agreement. This basic free-trade agreement would mean that exporters of pharmaceuticals from the country into the EU and from the EU into the UK would be confronted with tariff and non-tariff barriers. Exports of APIs from the UK, for example, could have to provide proof of GMP compliance in ways that Indian and Chinese API importers into the EU are obliged to do at the moment.

	A free-trade deal would give the UK the most freedom to draw up its own pharmaceutical regulations. But then, the UK government faces a series of dilemmas. How much can it risk introducing new regulations without undermining its trading position with a neighbouring market of 420 million? Instead of being, as at present, one of the most popular first-launch markets in Europe for non-European drug companies, will it become one of the least appealing?

	The more independent the UK becomes of the EU, the greater the threat of an exodus of pharmaceutical companies from the country into the EU. Even UK-owned drug producers may decide to focus on building a base in an EU country as the hub for a European supply chain. The UK is lucky to have two years to negotiate a withdrawal deal. It will take at least that long to sort out all the complexities of Brexit, particularly in the pharmaceuticals sector.

	1. European Medicines Agency and Heads of Medicines Agencies,  

EU Medicines Agencies Network Strategy to 2020-Working Together to Improve Health,

 EMA/MB/151414/2015 (London, 17 Dec. 2015).
	2. EMA, “Statement on the outcome of the UK referendum,” Press Release (London, 7 July 2016).

	When referring to this article, please cite it as S. Milmo, "Brexit Sparks Uncertainties," 

The pharmaceutical industry now braces itself for the consequences and complexities that could follow in the wake of the United Kingdom’s decision to leave the European Union.

Brexit Sparks Uncertainties

	Controls on pharmaceuticals in the environment (PIE) look likely to be tightened up in Europe at the European Union and national levels. The industry has broadly accepted the need for stricter regulations and guidelines, but there are concerns that some of the measures being proposed may be unnecessarily restrictive. Regulatory initiatives are being taken on several fronts. The European Commission, the Brussels-based EU executive, is working on a PIE strategy due for completion in the first half of 2017, which could be followed by regulations specific to pharmaceuticals.

	The European Medicines Agency (EMA), responsible for EU-wide medicines approvals, has just started consultations with stakeholders on a revision of its 10-year-old guideline on environmental risk assessments (ERAs) of new pharmaceuticals (1). There is mounting pressure for the agency’s guideline on GMPs to be extended to the environmental performance of pharmaceutical manufacturing facilities, particularly those making APIs for the European market, many of which are in India and China. This pressure comes as a result of studies (2) showing that plants making finished medicines and APIs are a much bigger source than previously thought of contamination of the environment by pharmaceuticals in comparison to that from usage and disposal.

	At the national level, some EU member states are now applying environmental criteria for the procurement of medicines for public sector healthcare services. Some of these criteria require drug suppliers to ensure that emissions from plants contracted to make medicines and APIs for them, especially those outside Europe, are properly monitored. Moves to impose stricter controls on pharmaceuticals in the environment stem from the big increase in the amount of academic and other research on the issue.


	One of the most influential PIE research programmes has been MistraPharma, a seven-year project funded by the Swedish Foundation for Strategic Environmental Research. It published its final report in May 2016 (2) based on research carried out by a number of Swedish universities as well as one from the United Kingdom. A broad range of Swedish stakeholders were also involved in the scheme, including representatives of regulators, the pharmaceutical industry, professional associations, and healthcare providers.

	Among its major findings was that contamination of the environment by pharmaceuticals is more extensive than previously estimated and that the levels of pollution from medicines and API manufacturing plants across the world are much higher than has been reported earlier. “The largest emissions of pharmaceuticals on earth do not arise from usage but from manufacturing discharges,” the report (2) says, with some of the worse culprits being antibiotics plants in India. In one Indian facility, MistraPharma researchers discovered that all the bacteria that they isolated were typically resistant to 30 out of 39 tested antibiotics while some were resistant to almost every tested antibiotic.

Recommendations on environmental controls


	The MistraPharma report made 10 recommendations, one of which states that risks to the environment from emissions from manufacturing sites should be included in ERAs. Among the other recommendations is that environmental risks should be included in the risk-benefit analyses by regulators before a new medicine is given market authorization, that ERAs should be updated in the light of new information after drug approvals, and that ERAs should be carried out on medicines marketed before 2006 when the EMA’s guideline on ERAs was first published. The report also suggests that all ERAs and information about manufacturing sites should be made publicly available.

	“Most stakeholders in Sweden agree with the recommendations,” Professor Christina Ruden, programme director and deputy head of Stockholm University’s environmental science and analytical chemistry department, told 

	“We also have a decision by the Swedish Government that Sweden should work toward a better handling of environmental aspects with pharma at the EU level. Sweden is now partly a forerunner with its national initiatives, such as greener procurement of pharmaceuticals. But to have a real impact, a change at the EU-level is of course needed in the long run.”


	In line with the policy of trade associations such as the Brussels-based European Federation of Pharmaceutical Industries and Associations (EFPIA), the Swedish pharmaceutical industry is opposing MistraPharma’s proposals that ERAs should be included in risk-benefit analyses on medicines. The European industry is also concerned about the growing demands, which was not included in MistraPharma’s recommendations, for GMP to be extended to include environmental standards at production sites, particularly emissions on pollutants.

	Calls for GMP to be broadened in scope have been reinforced by recent reports (3, 4) by non-governmental organizations (NGOs) such as the New York-based Sum of Us and by the Scandinavian financial group Nordea Asset Management. These reports provide evidence of extensive environmental pollution by pharmaceutical plants in India and China.

	“An extended GMP can be an effective means of protecting not only the environment but also human health because plant emissions can increase antimicrobial resistance,” Adela Maghear, pharmaceuticals policy officer, at Health Care Without Harm (HCWH), Brussels, said in an interview with 


	The need to tighten up guidelines on ERAs at the international level, including not just the EU but globally through bodies such as the World Health Organization (WHO), is one area where there is a broad consensus between industry, regulators, and NGOs. EMA issued a concept paper (5) on a revision of its 2006 ERA guideline in April 2016, which is now subject to a six-month consultation with stakeholders.

	“Since the 2006 EMA guideline, a clear improvement and consistency of the ERA dossiers has been observed,” says a spokesperson for the agency. “Transparency of ERA data has also been improved and information is made available in more detail and more consistently in the European public assessment reports (EPAR) published at the time of [recommended approval of medicines]. Still, EMA believes that further improvements in ERAs can be made.”

	In its concept paper (5), the agency pinpoints a number of aspects of environmental risk assessments that need to be reviewed. These areas include “approaches for substances with specific properties” such as persistent, bioaccumulative, toxic (PBT) compounds, endocrine disruptors, and mixtures of different chemicals that can have a combined environmental effect. There may also need to be changes to current environmental test strategies for pharmaceuticals, particularly when taking into account their pharmacodynamic and pharmacokinetic properties. Some improvements, however, such as the introduction of systems of data sharing and periodic updates of ERAs, would require changes to EU legislation, the ERA warns.


	Amendments to the EMA’s guidelines on GMP to extend it to environmental quality matters would be in a similar position. “The legal scope for GMP does not include inspections related to potential ERA pollution at the site of manufacture,” says the agency’s spokesperson. “Although changes in the legislation are not in the remit of the agency, if the scope is [changed], the EMA would adapt its guidelines accordingly.”

	The European Commission’s proposed PIE strategy, due to be published in 2017, could lead to new legislation or amendments to existing regulations, but these proposals are likely to be related to water quality policies. The Commission is already working on improvements to water legislation including criteria for placing pharmaceuticals and other compounds on watch or priority control lists. One major difficulty confronting the Commission is how to deal with mixtures of pollutants in water, which in the area of water quality MistraPharma highlighted as being a big challenge.

	Representatives of the European pharmaceutical industry have been expressing concerns about the levels and characteristics of emissions from pharmaceutical plants. But they believe that using GMP as a tool to deal with the problem would be a mistake.

	“GMP should remain focused on product quality and hence patient safety,” Bengt Mattson, environment and corporate responsibility manager at the Swedish research-based pharmaceutical industry association (LIF) told 

. “If its scope was changed to include environmental standards it would divert attention from product quality.”


	The industry’s opposition to ERAs being included in risk-benefit analyses of medicines for marketing approvals is based on similar concerns. “Marketing authorization decisions should be based on medical evidence and not environmental risks,” said Mattson, who is also co-chair of a PIE task force backed by the industry’s three main European associations-EFPIA, Medicines for Europe for generics, and AESGP for the European pharmaceutical wholesalers.

	The industry believes that some of its recently launched voluntary schemes can do a lot to deal with the anxieties among regulators, NGOs, and the general public about the impact of pharmaceuticals on the environment. These initiatives include its Eco-Pharmaco-Stewardship (EPS) scheme, supported by the three associations. This scheme covers the management of effuents from manufacturing units on which the industry has compiled a list of best practices to minimize risks to the environment.

	“Pharmaceutical companies in Europe are already carrying out audits of environmental standards in the manufacturing plants of APIs and other suppliers outside the region,” said Mattson. “Under the industry’s Pharmaceutical Supply Chain Initiative, information from these audits is being shared between companies.” The industry’s task over the next few years is to convince the regulators and politicians that it has a tight enough grip on environmental standards in its supply chains to make changes like extensions to GMP unnecessary.

Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use 

(London, June 2006).
	2. MistraPharma Research, “Identification and Reduction of 
	Environmental Risks Caused by Human Pharmaceuticals,” Final Report (Stockholm, May 2016).
	3. Sum of Us, “Bad Medicine--How the pharmaceutical industry is contributing to the global rise of antibiotic-resistant superbugs” (New York, 2015). 
	4. Norsea Asset Management. “Impacts of Pharmaceutical Pollution on Communities and Environment in India” (Stockholm, 2015).
	5. EMA, 

Concept paper on the revision of the ‘Guideline on the environmental risk assessment of medicinal products for human use’

 (EMEA/CHMP/SWP/4447/00 corr 2) (London, 28 April 2016).

The impact of pharmaceutical manufacturing on the environment has triggered demands for tighter environmental controls in EU and national legislations.

Pharmaceuticals in the Environment Spark Controversy

	The use of biosimilars continues to increase strongly in Europe, 10 years after the first biosimilar, a somatropin, was approved by the European Union (EU). With approximately 20 new biosimilars authorized for marketing across the EU since 2006, prescribing of the drugs is increasing at a rate of 11% a year, similar to the worldwide growth rate, according to figures from IMS (1).

	Biosimilar producers, regulators, and other key groups in the European healthcare sector, however, agree that the growth rate should be higher. This view was echoed by speakers at the annual Biosimilar Medicines Group Conference in London on April 28-29 2016, organized by Medicines for Europe, previously the European Generic and Biosimilar Medicines Association (EGA).

	There continues to be widespread scepticism in the region about the quality and safety of biosimilars, and sometimes their efficacy, among physicians and patients. This issue is often because of a lack of awareness about the nature of these medicines. A major doubt is frequently their degree of comparability with the original biologics. Yet both regulators and producers believe that more could be done to eliminate uncertainties about biosimilars by making improvements at the production and preclinical stages, for example by implementing the latest analytics and other imaging technologies to detect impurities and unacceptable differences in structures and functionalities.

	The EU was the first major regulator in the world to establish a legal framework for the marketing of biosimilars. This legislation has since been supplemented by an overarching guideline on standards for quality, safety, and efficacy of the products, which has been followed by a series of guidelines on class-specific and non-clinical and clinical aspects. These guidelines have been drawn up by the European Medicines Agency (EMA), the London-based EU-wide authority that approves biosimilars.


	Biosimilar versions of granulocyte-colony stimulating factor (G-SCF) have now gained a market share of more than 50%, Carol Lynch, global head of Sandoz Biopharmaceuticals said during the conference (2). The estimated cumulative savings from biosimilar epoetins had amounted to $480 million (€551 million) in Germany alone in five years, she added.

	The launch of biosimilars also stimulates growth in product-specific markets for biological treatments. In the United Kingdom, the size of the country’s market for filgrastim, a short-acting G-CSF, more than doubled from 2008-2014 (2) after the launch of a biosimilar version. Per Troein, vice-president, strategic partners, IMS Health, which published a study on the potential for biosimilars in Europe in March 2016 (3), said that as a result of a number of top-selling biologics coming off patent shortly, almost 50 new biosimilars are under development (3).


	The IMS study, however, has shown that not all EU markets are ready to profit from the benefits of the forthcoming new generation of biosimilars. This is because of a lack of competition in some countries and an absence of physicians at the heart of the decision-making process to give patients access to biosimilars. In this respect, education of physicians and other stakeholders about the advantages of biosimilars had become a crucial factor.

	There have been sharp differences between, and even within, countries in the level of uptake of individual biosimilars. Biosimilar infliximab, the first biosimilar monoclonal antibody (mAb) to be approved by EMA in 2013, has had an uptake varying from approximately 10-50%  in the five leading EU markets of France, Germany, Italy, Spain, and the UK, according to Troein (1). In the Nordic countries and the UK, the variation in prescribing of the product, which competes with Johnson & Johnson’s Remicade, a treatment for rheumatoid arthritis and similar conditions, has had a similar range of 20-50%. The differences were due to the presence or absence of strong national champions of the biosimilar versions, national tender systems, incentives to prescribers, and fragmented decision making within countries, Troein said (1).
	Benedicte Lunddahl, team leader, pharmacovigilance at the Danish Medicines Agency, pointed out that a key factor was the “information gap,” especially among physicians and patients, which was causing misunderstandings and lack of awareness about biosimilars. 

	The Danish Council for the Use of Expensive Hospital Medicines (RADS) recommended the use of Remsima, the biosimilar infliximab, in preference to Remicade because it was less expensive. Remsima, then marketed by Hospira in partnership with its developer Celltrion of Korea, won a national tender to supply it to all Danish hospital pharmacies that were able to switch patients to the product. The decision was opposed by doctors and patients’ organizations. “Patients are concerned about the new product [while] physicians are not comfortable about explaining the principle of biosimilarity,” Lunddahl explained (4).


	A drive was initiated to reassure doctors and patients including a pharmacovigilance action programme to encourage reporting of adverse effects, communications with patients groups, and wide availability of information. One important message to patients is that the variability between the reference product and a biosimilar is similar to the variability between batches in the production of any biological medicines, Lunddahl said. In other words, they both have an inherent variability.

	The view that quality aspects of comparability should be highlighted in communications on biosimilars was shared not only by the regulators but also the producers. “Biosimilars have to have the same or better quality when compared to their reference biologics,” said Klaus Martin, chief scientific officer, Polpharma Biologics and chair of the market access committee of the Medicines for Europe’s biosimilar medicines group. “When understanding [the issue of quality], it becomes evident that biosimilars are clinically equivalent to the original and can be switched safely,” he added in an interview with 


	EMA has been shifting to a policy of giving greater importance to analytical data at the production and preclinical stages when assessing applications for biosimilar approvals. At the start of EMA’s regulating of biosimilars, there were doubts about whether the existing analytical methods for characterizing biologicals, especially complex ones, were adequate, said Martina Weise, vice-chairman of the agency’s biosimilars working party (BMWP) who stressed she was speaking in a personal capacity. But since then, there had been rapid advances in analytical sciences. The efficiency of mass spectrometry had increased to such an extent that its sensitivity had soared 10,000 fold in 10 years and 10 million fold in 20 years, according to Weise (5).

	Biosimilar applications must now be supported by more state-of-the art analytical data with more detailed comparisons between structures and functions and more pharmacokinetic (PK) and pharmacodynamic information. Application dossiers have to give a quality target product profile (QTPP) based on the characterization of multiple batches of the reference product. If necessary, the manufacturing process would be adjusted to achieve the QTPP. 

 studies to characterize extensively the functions and activity of the molecule. “[This approach] is usually more sensitive in detecting differences than 

 studies,” said Weise, who is head of the diabetes/cardiology unit at Germany’s Federal Institute for Drugs and Medical Devices.


	Increasingly, regulators are viewing biosimilars as requiring assessments similar to those applied to changes in the manufacturing processes of original biologicals. These changes are being judged in a way that does not necessitate the provision of any clinical evidence. With biosimilars, the strategy is to require enough quality data from the production and preclinical stages to build a reliable scientific bridge to the clinical trial data of the original. The assessment of the comparisons between the physicochemical and functional data of a biosimilar with its reference product now corresponds with the regulatory assessment made between a new manufacturing process for an original product and its previous ones. The new process is, from the regulatory viewpoint, like that of a biosimilar’s.

	“Originator molecules have undergone multiple changes in their production processes,” said Martin. “A patient, who has, for example, been on Remicade for 10 years would have been treated with 15-25 biosimilars of the original molecule, as J&J introduced at least 36 process changes to the molecule, in some cases, significantly altering its physicochemical properties.”

	Often the genuine biosimilar is assessed more rigorously by the regulators than the process changes for the reference product. The big challenge is to convey this information to physicians, patients, and other stakeholders in such a way that they gain a full understanding of the quality issues with biosimilars.


	1. P. Troein, “ Biosimilars-More or Less,”  presentation at the 14th Annual Biosimilar Medicines Group Conference (London, April 28-29, 2016).
	2. C. Lynch, “The Biosimilar Market-Leader’s Perspective,”  presentation at the 14th Annual Biosimilar Medicines Group Conference (London, April 28-29, 2016.
	3. IMS Institute for Healthcare Informatics, “Delivering on the Potential of Biosimilar Medicines” (Parsippany, NJ, March, 2016). 
	4. B. Lunddahl, “Reducing the Information Gap among Stakeholders,” presentation at the 14th Annual Biosimilar Medicines Group Conference (London, April 28-29, 2016).
	5. M. Weise, “Evolving Landscape on Data Requirements to Demonstrate Biosimilarity-The EU Perspective,”  presentation at the 14th Annual Biosimilar Medicines Group Conference (London, April 28-29, 2016). 

More efforts are needed to raise awareness of biosimilars among physicians and patients in Europe and address scepticisms about the quality and safety of biosimilars.