out of the shadows - toprain preparation for implementation in february 2019, elements that will...

THE INTERNATIONAL JOURNAL FOR PROFESSIONALS IN REGUL ATORY AFFAIRS

APRIL 2017

PLUSDevelopments in the EU referrals procedure: Ten years onConducting Phase I clinical research in the EU versus USDiscussions on the adaptive pathways concept

OUT OF THE SHADOWSHow a new regulatory framework will help detect falsified medicines and safeguard the supply chain

2

Consultant Editors for this issue

Julie WarnerA� er studying physiology and immunobiology, Julie began her career in consultancy in 2003, working on many products across numerous disease areas from oncology to infectious diseases, before joining pharmaceutical companies to work on products in development for cardiovascular disease and oncology. Julie now works again in consultancy on a broad range of development projects. She has a special interest in orphan drugs, gene therapies, oncology, clinical trials and marketing authorisations, and has been involved with Regulatory Rapporteur since 2003.

Clare Matti Clare is the principal regulatory advisor for the Duke Clinical Research Institute (Duke University, US). She is a member of TOPRA’s North America Leadership Team and TOPRA’s Awards Working Party, and she also teaches courses on EU and Canadian regulations and on US drug trials.

Cover illustration: Image depicting counterfeit medicines – which are o� en di� cult to identify – and their threat to public health.

Photo credit: vipman/Shutterstock & NejroN/123RF

EDITORIAL BOARD

Editor in Chief Leslie Dowling, Director, Apex Reg Ltd, UK

Deputy Editor Davina Stevenson, Associate Director, International Regulatory Aff airs, Gilead Sciences International Ltd, UK

Associate Editor – Interviews Angela Stokes, Senior Director, Global Regulatory Consulting, INC Research, UK

Associate Editor – Meeting Reports Julie Warner, Director, Alan Boyd Consultants Ltd, UK

Consultant Editors Raj K Bains, Principal Consultant Pharmacovigilance, GxPconsult Ltd, UK Alex Bloom, Director of European Regulatory Aff airs, Cell Medica, UK Joan Boren, Regulatory Aff airs Manager, Development Solutions, PPD, UK Karen L Brown, Regulatory Aff airs Quality Assurance Manager, Europe, Africa and Central Eurasia, CooperVision, UK Will Drury, Senior Business Associate, Cyton Biosciences Ltd, UK Tim Felgate, Senior Consultant, NDA Regulatory Science, UK Ivan Fisher, Assistant Vice President, Regulatory Aff airs, Genpact Pharmalink – Global Regulatory Aff airs, UK Vera Franzén, Regulatory Aff airs Consultant, Vera Franzén Consulting AB,Sweden Andrew Germain, Associate Director Regulatory Aff airs CMC , G-Pharm Ltd, UK Richard Huckle, Senior Consultant, Regulatory, Pope Woodhead and Associates Ltd, UK Carol Huntington, Associate Director, Global Regulatory Aff airs, Premier Research, UK Patricia Hurley, Director, Development Solutions, Regulatory Aff airs, PPD, UK Clare Matti, Group Leader, Regulatory Services, Duke Clinical Research Institute, US Sobhey Nassar, Principal Regulatory Aff airs Executive, Norgine, UK Ash Ramzan, Principal Consultant, Woodley BioReg Ltd, UK Sarah Roberts, Vice President, Global Regulatory Aff airs, PRA Health Sciences, UK Birgit Roser, Consultant, Regulatory Aff airs, Human and Veterinary Medicines, Germany Leigh Shaw, Head of Regulatory Aff airs & QA, NightstaRx Ltd, UK Anita Sibal, Regulatory Aff airs Consultant, UK Natalie Thomas, Senior Consultant, Clinical Network Services Ltd, UK David Uguen, Director Regulatory Science, ONXEO SA, France

www.topra.org

THE

INTERNATIONAL

JOURNAL FOR

PROFESSIONALS

IN REGULATORY

AFFAIRS

THE INTERNATIONAL JOURNAL FOR PROFESSIONALS IN REGUL ATORY AFFAIRS

APRIL 2017

PLUSDevelopments in the EU referrals procedure: Ten years on

Conducting Phase I clinical research in the EU versus US

Discussions on the adaptive pathways concept

OUT OF THE SHADOWSHow a new regulatory framework

will help detect falsified medicines

and safeguard the supply chain

1

Contents Editorial 3 Falsified medicines: Anything but “fake news” Julie Warner

Focus – Falsified medicines

5 The Falsi� ed Medicines Directive – What does it really mean for stakeholders? Ash Ramzan

8 Requirements of the Falsi� ed Medicines Directive’s delegated act on safety features Syed Qadri

12 Insights on falsi� ed medicines in the legal supply chain Paul Hargreaves, Christopher Morris

17 Interview: Investing in quality Siniša Tomic, Head of Croatia’s regulatory agency, HALMED, interviewed by Angela Stokes

20 A review of developments in the EU referrals procedure Anne Lenihan, Vincent Wek, Ewa Filipowska, Sophie Van de Leest, Ashley Dukes, Ciaran Virk, Rachel Heafi eld, Phillip Cogley, Samuel Dixey

26 A comparison of UK versus US submission processes for Phase I clinical trial applications Harriet Edwards

29 Meeting report: European Medicines Agency’s Adaptive Pathways Workshop Richard Huckle

Regulatory Rapporteur is indexed on two Elsevier academic databases, Embase and Scopus. To access these go to embase.com/embase-pharmaceutical-research and info.scopus.com

Regulatory Rapporteur – Vol 14, No 4, April 2017

www.topra.org Regulatory Rapporteur – Vol 14, No 4, April 2017

EDITORIAL TEAMManaging EditorMadeleine [email protected]

Communications EditorRachel [email protected]

AdvertisingErik [email protected]

Licensing, reprints and library [email protected]

Director of Publishing ServicesJenine [email protected]

TOPRA o� ceTOPRA Publishing6th Floor, 3 Harbour Exchange, South Quay, London E14 9GE, UKTel: +44 (0) 20 7510 2560 Fax: +44 (0) 20 7537 2003E-mail: [email protected] Printed by Newman ThomsonBurgess Hill, West SussexISSN 1742-8955© 2017 The Organisation for Professionals in Regulatory AffairsAll articles published are the copyright of TOPRA, and should not be reproduced in whole or in part without the written permission of TOPRA Publishing.Views expressed in Regulatory Rapporteur are those of the contributors and not necessarily those of the editors or TOPRA. While every effort is made to ensure information is accurate, and articles are subject to peer review, conditions may change and readers are advised to consult current official texts and/or to seek appropriate professional advice before taking any regulatory action.TOPRA members can download this issue of Regulatory Rapporteur online at www.topra.org TOPRA is the registered trademark of The Organisation for Professionals in Regulatory Affairs Ltd, registered Community Trademark number 003182961. The TOPRA logo is covered by The Community Design registration numbers EU Des Reg No. 000055553-0001 and 0002.

Regulatory Rapporteur is free to TOPRA members. 1-year TOPRA membership: £1951-year TOPRA student membership: £351-year TOPRA concessionary membership:* £97.501-year library subscription: £550Current issue: £30Back issues: £50*Retired, maternity leave or on a work break

For more information go to page 14

TOPRA INDIA 2017: BUILDING REGULATORY EXCELLENCE16–18 May 2017 Ritz Carlton, Bangalore, India

For more information go to page 2

2

TOPRA INDIA 2017: BUILDING REGULATORY EXCELLENCE16–18 May 2017 | Ritz Carlton, Bangalore, India

Find out more and book your place

topraindia.org/rr

Bringing together regulators and industry experts from Europe and Asia, TOPRA India 2017 is a two–day congress focusing on how to build regulatory excellence and to get the European perspective.

Day one: The global regulatory environment

Day two: The challenges of bringing products into Europe and interacting with regulators

Day three: TOPRA’s established and respected Basics course in regulatory affairs*

One-day tickets available with one free ticket on all block bookings

*One-day introductory course for more junior members of the profession.

TOPRA 2017: Building Regulatory Excellence is supported by:

3

Not a day goes by now without something “fake” in the news (and it’s o� en the news itself ), making it hard to distinguish what is real from what is not. Sadly, our industry has also fallen prey to falsi� cation in recent years, as criminals have increasingly recognised an opportunity to make signi� cant amounts of money from the falsi� cation of medicines. According to the Royal Pharmaceutical Society in England, medicines are the second largest category of falsi� ed items imported into Europe (compared with 2004, when numbers were so low that they weren’t even recorded separately). However, with the introduction of the Falsi� ed Medicines Directive (FMD; 2011/62/EU), amending Directive 2001/83/EC, regulators aim to address this at a European level. Measures to counteract the growing problem of counterfeit products are also now in place in the US, in accordance with the FDA’s Global Strategic Framework for Spurious, Substandard, Falsi� ed, Falsely-labeled and Counterfeit (SSFFC) Medical Products.

With this edition focusing on the topic of falsi� ed medicines, our � rst article gives us an excellent overview of the current state of play relating to the FMD in Europe, where industry is coming to terms with its legal responsibilities. In preparation for implementation in February 2019, elements that will need to be in place by that date include manufacturing/packaging line upgrades, training in Blueprint so� ware, 2-D barcodes and tamper-evident packaging, updates/revisions to quality management systems, and supply chain mapping.

Meanwhile, over the past few years regulators have joined forces across the globe to discuss how best to combat the falsi� cation of medicines which, at best, puts the patient at risk of lower bene� t (less or no active ingredient) or, at worst, signi� cantly a� ects patient safety. In an ever increasing global regulatory environment, the only way this can be done e� ectively is by good communication and the sharing of information across regulatory and law enforcement networks. The scale of the criminal activity is evident at the level of just one regulatory agency, the UK Medicines and Healthcare products Regulatory Agency, in an article on the important work undertaken by the MHRA in this regard. The good news is that the vast majority of falsi� ed medicines are identi� ed before they reach retailers or patients; however, given the rising

number of cases, this is clearly a daily battle and, despite best e� orts in working with a number of agencies and bodies including the World Health Organisation, INTERPOL, and the Permanent Forum on International Pharmaceutical Crime, there are some cases which unfortunately do slip through the cracks.

As noted in our � nal focus article, the measures introduced by the FMD are many, and fall broadly into four “pillars”: safety features of medicines; supply chain and good distribution practice; measures covering active substances and excipients; and the sale of medicines by internet pharmacies. This article focuses on the delegated Regulation (EU) 2016/161 on safety features, the requirements of which must be adopted by pharmaceutical manufacturers by 9 February 2019 and, speci� cally, the signi� cant amount of work that is required between now and that date by companies and their stakeholders to make sure that the necessary systems are implemented and fully functional.

In conclusion, the threat to public health from falsi� ed medicines is real and growing on a daily basis; it continues to present tremendous challenges for regulators and for manufacturers and those involved in the supply chain of medicinal products. However, the measures currently or soon to be in place in many countries will provide a mechanism to prevent opportunities for these products to enter the supply chain; this may well be an uphill struggle, with regulators trying to stay one step ahead of the individuals and criminal networks responsible on a global basis but, for now, it appears as though the chips are in our favour.

Therefore, tonight’s real headline is that falsi� ed medicines are here... but hopefully not for long.

Editorial

AuthorJulie Warner, Director, Alan Boyd Consultants Ltd, UK

The good news is that the vast majority of falsifi ed medicines are identifi ed before they reach retailers or patients; however, given the rising number of

cases, this is clearly a daily battle

Falsi� ed medicines – Anything but “fake news”


4

THE FOUNDATION TO YOUR SUCCESS IN REGULATORY AFFAIRS

Book your place now at topra.org/rr-autumnintro2017

The regulatory function and the EU environment• The role and importance of the regulatory

affairs function and how it fits into the product development process

• The EU regulatory environment, the organisations involved and how legislation is developed

• Future developments in the pharmaceutical industry• The importance of regulatory strategy• Successful interaction with authorities.

The marketing authorisation application, science, content and structure• The fundamentals of chemical and pharmaceutical

development• The importance of good manufacturing and clinical

practice• The need for pharmacology, pharmacokinetic and

toxicology data• Clinical development including paediatrics and the

conduct of clinical trials• The content and structure of marketing authorisation

applications in the common technical document format

• How to be ready for electronic submissions and eCTD• The importance of product information; SmPCs,

labelling and leaflets.

EU regulatory procedures• The theory and practical reality of the centralised

procedure• The theory and practical reality of the decentralised

and mutual recognition procedures• How to choose and use the procedures• The importance of scientific advice.

Post-authorisation activities• Aspects of successful lifecycle management• The requirements and procedures for variations and

renewals• The importance of pharmacovigilance and risk

management.

Specialist core areas• An understanding of medical device technology• An understanding of biotechnology products• An understanding of abridged applications including

generics.

AUTUMN INTRODUCTORY COURSE 2017 | 13–17 November 2017 | Venue TBC

YOUR FIRST STEP TO A QUALIFICATION MSc in Regulatory Affairs Module 0 This foundation course can also be taken as the MSc module “Overview of EU Regulatory Affairs”. Delegates (who meet the MSc entry criteria) can attend this course to receive a thorough grounding in all the main pharmaceutical and device regulatory aspects, before completing related assignments as part of their first module leading to the MSc RA qualification.

5


Focus – Falsifi ed medicines

Introduction A falsi� ed medicine is any medicine that is not manufactured by the approved manufacturer (the marketing authorisation holder – MAH), contains too much, too little, or no active ingredient, contains another/undeclared active ingredient, is past its expiry date, is deliberately mislabelled, has fake packaging, or is in some way not as the authorised manufacturer intended. All of these situations have a direct impact on patient safety and there have been many documented cases of harm (including death) caused through falsi� ed medicines. While all of the information provided in this article is available through a number of channels including online, this article provides a collated summary to act as a point of reference.

This article is intended to provide an easy-to-follow overview of the background and history of the FMD before taking a closer look at the key elements. The operational implementation of the key elements is described in context of the overall output and e� ect on patient safety. Finally, this article provides a flavour of the current trends and potential risks and areas that are still unclear, and seeks to provide an expert narrative on the resolution of some of these areas.

Background and historyThe multi-billion dollar trade in falsi� ed medicines is well known and documented extensively. There have been many initiatives that have had varying degrees of success and global impact, but the risk to patients continues to drive regulatory authorities to develop and implement increasingly rigorous processes.

One of the most serious cases in Europe involved 72,000 packs containing 2.1 million doses with a retail value of £4.7 million. A� ecting seven batches of three medicinal products, it resulted in four Class 1 recalls and the UK’s Medicines and Healthcare products Regulatory Authority (MHRA) seizing 40,000 packs before they reached pharmacies. This operation was referred to as Operation Singapore as counterfeit products manufactured in Tianjin China were routed through Hong Kong and Singapore before being shipped to Belgium and then the UK; the flow of money was from the UK to China via Luxemburg and Mauritius.

Given the global nature and lucrative value of such counterfeits, there are already a variety of local and regional initiatives that have been developed and implemented to provide some level of assurance to patients and carers. These range from a relatively simple application of scratch codes by legitimate manufacturers that are scratched-o� by customers to reveal a code that is texted to a central data centre to verify the product’s provenance and authenticity. This system was launched in a number of African countries in 2009 and to date around 28 million veri� cations have taken place.

In the EU, Directive 2001/83/EC allows safety provisions to be enacted; amendments to Directive 2001/83/EC allowed the Falsi� ed Medicines Directive 2011/62/EU to be de� ned with the key safety requirements. These safety features were delegated to be implemented nationally in the Delegated Regulation EU/2016/161 which will be implemented by 9 February 2019. The evolution and summary of these requirements is provided in Figure 1.

The main parts of the requirements and their implementation as part of the FMD are discussed in the following sections of this paper.

The key parts of the FMDThere are three main strands to Directive 2011/62/EU that are further de� ned under the obligatory safety features (under the Delegated Regulation EU/2016/161) and which form part of the national competent authorities’ (NCAs) responsibilities for implementation. Active pharmaceutical ingredients (API) quality. While the requirements for APIs have always been implicit for good manufacturing practice (GMP)-compliant manufacturers, the FMD has made the � nished product releasing Quali� ed Person (QP) responsible for ensuring that APIs are manufactured within the principles of current GMP (cGMP). This requirement came into e� ect in July 2013. Its implementation has involved a wide range of activities that � nished products manufacturers have undertaken, typically by outsourcing upstream QP activities; these include:

Paper audit/assessment of API manufacturer’s quality management systems (QMS)

The Falsi� ed Medicines Directive – What does it really mean for stakeholders?

AuthorAsh Ramzan, Principal Consultant, Woodley BioReg Limited, UK.

KeywordsFalsifi ed Medicines Directive (FMD); 2001/83/EC; 2011/62/EU; Marketing authorisation application (MAA); Parallel import; Generics; Marketing authorisation holder (MAH); Quality management systems (QMS); Specials licence; Online pharmacies.

AbstractThe Falsifi ed Medicines Directive (FMD, 2001/83/EC as amended to 2011/62/EU) and its Delegated Regulation EU 2016/161 sets out the overall requirements that manufacturers of human medicinal products must meet as part of their legal responsibility. These responsibilities also extend to wholesalers, dealers and parallel importers. While it is widely known that all of the aspects of the FMD will come into force by 9 February 2019, the preceding (and related) requirements that have either already been implemented, or are in the process of being implemented, are less well understood.

This article serves to provide an overview and history of the Directive as well as including its key requirements, and how these are being fulfi lled by stakeholders and manufacturers. There is wide variability in the approaches being taken and the pace of progress, but one certainty remains; this Directive will be enforced for all manufacturers intending to supply human medicines into the EU.

6

Regulatory Rapporteur – Vol 14, No 4, April 2017 www.topra.org


Re� nement of existing API manufacturer’s QMS to align with QP requirements

Provision of robust quality technical agreement (QTA) Provision of alternative API suppliers where available, and termination of supply from non-compliant suppliers.The overall e� ect has been the implementation of robust, GMP-

consistent supply chains for APIs manufactured outside the EU; the requirements under the FMD have been ful� lled.Online pharmacies. The rapid growth in online pharmacies and the availability of prescription medicines was seen as a major risk factor to patient safety. Given the nature of the internet, this area is very di� cult to regulate and while the trade in “unauthorised” medicines will continue, consumers (patients) are being encouraged to only purchase products that display the online pharmacy logo. The requirements to register online pharmacies to obtain a certi� ed logo became obligatory from July 2015. Consumers are able to click on the approved online pharmacy logo that veri� es that the merchant is registered with the NCA and complies with the requirements of FMD online sales. The logo has the wording: “Click to verify if this website is operating legally” for ease of use by potential purchasers. If the online pharmacy is an approved supplier, clicking will take users to a webpage which lists not only the name of the supplier but its full postal address and the website address(es) at which it is approved to sell medicines online. Obligatory safety features (EU 2016/161). Two key safety features that are required as part of the FMD are a 2-D barcode and tamper-evident packaging. While the general minimal requirements are provided for in the FMD, the technical requirements that underpin these features have been delegated to Regulation EU 2016/161. These are discussed in further detail below.

2-D barcode: A unique identi� er (UI) in the form of a 2-D barcode as well as readable details of the batch number and expiry date must be included. While this is not its intended use, NCAs can decide whether this code will be used for reimbursement purposes.

Tamper-evident device: Tamper-evident packaging is an obvious visual deterrent to any attempts to tamper with the container closure system. The requirements for tamper-evident packaging include solutions from label seals and tear-o� strips to shrink-wrapping. Regardless of the option selected, each must be able to demonstrate that the container-closure system is as it was on leaving the manufacturing /QP release site and has not been tampered within the supply chain. The speci� c safety feature requirements and their implementation

are detailed in the Delegated Rule (EU 2016/161) to the FMD (EU Directive 2011/62/EU). These are summarised below.

Technical characteristics: The 2-D barcode must be included on all secondary packaging; this must comply with the requirements of ISO 15495. In addition to the barcode, a readable 20 alphanumeric character code that includes the expiry date and batch number must be included. All new marketing authorisation applications (MAAs) � led a� er April 2016 must include a unique identi� er. All existing / approved products have a 3 year transition period ending in February 2019. A serialised barcode will be required to be applied by parallel importers as part of their responsibilities under FMD.

Veri� cation of safety features: A system whereby the supply chain many be veri� ed must be implemented for all products. While this does not need to be a full track-and-trace system, it should be risk-based and enable the veri� cation of approved lots from the manufacturer to the pharmacy. This veri� cation system relies on the veri� cation of the tamper-evident device as well as the con� rmation of provenance using the unique identi� er. Parallel importers will have to ensure that relabelled blisters are packed into acceptable packs that do not compromise the integrity of the supply chain.

Repository system: A controlled electronic repository forms the backbone and framework against which the other elements of the FMD are delivered. The repository must allow approved

Figure 1: Summary of the development of FMD legislation and requirements.

7



manufacturers to upload details of unique identi� ers that can be tracked and veri� ed throughout the supply chain, and be decommissioned at the point of supply. The Delegated Rule allows stakeholders to establish and maintain this system; this is being undertaken by secureMed in the EU, which is under the supervision of competent authorities. The Blueprint system agreed by secureMed comprises a central EU hub linked to national/super-national repositories that will be interrogated by approved/veri� ed users. NCAs will be responsible for issuing user licences for the repository.

List of exceptions: As a general rule, all prescription products are subject to the FMD and all over-the-counter (OTC) products are exempt; there are however a number of exceptions to these rules. These include homeopathic medicines; medicinal gases; radionuclide generators and precursors; kits; advance therapy medicinal products (ATMPs); various solutions, media and extracts. Furthermore, a number of dispensers are also exempt from the FMD, including prisons, dentists, vets and opticians.

Limitations. One of the key limitations to the full implementation of the FMD is the delay in the selection of the Blueprint system that will provide the database structure and backbone to the electronic veri� cation against the European Medicines Agency (EMA) and local hubs. At the time of writing, the anticipated decision by the MHRA was overdue by two months.

The current state of playThe key stakeholders have varying degrees of understanding and preparedness for implementation of the FMD. The typical activities that are required to be in place for successful deployment include:

Manufacturing/packaging line upgrades (cost estimated by the MHRA to be around £150,000 per line)

Access to and training in Blueprint so� ware (estimated to be ranging £50,000 to £200,000+)

Serialisation sequences (2-D barcodes) Tamper-evident packaging Updates/revisions to QMS Supply chain mapping Sta� training.

Manufacturers and MAHs. Generally, manufacturers fall into one of two categories:

Innovators: Innovators/original MA applicants and holders are generally well down the path in preparing to implement the requirements of the FMD. This group is typically seen as the most cash-rich in terms of their products and their exclusivity.

Generics manufacturers: Generic pharmaceuticals manufacturers have a wider range if implementation positions, with larger manufacturers progressing at the same pace as the innovators. Smaller manufacturers appear to be seeking to “collaborate” with other smaller manufacturers and use trade bodies such as the British Generic Manufacturers Association (BGMA) to lobby regulators and decision-makers. Consequently, there are a considerable minority of smaller/national generics manufacturers that are starting to lag behind the implementation curve.

Wholesalers/distributors/brokers. This group of stakeholders is required to track the receipt and onward distribution of inventory and ensure the continued security of the supply chain. As these activities do not require any intervention with the product and product packs, this group will require access to the controlled repository and deployment of the Blueprint so� ware. These stakeholders are

therefore insulated against many of the more intricate requirements of the FMD. Parallel importers. Parallel importers are perhaps one of the most contentious group of stakeholders in the deployment of the FMD, given that they are not MAHs but will undertake some manufacturing activities such as labelling and repacking. This group will be impacted by the requirements for the provision of 2-D barcodes, tamper-evident packaging, and access to the repository and so� ware. A number of these stakeholders have considered the impact of the FMD and developed contingency plans to ensure their business is not impacted; the potential impact of the Brexit vote is of more concern given the potential risk to their supply chains. Manufacturers – specials licence holders. The manufacturers of products with a “specials” licence are exempt from the requirements of the FMD. Nevertheless, there are a handful of Specials manufacturers that have sought to understand and implement some parts of the FMD legislation. This is commendable and should be encouraged for others. Online pharmacies. The requirements for online pharmacies are already in force and implemented.

RisksAny major programme that seeks to overhaul the arrangements for the supply of pharmaceutical products will involve a wide range of risks. The FMD is no di� erent as its implementation will impact manufacturers, suppliers, brokers, distributors and patients. Despite the phased deployment of the FMD, tangible risks remain.

Clearly, one of the most obvious risks to the supply of drugs to the health service is if the requirements of the FMD are not met by stakeholders by the deadline of February 2019. The degree of impact will depend on the number of stakeholders and the number and types of product a� ected, and whether alternative treatments are available to switch patients.

From discussions with various stakeholders, it clear that the risks stem from factors outside their direct control. For example, delays in the identi� cation of so� ware solution providers and access to the secure databases carry signi� cant risks in successful deployment. Equally important are cost considerations. The capital investment required for line upgrades as well as the cost to MAHs for the overall deployment and implementation of the FMD has prompted many to reconsider the cost of goods, and to lobby to prevent non-paying bene� ciaries such as parallel importers to be denied access to the repository.

As the deployment activities continue, further discussions will no doubt ensure that will seek to tweak and amend the requirements, while the regulatory bodies continue to push back and stay aligned with the origins of the FMD.

ConclusionsThe Falsi� ed Medicines Directive (FMD, 2001/83/EC as amended to 2011/62/EU) and its Delegated Regulation EU 2016/161 will come into force in February 2019. This Directive represents a signi� cant set of changes to the manufacture and supply of pharmaceutical products that have been subject to signi� cant counterfeiting. The measures included within FMD will go a long way to assuring patient safety and product e� cacy.

As would be expected in such a signi� cant programme, there are still a number of areas of concern that could result in increased risks if they are not resolved in a timely manner. However, manufacturers and stakeholders have in the main responded positively and the majority have well-advanced plans for deployment by the deadline.

8



Introduction Drugs cost billions of dollars and take decades before � nally reaching the patient. There is, therefore, a negative impact on patients and companies when falsi� ed medicines enter the supply chain. The European Medicines Agency (EMA) de� nes counterfeits as being illegal copies of generic medicines that infringe on intellectual property rights, whereas falsi� ed medicines contain harmful substances, contain low amounts of the active ingredient and mimic real products. They are further de� ned as medicines of low quality or contain incorrect ingredients or doses, which are deliberately or fraudulently mislabelled with respect to their identity or source and

are contained in fake packaging.1 Although di� erences exist between falsi� ed and counterfeit medicines, the terms are used synonymously across the globe and this had led to a great deal of confusion. Yet, despite the di� erence in terminology, it’s universally known that, as they bypass the rigorous EU evaluation of safety, quality and e� cacy, such products are potentially dangerous and thus pose a major health threat to the public. In 2011, an existing directive was amended, resulting in the Falsi� ed Medicines Directive (FMD) 2011/62/EU, which entered into force in January 2013, with a view to blocking the entry of falsi� ed medicines into the EU supply chain and making it harder for medicines to be mimicked. The four main aspects covered by the FMD are the active pharmaceutical ingredient (API), safety features, distribution of medicines, and internet pharmacies.

This article will focus on the latest delegated act for safety features (Regulation (EU) 2016/161)2 which was adopted on 2 October 2015, published on 9 February 2016 and due to come into force on 9 February 2019. A DIA/TOPRA workshop on the FMD was held in Brussels in June 2016 comprising a panel of spokespeople from European health authorities and industry stakeholders. Their various thoughts and discussions revealed there was still much work to do; added complexities make meeting this target date challenging for pharmaceutical companies and drug manufacturers. As such, this article aims to outline the delegated act on safety features and its various requirements for stakeholders, with examples of how information will possibly be exchanged along the supply chain.

Regulation (EU) 2016/161In the event that falsi� ed medicines do enter the supply chain, the European Commission wanted to make the veri� cation of medicinal products possible at the point of sale. The delegated act for safety features (� rstly aims to clearly mark every pack with a unique identi� er (UI) made up of unpredictable serial numbers that would be registered to a pan-European database to provide veri� cation of authenticity. The aim is not for it to be a track-and-trace system, but rather one that will provide an end-to-end veri� cation to inform the user of its status at a near-instant speed of 300ms. Safety features only apply to medicines subject to prescription and only some non-prescription products on a case-by-case basis if those products are deemed at risk of falsi� cation; exceptions to this rule – known as the ‘white’ and ‘black’ list – are discussed later. Secondly, the outer packaging is required to have an anti-tampering device (ATD) to enable one to verify whether the pack has been opened or tampered with. The technical speci� cation for the ATD is not described in the Regulation and is up to the manufacturer to decide its nature.

European Medicines Veri� cation Organisation (EMVO)Established in 2015, the European Medicines Veri� cation Organisation (EMVO) is a group of stakeholders from di� erent channels of the supply chain representing the culmination of four years of intensive work towards a dependable and secure pharmaceutical veri� cation system.3 As part of the European Stakeholder Model’s (ESM)

Requirements of the Falsi� ed Medicines Directive’s delegated act on safety features

AuthorSyed Qadri, Regulatory Aff airs Associate, Jazz Pharmaceuticals.

KeywordsFalsifi ed Medicines Directive (FMD); FMD 2011/62/EU; Safety features; Regulation (EU) 2016/161; Unique Identifi er (UI); European Commission; Member state (MS); Counterfeit drugs; European Medicines Verifi cation Organisation (EMVO); European Medicines Verifi cation System (EMVS); European hub; National repository; 2-D barcode; Serialisation; White List; Black List; Risk-based verifi cation; Parallel importer (PI).

AbstractFalsifi ed medicines have a signifi cant negative impact on patients who expect the product they receive to be unadulterated. There has been a rise in falsifi ed medicines in Europe with their entry being at many points along the supply chain. The four main aspects of the Falsifi ed Medicines Directive 2011/62/EU in Europe (designed to tackle falsifi cation) are new qualifying criteria for the entry of active pharmaceutical ingredients (APIs) into Europe; safety feature requirements on the outer packaging; stricter guidelines on those involved in the distribution of medicines; and regulation of internet pharmacies. The Delegated Regulation (EU) 2016/161 on safety features was published on 9 February 2016 and requires all medicines subject to prescriptions in the EU to be verifi ed against a pan-European database during distribution along the supply chain and immediately before being dispensed to the patient. The Regulation sets out the requirements pharmaceutical manufacturers are expected to adopt before the deadline of 9 February 2019, by which time the ability to provide full operational end-to-end verifi cation of medicinal products across the EU is expected. The deadline may seem far off but much work is required by companies and their various stakeholders to ensure systems have been put in place and are in full working order.

9



common vision to protect patients, secure the legal supply chain and be proactive as market partners, the European Medicines Veri� cation System (EMVS) was designed to meet the requirements of the FMD by the very people who will use it day to day. Responsibility of the European hub, which links the national veri� cation systems throughout Europe, is also assumed by the EMVO. To date Germany is the � rst Member State (MS) to have contributed fully to the improved Europe-wide veri� cation system under EMVO through its securPharm system. Other countries have the option of joining an already existing veri� cation infrastructure designed by the EMVO referred to as the national Blueprint System Template.4

European Medicines Veri� cation System (EMVS) modelThe overall model designed by the EMVO for data exchange and veri� cation between the various stakeholders in the supply chain includes the manufacturers, national repositories of the member states (MS), wholesalers, pharmacies, distributors, brokers and parallel importers/distributors. Essentially, manufacturers (which include primary and secondary packagers as well as contract manufacturers) will conduct serialisation and then push the data to either the national repository of the MS or to a European hub. The hub in turn acts as a switch that will route the serialisation information down to the national repository where stakeholders within the supply chain will use the data to check the product’s authenticity.

Manufacturers will manage serialisation among themselves, the packaging sites and the contract manufacturers by installing coding into their lines. One aspect of the FMD which will require careful attention is that contract manufacturers o� en manufacture for multiple marketing authorisation holders (MAHs), therefore careful consideration will be needed to ensure this is implemented with due order.

The MS national repository system will contain all the serialised information and is set up by MS stakeholders. Although this can also be set up independently, it would require additional � nancial input to harmonise it with the other national repositories.

The European hub, governed by the EMVO, routes information to the national repositories and is not a database; rather, it connects the repositories to form a “central unit” allowing data to flow

between them. This design and aspect of direct provision to the national system is mandated by the delegated regulation.

Technical requirements of serialisation dataThere is an extensive amount of product data to be generated by the MAH about the product which includes the product code, name, form, strength, pack type/size, target market, MAH name and address and wholesalers authorised by the MAH to distribute on its behalf. In addition to this, requirements for serialisation (as mandated by the regulation), include a UI in the form of a 2-D barcode (data matrix ECC200) which is required to be of a minimum print quality. This information and the following should also be provided on the pack in human-readable format: 1 Manufacturer product code less than 50 characters (ISO compliant

to ISO 15459) 2 Serial number (maximum 20 characters; randomised)3 Batch number4 Expiry data5 Optional: National reimbursement number.

2-D barcodes are the only form of barcodes permitted for authentication and identi� cation of a medicinal product; quick response (QR) codes can be used, but not for the purposes of veri� cation. Further, in the case of packs made for more than one market with multiple languages which may have di� erent national reimbursement numbers, then multiple UIs can be used. Much attention should be paid to implementing the serialisation and 2-D barcodes, which has a big impact on the manufacturing process, and testing these codes before the deadline of 9 February 2019 is absolutely essential. In order to guarantee the uniqueness and traceability of the product pack, the serial number cannot not be re-used until one year a� er expiry or � ve years a� er insertion into the supply chain for sale (whichever is longer), a logic which will need to be built into the serialisation system to avoid duplication.

Distribution models A simpli� ed illustration of a typical distribution model can be seen in Figure 1 which shows what happens in a “normal” situation of distribution and veri� cation. Here, a product is serialised and

Figure 1: A basic distribution model.

Pharmaceutical drug manufacturer

EUROPEAN HUB Member state national repository

Wholesaler Pharmacy Patient

Data uploadVeri� cation at dispense

10



the product data described earlier is either sent directly to the MS national repository or to the European hub which then routes the data to the national repository. When the product is sent by the manufacturer to a wholesaler who then distributes to a pharmacy, the pack is then veri� ed and decommissioned at dispensing using the data uploaded by the manufacturer to the repository. Here, the wholesaler is not required to perform risk-based veri� cation as it receives the product directly from the manufacturer, unlike the next scenario. It is also noteworthy that installation of a veri� cation/decommissioning scanning system is the responsibility of the wholesalers and pharmacies.

In the case of more typical of industry practice, the product changes hands several times before reaching the patient, and so Figure 2 illustrates what happens when a supply chain involves multiple wholesalers or distributors. Here, data are uploaded either to the European hub or directly to the MS national repository and the product is sent to the � rst wholesaler directly from the manufacturer. The product then moves to the next wholesaler who is then required to perform risk-based veri� cation before it can be sold onto the pharmacy that performs the subsequent veri� cation/decommissioning on dispensing to the patient. This was identi� ed by regulators as one area which introduced an increased risk of entry of falsi� ed medicines into the drug supply chain, hence the additional step of risk-based veri� cation.

Another identi� ed risk area for suppliers is when products are returned from one wholesaler back to the one it who originally sold it. In this situation when a wholesaler returns the product, the original wholesaler who initially sold the product, on receipt of the product, must � rst perform risk-based veri� cation before the product can be sold again.

Veri� cation by wholesale distributors and pharmaciesRisk-based veri� cation is performed by wholesalers for products they possess which were not received directly from the manufacturer, from a wholesaler who does not hold a marketing authorisation (MA) or for which it is authorised by the MAH to store or distribute on its behalf. The only time, as pointed out by the delegated act, when

veri� cation is not required is if: (1) there is a change in ownership but the wholesaler still possesses the product, and (2) when the product is transferred to another facility owned by the same entity within the same MS. Outside of these situations, risk-based veri� cation is mandatory.

In cases where the product is distributed to bodies such as medical practitioners, veterinarians or veterinary product retailers, dentists, optometrists, paramedics, armed forces or police (civil protection), university researchers, prisons, schools and nursing homes, then the product must be both veri� ed and decommissioned (full list in Article 23). The delegated act provides flexibility to hospitals and pharmacies as to when veri� cation/decommissioning can take place (for example, either at the point of dispensing, which automatically decommissions the product, or as soon as they receive it from the supplier). Once a product has been dispensed and thus decommissioned, it is possible to reverse this only if: (1) reversal takes place in the same place where the original decommissioning took place, and (2) reversal is performed by the same person who was legally authorised to do so, and (3) it is done within ten days of when decommissioning originally took place, and (4) only if the pack has not expired, been recalled or withdrawn, marked for destruction, identi� ed as stolen or supplied to the public.5 Due to the way hospitals use medicines, packs may be opened many times; however, not all of the contents may be used, so in this case they are to be decommissioned when � rst opened.

Parallel importers and distributors Under the FMD, parallel importers (PIs) or distributors now face new regulations. Product requirements for PIs depend on whether the product has been repacked or relabelled, if it has been purchased from someone other than the original manufacturer or it is being sold to companies outside of the EU. As such, dependent on the speci� c requirements, these products will have to undergo either some or most of the mandated aspects of the FMD. New serialisation will be required for any products being introduced into the EU and these data are to be uploaded to the MS national repository similar to the manufacturer’s initial activity; this includes the serialisation

Figure 2: Distribution model with multiple wholesalers.

Pharmaceutical drug

manufacturer

EUROPEAN HUB Member state national repository

Wholesaler Wholesaler Pharmacy Patient

Data uploadVeri� cation at dispenseRISK-BASED VERIFICATION

11



information requirements outlined earlier for the UI. Veri� cation of authenticity before re-entry into the supply chain is required if the safety feature originally placed by the manufacturer is removed due to repackaging the product, if it is purchased from a pharmacy or wholesaler or is also a returned product. Finally, in the scenario where a product is sold to bodies outside the normal supply chain (eg, a veterinarian or dentist; see full list in Article 23) then not only must the products be veri� ed by the PI, but also decommissioned.

One example is when a PI repackages and relabels a product for sale into another EU market. On receiving the product it must � rst be veri� ed and decommissioned by the PI and then it can be repackaged/relabelled, a� er which it would be considered a new product. In this example, the product will need to be serialised again and the data uploaded to the European hub or directly to the national repository of the MS as before.

Exceptions to the rule: White and black listsArticle 54 of the regulation states that: “Medicinal products subject to prescription shall bear the safety features”, and: “Medicinal products not subject to prescription shall not bear the safety features” unless they have been listed in the delegated act by the Commission. Annex I and II of the Regulation (EU) 2016/161 provide two lists, namely, the “white list” and “black list”. The former lists prescription medicines that are exempt from safety features and the latter lists non-prescription medicines which, due to their increased risk of falsi� cation, are required to bear the safety features. Medicinal products in the white list include homeopathic products, radiopharmaceuticals, advanced therapy medicinal products (ATMPs), medical gases, certain solutions, contrast media, allergy tests and allergens. Omeprazole is currently the only non-prescription product present on the black list. Following this, one aspect for manufacturers to take into account is that some products could be classed as prescription medicines in one MS but not in another, so careful consideration will be needed on how this will be built into the serialisation system.

Transitional measuresTransitional measures have been stipulated for products packaged and released for sale on the EU market before 9 February 2019. These measures state that such products may be distributed and sold until their expiry date as long as they are not repacked or relabelled. Countries with serialisation or coding schemes currently in place, which include Belgium, Italy and Greece, have been granted additional transition time to meet the deadline by having the option to defer the application of Articles 1–48 by up to six years. In the June 2016 DIA/TOPRA workshop on Falsi� ed Medicines, there was indication from the Belgian national competent authority (NCA) that it would most likely not utilise this option and would aim to roll out the scheme before this date to “avoid trade hindrance with other countries as protection of patients is priority”.6

Reporting falsi� cationIn cases where tampering is suspected or there is doubt about a product’s authenticity then: (1) manufacturers shall not release the product for sale or distribution, (2) wholesalers shall not distribute, supply or export the product, and (3) pharmacies, hospitals and other persons authorised or entitled to supply medicinal products to the public shall not supply the product to the public. The person suspecting the falsi� cation or tampering shall also immediately inform the relevant NCA.

Repository supervisionThe national repository of each MS will be supervised by the NCA, which will oversee the functioning of any repository physically located in its territory, if necessary by means of inspections. NCAs may also contribute to the repository’s management and participate in the management board of any repository used in their territory. Additionally, reports of supervision activities will be shared with other NCAs, the EMA and the European Commission. It is noteworthy that this supervision and access by authorities is restricted to some � elds of action. MS can audit at European and national level with access to the repository for pack data kept in the national veri� cations system, but this is limited to reimbursement, pharmacovigilance and pharmacoepidemiology purposes only.

ConclusionThe FMD is focused on ensuring that medicines are harder to mimic and their entry into the supply chain is blocked, with attention to the API, safety features, distribution and internet pharmacies. Regulation (EU) 2016/161 on the safety features for prescription-only medicinal products introduces a new approach to the way medicines will be rigorously authenticated in the supply chain. One can appreciate that the FMD covers a whole array of situations which prevents adulteration of medicines along the supply chain, from manufacture right up to the point a patient receives the product. Not only does this protect businesses focused on helping patients, but it ensures that the medicines given to patients are safe, of good quality and e� cacious. Between now and 9 February 2019, the engagement of activities of pharmaceutical manufacturers with their respective stakeholders is extremely important to ensure the success of the FMD; with thousands of manufacturers in each country, this does not leave a lot of time. Those engaged in the falsi� cation of medicines are unfortunately always looking for ways to undermine measures such as those introduced by the FMD. Although at a European level we may have made the entry of falsi� ed products into the supply chain more di� cult, it still exists as a global issue. As such, the FMD can be seen as the paradigm of preventative measures to tackle the issue, with stronger relationships between regulators and industry for the betterment of patient safety in the future.

References1. European Medicines Agency. ‘Falsi� ed Medicines’. Available at: www.

ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000186.jsp (accessed 30 December 2016).

2. European Commission. Commission Delegated Regulation (EU) 2016/161, Offi cial Journal of the European Union. http://ec.europa.eu/health//sites/health/� les/� les/eudralex/vol-1/reg_2016_161/reg_2016_161_en.pdf (accessed 16 December 2016).

3. EFPIA. ‘New Landmark in � ght against counterfeit medicines with establishment of the European Medicines Veri� cation System’. Available at: www.efpia.eu/mediaroom/231/21/New-Landmark-in-� ght-against-counterfeit-medicines-with-establishment-of-the-European-Medicines-Veri� cation-System (accessed 30 December 2016).

4. EMVO European Medicines Veri� cation Organisation. ‘Veri� cation of Medicinal Products in Europe’. Available at: www.girp.eu/fi les/European-Medicines-Verifi cation-Organisation.pdf (accessed 10 Dec 2016)

5. European Commission. ‘Medicines veri� cation in Europe: What to expect in 2019’. Available at: http://ec.europa.eu/health//sites/health/� les/� les/falsi� ed_medicines/201602_stakeholders_workshop_� nal.pdf (accessed 23 December 2016).

6. S Qadri. ‘DIA-TOPRA Workshop on Falsi� ed Medicines’, Regulatory Rapporteur 2016;13:19-21.

12



IntroductionThe Falsi� ed Medicines Directive (FMD) states that a falsi� ed medicinal product means a medicinal product with a false representation of: (a) its identity, including its packaging and labelling, its name

or its composition as regards any of the ingredients including excipients and the strength of those ingredients;

(b) its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorisation holder; or

(c) its history, including the records and documents relating to the distribution channels used. Importantly, this de� nition does not include unintentional quality

defects and is without prejudice to infringements of intellectual property rights.

This paper focuses on the potential penetration of the legitimate supply chain by falsi� ed medicines and does not cover subjects such as the illegal import of unlicensed medicines, leakage of licensed medicines into the illegal supply chain and public education campaigns, etc.

The motivation to falsify medicines is the signi� cant � nancial reward with what appears to be low risk of detection with relatively low criminal sanctions, eg, under the Human Medicines Regulations 2012, a maximum of two years imprisonment and/or an unlimited � ne. However, there is usually more criminality involved in the process of falsifying medicines, such as money-laundering and fraud, both of which carry signi� cant criminal sanctions with up to ten years’ imprisonment. In addition, the ability of courts to con� scate

the proceeds of crime is a further deterrent. The � nancial rewards associated with falsi� ed medicines means

that they have come to the attention of Organised Criminal Groups (OCGs), to the shock of some wholesale dealers who have unwittingly purchased medicines from them. The powers that are available to the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) include:

Investigation and prosecution Entry to commercial premises/private dwellings Inspection seizure Surveillance powers under the Regulation of Investigatory Powers Act (RIPA) 2000

Pursuing the proceeds of crime under the Proceeds of Crime Act (POCA) 2002.To identify the operators involved in falsi� cation of medicines,

the MHRA has highly experienced intelligence analysts to identify the source of falsi� ed medicines, highly quali� ed � nancial investigators to “follow the money trail” and highly experienced investigating o� cers to determine the audit trail of the falsi� ed medicines. Once the operators have been identi� ed, they may be interviewed under caution (Police and Criminal Evidence Act 1984) by MHRA investigators. In serious cases, the operators may be arrested � rst by the National Crime Agency (NCA) or the local police on behalf of the MHRA.

The “Medicrime” ConventionThe Council of Europe developed the “Convention on the counterfeiting of medical products and similar crimes involving threats to public health” (known as the Medicrime Convention), the � rst international treaty criminalising acts involving illegal activity with medical products. The Convention was opened for signature in Moscow in 2011, and nine countries have rati� ed it. The Convention’s de� nition of the term “counterfeit” in Article 4(j) is “a false representation as regards identity and/or source”.

How does the MHRA investigate falsi� ed medicines?Aspects involved in the investigation of falsi� ed medicines by the MHRA include the use of intelligence, � nancial investigations, enforcement investigations, prosecutions, and European and international cooperation and communication. Each of these aspects is described in more detail below.Intelligence. The MHRA falsi� ed medicines intelligence analyst is responsible for providing a strategic worldwide overview of the threat posed by falsi� ed medicines to the UK and the EU. In order to do this the analyst collates and evaluates falsi� ed medicines cases from around the world in order to inform a threat assessment which seeks to identify:

Which medicines are most likely to be falsi� ed The origin of these falsi� ed medicines and who manufactures them The methods with which these medicines are most likely to enter

Insights on falsi� ed medicines in the legal supply chain

AuthorsPaul Hargreaves, Expert Inspector, and Christopher Morris, Intelligence Analyst; Medicines and Healthcare products Regulatory Agency, UK.

KeywordsFalsifi ed medicine; Falsifi ed Medicines Directive (FMD); Counterfeit; Supply chain; Investigation; Intelligence; Cooperation; Enforcement; Prosecution.

AbstractThe Falsifi ed Medicines Directive introduced an expanded defi nition of what used to be called counterfeit medicines. This new comprehensive defi nition has enabled EU regulatory agencies to classify more accurately the nature of the falsifi cation of the medicine. Examples are given of the many diff erent types of falsifi cation that have been identifi ed over the past few years. In most cases, the falsifi cation has been identifi ed before it reaches retail or patient level.

13



the UK and EU supply chains The routes taken by these medicines as they are transported from source to the end user

Any emerging trends in relation to the manufacture, transport and supply of falsi� ed medicines.As a result of this analysis, a “watchlist” of medicines is

produced which is then taken to the falsi� ed medicines stakeholder group. This group comprises law enforcement agencies, trade associations and industry representatives, to review/add value before agreement is reached. This list is circulated to bodies such as the UK Border Force so they are aware of products likely to be falsi� ed. The list is also used for market testing by inspectors who will take samples and submit them to the MHRA’s laboratory for authenticity checking. When speci� c falsi� ed medicines cases arise, the intelligence analyst is also responsible for:

Identifying the source of the falsi� ed medicine Establishing if any more of this falsi� ed medicine has potentially been supplied elsewhere

Assisting investigators with any criminal proceedings which may arise

Supplying and sharing any relevant and necessary information with appropriate regulatory and enforcement agencies within the UK and overseas.There is a range of other tactical options to identify falsi� ed

medicines which include, inter alia, whistleblowers, covert human intelligence sources (CHIS), test purchases, monitoring of internet sites, undercover operatives, surveillance and � eld intelligence. Financial investigations. Financial information can be a useful part of any investigative strategy, including those which seek to tackle criminality targeting the pharmaceutical sector. The assistance of a � nancial investigator (FI) should be considered at the outset of all investigations, speci� cally including those crimes motivated by � nancial gain or which involve a � nancially related modus operandi. Financial sources of information can support and impact many lines of enquiry that are set in relation to victims, witnesses and crime scenes, as well as the suspects. Evidence secured by an FI may assist in the following:

Identifying motives, associations and links to people and places Locating or identifying suspects, witnesses or victims Providing information on a suspect’s movements via the use of proactive, covert use of � nancial information

Identifying o� ences committed, including the potential tactical options a� orded by the use of money laundering o� ences (Proceeds of Crime Act 2002)

Identifying the use of other services such as phones, transport and amenities relevant to the case

Identifying assets and expenditure which are capable of con� scation to the bene� t of victims and the Crown.The use of an FI may signi� cantly reduce investigation costs and

save time, and there is also a reduced risk of collateral intrusion impacting on third parties not related to the criminality being examined.

It is virtually impossible to live in the UK without leaving some kind of � nancial footprint. In an investigation concerning falsi� ed medicines this will help identify cash movements between conspirators, physical movement or relevant actors, and the illegitimate creation of wealth which a Court may well have the power to remove. Enforcement investigations. On noti� cation or suspicion of falsi� ed,

counterfeit or unlicensed medicines being made available to the public – either through the legitimate supply chain, through website advertisements or other methodologies – an investigation will be raised. This will be allocated to an experienced MHRA investigator who will take steps to establish the veracity of the report.

Once this has been achieved then steps will be taken to obtain a sample of the product for analysis by MHRA-retained scientists or legitimate manufacturers. The sample will be obtained either by way of a test purchase or by physically visiting the source of the product. If established that the product is being supplied from a retail outlet then powers conferred by the Human Medicines Regulations 2012 permit entry and seizure of the product. If this is not the case then a warrant of entry will be applied for through the Magistrates Court.

Having seized the product and veri� ed that it is falsi� ed, counterfeit or unlicensed then the supplier will be interviewed under caution in accordance with the Police and Criminal Evidence Act 1984. Any o� ences that are established will be considered and, depending on the severity of the criminality uncovered, those responsible for the supply or the chain of supply will be dealt with either by way of bringing then into compliance with regulations and an o� cial warning, or criminal proceedings through the courts. Prosecutions. MHRA enforcement investigators prepare � les for the Crown Prosecution Service (CPS). The CPS decides whether or not a person or company should face prosecution for dealing in falsi� ed medicinal products. First of all the CPS must identify what, if any, o� ences have been committed. Regulations 37(11) and 43(13) of the Human Medicines Regulations (HMR) 2012 impose duties on manufacturer’s licence (MIA) holders and wholesale dealer’s licence (WDA) holders to inform the MHRA if they have grounds to know or suspect that a product is falsi� ed. Failure to do so is an o� ence. The Trade Mark Act 1994 creates further o� ences which may be committed by a person who possesses or supplies falsi� ed medicines. The CPS will consider if the evidence in the � le is su� cient to provide a realistic prospect of conviction for any of these o� ences. If it does then the CPS will go on to consider whether it would be in the public interest to prosecute the suspect. A prosecution will only be commenced if the answer to both questions is “yes”. Counsel may assist the CPS in reaching its decision and will usually represent the prosecution in the event that a falsi� ed medicines case goes to trial. Trade Mark Act o� ences carry up to ten years imprisonment and prosecuting counsel will address the judge on matters relevant to determining the appropriate sentence including the National Sentencing Guidelines.European and international cooperation and communication. E� ective cooperation and communication between drug regulatory agencies and enforcement agencies is essential to combat the scourge of falsi� ed medicines worldwide. Examples of this include:1 Permanent Forum on International Pharmaceutical Crime (PFIPC).

This is an international enforcement forum aimed at protecting public health through the exchange of information and ideas to foster mutual cooperation.

2 European Directorate for the Quality of Medicines (EDQM). The Committee of Experts on minimising the public health risks posed by counterfeiting of medical products and related crimes (CD-P-PH/CMED) is responsible for developing and promoting the implementation of multi-sectorial risk prevention and management strategies on counterfeit medical products. The Committee brings together healthcare and law enforcement o� cials from Council of Europe Member States, European institutions, pharmaceutical industries and trade, and international organisations. There

14



are several work strands including risk communication and an extensive training programme.

3 Europol and Eurojust. Europol provides a forum for the exchange of information with concerned member states and other involved countries to assist in further investigations when falsi� ed medicines have been identi� ed. It also provides assistance by deploying a mobile o� ce for real-time analysis and cross-checking of data during enforcement operations. Eurojust has a coordinating role which facilitates the swi� exchange of information, resolution of legal issues and an overview of the results from the enforcement action that are tailor-made for the needs of the involved judicial authorities.

4 INTERPOL. Criminals involved in pharmaceutical crime operate through informal global networks, as well as through traditional organised crime groups. INTERPOL is tackling these criminal rings by bringing together key players to foster inter-agency cooperation between police, customs and health regulatory agencies. INTERPOL provides expertise in intelligence gathering, planning and implementing an operation together with assisting with legal issues for cases that are brought to court.

5 World Health Organisation (WHO). Substandard, spurious, falsely labelled, falsi� ed and counterfeit (SSFFC) medical products. The WHO Member State Mechanism is the global forum at which countries can convene, coordinate, decide and organise activities to address SSFFC medical products. The Global Surveillance and Monitoring System for SSFFC medical products was launched in 2013 and is open to all member states, currently 113 countries, to provide technical support in emergencies, link incidents between countries and issue WHO medical product alerts.

6 Heads of Medicines Agencies (HMA) Working Group of Enforcement O� cers (WGEO). This was established in 2007 by the HMA to contribute to the protection of human and animal health and welfare. The primary aim of the WGEO is to:• Promote liaison and cooperation between member states and

agencies with the purpose of sharing information• Identify emerging threats to the legal manufacturing and

distribution chain• Coordinate communications and initiatives, exchanging

information with relevant working parties/groups and organisations

• Provide a valuable network for European counterparts to build trust, share experience, best practice and expertise relating to pharmaceutical crime

• Deliver a practical training platform – largely related to the four work-streams: wholesale and distribution; internet (illegal supply of medicines); falsi� ed medicines and training and education.

In 2016, WGEO members reported 11 incidents of falsi� ed medicines in their territories and 12 incidents of stolen medicines. While most of the stolen medicines were either anabolic steroids used by bodybuilders and controlled drugs, such as morphine, interestingly, there were a number of vaccines stolen. It is likely that these vaccines were intended to re-enter the legitimate supply chain as falsi� ed medicines by way of their history and distribution channels used.

MHRA operationsOperation Singapore. The largest known breach of the legitimate supply chain in the EU occurred in 2007 in which counterfeit/falsi� ed medicines reached patient level. The three di� erent medicines involved were intended for the treatment of psychosis, prostate

cancer and heart disease, and 72,000 packs (more than two million doses) penetrated the UK supply chain. The MHRA seized 40,000 packs before they reached pharmacies and another 7,000 packs were retrieved through Class 1 recalls. Unfortunately, 25,000 packs reached pharmacies and patients. The products contained between 50% to 80% active substance and unknown impurities and unknown dissolution pro� les.

The products were manufactured in China, shipped to Hong Kong and then to Singapore. They were then shipped and customs-cleared in Belgium. From there, they were transported by road to the UK. The retail value of the goods was £4.7 million. Five men were arrested and subsequently sent for trial at Croydon Crown Court, the charges being: conspiracy to defraud; trademark violations; Medicines Act o� ences; and Companies Act o� ences. Peter Gillespie, an ex-pharmaceutical parallel importer and wholesale dealer was sentenced to eight years in prison for fraud and money-laundering o� ences. Operation Handcra� . In February 2016, a joint activity was undertaken by Her Majesty’s Revenue & Customs, Greater Manchester Police, Home O� ce Visas and Immigration, the MHRA, Trading Standards and the Intellectual Property O� ce, with more than 100 o� cers involved. The purpose was to target illegal activity involving intellectual property rights being conducted in what has been termed the UK’s “Counterfeit Street”, based in the Cheetham Hill area of Manchester and consisting of a few streets containing shops and warehouses supplying counterfeit consumer goods across the North West. The MHRA was involved as intelligence suggested that unlicensed lifestyle medicines were being openly traded from shops in the area. Ten arrests were made, with six for immigration o� ences. The items seized included cigarettes, tobacco, medical tablets – in total 20,000 tonnes of counterfeit goods. The MHRA seized around 50,000 doses of medicines, mostly from vans and cars parked in the street being used as untraceable storage sites.The MHRA used a specially trained “sni� er dog” to sni� out the medicines. Table 1 highlights the list of products seized during this operation.

Case studiesCase study 1: False representation of history. A high-value medicine was being shipped and was temporarily stored in a secure warehouse on a Saturday night. Thieves broke into the warehouse, removed the CCTV server so that they could not be identi� ed and then stole the medicine.

Table 1: Products seized as a result of Operation Handcra� .

Product seized Doses Value

Zoplicone 7.5mg 16,580 £16,580

Kamagra Jellies 4 £12

Sildamax 7,630 £21,990

Diazepam 10mg 23,810 £23,810

Citalopram 20mg 196 £196

Sildigral 10mg 10 £30

Viagra 1,700 £35,000

Totals 49,930 £97,618

15



By midday the following Monday, the medicine was being sold to licensed wholesale dealers at a large discount. A “non-urgent information” (NUI) communication was immediately sent to all wholesale dealers alerting them to the situation. A small quantity entered the legitimate supply chain and was quarantined. The remaining medicine was subsequently recovered some weeks later from a parked van following receipt of information.Case study 2: False representation of a medicine’s composition. A hospital oncology clinic in Europe administered high-value oncology medicines on a certain day each week. The clinical waste bins were searched and empty vials, cartons and leaflets were stolen. The empty vials were � lled with water and the plastic caps were stuck with glue back onto the vials. The vials entered the legitimate supply chain but were quickly identi� ed as the real product was a powder, not a liquid. Subsequent investigations found that 13 bogus wholesale dealers had been involved in the distribution of this falsi� ed medicine to six licensed wholesale dealers.Case study 3: Counterfeit erectile dysfunction (ED) medicine.Operation Daniel was an investigation and prosecution of a family and friends criminal enterprise selling a counterfeit ED medicine. The money laundered or obtained through fraud by all the defendants totalled £8,444,896. On 13 April 2015 at the Old Bailey in Central London, 12 individuals received sentences ranging from six years imprisonment to suspended sentences to include unpaid work.Case study 4: False representation of a medicine’s identity, name and ingredients. An antineoplastic medicine in capsule form was dispensed to patients in a retail pharmacy. The empty bottles were

re� lled with calcium capsules and resealed by the pharmacist and were then sold back into the legal supply chain. The bottles were then parallel exported where the substitution was identi� ed.Case study 5: False representation of a medicine’s packaging and labelling and its history relating to the distribution channels used. An HIV/AIDS medicine was distributed in Africa. A signi� cant quantity was then misappropriated, relabelled and repackaged with a current EU batch number and expiry date. A patient in a European HIV/AIDS clinic noticed that the medicine was of a darker colour than normal. The subsequent investigation showed that the repackaged medicine had been shipped from South Africa to Switzerland by air. It was then transported to Antwerp and stored in an unlicensed commercial warehouse. Small quantities were then transported by road to licensed wholesale dealers along with falsi� ed documents with regard to the medicine’s provenance.

ConclusionWhile the risk of falsi� ed medicines penetrating the legitimate supply chain to patient level is very low, the � nancial gains are substantial and so there are continued attempts being made to penetrate the supply chain. The EU Falsi� ed Medicines Directive (2011/62/EU) was introduced to lower the risk and raise awareness, but it is only part of the story in the � ght against falsi� ed medicines. Operationally, it is the inter-agency and inter-country cooperation through Europol, INTERPOL, WGEO, etc, that is at the forefront of the detection and prevention of falsi� ed medicines from penetrating the legitimate supply chain.

2–4 October, Park Plaza Victoria Hotel, London, UK HUMAN PHARMACEUTICALS | MEDICAL DEVICES | VETERINARY MEDICINES

The only conference entirely focused on healthcare regulatory affairs comes to London in 2017.

Find out more and register your interest: toprasymposium.org/rr

LONDONTOPRA Annual Symposium 2017

Collaboration | Strategies | SolutionsGlobal regulatory approaches to improve healthcare

Organised in partnership with the Medicines and Healthcare products Regulatory Agency

SYMPOSIUM BOOKINGS NOW OPENSave £165 with our early booking rate, valid until 30 June 2017

16

For more information or to book your place visit topra.org/rr-nmdl17

EXPLORE THE IMPLICATIONS OF THE NEW DEVICE & IVD REGULATIONS THE NEW EU MEDICAL DEVICE REGULATIONSOne-day course | 22 May 2017Radisson Blu Royal Hotel, Brussels, Belgium

2017 marks the introduction of a major change to the way medical devices and IVDs are regulated in the EU. Prepare for and explore the strategic implications of the new EU medical device regulations. Speakers from the EU Commission, the Dutch device ministry, the German Federal Ministry of Health, Competent Authorities, notified bodies, lawyers and industry will discuss the new regulations covering medical devices and IVD medical devices and the imminent changes to the regulations as well as the impact on current and future resources in industry and notified bodies.

The afternoon will break into small groups to discuss the concerns raised throughout the morning and to think strategically about how these concerns might be addressed. Each group will be led by experts.

6

17


Meet the regulators – Interview

Q: Could you tell our readers about your background, what attracted you to the regulatory arena and how you came to join the agency?

A: A� er completing my graduate studies in medicinal biochemistry and obtaining a PhD at the Friedrich Schiller University Jena, I spent three postdoctoral years in Canada at the National Research Council of Canada and McGill University Health Centre. Following this I gained valuable work experience in Croatian government institutions in the � eld of European integrations, as well as at one of Croatia’s leading pharmaceutical companies. This path naturally led me to the � eld of regulating medicines. I joined HALMED from the � rst day of its establishment in October 2013, was the � rst Head of HALMED and remained in this position until November 2011. In November 2015 I was elected Head of Agency for the third mandate.

Q: What does your current role involve, and what are your favourite aspects of this role?

A: My responsibilities as Head of HALMED primarily involve protecting and promoting public health through the regulation of medicinal products and medical devices. Currently, HALMED has more than 200 employees, and the majority are highly educated and competent experts in the � eld of pharmacy, medicine, biochemistry and other natural sciences. My role encompasses a wide range of tasks aimed at ensuring the proper functioning and continuous improvement of HALMED, while addressing the challenges in di� erent areas of the agency’s work. Croatia joined the EU quite recently – within the past � ve years – so positioning ourselves in the EU regulatory network and consolidating our activities are crucial activities at the moment. My favourite aspect of the role I have been entrusted with is working with people, seeing the enormous potential of their competencies and talents that can be driven with the appropriate motivation and encouragement. My greatest satisfaction is seeing that HALMED is developing in the right direction and is truly ful� lling its task of protecting public health.

Q: What changes have you introduced to the agency since you took on the role, and what are your aims for future changes?

A: Having been involved with HALMED since its establishment, I have experienced all stages of its development. This is why it makes me quite content to see it growing, maturing and following the path of success which has been paved from the beginning. Since I took on my role as head, we have been taking steps towards the further optimisation and consolidation of administrative procedures, so as to ensure faster availability of medicines to our patients. Also, some units have been

reorganised with the aim of optimising the agency’s activities, and our next steps will include even greater involvement in EU procedures. Moreover, we will work towards strengthening our teams of assessors and achieving a greater level of transparency in our procedures, while also consolidating our established activities in order to ensure long-term sustainability of the institution.

Q: How has your agency been a� ected by the increasing requirements for transparency in regulatory processes?

A: I consider transparency to be one of the crucial aspects of ensuring a well-functioning regulatory system, building greater trust in the decisions made by regulatory bodies. I’m glad to say that HALMED has fully implemented the transparency requirements of Directive 2001/83/EC and its amendments. We are proactive in publishing all relevant information from HALMED’s scope of work on our website. In 2015 we redesigned and segmented our website to make it more user-friendly and to make this immense amount of information more transparent and accessible. For quite some time we have been publishing the agendas and minutes of our scienti� c committees, the committee members’ CVs and declarations of interest (DoI) and the outcomes of our competitions etc. We are fully aware of our task of informing our stakeholders, thus we aim to provide them with all the information they need. They have increasingly recognised this, perceiving us to be a trustworthy source of information in the � eld of medicines and medical devices. Lately we have also been receiving an increased number of requests based on the Freedom of Information Act, primarily related to the safety and quality of vaccines. We take these requests very seriously and fully acknowledge the citizens’ rights to information.

Q: What are your views on the centralised, decentralised and mutual recognition procedures (CP/DCP/MRP)?

A: These procedures undoubtedly bring many bene� ts to member states and their citizens; they contribute to the faster availability of medicines and provide a number of opportunities, particularly for smaller member states such as Croatia. Since Croatia joined the EU in July 2013 and began participating in DCPs and MRPs, marketing authorisation holders (MAHs) based outside of Croatia have increasingly considered our market for placement of their medicinal products. At the same time, Croatian MAHs received easier and faster access to a wider market for their activities.

From a regulatory perspective, these procedures provide a harmonised view of member states and common decision-making. Furthermore, they require a single procedure and one commonly

Investing in qualityMr Siniša Tomić, PhD, Associate Professor, Head of the Agency

for Medicinal Products and Medical Devices (HALMED), Croatia,

discusses the agency’s methods to position itself in the EU

regulatory network. Interview conducted by Angela Stokes,

Senior Director, Global Regulatory Consulting, INC Research

18



accepted dossier for placing a medicinal product in more member states, which certainly contributes both to e� ciency and to faster availability of medicines. These procedures also bring closer cooperation of national regulatory bodies, exchange of information and an important flow of knowledge and experience in the process. However, harmonisation of member states in MRP and DCP could be developed even further. Moreover, the availability of CP medicines in small member states remains an important issue that should continue to be addressed in the future, and hopefully resolved in the shortest possible time.

Despite being part of the EU for a relatively brief period of time, Croatia and HALMED have so far managed to successfully participate in a signi� cant number of common EU procedures. In doing so, we have strived to maintain a high quality of assessment reports and expert questions for MAHs during these procedures. In addition, we have strictly adhered to timelines and maintained the competitive prices of our procedures, which has been recognised by the applicants. We have also successfully taken up our role in a couple of CP procedures so far. Our representatives are active members of the Committee for Medicinal Products for Human Use (CHMP), the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), the Pharmacovigilance Risk Assessment Committee (PRAC) and all other relevant European Medicines Agency (EMA) and Heads of Medicines Agencies (HMA) scienti� c committees, working groups and parties.

Q: What are your views on the planned new medical devices regulations?

A: I think that the medical devices legislation will result in an improved, more monitored system which will ensure more information for the users along with contributing to the safer use of medical devices. In my view, these changes to the legislation will have a positive impact on the overall transparency of the system. I also commend the shi� to a more centralised regulation of medical devices as it will provide a better overview of the speci� c situation on the markets for each member state, allowing for more pro� cient market surveillance and improved coordination of member states in this � eld. I believe that making the European Databank on Medical Devices (EUDAMED) publicly available will be extremely bene� cial, as it will allow users to quickly and easily verify if the medical device is legally placed on the market. Also, in line with the approaching changes and our continuous e� orts, we are preparing to make the Croatian vigilance system even stronger.

Q: What is the average length of time it takes the agency to assess marketing applications and approve applications, variations and renewals?

A: We are putting signi� cant e� orts into complying with the set timeframes, and responding to applications in the fastest and highest quality manner possible. As a result, all of the applications we receive for granting marketing authorisations are assessed and either approved or rejected within the timeframe. In this way we strive to enable applicants to place their medicines on the market as soon as possible following a positive scienti� c assessment. We are especially proud of our promptness in the national phase of MRPs and DCPs.

As for variations, we are all aware of the high number of applications that are being submitted to the national agencies. Despite a certain backlog – which we are reducing – we make sure that all variations that could a� ect the medicinal product’s availability on the market are resolved within the timeframe. Our e� orts can be seen through the number of variations we completed last year, which exceeded the

number of applications received. We plan to maintain this successful approach in the future.

Q: Does your agency conduct health technology assessment (HTA) or is there a separate body that carries out economic assessment of medicinal products? A: Economic assessment of medicinal products in Croatia is done by the Agency for Quality and Accreditation in Health Care and Social Welfare, which is the national body responsible for the process of assurance and improvement of healthcare, accreditation in healthcare and HTA. However, HALMED cooperates with the agency and provides full support where necessary.

Q: Do you have a strategy to combat the distribution of falsi� ed/counterfeit medicines? A: In order to combat this danger in Croatia, HALMED has established a strong collaboration with the Ministry of Health, the Customs O� ce and the Ministry of Interior A� airs. Thanks to our continuous e� orts, no counterfeit or falsi� ed medicine has ever been found in the legal distribution chain in Croatia.

HALMED is also actively included in INTERPOL’s Operation Pangea, and was heavily involved in signing the Council of Europe’s MEDICRIME Convention. Furthermore, we regularly participate in public campaigns raising awareness of the risks posed by counterfeit and falsi� ed medicines. For years we have been educating patients about safety concerns with the online sale of medicines, instead advising them to buy medicines exclusively at authorised medicines sales points, where they are certain to receive approved e� cient, safe and quality medicines. Currently, the law that would allow online pharmacies to operate in Croatia has not yet been put in place. As soon as this happens, we aim to conduct a public educational campaign promoting veri� ed online pharmacies and warning patients about the dangers of falsi� ed medicines.

Q: Are there any important updates to your country’s legislation that we need to keep up-to-date with?

A: We plan to continue keeping up with the changes in the EU legislation and thoroughly transposing them into our laws and bylaws. In addition, we are in the process of introducing minor amendments to our law on granting marketing authorisations for medicinal products, with the primary aim of improving the process of dossier submission.

Q: What do you see as the biggest challenges facing your agency in the next � ve years? What are your key objectives?

A: Taking into account our public health role, I strongly believe that we need to engage more in � nding solutions for achieving sustainability of our regulatory system. Firstly, I believe that we can, and should, do more in relation to optimising and streamlining our administrative procedures, as this in turn lowers the cost for the users of HALMED’s services. In this way, we can facilitate the position of manufacturers and MAHs in the current economic situation, bearing in mind the need for ensuring patients have timely availability of e� ective and safe therapies. This is why we submitted a proposal for the simpli� cation of administrative procedures to the Ministry of Health.

At the same time, we have to be more actively involved in EU procedures. An absolute prerequisite in this regard are competent experts, who will be able to conduct the most complex tasks and

19



assume even greater responsibility, and whose development will follow the demands of an increasingly competitive market. We have been eagerly working on the specialisation and professional development of our assessors and other experts, and we will certainly continue to invest in the education and training of HALMED’s employees.

Q: What have been your agency’s key successes to date? What have you been most proud of? A: In my opinion, Croatia has a very good medicines regulatory system. Many segments of HALMED’s activities have been identi� ed as good practices both on a European and global scale. In particular, I would like to emphasise the orderliness of our system, our compliance with the EU acquis [the body of common rights and obligations which is binding on all EU member states] and our agency’s excellent preparation for functioning in the integrated EU arena. Our extensive long-term preparations resulted in HALMED’s successful involvement in the EU authorisation procedures; almost immediately a� er joining the EU we managed to fully adopt the new tasks and our role in the network. In this way we have been able to ensure that medicines and medical devices that reach our citizens are safe, e� ective and of high quality. Without doubt, the most important factor determining success has been HALMED’s employees, who have been doing an amazing job. Q: How closely does your agency work with the EMA and the US FDA? A: We work very closely with the EMA and actively conduct all our related tasks. We had already begun our cooperation in 2006, long

before Croatia’s accession to the EU. Our experts are now members of all the EMA committees and a great number of its working parties. We take part in assessments and referrals, take up rapporteurships, co-rapporteurships and peer reviewing. We actively participate at HMA meetings along with other national competent authorities (NCAs), where we host the Benchmarking of European Medicines Agencies Steering Group (BEMA SG). Additionally, we have our national experts seconded to the EMA. Cooperation with the US FDA is primarily carried out in the � eld of good manufacturing practice (GMP) inspections through the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S).

Q: Who is your role model, and why? A: I do have some inspirational � gures, but the greatest inspiration comes from my toughest failures, experiences and capabilities. I would have to say that in the pre-EU period HALMED was greatly inspired by the Spanish Medicines Agency which was our partner agency in a Twinning Light Project aimed at strengthening our capacity.

Q: And � nally, on a more personal note, what is your favourite holiday destination? A: Luckily, Croatia has a variety of interesting sites and natural beauty, so there are plenty of places to choose from. In summer one can stay in the mountains and take a trip to the coast or islands during the day. Personally my favourite destinations are Gorski Kotar in Croatia’s hinterland and the Island of Korčula in the south.

TO DO LIST 2017Join the gym KSpring clean the house G

eat healthy nGet a new qualification J

Become a TOPRA postgrad ASAP!

Turn your ‘to do’ into a ‘want to’Join a select group of highly qualified regulatory experts and become an extremely sought-after regulatory professional, with knowledge that makes you stand out from your non-qualified peers. We can help you broaden and develop your specialism with a TOPRA postgraduate certificate, diploma or MSc – a qualification that will take into account your work-life balance and help you get 2017 off to a great start.

Take the next step by visiting topra.org/rr-nextstep17

IN PARTNERSHIP WITH THE UNIVERSITY OF HERTFORDSHIRE

20


Pharmacovigilance

IntroductionReferral procedures are used to resolve issues concerning the safety or bene� t–risk balance of medicinal products authorised in the EU. In a referral, usually the medicinal product(s) is “referred” to the European Medicines Agency (EMA) so that a scienti� c assessment is conducted, leading to a recommendation for a harmonised position across the EU. A referral procedure can be initiated by the European Commission (EC), the EMA, and any EU member state (MS) or by the marketing authorisation holder (MAH). The referral procedures are

described under Articles 32, 33 and 34 of Directive 2001/83/EC (as amended), Article 13 of Regulation No 1234/2008/EC and Article 20 of Regulation No 726/2004/EC.2,3,4 The referral procedures are summarised in Table 1.5

Pharmaceutical legislation has created a binding EU arbitration mechanism that may be implemented on the basis of the following articles:2,3,4

Article 13 of Regulation No 1234/2008/EC. Introduced in January 2010 and replaced the Article 6(12) referrals. Initiated because of disagreement between MS following a Type II variation or worksharing procedure for nationally authorised medicines, within 30 days on the grounds of “potential serious risk to public health”. The matter is initially referred to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for consideration. If the issues can’t be resolved by the CMDh, it is then referred to the Committee for Medicinal Products for Human Use (CHMP).3,5,6,7

Article 20 of Regulation No 726/2004/EC. Initiated by the Commission or MS in case of manufacturing or quality or safety issues for centrally authorised medicines. Safety-related issues are referred to the PRAC for recommendation before a CHMP opinion is adopted.4,5,8

Article 29 (4) of Directive 2001/83/EC, as amended. Initiated because of disagreement between MS in the mutual recognition or decentralised framework on the grounds of a “potential serious risk to public health”.2,5

Article 30 of Directive 2001/83/EC, as amended. Initiated to obtain harmonisation of divergent decisions within the EU for nationally authorised medicines.2,5

Article 31 of Directive 2001/83/EC, as amended. Initiated where the interests of the EU are involved in relation to quality, e� cacy and safety/risk to public health.2,5

Article 107i of Directive 2001/83/EC, as amended. Initiated to obtain a CHMP opinion further to the suspension or revocation of the marketing authorisation (MA) of a medicinal product in any MS as a result of pharmacovigilance data.5 Introduced in July 2012 and replaced the Article 36 referrals and Article 107 procedures. An MS or the Commission can also initiate an Article 107i referral if it is informed by the MAH that it has interrupted supply of a product to the market, has taken action or intends to take action to withdraw a product from the market, or is not planning to renew an MA for safety reasons. The PRAC is involved in the assessment of Article 107i referral procedures.5

Since publication of the referral article in 20071 there have been a number of changes to the legislative environment of the EU pharmaceutical industry. In January 2010, the new variation legislation (Regulation No 1234/2008/EC) was introduced “in order to establish a simpler, clearer and more flexible legal framework, while guaranteeing the same level of public and animal health

A review of developments in the EU referrals procedure

AuthorsAnne Lenihan, Director Regulatory Aff airs, Pfi zer; Vincent Wek, Bluefi nch Medical; Ewa Filipowska, Senior Manager, Regulatory Aff airs, Pfi zer; Sophie Van de Leest, Director Regulatory Aff airs, Pfi zer; Ashley Dukes, Industrial Trainee, Regulatory Aff airs, Pfi zer; Ciaran Virk, Industrial Trainee, Regulatory Aff airs, Pfi zer; Rachel Hea� eld, Industrial Trainee, Regulatory Aff airs, Pfi zer; Phillip Cogley, Industrial Trainee, Regulatory Aff airs, Pfi zer; Samuel Dixey, Industrial Trainee, Regulatory Aff airs, Pfi zer.

KeywordsArbitration; Referrals; Article 20; Article 13; Harmonisation; Pharmacovigilance Risk Assessment Committee (PRAC); European Commission; Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh); Committee for Medicinal Products for Human Use (CHMP).

AbstractThis article provides a review of referrals completed from May 2007 to December 2016 and is an update of a previous Regulatory Rapporteur article, published in September 2007, which reviewed referrals completed from May 1996 to May 2007.1 We discuss what has changed in the referral environment since 2007 compared with the previous 11 years (ie, from May 1996 to May 2007). It would appear that the changes in the pharmacovigilance legislation and the introduction of the Pharmacovigilance Risk Assessment Committee (PRAC) initially increased referrals, with new practices and processes to support timely, high-quality assessments; to optimise the safe and eff ective use of medicines though drug labelling changes and, when necessary, restrictions. However, over the past few years, there has been a substantial decrease in the number of referrals, which could be attributed to the eff ectiveness and transparency of the PRAC in assessing and monitoring the safety of medicines authorised in the EU.

21


Pharmacovigilance

protection”.3 In July 2012, the new pharmacovigilance legislation came into e� ect across the EU (Regulation No 1235/2010/EC), which established the PRAC as the committee within the EMA responsible for assessing and monitoring safety issues for human medicines.8

The PRAC has a broad role covering all aspects of pharmacovigilance, including new safety signals; urgent and non-urgent EU procedures; risk management plans (RMPs); post-approval safety studies; pharmacovigilance inspections and the list of medicines under additional monitoring. As a result, safety-related referrals are now assessed by the PRAC and then either by the CHMP or, for nationally authorised medicines, by the CMDh.5 The EMA’s renewed focus on putting patients at the centre of pharmacovigilance activities means the PRAC’s full membership also includes patient representatives with voting rights. The PRAC is also involved in the assessment of pharmacovigilance-related referrals (Article 20, Article 31 and Article 107i) and adopts a list of questions to be addressed by the MAH(s).5 The work of the PRAC has been characterised by an unprecedented level of transparency before, during and a� er the meetings, with real-time publication of agendas, meeting highlights, noti� cations of referrals, lists of questions and minutes available on the EMA website.9

As a result of these legislative changes, some referrals mentioned

in the 2007 Regulatory Rapporteur article have either been modi� ed or replaced by newer referrals; for example, Article 35 and 36 referral procedures are no longer applicable and have been replaced by Articles 31 and 107i since July 2012.1 Article 13 is a new referral procedure that was introduced in January 2010 with the new variation legislation (Regulation No 1234/2008/EC).3,10 Not within scope of this article is the Article 29 paediatric referral (introduced under Regulation No 1901/2006/EC in January 2007), which can be triggered by an MAH when applying for a new indication, new pharmaceutical form or new route of administration for use in children for a product authorised under Directive 2001/83/EC, as amended.10,11 Therefore, Article 29, the “Mutual Recognition Referral” procedure from the previous article, has been reclassi� ed as Article 29(4) to distinguish it from the Article 29 paediatric referral.10

The Commission’s role in referral procedures starts following receipt of the CHMP opinion, or the CMDh position by majority.5

A referral procedure is considered completed when a decision is issued by the Commission. This decision for nationally authorised medicines is addressed to the MS, with the information about the decision reported to the applicant/MAH for information. The MS must adopt the Commission’s decision within 30 days of its noti� cation.5 The countries with nationally authorised licences only,

Table 1: Union referral overview.5

Referral Article

Referral type Who may start referral?

Which parties are concerned?

Can application be withdrawn or referral stopped?

13 Variation/ worksharing referral

RMS All MS involved in the MRP/DCP (RMS & CMSs) variation procedures or all MS involved in the worksharing procedure

MAH may withdraw the application at any time. However, this will not stop the topic being discussed within the CMDh and another referral procedure eventually being initiated. The referral can be stopped only if the MAH withdraws the application/authorisation in all MS.

20 Referral of centrally authorised products

The Commission

EMA The referral can be stopped only if the MAH withdraws all of the centrally authorised marketing authorisations concerned. The adoption of temporary measures by the MS/Commission will not stop the procedure.

29(4) Mutual recognition and decentralised referral

RMS All MS involved in the MRP/DCP (RMS & CMSs)

MAH may withdraw at any time. However, this will not stop the topic being discussed within the CMDh and a referral procedure eventually being initiated. The referral can be stopped only if the MAH withdraws the application/authorisation in all MS.

30 Harmonisation referral

Any MS, the Commission or MAH

All MS where MA is authorised

The referral can be stopped only if the MAH withdraws the application/authorisation in all MS.

31 Union interest referral

Any MS, the Commission or MAH

All MS where MA is granted, refused, withdrawn

The referral can be stopped only if the MAH withdraws the application/authorisation in all MS. The adoption of temporary measures by the MS/Commission will not stop the procedure.

107i Urgent union procedure

MS or the Commission

All MS where MA is granted, refused, withdrawn

The referral can be stopped only if the MAH withdraws the application/authorisation in all MS. The adoption of temporary measures by the MS/Commission will not stop the procedure.

EC = European Commission, MS = Member State, MAH = Marketing Authorisation Holder, CMSs = Concerned Member States, RMS = Reference Member States, MRP = Mutual Recognition Procedure, DCP = Decentralised Procedure.

22


Pharmacovigilance

if applicable, should take appropriate measures to harmonise their authorisation and summary of product characteristics (SmPC) with the one approved by the Commission. This decision is binding to all addressees,12 and the decision for centrally authorised medicines is addressed to the applicant/MAH.

Timetables and procedural guidance for referrals5

Detailed timetables and procedural guidance for the referral procedures can be found on the EMA’s website and/or Chapter 3 of the notice to applicants (NtA)5 as follows:

Article 13 of Regulation No 1234/200813

Article 20 of Regulation No 726/200414,15

Article 29(4) of Directive 2001/83/EC, as amended16

Article 30 of Directive 2001/83/EC, as amended17

Article 31 of Directive 2001/83/EC, as amended18,19

Article 107i of Directive 2001/83/EC, as amended.20 Advice on implementing the outcome of a referral procedure

for nationally authorised products following the Commission’s decision is provided in the guidance: “CMDh Recommendation for implementation of Commission Decisions or CMDh agreements following Union referral procedures where the marketing authorisation is maintained or varied, September 2014”. 21

Regardless of the opinion (positive or negative), the scienti� c conclusions on each referral (generated by the EMA) are provided in the annexes to the CHMP opinion in accordance with Article 32 of Directive 2001/83.5

Information relating to each of the referrals will be publicly announced by the EMA in the CHMP press release and the CHMP monthly report published on the EMA website at key stages of the process. In cases of pharmacovigilance-related referrals, the EMA announces the start of the referral in the PRAC meeting highlights.9

When the MAH disagrees with the opinion/recommendation, the MAH is allowed to request a re-examination no later than

15 days a� er receipt. A� er this date, no re-examination is possible and the opinion/recommendation is considered to be agreed. The re-examination procedure allows the applicant 60 days to forward the grounds for appeal to the EMA. The CHMP/PRAC have a further 60 days to consider the re-examination and adopt a � nal opinion/recommendation.5

Following a review of the EMA referral database for referrals concluded between May 2007 and December 2016, it appears there have been a number of re-examinations, for example Ciclosporin IDL (Commission Decision 22 July 2010) and Teicoplanin Hospira (29 January 2010).22, 23,24 In both cases, the original CHMP opinions were upheld a� er re-examination.

EMA referral database analysis 22

This section provides a summary of Articles 13, 20, 29(4), 30, 31 and 107i referrals from the EMA referral database concluded between May 2007 and December 2016.22 Details of all completed referrals can be accessed from the EMA website.22

Figure 1 shows the number of referrals per year remained consistent between 2007 and 2013. In 2010 and 2012, the number of referrals dropped, which seemed to coincide with the introduction of the new variation legislation (Regulation No 1234/2008/EC) and the new pharmacovigilance legislation (Regulation No 1235/2010/EC) in 2010 and 2012 respectively. In 2009 and 2011, there were 30 referrals, which is the highest number of annual referrals within the past 18 years.1 This represents a 50% increase when compared to the highest number of referrals per year in the previous analysis (ie, 20 in 2006 compared to 30 in 2009 and 2011).1 The main reasons for the increase in referrals could be attributed to:

SmPC harmonisation project (2001 – Heads of Agencies, CMDh) Ongoing activities of the Pharmacovigilance Working Party (responsibility now transferred to the PRAC)

Shi� of regulatory environment from national to pan-European

Figure 1: Completed referrals from May 2007 to December 2016.

*Articles 5(11), 6(12) & 6(13) procedures became obsolete from January 2010; Article 36 referral procedures became obsolete from July 2012; Article 29 procedures were reclassifi ed as Article 29(4) to distinguish from Article 29 paediatric referral; Article 107 procedures became obsolete from July 2012.

23


Pharmacovigilance

Increased focus on the bene� t–risk pro� le of products.However, between 2014 and 2016, the number of referrals per

year decreased from 12 to � ve. The reason for this decrease could be attributed to the e� ectiveness of the PRAC in ful� lling its broad responsibility of assessing and monitoring the safety of medicines authorised in the EU. This includes identifying new safety signals, carrying out pharmacovigilance inspections, and publicising its activities on a monthly basis.

Overall, the data in Figure 1 show that in more than nine years from May 2007 to December 2016, there have been a total of 213 referrals compared with 94 referral procedures concluded between May 1996 and May 2007, which supports the conclusion in the original article that referral procedures were likely to increase in the following years.1

Figure 2 shows the number of referrals completed each year between May 2007 and December 2016 for each of the di� erent articles including the median duration. A summary of the data in Figure 2 is provided below:

Article 13 referrals: A total of four completed. A review of the data showed the median duration was 8.5 months, the shortest was four months, and the longest was 11 months.

Article 20 referrals: A total of 11 completed. A review of the data showed the median duration was eight months, the shortest was two months, and the longest was 14 months.

Article 29(4) referrals: A total of 60 completed. A review of the data showed the median duration was nine months, the shortest was four months, and the longest was 48 months.

Article 30 referrals: A total of 52 completed. A review of the data showed the median duration was 15 months, the shortest was six months, and the longest was 28 months.

Article 31 referrals: A total of 53 completed. A review of the data showed the median duration was 15 months, the shortest was � ve

months, and the longest was 29 months. Article 107i referrals: A total of four completed. A review of the data showed the median duration was six months, the shortest was � ve months, and the longest was seven months.In summary, the duration of the di� erent types of referrals varied

due to the complexities of the issues raised. Figure 2 also shows that on average the procedures of Articles 30 and 31 took longer to complete, followed closely by those of Article 29(4). By contrast, Article 107i referrals took a shorter time to complete.22 Figure 2 also shows that between May 2007 and December 2016, the focus has been on Articles 29(4), 30 and 31 referrals. This would appear to be as a result of SmPC harmonisation and consolidation of safety information across product classes in the EU. Article 13 referrals are usually initiated because of disagreement between MS following a Type II variation or worksharing procedure for nationally authorised medicines. The low number of Article 13 referral procedures completed suggests disagreements rarely occur between MS during variation procedures. A review of the referral website shows that three of four completed Article 13 referrals concerned the addition of a new indication to authorised medicines.22 Referral procedures are complex and require a huge amount of time and resources. The low numbers of Articles 20 and 107i referral procedures (11 and four respectively) could be attributed to the complexities associated with these types of pharmacovigilance-related referral procedures which also involve assessment by the PRAC.

ConclusionSince 2007, there have been a number of changes to the EU legislative environment including the introduction of the new variation legislation in 2010 (Regulation No 1234/2008/EC) and the new pharmacovigilance legislation in 2012 (Regulation No 1235/2010/EC).

Figure 2: Duration of the different referrals from May 2007 to December 2016.

24


Pharmacovigilance

A review of the EMA referrals database showed that the number of referrals per year remained steady between 2007 through to 2013 with the highest – 30 – observed in 2009 and 2011. It would appear that the changes in the pharmacovigilance legislation and the introduction of the PRAC initially increased the number of referrals due to new practices and processes to support timely, high-quality assessments of bene� t–risk, to optimise the safe and e� ective use of medicines though drug labelling changes and, when necessary, restrictions. However, over the past few years, there has been a substantial decrease in the number of referrals (from 12 in 2014 to � ve in 2016), which could be attributed to the e� ectiveness of the PRAC in assessing and monitoring the safety of medicines authorised in the EU.

With the ever-increasing focus on continued positive bene� t–risk pro� les of medicinal products, referral procedures provide a framework to address safety matters in a pan-European way. The e� ectiveness and transparency of the PRAC in carrying out its broad mandate means the trend towards single � gures in referral procedures completed per year may be here to stay. Dr Peter Arlett, Head of Pharmacovigilance and Epidemiology at the EMA, recently stated that, “Pharmacovigilance has evolved rapidly and the evolution continues. It should never stop, because if it stops, then we are not having evidence-based process improvement”.25 The reduction in the number of referrals over the previous years could be seen as an example of this evidence-based process improvement.

References 1. A Lenihan, V Wek, K Cox. ‘Referrals, referrals, referrals’, Regulatory

Rapporteur, September 2007. https://embed.topra.org/sites/default/

� les/regrapart/1/630/2007N09_Focus.pdf (accessed 9 February 2017).

2. Directive 2001/83/EC. www.edctp.org/� leadmin/documents/ethics/

DIRECTIVE_200183EC_OF_THE_EUROPEAN_PARLIAMENT.pdf (accessed

9 February 2017).

3. EMA Commission Regulation (EC) No 1234/2008 of November 2008.

http://ec.europa.eu/health/� les/eudralex/vol-1/reg_2008_1234/

reg_2008_1234_en.pdf (accessed 9 February 2017).

4. Regulation (EC) No 726/2004. http://eur-lex.europa.eu/LexUriServ/

LexUriServ.do?uri=OJ:L:2004:136:0001:0033:en:PDF (accessed

9 February 2017).

5. Notice to Applicants, Volume 2A, Chapter 3. http://ec.europa.eu/

health/� les/eudralex/vol-2/2014-05_vol2a_chap_3.pdf (accessed

9 February 2017).

6. CMDh referrals. www.hma.eu/26.html (accessed 9 February 2017).

7. CMDh Questions & Answers – CMDh referrals. www.hma.eu/

� leadmin/dateien/Human_Medicines/CMD_h_/Questions_Answers/

CMDh_167_2005_Rev10_tracked_2014_02.pdf (accessed 9 February

2017).

8. Regulation (EU) No 1235/2010 amending, as regards pharmacovigilance

of medicinal products for human use, Regulation (EC) No 726/2004, and

Regulation (EC) No 1394/2007 on advanced therapy medicinal products.

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:348:

0001:0016:EN:PDF (accessed 9 February 2017).

9. PRAC: Agendas, minutes and highlights. www.ema.europa.eu/ema/

index.jsp?curl=pages/about_us/document_listing/document_

listing_000353.jsp&mid=WC0b01ac05805a21cf (accessed 9 February

2017).

10. EMA. Referral procedures. www.ema.europa.eu/ema/index.

jsp?curl=pages/regulation/general/general_content_000150.

jsp&mid=WC0b01ac05800240d0 (accessed 9 February 2017).

11. Regulation (EU) No 1901/2006, amending Regulation (EEC) No

1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation

(EC) No 726/2004. http://ec.europa.eu/health/� les/eudralex/vol-1/

reg_2006_1901/reg_2006_1901_en.pdf (accessed 9 February 2017).

12. European Union decisions. http://eur-lex.europa.eu/legal-content/EN/

TXT/?uri=URISERV%3Aai0036 (accessed 9 February 2017).

13. Questions and answers: Article 13 referral procedures. http://www.ema.

europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_

detail_000173.jsp&mid=WC0b01ac0580a8053b (accessed 9 February

2017).

14. Q&A: Article 20 pharmacovigilance procedures. http://www.ema.


detail_000018.jsp&mid=WC0b01ac0580024e97 (accessed 9 February

2017).

15. Questions and answers: Article 20 non-pharmacovigilance procedures.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_

and_a/q_and_a_detail_000174.jsp&mid=WC0b01ac0580a808bc

(accessed 9 February 2017).

16. Questions and answers: Article 29(4) referral procedures. http://www.

ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_

and_a_detail_000177.jsp&mid=WC0b01ac0580a8053c (accessed

9 February 2017).

17. Questions and answers: Article 30 referral procedures. http://www.ema.


detail_000175.jsp&mid=WC0b01ac0580a808bf (accessed 9 February

2017).

18. Questions and answers: Article 31 pharmacovigilance referrals. http://

www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_

and_a/q_and_a_detail_000144.jsp&mid=WC0b01ac0580789970


19. Questions and answers: Article 31 non-pharmacovigilance referrals.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_

and_a/q_and_a_detail_000176.jsp&mid=WC0b01ac0580a808c0


20. Questions and answers: Urgent Union procedures (Article 107i). http://

www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_

and_a/q_and_a_detail_000131.jsp&mid=WC0b01ac058061f6�


21. CMDh Recommendation for Mutual Recognition Procedure a� er

� nalisation of a referral procedure with a positive decision by the

Commission. http://www.hma.eu/� leadmin/dateien/Human_

Medicines/CMD_h_/procedural_guidance/PostReferral_Phase/

CMDh_318_2014_Rev00_2014_09.pdf (accessed 9 February 2017).

22. EMA website – extensive list of referred applications to date. www.ema.

europa.eu/ema/index.jsp?curl=pages/medicines/landing/referral_

search.jsp&mid=WC0b01ac05805c516f (accessed 9 February 2017).

23. EMA. Questions and answers on the referral for Ciclosporin IDL and

associated names capsules containing ciclosporin 25 mg, 50 mg

and 100 mg. www.ema.europa.eu/docs/en_GB/document_library/

Referrals_document/Ciclosporin_IDL_29/WC500014287.pdf (accessed

9 February 2017).

24. EMA. Questions and answers on the referral for Teicoplanin Hospira

powder and solvent for injection containing 200 or 400 mg teicoplanin.

www.ema.europa.eu/docs/en_GB/document_library/Referrals_

document/Teicoplanin_Hospira_29/WC500014116.pdf (accessed

9 February 2017).

25. Dr P Arlett. ‘Fostering the Future’, Regulatory Rapporteur, Vol 14, No 2,

February 2017:5-9.

25


Clinical trials

IntroductionThe UK is widely regarded as a global leader of clinical research, largely due to a robust history of conducting a signi� cant number and variety of clinical trials. Despite a decline in the number of CTAs submitted to the MHRA between 2008 and 2010, the volume of applications has stabilised over recent years and increased by 11% in 2015 compared to the previous year.1 Increases have also been observed globally, but at a lower rate of approximately 7%.2 Data from the European Union Drug Regulatory Authorities Clinical Trials database (EudraCT) database demonstrate that the UK is a leading country for Phase I clinical research, reporting a 32% share of all CTAs made within the EU for Phase I clinical trials in 2015.3 Data provided by the Association of the British Pharmaceutical Industry (ABPI) further support this claim, and illustrate that the UK conducted more Phase I clinical trials in 2013–2014 than any other EU country, rivalled only by Germany in second position.4 The UK may be chosen as a location to conduct early phase clinical research for many reasons including the availability of diverse and extensive experience of clinical research and the high regard for the MHRA, which is viewed as a world-leading authority in terms of standards and influence.

Recent analysis demonstrates that globally there are 3,687 companies progressing an aggregate of 13,718 molecules through the industry drug development pipeline. The top 25 pharma companies worldwide are responsible for roughly 25% of all molecules, with the other companies generally developing smaller portfolios sometimes consisting of only one drug candidate.5

Around 95% of these companies are headquartered outside of the UK, with the majority (48%) located in the US.5 Consequently, the US has become a major centre for early stage clinical research, and a signi� cant infrastructure has evolved to support this work. The US has more than 70 Phase I service providers with a total bed capacity of around 5,500, compared to the capacity in the UK of around 800 beds delivered by 16 Phase I providers. Given the abundance of companies performing early phase clinical trials in the US, it is clear that the UK has to compete on a global scale to attract clinical trials.

Many factors are taken into consideration when a US-based drug development team contemplates undertaking its clinical research in the UK. These include geographical location and previous experience, but it is highly likely that one of these contributing factors will also be the regulatory environment. Therefore it is important to understand how the UK regulatory environment can help to influence these decisions and encourage US clients to conduct Phase I clinical research in the UK. In order to do this a � rm knowledge of the regulatory process in the US and how this di� ers from the UK is essential. Much of the UK information is common with other individual European member state (MS) CTA requirements, however, this article will focus only on the UK due to the current national environment for clinical trials.

Overview of the CTA and IND applications For a clinical trial to take place in any MS, a CTA must be submitted and approved by the regulatory competent authority (CA), and a favourable opinion/approval must also be received from one or more ethics committee (EC). The MHRA are the responsible CA in the UK, and a favourable opinion must also be received from a certi� ed Research Ethics Committee (REC). Phase I clinical research that is conducted using healthy volunteers is eligible for a shortened assessment period with initial feedback being received in 14 calendar days, unlike later phase trials which carry a commitment to be reviewed in 30 days.6 The CTA is a submission that is applicable to only one speci� c study and, once approved, enables the initiation of the clinical phase of that study.

In contrast, an IND application is a submission concerning one speci� c product, molecule or a new indication for an existing marketed product. Therefore, multiple studies can be submitted to the FDA as part of a single IND, which will remain open and active throughout the lifecycle of the molecule, including a� er the sponsor opens a new drug application (NDA) to seek authorisation to market the drug commercially. An IND may become inactive if a sponsor proactively terminates the application, or if there has been no activity for a period of two years.7 In order to conduct a clinical trial in the US, an approval must be received from an Institutional Review Board (IRB). However, unlike in the UK where an o� cial approval letter must be received from the MHRA prior to study initiation, communication of approval is not required from the FDA before the start of clinical activities. Tacit approval is assumed and the clinical phase of the study may be initiated a� er 30 days of an application being validated. There are two possible outcomes following FDA assessment; one of which is activation or default allowance of the submission, inferred by no concerns or questions raised by the FDA during the 30 day review period. This e� ectively constitutes approval,

A comparison of UK versus US submission processes for Phase I trial applications

AuthorHarriet Edwards, Regulatory Aff airs Manager, Quotient Clinical Limited, Nottingham, UK.

KeywordsClinical trial application (CTA); Investigational new drug (IND); Medicines and Healthcare products Regulatory Agency (MHRA); US FDA; Phase I clinical trial; Investigational medicinal product (IMP).

AbstractThe UK is currently a dominant global leader of clinical research; however, it must attract companies from overseas, particularly the US, to conduct early phase clinical trials in the UK. A signifi cant proportion of companies contributing to new drug development are headquartered in the US where early phase clinical infrastructure is much greater. Therefore the UK regulatory environment must remain competitive if it is to provide a viable alternative to the US for the conduct of early phase clinical research. Although many of the principles can be applied to any individual EU member state clinical trial application (CTA), this article compares and contrasts the submission processes for UK-based CTAs to the Medicines and Healthcare products Regulatory Agency (MHRA) and US investigational new drug (IND) applications to the US FDA.

26


Clinical trials

although it is not referred to as such. The other possible outcome of an initial IND submission is clinical hold which will be issued if the assessor deems there is a de� ciency in the application. The issue of a clinical hold notice by the FDA may be to delay a proposed clinical study subject to receiving further satisfactory information, or it may be issued to suspend an ongoing study. As the IND may already have several clinical studies activated, it is possible to apply a clinical hold to some or all of the studies registered under that IND. A clinical hold may be issued for many reasons including insu� cient information preventing bene� t–risk from being assessed; unreasonable levels of risk imposed on subjects; inappropriately quali� ed investigators or the inclusion of a drug intended to treat both genders, but that excludes one due to the risk of developmental or reproductive toxicity.8 As with a noti� cation of grounds for non-acceptance (NGNA) from the MHRA, following receipt of a clinical hold notice, the sponsor must wait until the FDA has issued noti� cation that the proposed study may proceed.

Requirements for CTA and IND applicationsAlthough the submission and approval processes for CTAs and INDs di� er, the core documentation required for the submission to be considered valid is largely the same.

Both applications require the submission of an application form (EudraCT Annex 1 Form for a CTA, or Form FDA 1571 for IND); the investigator’s brochure (IB) for the molecule detailing all available non-clinical and clinical data on the investigational medicinal product (IMP) along with a section on bene� t–risk; and � nally a clinical protocol. There is however a di� erence in the level of detail required in the protocol. For Phase I trials, the FDA state that protocols should provide an outline of the study only so they may be less detailed and more flexible than later phase trials. For a CTA there is no such discrimination in the guidance,9 and it is actually stated that for � rst-in-human (FIH) clinical trials additional guidance should be followed.

Both applications permit electronic submissions, although the

Table 1: Di� erences between a CTA and an IND.

Regulatory process CTA IND

Country UK (national not pan-EU) US

Regulatory authority MHRA FDA

Purpose One CTA per clinical trial. One IND for one molecule, product or a new indication for an already marketed product.

When is it required? To enable the conduct of any clinical trial concerning a medicinal product (de� ned using the set MHRA algorithm) within the UK.

Whenever a clinical study is initiated in the US on an unapproved drug or biologic product, or on an approved drug with a new indication, population, route of administration, change in formulation which increases the risk, or signi� cant change in dosing regimen.

Pre-submission advice Scienti� c advice may be sought from the MHRA – costs vary from approximately £2,200 – £4,500 depending on topic(s) of discussion15

A pre-IND meeting may be arranged to talk through the proposed clinical trial (free of charge). This should be scheduled within 60 days of FDA receipt of meeting request.16

Timelines Up to 14 days for initial review. If a NGNA is received, the sponsor has up to 14 calendar days to respond. A � nal decision will be provided by the MHRA within 60 days of validation of initial submission.

Pre-submission timelines are usually � ve–six months from requesting a pre-IND meeting with the FDA, with 30 days to review the initial submission. If a clinical hold is imposed, the FDA has 30 days to provide a response to the sponsor’s comments (30-day clock will not start until a complete response is received).

Submission format Electronic via CESP Electronic via the electronic submissions gateway (ESG). Paper

via the Center for Drug Evaluation and Research (CDER); or the

Center for Biologics Evaluation and Research (CBER) for biologic

products.

Requirements for quality information

• QP declaration (when material is received from outside the EU)

• MIA(IMP) or importers authorisation.

No requirement to comply with cGMP until Phase II/III trials and no evidence of this is required for submission.

Legislation Directive 2001/20/EC Code of Federal Regulations (CFR) Title 21 Part 312

Guidance available (CT-1) 2010/C 82/01.9 CHMP/QWP/185401/2004, “Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials.”12

Guidance for industry: “Content and format of investigational new drug applications (INDs) for Phase 1 studies of drugs, including well-characterized, therapeutic, biotechnology derived products”10

Amendments Substantial or non-substantial. Substantial amendments require approval, taking up to 35 days. Non-substantial amendments may be implemented without approval but the MHRA should be noti� ed of this at the next substantial amendment submission.

Protocol or information. Both types of amendment require submission but do not require approval. However, protocol amendments must be approved by an IRB before implementation. If the sponsor wants the FDA to comment, a request for this should also be submitted.

Maintenance No speci� c regulatory actions, although if the clinical trial is ongoing for more than one year, a development safety update report (DSUR) will be required.

Annual Reports.

27


Clinical trials

MHRA (as of February 2016) has now transferred to an entirely electronic format, with applications made through the common European submission portal (CESP). Alternatively, the FDA still allow paper submissions as well as those submitted in the electronic common technical document (eCTD) format. This is due to change by 2018 with electronic submissions becoming mandatory for IND submissions.

Despite similarities in application requirements, there are also a number of di� erences (see Table 1). The CTA is not considered valid without a EudraCT number, which is generated through the EudraCT database and is unique to that clinical trial. This is not required for an IND, although a unique IND number will be assigned following submission to FDA. With regard to documentation, the CTA requires a covering letter outlining speci� c details of the trial such as whether it involves the � rst administration to humans, details of any scienti� c advice sought for the trial and pertinent information regarding the trial population. For the IND a cover letter is not required, but it is compulsory to include an introductory statement detailing the development plan for the molecule enabling the FDA to put the proposed clinical study into perspective and anticipate the sponsor’s needs.10

Chemical and pharmaceutical quality information The principal focus of both applications is the technical pharmaceutical information regarding the quality of the IMPs to be used in the proposed clinical trial. This includes the composition(s) and chemistry, manufacturing and controls (CMC) for the drug substance through to the � nal drug product. The purpose of this quality information is to provide assurance of the identity and other suitable standards of both drug substance and drug product, ensure appropriate critical quality attributes are met using critical manufacturing parameters and provide a scienti� cally reasoned assessment of the IMP to justify its use in the clinical trial.

The CMC information and data supplied can be fairly limited in CTAs for Phase I trials, as the only data required are those available at the time to con� rm suitability of the speci� c drug substance and drug product to be used in a small-scale healthy volunteer trial. In contrast IND applications tend to contain more detailed information for Phase I trials as this will be built on throughout the lifecycle of the IND, encompassing all phases of development and eventually forming part of the NDA. However, although descriptive information may be more detailed the data requirements for an IND may be less than a CTA.

CTAs may include simpli� ed investigational medicinal product dossiers (IMPDs) if some of the pertinent information has already been assessed and approved by the MHRA. A reference to the EudraCT number under which the information was submitted will su� ce, providing there have been no changes since this assessment. A currently approved summary of product characteristics (SmPC) may also be submitted in place of a full IMPD if the product to be used in the trial has a marketing authorisation (MA) and is being used according to that MA. As the IND is a progressive submission – adding to and building upon previously submitted information regarding that molecule – there is no such need to provide references to other applications.

The main di� erences between the CMC requirements for a CTA and IND application surround quality declarations and stability requirements. For a CTA, a copy of the Manufacturer’s Authorisation for IMPs (MIA(IMP)) providing evidence that the site of manufacture is authorised to make IMPs compliant with the EU’s good manufacturing practice (GMP) is essential. However there is no equivalent stipulation in the US as adherence to GMP for IMPs in Phase I clinical trials is not required, provided they do not meet exclusion criteria set out in the current good manufacturing practice (cGMP) for Phase I clinical trials.11

Any drug product material (including drug product intermediates) that may be received from outside the EU for use in a UK clinical trial must be accompanied by a quali� ed person’s (QP) declaration, stating that the material and/or the assembly of that material has been made or conducted to EU equivalent GMP. There are no such requirements for importation of drug products (including drug product intermediates) into the US. The only condition is that the recipient of the material being imported is the sponsor, named principal investigator (PI) or a local representative of a foreign sponsor named in the IND. Material may be exported subject to the receiving country’s local requirements.

For both drug substance and drug product IMPD sections within an IND, it is speci� ed that neither detailed stability data nor stability protocols should be submitted; only a brief description of stability studies and methods are required. Preliminary tabular data may be submitted, but the amount of data available will be commensurate to the stage of development. The FDA regulations for INDs state that stability data is needed to demonstrate that both drug substance and drug product are within acceptable chemical and physical limits for the proposed duration of the trial, but “if very short-term tests are proposed, the supporting stability data can be correspondingly very limited.” Accelerated data is usually provided in an IND application and shelf life is based on the extrapolation of this. However, the CTA requires presentation of available data in tabular format along with the critical stability parameters or references to pharmacopoeial monographs where appropriate.12 A suitably assigned shelf life or retest period should be stated, based on the stability pro� le of the drug substance and available IMP data, although accelerated data may also be presented. If there is an intention to extend the shelf life beyond what is stated in the IMPD, a proposal for shelf life extension should also be included, unlike the IND where this level of detail is not necessary.

The expectations for retest periods and shelf life assignments di� er between CTAs and INDs. For the CTA, retest periods and/or shelf life assignments accompanied by the justi� cations for these are essential. However the emphasis is not as great in an IND and expiration dating is not required for IMPs with the exception of reconstituted drug products. There is no requirement for a drug substance to have a retest date if it is being submitted as part of an IND application.

Maintenance As information submitted in a CTA is applicable to the proposed clinical trial speci� ed in that CTA only, there is no requirement to maintain the CTA once the trial has ended following submission of an end of trial noti� cation and clinical trial report. However, should any of the approved information change during the course of the trial, an amendment may need to be submitted to the MHRA for review and approval. Amendments are either classed as substantial or non-substantial, depending on the impact the change has to the scienti� c value and integrity of the study as well as to the safety of trial subjects. Only substantial amendments require approval, which can take up to 35 days.13

Unlike the CTA, an IND application remains operational throughout the molecule/product lifecycle or until it is inactivated. Therefore there is a requirement to maintain the IND, and annual reports containing information on submissions made during the year, as well as a plan for the forthcoming year and a copy or reference to the current IB, should be submitted within 60 days of the e� ective date anniversary.14 As part of IND maintenance, safety reports should also be submitted and unlike a CTA, the FDA must be noti� ed of suspected unexpected serious adverse reactions (SUSARs) and relevant safety � ndings from other studies. Similar to the obligations of a CTA, if any of the information changes from that which was originally submitted, an amendment

28


Clinical trials

is required. Changes can fall into one of two categories: protocol amendments incorporating changes to existing protocols, a new protocol or investigator; and information amendments encompassing new toxicology, CMC or other technical information, updated IBs or clinical study reports and noti� cations of trial discontinuation.

Advantages of the US and the UKThere are a number of advantageous factors in the IND application process that may cause retention of early phase research in the US. These include, but are not limited to, less data requirements for stability packages as well as fewer obligations with respect to the adherence to GMP and provision of quality documentation. The IND application o� ers a “live” submission process throughout all phases of development up to commercialisation, where amendments and updates may be submitted on a continual basis without the need to wait for approvals, which also adds incentive to conducting early phase research in the US. Adding these factors to a signi� cantly larger clinical capacity and the variety of available service providers ensure the US remains the largest conductor of early phase clinical trials.

Despite the advantages of the US, the UK o� ers a robust argument for attracting US-based clients to relocate their early phase research to the UK. The UK is already at an advantage with regard to the status of the MHRA which is viewed as one of the world-leading health authorities – guaranteeing a thorough and pragmatic review, o� ering favourable timelines and remaining responsive throughout the application process. The provision of feedback and the level of interaction between the assessor and sponsor as routine practise is another positive. This interaction provides a level of reassurance to the sponsor that development work is scienti� cally justi� ed and progressing in the correct direction. However, this must continue in order for the UK to be selected as a location for conducting Phase I research, particularly with regard to timelines. Internal metrics generated at Quotient Clinical Ltd have shown that US sponsors rate the MHRA as “very positive” with regard to timelines when compared with other countries they have used to conduct Phase I research, and this was one of the main reasons for choosing the UK.

Other signi� cant advantages include the requirement for adherence to GMP and the need to supply quality documentation from early Phase I research. These requirements mean that the UK is widely respected for high standards, inferring that research conducted in the UK is of the highest quality possible for that phase of development.

Conclusions There are many factors to be taken into consideration when choosing a suitable location to conduct early phase research. However, the status of the country’s regulatory environment is key – and may even be the deciding factor – in making this decision. The UK is a global leader in innovation and conduct of clinical trials. However, the majority of drug development companies are located outside of the UK, so there is a requirement to attract these companies from overseas if the UK is to remain influential in conducting clinical trials. Thus the status of the UK’s regulatory environment, particularly when the variety and competitiveness of service providers are much greater in the US, may help persuade potential US-based clients to relocate. The similarities between CTA and IND can provide a level of familiarity and reassurance to these clients, o� ering them a viable alternative to US-based submissions. Di� erences in the CTA submission process, such as quality requirements coupled with favourable timelines, flexibility and responsiveness of the MHRA may be viewed as advantageous and encourage US-based clients to conduct some, if not all, of their

early phase research in the UK. The MHRA timelines for Phase I trials are one of the biggest influences when choosing to submit CTAs in the UK. So despite the ever-changing regulatory environment and upcoming implementation of the new EU clinical trial regulation, this must continue to ensure sponsors become repeat customers for the UK.

References 1. C Whitty. ‘Clinical Trials in the United Kingdom An update from the Chief

Scienti� c Advisor at the Department of Health, Professor Chris Whitty, CB FMedSci’, March 2016.

2. I Lloyd. ‘Citeline Pharma R&D Annual Review 2015’. Available at: https://citeline.com/wp-content/uploads/2015/02/CITIF_RD_AnnualReview_031715.pdf (accessed 9 June 2016).

3. European Clinical Trials Database. Available at: https://eudract.ema.europa.eu/results-web/ (accessed 6 June 2016).

4. Adapting the Innovation Landscape, UK Biopharma R&D Sourcebook (2015). Available at: www.abpi.org.uk/our-work/library/industry/Documents/ABPI_RD_Sourcebook.pdf (accessed 9 June 2016).

5. I Lloyd. ‘Blockbuster Trends and Rising Starts of Global R&D’, 2016. Available at: https://citeline.com/wp-content/uploads/Blockbuster-Trends-and-Rising-Stars-of-Global-RD.pdf (accessed 1 June 2016).

6. MHRA. ‘Assessment of your Submission’. Available at: www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-authorisation-in-the-uk#assessment-of-your-submission (accessed 31 May 2016).

7. Code of Federal Regulations Title 21, Volume 5 ‘21CFR312.45’, last updated 1 April 2016. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.45 (accessed 2 June 2016).

8. US FDA. IND Application Procedures: Clinical Hold. Available at: www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm362971.htm (accessed 4 June 2016).

9. Communication from the Commission – Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the noti� cation of substantial amendments and the declaration of the end of the trial (CT-1) 2010/C 82/01, Offi cial Journal of the European Union, C82/1 2010.

10. Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology Derived Products, 1995. Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071597.pdf (accessed 5 June 2016).

11. FDA. ‘cGMP for Phase I Investigational Drugs’, July 2008. Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070273.pdf (accessed 29 May 2016).

12. CHMP/QWP/185401/2004, Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials, 31 March 2006. Available at: http://ec.europa.eu/health//sites/health/� les/� les/eudralex/vol-10/18540104en_en.pdf. (accessed 06 June 2016)

13. MHRA. ‘Clinical trials for medicines: manage your authorisation, report safety issues’, 2014. Available at: www.gov.uk/guidance/clinical-trials-for-medicines-manage-your-authorisation-report-safety-issues (accessed 6 June 2016).

14. Code of Federal Regulations Title 21, Volume 5 ‘21CFR312.33’, last updated 1 April 2016. Available at: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.33 (accessed 27 May 2016).

15. MHRA ‘Statutory Guidance: Current MHRA Fees’, 2016. Available at: https://www.gov.uk/government/publications/mhra-fees/current-mhra-fees#scienti� c-advice-meetings-fees (accessed 2 June 2016).

16. FDA. ‘Guidance for Industry Formal Meetings between the FDA and Sponsors or Applicants’. Available at: www.fda.gov/downloads/Drugs/.../Guidances/ucm153222.pdf (accessed 13 June 2016).

29


Meeting report – Early access to medicines

Adaptive pathways workshopThe European Medicines Agency hosted a workshop to discuss the adaptive pathways concept for the development of medicines. Reported by Richard Huckle, Senior Consultant, Pope Woodhead & Associates Ltd, UK

IntroductionA workshop held by the European Medicines Agency (EMA) on 8 December 2016 saw representatives from industry (pharma, biotech, small and medium-sized enterprises (SMEs) etc), patient groups, health technology assessment (HTA) bodies, regulators, payers and academia meet to discuss and gather perspectives on the adaptive pathways (AP) concept. Professor Guido Rasi, EMA Executive Director, and Tomas Salmonson, Medical Products Agency, Sweden/EMA CHMP and Workshop Chair, opened the meeting, recognising the considerable interest from these stakeholders that the adaptive pathways concept has generated.

Setting the sceneAn adaptive pathway for a medicine features a conditional marketing authorisation for a novel treatment in a targeted patient population. This conditional authorisation is granted on the assumption that such populations will bene� t from earlier access to new therapies. Although this starting population will demonstrate a clear safety and e� cacy pro� le, the nature of the conditional authorisation allows a company to generate and validate additional clinical endpoints. As a result, an adaptive pathways approach o� ers a unique solution in which patients achieve earlier access to therapies in areas of high unmet need whilst allowing a marketing authorisation holder (MAH) to produce additional data and clinical evidence. In this way, an adaptive pathway can operate as a type of “heightened randomised controlled trial (RCT)” development scheme that utilises a multi-stakeholder approach to evidence generation and utilisation. This approach allows a variety of stakeholders (eg, regulators, HTA bodies, payer groups, patient organisations, MAHs) to agree on the evidence generation needs for reducing clinical uncertainty, supporting additional claims, or expanding the target population.

The general perspective on, and challenges for, early access to medicines were introduced by Andrzej Rys, Health and Consumers DG, European Commission, who referred to the debate on access to medicines at the European level, and noted that patients with the highest unmet need are not always a top priority in medicinal development. Development programmes tend to focus on those patient populations that can provide robust supporting data for novel therapies – demonstrating clear safety and e� cacy pro� les – rather than the patient populations with greatest need.

Francesca Cerreta, Senior Scienti� c O� cer at EMA (Adaptive pathways/Geriatrics/Scienti� c Advice), de� ned the role of the regulators to facilitate early access to medicines of major public health interest. This optimises the use of existing legal tools (conditional marketing approval, scienti� c advice etc), and development support initiatives such as PRIME (Priority Medicines) scheme and the Innovation Task Force (ITF). The experience gained from the adaptive pathways pilot for further discussion in this workshop included: (1)

patients and healthcare professionals’ involvement and perspective on unmet need; (2) methodological challenges to the use of real-world evidence (RWE); (3) conditions to facilitate input from downstream decision-makers. The format of the workshop included presentations given by speakers to introduce the topics, followed by comments from stakeholder groups and then an open floor discussion.

De� ning the scope of the adaptive pathways concept, Hans-Georg Eichler, Senior Medical O� cer, EMA, went on to reiterate its intention to address patients’ unmet medical needs. The concept seeks to maximise the positive e� ect of new medicines by balancing timely access for patients likely to bene� t most, with the need for adequate, evolving information on the bene� ts and risks of a new medicine. A key feature of adaptive pathways is its “lifespan approach” to learning. As part of this, all involved stakeholders agree upfront on a plan of post-licensing knowledge generation for a medicine before it is authorised, and the MAH commits to carrying out this plan, which is a legally binding regulatory obligation. The bene� t–risk pro� le and, when required by the relevant national bodies, the “value” of a medicine will be re-assessed and revised as more knowledge is gained. Bene� t–risk must always be positive for the treatment-eligible population. The access versus evidence conundrum has always been acknowledged: where, “the bene� t to public health of the immediate availability on the market – outweighs the risk inherent in the fact that additional data are still required”. This is not a lowering of the standards and remains within Regulation EC No 507/2006. RCTs are the methodology with the highest internal validity (“≠ gold standard”, not black and white). However, for an e� cient increase in knowledge of bene� ts and risks, the full evidence spectrum (RCTs, pragmatic trials, observational studies) should be embraced. RWD complements rather than replaces RCTs (where feasible). Pre- and post-licensing evidence generation are not two di� erent lives, but one continuous life.

Another key aspect of the adaptive pathways approach is its focus on bringing together all relevant stakeholders – patients, healthcare professionals, regulators, HTA bodies and payers. Dialogue with those involved in the development of medicines is important throughout the lifespan of the medicine: early on to help determine which medicines could be appropriate for adaptive (iterative) development; then to jointly agree a data generation plan to meet the needs of regulators, HTA bodies and payers and then, when the medicine has reached patients, to ensure the use of the medicine (ie, how it is prescribed) is monitored and managed.

Topic 1: Adaptive pathways: Perspectives of patients and healthcare professionals on addressing patient needsRepresentative patients’ views on the products selected for the adaptive pathways pilot were introduced by Rafał Swierzewski, European Cancer Patient Coalition (ECPC)/EMA and The Patients’ and Consumers’ Working Party (PCWP). Patients’ recommendations

30



included: the enhancement of resources (human and � nancial) to develop and facilitate AP accordingly, increasing interest and patients’ bene� ts. Stronger and sustainable collaborations between regulators (at a national level) and patient groups are needed, and follow-up of AP a� er patients participate in the trials, informing those patients on the development and giving them options for future treatments. There also needs to be more scienti� c trust in RWD, not just from the regulators, but also the HTAs and payers. The ultimate decision on a medicine’s use should be le� to the patient and his/her healthcare provider. It should be up to the patient to decide to accept the risk of treatment.

The consumer representatives’ views on the products selected for the adaptive pathways pilot were presented by Francesca Cattarin, Bureau Européen des Unions de Consommateurs (BEUC). She described the scope of the AP project as quite vague, originally being presented as a pilot project whose objective was to give patients timely access to treatments in the case of an unmet medical need. However, the criteria for qualifying products falling under the scheme were ambiguous, and reference was made to the similar concept of “high medical needs”. But there is no obvious de� nition of the two, despite being the basis for adaptive pathways.

Medicines approved through expedited programmes with post-marketing controls raise even more concerns because of the shi� ing burden of proof from pre-marketing to post-marketing authorisation. This means that regulators will have to rely on the MAH to submit additional data in order to complete the pro� le of the medicines. The concept of adaptive pathways builds on the use of registries to collect RWD and monitor the small group of patients for which the medicine has been authorised. Registries are expected to contain information such as the natural history of the disease, the adherence to treatment, its e� ectiveness, long-term outcomes, drug utilisation, the time to treatment failure and many other criteria. However, patient registries are still not fully operational; MAHs and regulators still face many challenges in using existing registries or establishing new ones. These include a lack of coordination between initiatives at national and international levels, harmonised protocols, scienti� c methods and data structures, data-sharing and transparency and sustainability. The performance information on registries is still being collected, therefore relying on such registries to get real data could be risky and the agency might not obtain the data it needs for the assessment of medicines safety. Also, support for the costs of registries remains uncertain. Altogether, this means that, at present, it is not possible to guarantee that medicines approved under adaptive pathways are used only in the small population of patients they have been authorised for and are appropriately monitored.

During the discussion it was suggested there should be a list of conditions which meet the criteria for unmet medical need, but these are said to be su� ciently de� ned in Commission Regulation (EC No 507/2006) [“a condition for which there exists no satisfactory method of diagnosis, prevention or treatment authorised in the Community or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those a� ected”] and such a list would be very lengthy, di� cult to maintain and still open to interpretation.

Topic 2: Avenues of knowledge generation throughout a medicine’s lifespan This session was chaired by Peter Mol, CBG-MEB/UMCG. Alison Cave, Principal Scienti� c Administrator, EMA, began the session by de� ning RWD as data that are collected outside the constraints of conventional

RCTs. The data can be obtained from prescription databases (drug utilisation); registries (existing disease registries/new product registries); claims data; electronic health records (primary care data, hospital records); patient and caregiver surveys; or be patient-derived data (via smart phone or web-based technologies, social media). Dr Cave gave various examples of existing RWE such as post-approval safety studies and highlighted the increasing use of RWE for understanding the prescribing landscape, e� ectiveness studies, delivering outcomes for HTA, and rapid cycle evaluation of medicines.

Observational Health Data Science and Informatics (OHDSI) showed that there is substantial variation in treatment practice for depression across data sources, health systems, geographies, and over time. There was a consistent heterogeneity in treatment choice as no source showed one preferred � rst-line treatment (11% of depressed patients followed a treatment pathway that was shared with no one else in any of the databases). Use of RWE can help identify the most appropriate comparator group: registry data have been used to support an extension of indication, and the example of Soliris was provided. Soliris (eculizumab), a C5 inhibitor, was approved in June 2007 for paroxysomal nocturnal haemoglobinuria in a restricted patient population with a prior history of transfusions. A comparison of outcomes recorded by the registry in patients with no transfusion history treated or not with eculizumab enabled an extension of the indication to patients with haemolysis with clinical symptom(s) indicative of high disease activity, regardless of transfusion history. However, these examples were not prospectively planned studies. However, adaptive pathways utilise a prospectively designed, iterative development plan, incorporating RWE to complement RCTs in the post-authorisation phase, together with early involvement of HTA and other downstream decision-makers. Opportunities for RWD exist throughout development, such as characterisation of disease progression and unmet need, identi� cation of the target population and validation of surrogate endpoints. RWD options also exist during the authorisation phase, with open-label extension studies in a registry, and drug utilisation studies to monitor use and con� rming long-term safety. During post-authorisation RWD can be utilised to address uncertainties, access quality of life metrics and evaluate risk management activities.

There remain multiple challenges in RWE exploitation; integration of multiple databases may be needed to increase power in order to study rare diseases or outcomes or diverse populations. While RCTs will remain central to decision-making at authorisation, there are multiple opportunities for RWE to add to the evidence base to support the AP process. A clear understanding of the strengths and limitations of the available datasets, and of where they can add the most value, will be essential in the design of RWE studies to complement RCTs in the post-authorisation phase. Early and frequent engagement between all stakeholders will be key for success.

Robert Hemmings, MHRA/EMA CHMP/EMA SAWP, began his presentation with the statement that drug development evolves but is underpinned by the RCT. However, some scenarios challenge the RCT (such as self-evident causality [attribution], [very] rare diseases, extensive follow-up requirements, ethical/feasibility issues, and an unsuitable primary objective). Randomisation (together with blinding) is the most important design technique for avoiding bias in clinical trials. Controlling studies allows discrimination of patient outcomes caused by the test treatment from outcomes caused by other factors. Trials should ensure that groups are treated similarly in the course of the study to estimate e� ects attributable to treatment.

31


Meeting report – Veterinary medicines

RCT data should be augmented with additional data generation techniques, and an AP approach provides the opportunity to capture RWE. As the volume of data grows, the target population can be re� ned, thereby reducing uncertainty and allowing for a perpetual evaluation of the therapy through the collection of post-approval data.

The AP development plan should still address the regulatory requirements yet align with requirements of other stakeholders. Data sources, design and methodology used should produce estimates of interest without important and signi� cant bias and have endpoints/results “actionable” for decision-making, including an “exit strategy” (which could be defaulting to a conventional development pathway if successful milestones are not achieved). RWD is currently in use for regulatory decision-making, including approvals, with potential for increased utility in AP paradigms. Studies must deliver actionable results which are underpinned by sound methodology (ie, without compromising quality). Finally, dialogue with all stakeholders is not trivial, it requires competence, capacity and experience.

Ashley Woodcock, University of Manchester, Clinical Lead, and David Leather, GSK, presented the Salford Lung Study (SLS) as an example of bridging from e� cacy to e� ectiveness in a single study, while demonstrating value for money and bene� t for patients in a large-scale trial that was designed to be as close to the real world as possible, and maintaining the rigour of an RCT. SLS is a closely monitored e� cacy trial involving groups of patients who were selected on the basis of entry criteria (the only inclusion criteria were a diagnosis of chronic obstructive pulmonary disease (COPD) or asthma, and the occurrence of an exacerbation in the three years before joining the study). This unique study, which reported headline results in May 2016, was designed to evaluate Relvar/Ellipta (fluticasone furoate/vilanterol) in patients with COPD, compared with their “usual care” administered in an everyday clinical practice setting. The study was made possible with a pioneering collaboration between GSK, academia, healthcare commissioning groups, hospitals and an entire regional healthcare community. It enrolled 2,802 patients, used a linked database to gather real-time data, and had a unique process for identifying and reporting of serious adverse events within the study, all while ensuring data quality. Drop-out rates were signi� cantly less for SLS compared with other large clinical studies (7% compared with 16.6%–44% for other studies). The study illustrated just how resource-intensive these studies are: more than 300 study sta� and 3,000 GP and pharmacy sta� trained in good clinical practice (GCP) were involved, and >235 million rows of data were generated (with in-depth interviews currently being conducted post study-exit to identify and assess additional patient outcomes). There is a second SLS currently being conducted in patients with asthma.

Topic 3: From bench to bed: involvement of all relevant parties in the delivery of medicines for unmet medical needsThe current evidence strategy for approving drugs is designed for regulation and not to support HTA and payer decisions. There is “an absolute need” to integrate the requirements of the stakeholders downstream of approval in drawing up the product development plan, according to Sarah Garner, Associate Director, NICE Science Policy and Research. The adaptive framework has facilitated the involvement from other decision-makers (not just regulatory) in designing that development plan, with the starting point being a “safe harbour” discussion in which stakeholders can freely discuss development options and the pros and cons of various trial designs. It is envisaged that this is followed by early evidence generation, parallel regulatory

review and HTA, leading onto conditional licensing and reimbursement of drugs in speci� c patient populations, allowing RWE to be gathered to con� rm/review/extend approvals. However, pharma companies are still very cautious and in many cases, FDA requirements are still driving development decisions (which may be divergent or at least not required in meeting the EU expectations). Also, there is a lack of understanding about the potential role of RWE and some companies are unaware of the need to demonstrate the “value proposition”. Solutions can only be found by changing the culture of interactions and building trust between the stakeholders, which could be helped by all sectors to working more closely together (optimising available resources). For RWD, reference was made to the “GetReal” project (www.imi-getreal.eu/) and ADAPT-SMART (http://adaptsmart.eu/). These are both projects under the umbrella of the Innovative Medicines Initiative (IMI), an EU public-private collaboration bringing together patient organisations, HTA bodies, regulators, payers, academia and industry in a parallel project to the EMA’s adaptive pathways, which seek to establish collaborative solutions that could be used in adaptive pathways, including tools and methodologies.

Leeza Osipenko, Senior Scienti� c Adviser, Scienti� c Advice Programme, NICE, reiterated that NICE is fully supportive of expedited routes intended to get products to patients that are innovative/transformative and address unmet medical needs. Early scienti� c advice has been a mainstay of the regulatory process for a number of years and, as a result, commercial success now requires more than just a marketing authorisation. In addition to “traditional” clinical data, companies must ensure that relevant payer evidence is generated as part of their development programmes. There are existing tools that can help explore uncertainties (eg, post-authorisation e� cacy studies, RWE generation, price negotiation, risk-sharing schemes), and both the industry and regulators should use and design them with a focus on overcoming the challenges presented by limited evidence generated in the early stages of AP. Critically, the � rst step in achieving this will be an increase in the engagement and communication between industry and the regulators, and scienti� c advice o� ers such an opportunity. But, to gain maximum bene� t from scienti� c advice, industry needs to approach HTAs early in product development, to understand the types of advice agencies can give, and to ask the right questions.

Ad Schuurman, President of MEdEV, Zorginstituut Nederland, outlined several questions to be addressed so EU payers can implement the AP framework. Budgets paying for drug cost during APs should come from a central EU budget, thus assuring no di� erential prices in EU member states. Then a� er the full marketing authorisation, all member states can conclude their own pricing negotiations (or do so together). A low starting price will incentivise the industry to complete development as soon as possible and will give member states a better starting point for negotiations. Payers want control on costs and have proposed an adaptive reimbursement and mutually acceptable prices. Adaptive pathways should be restricted to special cases, where patients cannot be expected to wait for clinical development and full bene� t–risk evaluation to take place (ie, those patients who would deteriorate irreversibly or die), or urgent public health protection.

Evert Jan van Lente, Director EU-A� airs, AOK Bundesverband, gave a presentation focused on the problems encountered with fast-track approvals in Germany. In Germany, patients have access to all products with marketing authorisation. New products undergo an HTA by IQWiG [the Institute for Quality and E� ciency in Health Care] to assess added bene� t of the drug as a basis for price negotiations and quality assurance measures (with exceptions for orphan drugs).

32



Around 10% of HTAs are related to fast-track approvals. However, insu� cient evidence at the time of marketing authorisation leads to the valuation: “no quanti� able bene� t” or “no added bene� t” leading to pricing based on the comparator (however, in many cases there is no direct comparator for products being developed for unmet needs). Payers could therefore pay a high price for an ine� ective/unsafe drug. So, what is needed at the EMA level? High level pre-marketing evidence must remain to demonstrate e� cacy and safety, with fast-track approvals only in exceptional cases (high unmet medical need, major therapeutic advantage) where the highest possible levels of evidence at the time of (conditional) marketing authorisation should be applied. In cases of non-compliance of manufacturers with post-approval obligations under conditional marketing authorisation, the EMA should establish clear sanctions. The concept of post-marketing evidence generation should be developed with the obligation of transparency on trial design and results, and patients must be informed on the status of the drug.

In the following floor discussion, Anne-Virginie Eggimann, bluebird bio, and Toby Toward, Immunocore Ltd, represented companies with products in the AP pilot (LentiGlobin BB305, a gene therapy medicinal product for the treatment of transfusion dependent beta-thalassemia, and IMCgp100, a T cell receptorbased biological drug to treat metastatic uveal melanoma, respectively). They briefly described their experiences with the parallel (EMA-HTA) advice. Both agreed that participation was bene� cial to the development programme, in particular in gaining the perspective of the HTAs. However, it was regarded as quite resource-intensive, especially for smaller companies

who may not necessarily have the required competence, capacity and experience in-house; in addition, only a limited number of HTAs were involved. Further, these interactions did not typically generate agreed meeting minutes, with the EMA providing minutes through its normal scienti� c advice process.

Spiros Vamvakas, Head of Scienti� c Advice, EMA, and Andrzej Rys brought the workshop to an end with closing remarks. All regulatory decisions are based on evidence and the standards do not change. A targeted subgroup based on high unmet need might permit granting of a conditional marketing authorisation with commitment for the provision of additional data. This additional data can be derived from RCTs/observational/RWD sources, but whatever the source, it is key to understand the strengths and limitations of each. None of this is new; RWD has been employed in di� erent aspects of regulatory decision-making for some time. Prospective planning is key, along with understanding how the approach will unfold over the lifecycle, and planning for iterative decisionmaking. Dialogue is not trivial; it is resource-intensive with all stakeholders which needs competence, capacity and experience. Drug development evolves but is underpinned by RCTs. When moving away from the RCT paradigm, it is important to remember the bene� ts of each part (R, C and T) .

DisclaimerThis article reflects our reporter’s views on the presentations at this meeting.

BECOME AN EFFECTIVE ADVISER ON CMC REQUIREMENTSREGULATORY REQUIREMENTS FOR A NEW ACTIVE SUBSTANCE: QUALITY2.5-day course | 31 May – 2 June 2017 | InterCity Hotel Berlin, Germany

If you are involved in chemistry and pharmacy data documentation, you need to understand and provide effective advice on the regulatory issues that will arise.This course will cover:• Active pharmaceutical ingredient (API) manufacture and in-process controls• Nomenclature and characterisation of the API• Developing specifications for the API• Pharmaceutical development and manufacture of the drug product• Stability of the drug product• Good manufacturing practice – supply chain considerations.

Take this course as your first module towards an MSc, postgraduate diploma or postgraduate certificate in regulatory aff airs.

For more information or to book your place visit topra.org/rr-nasqmasterclass17

16IN PARTNERSHIP WITH THE UNIVERSITY OF HERTFORDSHIRE

33

THE FOUNDATION FOR YOUR CAREER IN MEDICAL DEVICE REGULATORY AFFAIRS

This intensive three-day programme, researched by some of the industry’s leading regulatory experts, has been designed for regulatory professionals wishing to develop their basic knowledge and for regulatory experts with a pharmaceutical background to gain a working knowledge of Medical Device Regulatory Affairs.

Key features:• A valuable combination of lectures and interactive case

studies that help you to put theory into practice• An international speaker panel with representatives

from regulatory agencies, notified bodies, industry and contract houses

• Unique opportunities to meet and interact with peers and network with a large variety of leading industry and regulatory agency specialists.

MEDICAL DEVICE REGULATORY AFFAIRS INTRODUCTORY COURSEThree-day course | 7–9 June 2017 | London, UK

Find out more: book your place at

topra.org/rr-meddevintro17

15

YOUR FIRST STEP TO A QUALIFICATION MSc in Regulatory Affairs Module 12 This course can also be taken as the MSc module “Medical Device Regulatory Affairs”. Delegates (who meet the MSc entry criteria) can attend this course to receive a thorough grounding in all the main pharmaceutical and device regulatory aspects, before completing related assignments as part of their first module leading to the MSc RA qualification.

34

GET ON BOARD AS A SPONSOR AT ONE OF THE MOST PRESTIGIOUS REGULATORY EVENTS OF THE YEARAlign your company with the ethos of the Awards for Regulatory Excellence throughout 2017 and have a high-profile presence at the ceremony as either an Awards Champion, or make even more impact as a Premier Supporter, through exclusive support of the category that most reflects your company’s values and qualities.

HORIZON SPONSORINNOVATION SPONSOR CHAMPIONS

8 November 2017 | London, UK | regulatoryaffairsawards.org

2017AWARDS FOR REGULATORY EXCELLENCE

CONTRIBUTIONFUTURES HORIZON

INNOVATION

INSPIRATION

SUPPORT LIFETIME ACHIEVEMENTEDUCATION

COMMUNICATION

Don’t delay – become a Category Sponsor or Awards Champion today!Visit regulatoryawards.org/sponsor or email [email protected]

ALIGN YOURSELF WITH EXCELLENCE