REGULATORY NEWSLETTEROctober - December 2017

www.cromsource.com

www.cromsource.com

Page 2 of 33Regulatory Newsletter Issue 20 October - December 2017

Introduction CROMSOURCE is committed to sharing our expertise with our clients and future clients. This reflects the first part of our ‘Advise Agree Deliver’ motto! In this spirit we have pleasure in making available this issue of our Regulatory Newsletter.

This newsletter is put together by our expert regulatory team and tracks the changes occurring in European and US regulations relating to clinical research performed in both medicinal products and medical devices.

The Newsletter is a quarterly publication distributed via email and posted on the CROMSOURCE website. We hope you find this information useful, and welcome feedback, questions and suggestions.

Contact us on cromsource@cromsource.com at any time.

GUARANTEED FIXED PRICE BUDGET

GUARANTEED ENROLMENT & TIMELINES

TIME, COST & QUALITY GUARANTEEDEND-TO-END GUARANTEE

GUARANTEED ENROLLMENT & TIMELINES

It’s a simple concept, really. Quality data. On time. On Budget. Guaranteed. At CROMSOURCE we believe experts should keep their word. With more than 20 years of success we provide the industry’s only End-to-End Guarantee™. Starting at the RFP stage with our uniquely detailed Feasibility Plus™ process we guarantee:

We know that budgets must be competitive, and you can rest assured that our End-to-End GuaranteeTM does not come with a premium price. As an ISO-certified organization, you can also rest easy about quality. Don’t you owe it to your project to learn more? Contact us to request more information.

1. Your study will start on time

2. We will enroll 100% of the contracted patients

3. We will finish on time with a set date for database lock

4. The price you contracted is the price you pay.

There will be no CRO-initiated changes-in-scope.

Passionate about your projects.High quality, on time, on budget.

Guaranteed.

www.cromsource.com

Page 3 of 33Regulatory Newsletter Issue 20 October - December 2017

Contents Abbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

NEWS FROM EUROPE: MEDICINAL PRODUCTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

News from the European Commission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

New GMP Guidelines for Advanced Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

The EC consults on the revision of annex 1 on Manufacturing of sterile medicinal products . . . . . . . . . . . . . . . . . . . . . . 8

News from the European Medicines Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

EduraVigilance launched . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Pharmacovigilance fees to rise in January 2018 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Guidelines coming into effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Guidelines published . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Guidelines under public consultation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

News from the International Conference of Harmonization (ICH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Lower subscription rates and new translations plans in MedDRA - ICH updates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Genomic Sampling and Management of Genomic Data - E18 will shortly come into effect . . . . . . . . . . . . . . . . . . . . . . . 15

Other Initiatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

The Clinical Trials Facilitation Group updates the guidance for the reference safety information (RSI) for clinical trials . . . 15

News from individual countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Austria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Czech Republic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Denmark . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

France . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Ireland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Spain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

The united Kingdom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

NEWS FROM EUROPE: MEDICAL DEVICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

News from the European Commission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

New lists of harmonised standards for medical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Update of borderline device classification manual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

www.cromsource.com

Page 4 of 33Regulatory Newsletter Issue 20 October - December 2017

News from individual countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

The Netherlands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

The United Kingdom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Other “hot” topics in the EU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Brexit Updates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

MDR/ IVDR - latest status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

NEWS FROM THE UNITED STATES OF AMERICA: DRUGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

News from the FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

FDA Adverse Events Reporting System (FAERS) Public Dashboard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Orphan Products Clinical Trials Grants Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Expanded Access Requirements Simplified . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Guidance Document Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

NEWS FROM THE UNITED STATES OF AMERICA: MEDICAL DEVICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

News from the FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Breakthrough Device Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Medical Device Innovation Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Guidance Document Update . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Link to all FDA guidance documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

www.cromsource.com

Page 5 of 33Regulatory Newsletter Issue 20 October - December 2017

AbbreviationsAcronym DefinitionAEMPS Agency of Medicines and Sanitary Products (Spain)AMG German Drug ActANSM National Agency for the Safety of Medicine and Health Products (France)AS Ankylosing SpondylitisASD Autism Spectrum DisorderATMP Advanced Therapy Medicinal ProductBASG Austrian Federal Office for Safety in Health CareBCP Business Continuity PlanCAMD Competent Authorities for Medical DevicesCCMO Central Committee for Research Involving Human Subjects (The Netherlands)CE Commission EuropéenCEN European Committee for StandardizationCENELEC European Committee for Electrotechnical StandardizationCER Clinical Evaluation ReportCHMP Committee for Medicinal Products for Human UseCPP French Ethics CommitteeeCTD the electronic common technical documentCTFG Clinical Trials Facilitation GroupCTR Clinical Trials RegulationDHPC Direct Healthcare Professional CommunicationDMA Danish Medicine Agency ( Denmark)EAP Expedited Access PathwayEBA European Banking AuthorityEEA European Economic AreaEEC European Economic CommunityEMA European Medicines AgencyEMRN European Medicines Regulatory NetworkEN European NormETSI European Telecommunications Standards InstituteEU European UnionEVCTM Eudravigilance Clinical Trials ModuleFAERS FDA Adverse Events Reporting SystemFDA (United States) Food And Drug Administration

www.cromsource.com

Page 6 of 33Regulatory Newsletter Issue 20 October - December 2017

Acronym DefinitionGCP Good Clinical PracticeGDPR General Data Protection RegulationGMP Good Manufacturing PracticeGVP Good Pharmacovigilance Practices (Guidelines For)HRA Health Research AuthorityHPRA Health Products Regulatory Authority ( Ireland)IB Investigator BrochureICF Informed Consent FormICH International Conference of HarmonizationICSR Individual Case Safety ReportIMP Investigational Medicinal ProductIMPD Investigational Medicinal Product DossierIND Investigational New Drug (US)IRB Independent Review BoardISO International Standard OrganisationIVD In Vitro DiagnosticIVDR In Vitro Diagnostic RegulationMD Medical DeviceMDCG Medical Device Coordination GroupMDDT Medical Device Development ToolMDR Medical Device RegulationMEDDEV Medical Devices: Guidance Document from the European CommissionMedDRA Medical Dictionary for Regulatory ActivitiesMHRA Medicines and Healthcare products Regulatory AgencyNB Notified BodyNCA National Competent AuthorityNHS National Health Service (UK)NIS Non-Interventional StudiesOJEU Official Journal of the European UnionPASS Post-Authorization Safety StudyPSUR Periodic Safety Update ReportsPUP Previously Untreated PatientsQRM Quality Risk ManagementREC Research Ethics Committee

www.cromsource.com

Page 7 of 33Regulatory Newsletter Issue 20 October - December 2017

Acronym DefinitionRSI Reference Safety InformationRSV Respiratory Syncytial VirusSAR Serious Adverse ReactionsSmPC Summary of Product CharacteristicsSpA SpondyloarthritisSSCP Summary of Safety and Clinical PerformanceSUSAR Suspected Unexpected Serious Adverse ReactionsSUKL State Institute of Drug Control (Czech Republic)UDI Unique Drug IdentifierUK United KingdomUMC Uppsala Monitoring CentreUS United StatesVHP Voluntary Harmonisation ProcedureVTE Venous ThromboembolismWHO World Health Organization

www.cromsource.com

Page 8 of 33Regulatory Newsletter Issue 20 October - December 2017

NEWS FROM EUROPE: MEDICINAL PRODUCTSNews from the European CommissionNew GMP Guidelines for Advanced Therapies

On 22 November 2017, the European Commission adopted The Guidelines on Good Manufacturing Practice (GMP) specific to Advanced Therapy Medicinal Products (ATMPs). ATMP manufacturers should comply with these Guidelines no later than 22 May 2018.

These Guidelines develop the GMP requirements which should be applied in the manufacturing of ATMPs that have been granted a MA, and ATMPs that are being tested or used as reference in a clinical trial (i.e. advanced therapy IMPs). These Guidelines do not apply to medicinal products other than ATMPs but as the guideline scope states, “ In turn, the detailed guidelines referred to in the second paragraph of Article 47 of Directive 2001/83/EC4 and Article 63(1) of Regulation (EU) No 536/2014 do not apply to ATMPs, unless specific reference thereto is made in these…The Guidelines take a risk-based approach, allowing manufacturers some flexibility in their processes and control systems, depending on the level of risk. In addition, the Guidelines describe the traceability data that ATMP manufacturers should keep for 30 years in accordance with Article 15 of ATMP Regulation (EC/1394/2007).”

For the manufacturers of ATMPs, the current established processes will need to be checked in accordance with the new guidelines to determine whether some changes or additional activities will be necessary.

Source: http://ec.europa.eu/newsroom/sante/newsletter-specific-archive-issue.cfm?newsletter_service_id=327&newsletter_issue_id=6070&page=1&fullDate=Wed%2022%20Nov%202017&lang=default

The Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_atmps.pdf

The EC consults on the revision of Annex 1 on Manufacturing of sterile medicinal productsOn 20 December 2017, the European Commission launched the revision of Annex 1, on Manufacturing of sterile medicinal products, of the EudraLex volume 4 for public consultation. The consultation end date is 20 March 2018. Comments should be submitted to SANTE-REVISION-ANNEX-1@ec.europa.eu using the template available at the European Commission website in Public consultation section.

The new added section in “the Scope” states that, “This Annex provides general guidance that should be used for all sterile medicinal products and sterile active substances, via adaption, using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented in the final product.” The consultation document also informs that the recommendations can be applied to “manufacture of other products that are not intended to be sterile (such as certain liquids, creams, ointments and low bioburden biological intermediates) but where the control of microbial, particulate and pyrogen contamination, to reduce it as far as possible, is considered important.”

Key changes for Annex 1 are:• “Introduction of new sections: scope, utilities, Environmental and process monitoring sections and glossary• Introduction of QRM Principles• Restructured to give more logical flow• Added detail to a number of the previous sections to provide further clarity.”

More information how to submit contributions, access to consultation document, template and contact details are available here: https://ec.europa.eu/health/human-use/quality/developments/pc_2017_12_sterile_medicinal_products_en

www.cromsource.com

Page 9 of 33Regulatory Newsletter Issue 20 October - December 2017

NEWS FROM THE EUROPEAN MEDICINES AGENCY The source of each news item below is the EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/home/Home_Page.jsp&mid=

EudraVigilance launched On 22 November 2017, the European Medicines Agency (EMA) launched a new and improved version of EudraVigilance. The new system has enhanced features for the reporting and analysis of suspected adverse reactions, to support stronger safety monitoring of medicines and more efficient reporting process for stakeholders.

The enhancements and expected benefits of the new EudraVigilance are: • Simplified reporting of individual case safety reports (ICSR) and reduced duplication of efforts, as MA holders no longer have to provide these reports to National Competent Authorities (NCAs), but can send them directly to EudraVigilance

• Better detection of new or changing safety issues, enabling rapid action by regulators to protect public health

• Enhanced interoperability based on the use of the ISO/ICH agreed standard for individual case safety reports

• Better searchability and more efficient data analysis

• Increased system capacity to support large volumes of users and reports

• More efficient collaboration with the World Health Organization (WHO) as EMA will make the reports of individual cases of suspected adverse reactions within the EEA available to the WHO Uppsala Monitoring Centre (UMC) directly from EudraVigilance; Member States will no longer need to carry out this task.

Sources: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000679.jsp&mid=WC0b01ac05800250b5

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/11/news_detail_002858.jsp&mid=WC0b01ac058004d5c1

Pharmacovigilance fees to rise in January 2018 The EMA charges and collects fees from pharmaceutical companies for carrying out pharmacovigilance activities. The new adjusted fees for pharmacovigilance applications were adopted by the European Commission and sent for consultation with the Council and Parliament. Once the consultation ends and the amended regulation is published in the Official Journal of the European Union (OJEU) the revised fees for pharmacovigilance application will be published; this is expected in mid-January 2018.

The Agency charges two types of fees for pharmacovigilance activities:

• Procedure based fees for:

− single assessment of Periodic Safety Update Reports (PSURs);

− assessment of Post Authorisation Safety Study (PASS) protocols and study results;

− pharmacovigilance- related referrals.

• An annual fee, charged for nationally authorised medicines only.

The total increase of fees will be 1.4 % due to the 2015 inflation rate of 0.2% and the 2016 inflation rate of 1.2%.

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/12/news_detail_002877.jsp&mid=WC0b01ac058004d5c1

www.cromsource.com

Page 10 of 33Regulatory Newsletter Issue 20 October - December 2017

More about type of fees, calculating, paying of fees and Q&A are available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000632.jsp&mid=WC0b01ac058089682b

Guidelines coming into effect Good Pharmacovigilance Practices (GVP) guidelines The following revised guidelines on GVP came into effect on 13 October 2017: • Module VIII – Post-authorisation safety studies (Rev 3), revised to be aligned with Module VI on Individual case safety report (ICSR) submission and management; http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129137.pdf

• Module XV – Safety communication (Rev 1), revised in light of experience and working practices at Member States’ and EU level. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/01/WC500137666.pdf

The following GVP annexes were also updated and came into effect on 13 October 2017:

• Annex I - Definitions (Rev 4) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500143294.pdf

• Annex II – Templates: Direct Healthcare Professional Communication (DHPC) (Rev 1); http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/01/WC500137665.pdf

• Annex II – Templates: Communication Plan for Direct Healthcare Professional Communication (CP DHPC) (EMA/334164/2015); http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2017/10/WC500236401.pdf

• Annex V – Abbreviations (Rev 1). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC500142281.pdf

The following revised guidelines on GVP came into effect on 22 November 2017:

• Module VI Addendum I – Duplicate management of suspected adverse reaction reports, (Guideline on electronic reporting modalities of ICSRs and on the roles and responsibilities of parties in the operation of duplicate detection and management of reports of suspected adverse reactions); http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/08/WC500232765.pdf

• Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products (Rev 2), (Guidance on submission, validation and management of ICSRs; duplicate detection and data quality management; management of individual reports of off-label use and management of reports from post-authorisation efficacy studies);\ http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/08/WC500232767.pdf

• Module IX – Signal management (Rev 1), which streamlines the signal management process in the light of experience gained with the 2010 pharmacovigilance legislation and to support the new EudraVigilance functionalities.; http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/10/WC500236408.pdf

www.cromsource.com

Page 11 of 33Regulatory Newsletter Issue 20 October - December 2017

• Module IX Addendum I – Methodological aspects of signal detection from spontaneous reports of suspected adverse reactions, which updates some of information from the Guideline on the Use of Statistical Signal Detection Methods in the EudraVigilance Data Analysis System (Rev. 1). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/10/WC500236405.pdf

Guidelines published Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials This guideline was published on 26 October 2017 and will enter into effect on 26 April 2018. It will replace the Guideline from May 2012 available at EudraLex Volume 10: Clinical Trials, Chapter III - Quality of the investigational medicinal product. The revision of this Guideline was prepared by the Committee for Medicinal Products for Human Use (CHMP) Biologics Working Party with a mandate from the European Commission, to facilitate the implementation of Regulation (EU) No. 536/2014. This guideline addresses the specific documentation requirements on the biological, chemical and pharmaceutical quality of investigational medicinal product (IMP) containing biological/biotechnology derived substances. In addition, the guideline lists changes to the IMP and Auxiliary Medicinal Product with a need to request a substantial modification to the Investigational Medicinal Product Dossier (IMPD). It applies to cases where no ‘simplified’ IMPD is submitted.

ATMPs are excluded from this guideline.

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000951.jsp&mid=WC0b01ac058002956c

Published guideline: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/10/WC500237742.pdf

Guideline on the Clinical Investigation of Medicinal Products for the Treatment of Axial Spondyloarthritis Published on 31 October 2017, this guideline comes into effect on 01 May 2018.

Guidance is provided on the clinical development and evaluation of medicinal products for the systemic treatment of Axial Spondyloarthritis (SpA), including both ankylosing spondylitis and non-radiographic axial SpA forms.

Revision 1 has taken into account that clinical practice has evolved since publication of the previous guideline and acknowledges that patients with axial SpA who do not fulfil the modified New York criteria of ankylosing spondylitis (AS) can present with disease activity and functional impairment similar to those observed in patients with AS. These patients, captured under the term non-radiographic axial SpA, are considered in this revised CHMP guideline. The new guideline also reviews relevant treatment goals, new outcome measures for the treatment as well as the design of confirmatory trials in the light of the currently available treatment options.

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001137.jsp&mid=WC0b01ac0580034cf4

Published guideline: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/10/WC500237893.pdf

www.cromsource.com

Page 12 of 33Regulatory Newsletter Issue 20 October - December 2017

Guideline on the clinical development of medicinal products for the treatment of Autism Spectrum Disorder (ASD) This guideline was published by the EMA on 9 November 2017 and will come into effect on 1 June 2018. Guidance is provided on diagnostic criteria, definition of target treatment populations and efficacy and safety criteria for clinical trials intended to establish the efficacy and safety of treatments for autism spectrum disorder. It addresses specific age-category problems (childhood vs. adulthood) and also considers the need for comparative studies.

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001155.jsp&mid=WC0b01ac0580034cf5

Published guidelines: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/11/WC500238886.pdf

Guideline on the evaluation of anticancer medicinal products in man - Revision 5 This guideline was published on 20 November 2017 and will be effective from 01 April 2018. The purpose of the 5th revision is to address current changes in the therapeutic landscape that affect requirements with regards to collection and reporting of safety data in order to inform the benefit-risk evaluation, including a need for more differentiated and detailed safety data presentation. The aim of this guideline is also to underline the importance of exploratory studies in order to identify the most appropriate target population in addition to the usual aims: to define dose, schedule, tumour type and line of therapy. The guideline provides possible ways to classify anti-cancer drugs such as direct anti-tumoural vs. indirect anti-tumoural, or based on pharmacology or molecular target (e.g. hormones, immune modulators, nuclear-targeting, signal-transduction targeting, etc.) The role of biomarkers is also emphasised.

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001122.jsp&mid=WC0b01ac0580034cf3

The guidelines: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/11/WC500238764.pdf

Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials This was published on 28 November 2017 and will come into effect on 28 May 2018. It will replace the Guideline from March 2006 available at EudraLex Volume 10: Clinical Trials, Chapter III - Quality of the investigational medicinal product.

The revision of this Guideline was prepared to facilitate the implementation of Regulation (EU) No. 536/2014 on clinical trials on medicinal products for human use and to be seen in connection with that Regulation.

It addresses the documentation on the chemical and pharmaceutical quality of IMPs and Auxiliary Medicinal Products containing chemically defined drug substances, synthetic peptides, synthetic oligonucleotides, herbal substances, herbal preparations and chemically defined radio- active/radio-labelled substances to be submitted to the competent authority for approval prior to beginning a clinical trial in humans. It includes the requirements for IMPs and Auxiliary Medicinal Products to be tested in phase I, phase II, phase III and phase IV studies as well as the requirements for modified and unmodified comparator products and IMPs to be tested in generic bioequivalence studies. The guidelines lists a changes to the IMP and Auxiliary Medicinal Products with need to request a substantial modification to the Investigational Medicinal Product Dossier (IMPD).

www.cromsource.com

Page 13 of 33Regulatory Newsletter Issue 20 October - December 2017

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000796.jsp&mid=WC0b01ac0580028eb3

Published guidelines: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/11/WC500239381.pdf

Guidelines under public consultation Draft guideline on the clinical evaluation of medicinal products indicated for the prophylaxis or treatment of respiratory syncytial virus (RSV) disease This was published for consultation by the EMA on 30 October 2017. The consultation end date is 31 April 2018. Comments should be submitted to: vwp@ema.europa.eu. Summary: The guideline covers the clinical development of vaccines and monoclonal antibodies for the prevention of RSV disease and direct acting antiviral agents for the treatment of RSV disease. The focus is on the assessment of safety and efficacy in populations most likely to develop RSV lower respiratory tract infection and severe RSV disease, including (newborn) infants and toddlers, older children predisposed to develop severe RSV disease and the elderly. The guideline also addresses vaccination of pregnant women with the aim of preventing RSV disease in their infants. The draft guideline proposes some considerations on nonclinical investigations of efficacy and risk of vaccine-associated enhanced disease to support clinical trials with preventive or therapeutic products directed at RSV.

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500237868&mid=WC0b01ac058009a3dc

Draft guideline: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/10/WC500237868.pdf

Concept paper on the need for a paediatric addendum of the guideline on clinical investigation of medicinal products for the treatment and prophylaxis of venous thromboembolic disease This paper was published for consultation on 31 October 2017. The consultation end date is 31 January 2018. Comments should be submitted to: cvswpsecretariat@ema.europa.eu.

Summary: A number of new EMA guidelines related to clinical investigation of medicinal products for the treatment and prophylaxis of venous thromboembolism (VTE) are already available but recommendations are applicable only to adults. In contrast to adults, VTE in children is a rare event, but represents a significant management dilemma that requires therapeutic intervention. A paediatric addendum to the guidelines on clinical investigation of medicinal products for the treatment and prophylaxis of VTE is considered necessary to discuss and make methodological recommendations adapted to children.

Source: http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500237911&murl=menus/document_library/document_library.jsp&mid=0b01ac058009a3dc

Concept paper: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/10/WC500237911.pdf

www.cromsource.com

Page 14 of 33Regulatory Newsletter Issue 20 October - December 2017

EMA issues two revised guidelines on factor VIII products for consultation On 30 October 2017, the European Medicines Agency (EMA) issued two draft revised guidelines: Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products and Guideline on core SmPC for human plasma derived and recombinant coagulation factor VIII products. For both guidelines the deadline for consultation is 31 January 2018 and comments should be submitted to: BPWPsecretariat@ema.europa.eu

The first guideline describes the information to be documented when an application for a MA for recombinant or human plasma-derived factor VIII products is made for use in treatment and prevention of bleeding in patients with haemophilia A. It covers clinical investigations to be conducted pre- and post-MA. Guidance is also provided for authorised products where a significant change in the manufacturing process has been made. The second guideline describes the information to be included in the SmPC for human plasma derived and recombinant coagulation factor VIII products, which are indicated for use in the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

That two guidelines are being revised by EMA due to the fact that, “the conduct of sufficiently informative clinical trials in previously untreated patients (PUPs) to estimate important characteristics of single products is considered difficult”. The EMA says in the guidelines that sponsors will no longer be required to conduct “formal PUP studies. However, every PUP should be closely monitored with regards to treatment performance and inhibitor development through a well-defined and well-managed disease Registry”.

Source and draft guidelines: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/clinical_blood_products/general_content_001041.jsp&mid=WC0b01ac0580032ec8

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/clinical_blood_products/general_content_001043.jsp&mid=WC0b01ac0580032ec8

News from the International Conference of Harmonization (ICH) Lower subscription rates and new translations plans in MedDRA - ICH updates The Medical Dictionary for Regulatory Activities (MedDRA) Management Committee meeting took place on 11-12 November 2017 in Geneva, Switzerland. According to the ICH press release, MedDRA “is a rich and highly specific standardised medical terminology developed by ICH to facilitate sharing of regulatory information internationally for medical products used by humans. It is used for registration, documentation and safety monitoring of medical products both before and after a product has been authorised for sale. Products covered by the scope of MedDRA include pharmaceuticals, vaccines and drug-device combination products”. (http://www.ich.org/products/meddra.html) During the meeting the Committee announced that there will be a further reduction in MedDRA subscription rates in 2018 and MedDRA will start providing local language training support in countries in Central America and South Korea, and in China in 2019. In addition, MedDRA will be translated Korean and Russian languages to bring the total number of languages in the dictionary to thireteen. Currently, MedDRA is available in English, Chinese, Czech, Dutch, French, German, Hungarian, Italian, Japanese, Portuguese and Spanish.

Source: http://www.ich.org/ichnews/newsroom/read/article/press-release-ich-meddra-management-board-meeting-in-montreal-canada-may-2017-copy-1.html Press release from Geneva: http://www.ich.org/fileadmin/Public_Web_Site/News_room/B-Press_Releases/MedDRA_Press_Releases/MedDRA_Press_Release_Geneva_2017_1111.pdf

How to subscribe to MedDRA : https://www.meddra.org/subscription/subscription-form Subscription rates: https://www.meddra.org/subscription/subscription-rate

www.cromsource.com

Page 15 of 33Regulatory Newsletter Issue 20 October - December 2017

Genomic Sampling and Management of Genomic Data - E18 will shortly come into effect The ICH guideline E18 on harmonised principles of genomic sampling and management of genomic data in clinical studies reached step 5 (final) and has been adopted by the EMA. The guideline will enter into effect in the EU on 28 February 2018.

ICH description: “This new guidance is proposed to provide guidance on genomic sample collection to evaluate efficacy and safety of a drug for regulatory approval. In the past years, genomic information has been increasingly included in drug label relevant for the benefit/risk evaluation of a drug. To accumulate such data during drug development and throughout the product life cycle, genomic samples should be collected in clinical trials and other studies following a certain methodology and be stored for certain periods. It has been reported that collection rate of such samples is still low in many ICH regions and it has been deemed necessary to harmonise the guidance that was already published independently by the different ICH regulatory authorities”. http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html#17

Source and access to guideline: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/md_pharmacogenomics/general_content_001300.jsp&mid=WC0b01ac058002958e

Other Initiatives The Clinical Trials Facilitation Group updates the guidance for the reference safety information (RSI) for clinical trials A clinical trials facilitation group (CTFG) has been established in 2004 by the Heads of Medicines Agencies to coordinate the implementation of the EU clinical trials directive 2001/20 EC across the member states. CTFG acts as a forum for discussion to agree on common principles and processes to be applied throughout the European medicines regulatory network (EMRN) and also promotes harmonisation of clinical trial assessment decisions and administrative processes across the NCAs. http://www.hma.eu/ctfg.html

In November 2017, the CTFG updated a Question &Answers (Q&A) document on Reference Safety Information (RSI), following detailed discussions between NCAs and sponsors, which arose from Clinical Trial Application and substantial amendment procedures as well as GCP inspections. The RSI is contained in the SmPC for marked products and the Investigator’s Brochure (IB) for non-marketed products. The primary purpose of the RSI is to serve as the basis for expectedness assessments of ‘suspected’ serious adverse reactions (‘suspected’ SARs) by the sponsor for expedited reporting of suspected unexpected serious adverse reactions (SUSARs) and annual safety reporting.

The CTFG highlights that the RSI in the IB cannot be regarded the same way as the undesirable effects listed in the SmPC, as pharmacovigilance rules for both in clinical trials are different as are the purpose and means of approval of the IB and SmPC, but it is recommended that the RSI section of an IB should emphasize a broader description of the safety profile of the IMP in addition to the RSI “e.g. tabular presentations of all observed adverse reactions (i.e. including non-serious adverse reactions, suspected SARs that have occurred only once, and fatal and life-threatening SARs that are considered unexpected and not included in the RSI)”.

It is recommended to include the broader description of the safety profile in IB “either in a subsection on Safety under ‘Effects in Humans’ or in the section ‘Summary of Data and Guidance for the Investigator’, in accordance with ICH E6 (R2) guidance, to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial”.

www.cromsource.com

Page 16 of 33Regulatory Newsletter Issue 20 October - December 2017

The CTFG answers a range of questions regarding RSI for IB and SmPC that have arisen from sponsors, applicants and NCAs in the member states in the EU.

Most of the EU NCAs recommend full compliance with the Q&A document updated by CTFG. For example, the British NCA, the Medicines and Healthcare products Regulatory Agency (MHRA), recommends full compliance from mid-February 2018 while the Danish NCA, the Drug Medicine Agency encourages a sponsors to update their IBs according to Q&A document within the next 3 months from their announcement on 11 December 2017.

Source: http://www.hma.eu/ctfg.html

CTFG updated Q&A document: http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2017_11_CTFG_Question_and_Answer_on_Reference_Safety_Information_2017.pdf

The MHRA recommendations: https://www.gov.uk/guidance/clinical-trials-for-medicines-manage-your-authorisation-report-safety-issues

The DMA recommendations: https://laegemiddelstyrelsen.dk/da/nyheder/2017/vaesentlig-opdatering-af-spoergsmaal-og-svar-om-reference-dokumentet-rsi-ved-kliniske-forsoeg/

News from Individual Countries Austria The new fees since 1 January 2018 In December 2017, the Austrian Federal Office for Safety in Health Care (BASG) published updated fee guidelines, “Verordnung des Bundesamtes für Sicherheit im Gesundheitswesen über den Gebührentarif gemäß GESG”. The new fees apply from 01 January 2018 and have been changed to the following:

Clinical Trials phase I-III

Clinical Trials Phase IV

Notification of a compassionate use program pursuant to § 8a AMG on the basis of an opinion from the Committee on Human medicines

Notification of a compassionate use program pursuant to § 8a AMG without submission of an opinion from the Committee on Human medicines

Notification of non-interventional studies (NIS) pursuant to § 2a (3) AMG

Clinical Investigations

Substantial Amendments

Source: https://www.basg.gv.at/ueber-uns/tarife/The%20fee%20guidelines%20in%20German:%20https://www.basg.gv.at/index.php?eID=tx_nawsecuredl&u=0&g=0&t=0&hash=753cdddc9252e1d58a8c6173335326b8f4a9de04&file=fileadmin/user_upload/171211_Gebuehrentarif.pdf

Czech Republic General Data Protection Regulation and clinical trials - SUKL notification On 8 December 2017, the State Institute of Drug Control (SUKL), the Czech Republic Regulatory Agency published notification for clinical trials sponsors/applicants to submit consent forms to clinical trials subjects with the hand-over of personal data in a separate consent document approved by the EC. The notification has been issued with regard to the General Data Protection Regulation (GDPR), which replaces the Data Protection Directive 95/46/EC and was designed

3100€

1559€

520 €

1559 €

623 €

3100 €

517 €

www.cromsource.com

Page 17 of 33Regulatory Newsletter Issue 20 October - December 2017

to harmonise data privacy laws across Europe, to protect and empower all EU citizens’ data privacy and to reshape the way organisations across the region approach data privacy. Enforcement date of GDPR is 25 May 2018. (https://www.eugdpr.org/) The SUKL also informed that sponsors/applicants should submit the separate consent document for personal data together with a declaration stating that “personal data protection as required by the GDPR shall be safeguarded during data hand-over…The approval of the document by the ethics committee shall refer solely to the clarity of the text for trial subjects, rather than compliance with the GDPR”.

Source: http://www.sukl.eu/medicines/kh-vs-gdpr-smernice-na-ochranu-osobnich-udaju

Denmark The new fees applicable from 1 January 2018 The Danish Medicine Agency published executive order on fees for clinical trials applicable from 01 January 2018 to 31 December 2018.

Application for authorisation of a clinical trial

Application for authorisation of a clinical trial of a medicinal product, for which a marketing authorisation has been issued in an EU country or an ICH country

Application for amendment of a clinical trial

Annual fee for clinical trials: The annual fee is payable per year started and until national completion, however, not for the first year after authorisation of the trial. The annual fee only applies to trials for which the DMA has received an application after 30 June 2017. Source: https://laegemiddelstyrelsen.dk/en/licensing/clinical-trials/fees/

France Information to clinical trials sponsors: Set up of Unit in charge of “Early phase Clinical Trials” and consequences for sponsors The National Agency for the Safety of Medicine and Health Products (ANSM), the French NCA, has stated that since 18 December 2017 a separate, dedicated Unit entitled “Division of Authorization and Innovation Policies” will handle all responsibilities for management of all early phase clinical trials procedures in France including both national procedures (“classic” or “Pilot Phase-EU regulation”) and European Voluntary Harmonisation Procedures. “Early phase clinical phase “is defined by the ANSM as first in human, “those which generate initial knowledge in humans on tolerability, safety, pharmacokinetics and pharmacodynamics for medicines” and “phase 1 or phase1-2 trials (as soon as phase 1 takes place in the French territory)”. The Unit will not be involved with clinical trials that involve cell and gene therapy products, medical devices, vaccines, cells, tissue or organs. The ANSM set up a brief information note about the change for sponsors in English and French dated 8 December 2017: http://ansm.sante.fr/Activites/Medicaments-et-produits-biologiques/Avis-aux-promoteurs-Formulaires/(offset)/2

Pilot phase report On 18 November 2017, the ANSM published a two-year assessment report for the pilot phase of the EU Clinical Trail Regulation 536/2014 (TR) in France and established to reach 50 % of projects in pilot phase by the end of 2018. On 28 September 2017, the ANSM recorded 260 applications submitted as part of the pilot phase in which 210 files were managed in the context of pilot phase and 50 were either non- responsive or could not be managed on time by the designated CPP (French Ethics Committee). Almost half of submitted clinical trials in pilot project concerned oncology and haematology indications. On 28 September 2017 193 applications were approved with 127 obtaining clinical trials authorisation and a favourable opinion from designated CPPs. The average time of processing was 68.9 days. According to CTR, the total timeline for assessing clinical trials authorisation without question is 60 days and the total if questions are issued is 91 days.

DKK 46,514

DKK 23,428

DKK 4,852

DKK 13,076

www.cromsource.com

Page 18 of 33Regulatory Newsletter Issue 20 October - December 2017

The ANSM encourages sponsors and applicants to submit clinical applications in accordance with the pilot phase and provides further updated guidelines in English.Source and guidelines for sponsors/applicants : http://ansm.sante.fr/S-informer/Points-d-information-Points-d-information/Autorisation-des-essais-cliniques-de-medicaments-l-ANSM-fixe-l-objectif-d-instruire-la-moitie-des-demandes-dans-le-cadre-de-la-phase-pilote-du-re-glement-europeen-d-ici-fin-2018-Point-d-Information

IrelandThe Irish Competent Authority has initiated a national Pilot Project against CTR The HPRA, the Irish Competent Authority has initiated a national Pilot Project, in conjunction with the ethics committees, to prepare for implementation of the Clinical Trials Regulation in Ireland. The project will run until the implementation of the Regulation in 2019. In December 2017 the HPRA published the Guide to Clinical Trials Regulation (EU) No. 536/2014 Pilot Project – Ireland.

Source: http://www.hpra.ie/homepage/medicines/regulatory-information/clinical-trials The guide: http://www.hpra.ie/docs/default-source/publications-forms/guidance-documents/guide-to-clinical-trials-regulation-(eu)-no-536(2014)-pilot-project---ireland.pdf?sfvrsn=4

SpainSUSAR notification in Spain- information note On 26 December 2017, the Spanish Agency of Medicines and Sanitary Products (AEMPS) published information note about reporting to EudraVigilance Clinical Trials Module (EVCTM) of SUSARs communicated in Spain in a clinical trials and validation rules about reporter state.The information note refers to article 52 of Royal Decree 1090/2015 which states that every SUSAR with IMP occurring in patients included in a clinical trial in Spain shall be available to the competent bodies of the Autonomous Community “in real time through the clinical trial information system” and as it has been indicated in the “Note for guidance – EudraVigilance Human – Processing of safety messages and individual case safety reports (ICSRs) ”, appendix H related to local specific requirements. The Autonomous Community in Spain is an additional regional Competent Authority which is involved in cases of Non-investigational studies.

After launching new EVCTM system on 22November 2017, the EMA has implemented the following validation in the EudraVigilance making mandatory the field to enter the Autonomous Community and their codes:

• If [ICH E2B (R2) A.2.1.3 reporter country] = “ES” then the Autonomous Community code in [(ICH E2B (R2) A.2.1.2 reporter state] must be provided being a value among 00-19.

• If A.1.1 [ICH E2B (R2) A.1.1 primary source country] is “ES” then at least one reporter [ICH E2B (R2) A.2.1.3 reporter country] section must have reporter country = “ES”.

• The code “00-Unknown”, foreseen in the EU Individual Case Safety Report (ICSR) Implementation Guide, could be exceptionally used in those cases where the Autonomous Community is unknown.

• Cases not fulfilling this validation will be refused by EudraVigilance.

www.cromsource.com

Page 19 of 33Regulatory Newsletter Issue 20 October - December 2017

The notification of SUSARs according to these new requirements with the Autonomous Community of the reporter listed is mandatory. For sponsors who need to adequate their systems to new requirements, this can be postponed until 22 January 2018.

Source: https://www.aemps.gob.es/en/informa/notasInformativas/medicamentosUsoHumano/invClinica/2017/NI-MUH_20-2017-notifica-reacciones-adversas-EudraVigilance.htm

Information note in English: https://www.aemps.gob.es/en/informa/notasInformativas/medicamentosUsoHumano/invClinica/2017/docs/NI-MUH_20-2017-notifica-reacciones-adversas-EudraVigilance.pdf

And in Spanish: https://www.aemps.gob.es/informa/notasInformativas/medicamentosUsoHumano/invClinica/2017/docs/NI-MUH_20-2017-notifica-reacciones-adversas-EudraVigilance.pdf

The United Kingdom Preparation for the EU Clinical Trials Regulation The Health Research Authority (HRA) for the National Health Service (NHS) in England and in the United Kingdom is working in close cooperation with the MHRA with respect to Research Ethics Committee (RECs) to prepare for the new Clinical Trial Regulation (CTR) (EU) 536/2014, expected in 2019. Although it is still unknown whether the CTR will apply in the UK due to Brexit, both institutions are going to be ready for “pilot programme” available for an applicants in April 2018: “This programme will invite sponsors to submit applications for review under the live pilot programme, following the rules, processes and timelines of the regulation. The result will be a single UK output which will act as the REC opinion and the Clinical Trial Authorisation.”

Source: https://www.hra.nhs.uk/about-us/news-updates/preparing-uk-eu-clinical-trials-regulation-2019-and-beyond/

01 ANDALUCÍA02 ARAGÓN03 ASTURIAS04 ISLAS BALEARES05 CANARIAS06 CANTABRIA07 CASTILLA LEÓN08 CASTILLA-LA MANCHA09 CATALUÑA10 COMUNIDAD VALENCIANA11 EXTREMADURA12 GALICIA13 COMUNIDAD DE MADRID14 MURCIA

15 NAVARRA16 PAÍS VASCO17 LA RIOJA18 CEUTA19 MELILLA

www.cromsource.com

Page 20 of 33Regulatory Newsletter Issue 20 October - December 2017

NEWS FROM EUROPE: MEDICAL DEVICES News from the European Commission New lists of harmonised standards for medical devices On 17 November 2017, in the Official Journal of the European Union, the European Commission published a new list of references of harmonised standards including the replacement of EN ISO 13485:2012 with EN ISO 13485:2016. The manufacturers of medical devices, active implantable devices and in vitro diagnostic (IVD) devices can use new harmonised standards to demonstrate their products, services, or processes comply with EU law. A harmonised standard is defined as a standard developed by a recognised European standards organisation, such as the European Committee for Standardization (CEN), the European Committee for Electrotechnical Standardization (CENELEC) or the European Telecommunications Standards Institute (ETSI) http://ec.europa.eu/growth/single-market/european-standards/harmonised-standards_en The updated lists of references of harmonised standards were published in support of Directive 93/42/EEC on medical devices (10 new references), Directive 90/385/EEC on active implantable medical devices (2 new references), Directive 98/79/EC on IVD medical devices (3 new references).

Source: http://ec.europa.eu/growth/content/new-references-harmonised-standards-medical-devices-active-implantable-medical-devices-vitro_en

New lists of harmonised standards in 23 languages: http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=OJ%3AC%3A2017%3A389%3ATOC

Update of borderline device classification manual In December 2017, the European Commission released an update of Manual on Borderline and Classification in the Community regulatory framework for medical devices. “Borderline cases are considered to be those cases where it is not clear from the outset whether a given product is a medical device, an in vitro diagnostic medical device, an active implantable medical device or not. Or alternatively, borderline cases are those cases where the product falls within the definition of a medical device but is excluded from the Directives by their scope. Where a given product does not fall within the definition of medical device or is excluded by the scope of the Directives, other Community and/or national legislation may be applicable.” The European Commission added twelve new additional types of products and presented their outcome: 1. Products intended to reduce the effect of alcohol – classified as no medical device2. Radiation shields – classified as no medical device3. D-mannose for the prevention of urinary tract infections- classified as no medical device4. Solution of 8-MOP in extracorporeal photochemotherapy- classified as no medical device5. Alum styptic pencils- classified as medical device Class IIa6. Microplate washers- classified as no medical device7. Tissue expanders used in the breast - classified as medical device Class III8. Dura guard for use with a craniotome - classified as medical device Class III9. Heart bypass machine- classified as medical device Class III10. Liquid nitrogen for cryopreservation of cells and tissues of human origin for medical purpose - classified as medical device Class IIa11. Mobile application for managing pictures of moles - classified as no medical device12. Mobile application for the assessment of moles - classified as medical device Class I

The classification rules were laid down in accordance to Medical Devices Directive (1993/42/EEC), the Active Implantable Medical Devices Directive (190/384/EEC), In Vitro Diagnostic Medical Devices Directive (1998/79/EEC) and serves as a complement to MEDDEV 2.1/3 Rev. 3: Borderline products, drug-delivery

www.cromsource.com

Page 21 of 33Regulatory Newsletter Issue 20 October - December 2017

products and medical devices incorporating, as integral part, an ancillary medicinal substance or an ancillary human blood derivative. According to new Medical Device Regulation (MDR) and IVD Regulation (IVDR) provisions, it will be the responsibility of each member state to determine whether a product is or is not within the scope of the regulation. Article 4.1 of the MDR states that “… upon a duly substantiated request of a member state, the commission shall, after consulting with the Medical Device Coordination Group (MDCG) … determine whether or not a specific product, or category or group of products, falls within the definitions of ‘medical device’ or ‘accessory for a medical device.” It is considered that under both MDR and IVDR, it is likely the MDCG and any assigned expert panel will continue to use the manual as a guide to assist in the determination process.

Source: https://ec.europa.eu/growth/sectors/medical-devices/specific-areas-development_en

Manual for downloading: http://ec.europa.eu/DocsRoom/documents/26785/attachments/1/translations

News from Individual Countries The Netherlands The CCMO published the Guide for new regulations MDs and IVDs On 15 December 2017, the Centrale Commissie Mensgebonden Onder (CCMO), the Dutch Competent Authority informed about publishing the Guide for new regulations medical devices and in vitro diagnostics to help manufacturers, distributors, importers, healthcare providers and healthcare institutions be prepared for these changes in time. The Guide was prepared in cooperation with the Ministry of Health, Welfare and Sport, Health And Youth Care Inspectorate and the Dutch National Institute for Public Health and the Environment. The Guide contains the most important changes in MDR and IVDR written in brief interactive document on 22 pages in Dutch.

Source: http://www.ccmo.nl/en/news-archive/guide-for-new-regulations-medical-devices-and-in-vitro-diagnostics-only-in-dutch#

The Guide in Dutch: http://www.ccmo.nl/attachments/files/handreiking-med-hulpmiddelen-opmaak-def.pdf

The United Kingdom MHRA requests advanced notice of an intention to submit a clinical investigation On 23 October 2017, MHRA published a note for sponsors and applicants stating that notification is required for advanced notice of an intention to submit new clinical investigation. In practice, if the manufacturer is planning to submit a clinical investigation in the United Kingdom, MHRA requests that the intention to submit is sent via email to devices.regulatory@mhra.gov.uk. In addition, the announcement should contain some basic details about the investigational device, the intended population, the type of study, and estimated application date to the MHRA. Such notification to MHRA will not be required for medical devices that are CE marked for the purpose under investigation.

Source: https://www.gov.uk/guidance/notify-mhra-about-a-clinical-investigation-for-a-medical-device#history

www.cromsource.com

Page 22 of 33Regulatory Newsletter Issue 20 October - December 2017

Sources: https://europa.eu/newsroom/highlights/special-coverage/brexit_en http://www.consilium.europa.eu/en/policies/eu-uk-after-referendum/

EMA publishes Business Continuity Plan in full The EMA business continuity plan (BCP) to ensure operational continuity while the Agency prepares for its relocation and the UK’s withdrawal from the EU was published in full on 13 October. It assigns EMA activities to three categories of priority according to their impact on public health and the Agency’s ability to function. The BCP enables EMA to deliver its highest priority activities and to temporarily scale back or temporarily suspend lower priority activities if required.

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/10/news_detail_002828.jsp&mid=WC0b01ac058004d5c1

Guidance: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/10/WC500236755.pdf

EMA to relocate to Amsterdam, the Netherlands On 20 November, the long-awaited announcement was made that the EMA will relocate to Amsterdam in the Netherlands. The European Banking Authority (EBA) will relocate to Paris, France.

EMA now has just over 16 months to prepare for the move and take up its operations in Amsterdam on 30 March 2019 at the latest. The Agency’s new permanent headquarters, the tailor-made Vivaldi building, are planned for completion in November 2019. The Dutch government will offer temporary premises to EMA from 1 January 2019 until the building is ready. EMA and the Netherlands have agreed a joint governance structure to steer and oversee the relocation project

Other “hot” topics in the EUBrexit Updates

October 13th: EMA Business Continuity Plan published in full

20th: European Council (Article 50) agrees to commence preparation for phase 2 Brexit talks

December1st: European Comission and EMA publish Q&A document Rev 1

15th: European Council (Article 50) confirms phase 2 of Brexit negotia-tions with the UK can commence

November10th: 6th round of Brexit negotations commence

20th: EMA to relocate to Amsterdam, the Netherlands

20th: UK House of Commons publishes briefing paper

24th: EMA publishes procedural guidance for pharmaceutical companies

www.cromsource.com

Page 23 of 33Regulatory Newsletter Issue 20 October - December 2017

Sources: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_001893.jsp&mid=WC0b01ac0580cb2e5c http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/11/news_detail_002857.jsp&mid=WC0b01ac058004d5c1

Briefing Paper published by UK House of Commons The UK House of Commons Library published a briefing paper on Brexit and medicines regulation on 20 November 2017. Although not a position statement, it gives an overview of current medicines regulation in the UK and the relationship with the EMA and regulatory agencies in EU Member States. Options for future UK regulation post-Brexit are presented such as a mutual recognition arrangement between the UK and EU and a more ambitious arrangement whereby the MHRA and EMA would abide by each other’s recommendations to authorise new medicines. The briefing paper also discusses possible changes to the current UK authorisation process to maintain efficiency without compromising quality, for example, approval of medicines based on authorisations from other markets like the US, Australia and Japan. The paper is narrowly focused on medicines regulation and does not discuss potential changes to research funding and clinical trials regulation following Brexit.

Source: http://researchbriefings.parliament.uk/ResearchBriefing/Summary/CBP-8148

Briefing paper: http://researchbriefings.files.parliament.uk/documents/CBP-8148/CBP-8148.pdf

Procedural Guidance for Pharma Companies published by EMA EMA published a procedural guidance document on 24 November outlining the practical and simplified requirements that companies should follow when they apply for changes to their marketing authorisation to allow for the continued marketing of their medicine in the European Economic Area after the UK withdraws from the EU.

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/11/news_detail_002862.jsp&mid=WC0b01ac058004d5c1

Guidance: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/11/WC500239369.pdf

EMA Updates Q&A Guidance on Brexit On 01 December, revision 1 of the Questions and Answers (Q&As) document on Brexit was published. This has been drafted jointly by the European Commission and EMA and replaced the initial Q&A list published on 31 May.

New Q&As and additional clarification are provided in this version including:

• Location of establishment of a company, orphan designation holders; qualified persons for pharmacovigilance (QPPVs) and companies’ manufacturing and batch release sites. • Effects of Brexit on marketing authorisation applications • Authorisation of different types of products, such as generic, hybrid and biosimilar medicines

Of note, “bioequivalence studies that have been conducted with a medicinal product sourced in the UK can be used in generic/hybrid marketing authorisation applications only if the marketing authorisation for that application will be granted before 30 March 2019”. Applicants may consider contacting the competent authority to discuss the particular circumstances of their application in exceptional cases where bioequivalence studies are intended for use in new applications which will be submitted before 30 March 2019 and these bioequivalence studies have been already completed.

www.cromsource.com

Page 24 of 33Regulatory Newsletter Issue 20 October - December 2017

Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/12/news_detail_002864.jsp&mid=WC0b01ac058004d5c1

Guidance: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/05/WC500228739.pdf

MDR/ IVDR - latest status Following the entry into force of the MDR in May 2017, with a 3-year transition period, the medical device industry faces a demand for increased clinical study data for many new products as well as devices already on the market subject to mandatory re-registration. The IVDR, which also entered into force in May 2017, but with a 5-year transition period, also has an increased requirement for clinical evidence. As a general rule, clinical evidence should be sourced from performance studies to be carried out under the responsibility of a study sponsor. Recent developments which followed the entry into force of the MDR and the IVDR are summarised below.

The first implementation act (EU 2017/2185) published The first implementation act to be published following the coming into force of MDR and IVDR concerns drawing up of codes and corresponding devices. Annex I of the published Regulation consists the list of codes and corresponding types of devices for MDR. Annex II consists of the list of codes related to IVDR. It was published by the European Commission in OJEU on 23 November 2017 as Commission Implementing Regulation (EU) 2017/2185 “on the list of codes and corresponding types of devices for the purpose of specifying the scope of the designation as notified bodies in the field of medical devices under Medical Device Regulation MDR and IVDR”. The Commission Implementing Regulation entered into force the day following its publication in the OJEU to allow first notified bodies to use new codes laid down in Implementing Regulation and to submit their applications designed under MDR and IVDR on 26 November 2017.

Source: http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2017.309.01.0007.01.ENG&toc=OJ:L:2017:309:TOChttp://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2017.309.01.0007.01.ENG&toc=OJ:L:2017:309:TOC

First Notified Bodies ready to seek designation against MDR/IVDR 26 November 2017 was the first day Notified Bodies (NBs) could apply for designation under the MDR and the IVDR. On 8 November 2017, the European Association for Medical Devices of Notified Bodies, known as “Team-NB”, reported that 84% of NBs intended to submit their application in November 2017, 8% in December 2017 and 8% in 2018. 23 members of Team–NB declared their intention to submit an application to be designated against MDR; 8 of those NBs also intend to be designated under IVDR. (See the list).

Source: http://www.team-nb.org/team-nb-has-collected-information-from-members-about-their-re-application/

Competent Authorities’ road map for implementation of MDR/IVDR published The EU Competent Authorities for Medical Devices (CAMD) is an umbrella group, under which the national competent authorities in the EU work to enhance the level of collaborative work in what is a single market for medical devices. On November 15, 2017, CAMD Executive Group’s EU MDR/IVDR implementation task force released a road map which outlines key challenges and steps for multiple technical work streams during the implementation phase of the new regulations.

www.cromsource.com

Page 25 of 33Regulatory Newsletter Issue 20 October - December 2017

The road map divides the implementation work into eight categories with lists of activities, the priority levels, and recommended responsible partners and owners stated. The eight categories are: 1. Clinical Evaluation & Clinical Investigation (MD); Performance Evaluation & Performance Studies (IVD) 2. Scope & Classification 3. Notified Bodies & Conformity Assessment 4. Post-Market Surveillance & Vigilance for both MD and IVD 5. Eudamed & Unique Device Identifier (UDI) 6. Market Surveillance 7. IVD-specific Issues 8. Over-arching & Cross-cutting Priorities

Some examples of high priority activities include: clinical work evaluation package; guidance on classification for IVDs with practical examples; guidance on requirements for vigilance reporting and developing and agreeing on terminology for MD/IVD Adverse Nomenclature and patient harm. Of the activities relating to “Clinical Evaluation & Clinical Investigation” category, the highest priority has been allocated to Clinical evaluation work package, including: guidance on equivalence, well established technologies, clinical evidence; gap analysis of MEDDEV 2.7/1; contribution to relevant Implementing Acts; work on interface between various documents/reports e.g. Clinical Evaluation Report (CER), Summary of Safety and Clinical Performance (SSCP), Periodic Safety Update Report (PSUR).

Source: http://www.camd-europe.eu/

NEWS FROM THE UNITED STATES OF AMERICA: DRUGS News from the FDA FDA Adverse Events Reporting System (FAERS) Public Dashboard The Adverse Events Reporting System (FAERS) database is designed to support the FDA’s post-marketing safety surveillance program for drug and therapeutic biologic products. On September 28, 2017, FDA launched a new user-friendly search tool that will offer healthcare providers and consumers more transparency and easier access to data on adverse events associated with drug and biologic products. The FAERS Public Dashboard is a highly interactive web based user-friendly tool that will allow FAERS queries to be easily managed in the database for post-marketing drug safety and monitoring purposes.

This new tool, the FAERS Public Dashboard (Fig 1), enables users to search for data by criteria such as drug/biological product, year, category (foreign or domestic), or by report type, (reporter, reporter region or report seriousness).

www.cromsource.com

Page 26 of 33Regulatory Newsletter Issue 20 October - December 2017

https://fis.fda.gov/sense/app/777e9f4d-0cf8-448e-8068-f564c31baa25/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis

Figure 1 - FDA Adverse Events Reporting System Public Dashboard The FDA “anticipates that this new tool will help to spur the submission of more detailed and complete reports from health care providers and consumers” and goes on to note that “complete and detailed reports are immensely helpful to the agency when identifying safety signals and choosing particular products for further scrutiny”. However, as FDA cautions, there are limitations to this data. “While FAERS contains reports on adverse events associated with a particular drug or biologic, this does not mean that the drug or biologic caused the adverse event. Importantly, the FAERS data by themselves are not an indicator of the safety profile of the drug or biologic.” There may be duplicate and incomplete reports in the system. The information contained in the reports has not been verified. The data from the reports cannot be used to estimate the incidence rates of the reactions.

Press Announcement: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578105.htm

Dashboard: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm070093.htm

Orphan Products Clinical Trials Grants Program On October 6, 2017 FDA announced it had that it has awarded 15 new clinical trial research grants totaling more than $22 million over the next four years to boost the development of products for patients with rare diseases. These grants were made possible by the Orphan Products Clinical Trials Grants Program. The goal of this program is to encourage clinical development of drugs, biologics, medical devices, or medical foods for use in rare diseases. “The clinical trials grant program is an important part of the FDA’s ongoing commitment to encouraging and supporting the development of safe and effective therapies for rare diseases,” said Rachel Sherman, M.D., M.P.H, FDA’s principal deputy commissioner. “The grants awarded this year will support needed research in a range of rare diseases that have little, or no, treatment options for patients.” Information on the Orphan Products Clinical Trials Grant Program https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/WhomtoContactaboutOrphanProductDevelopment/ucm134580.htm

www.cromsource.com

Page 27 of 33Regulatory Newsletter Issue 20 October - December 2017

Orphan Products Clinical Trials Grants Program: https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/whomtocontactaboutorphanproductdevelopment/default.htm

Press Announcement: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm579366.htm

FDA Blog: https://blogs.fda.gov/fdavoice/index.php/2017/09/fda-is-advancing-the-goals-of-the-orphan-drug-act/

Expanded Access Requirements Simplified Expanded access, also known as compassionate use, refers to a program that provides investigational drugs to patients with serious conditions that are not able to participate in a clinical trials and for whom there is no therapeutic alternative. This is a voluntary program. The patient, treating physician and pharmaceutical company providing the drug must all agree to participate. The physician must apply to FDA in order to participate in this program. If the pharmaceutical company agrees, they must grant FDA permission to access their Investigational New Drug (IND) file.

On October 3, 2017, FDA announced it was streamlining this process by providing an updated form and three guidance documents. Information on the individual guidances is provided in the Guidance Document Update section.

1. Form FDA 3926 [Individual Patient Expanded Access Investigational New Drug Application (IND)] is completed by the physician. FDA has revised this form by reducing the amount of information that must be submitted and the time required to complete it. 2. Guidance for Industry - Individual Patient Expanded Access Applications: Form FDA 3926 3. Guidance for Industry - Waiver of IRB Requirements for Drug and Biological Product Studies 4. Guidance for Industry - Expanded Access to Investigational Drugs for Treatment Use - Questions and Answers

Form FDA 3926: https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM504572.pdf

Form FDA 3926 Instructions: https://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm504574.pdf

FDA Blog: https://blogs.fda.gov/fdavoice/index.php/2017/10/expanded-access-fda-describes-efforts-to-ease-application-process/

Guidance Document Update Between September 16, 2017 and December 15, 2017, FDA published over 100 guidances on a variety of subjects. Brief summaries of the guidance documents most applicable to CROMSOURCE and its customers are presented below. A link to all FDA guidance documents is included at the end of this section.

Individual Patient Expanded Access Applications: Form FDA 3926 Final: September 2017 Summary: The purpose of this guidance is to describe the Expanded Access program. As noted by FDA, section III of this guidance was updated in order “to clarify the IRB review requirements for individual patient expanded access treatment use of investigational drugs. The changes to Form 3926 are intended to allow for a waiver of the requirement for review and approval at a convened IRB meeting if the physician obtains concurrence by the IRB chairperson (or designated IRB member) before the treatment use begins”.

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm432717.pdf

www.cromsource.com

Page 28 of 33Regulatory Newsletter Issue 20 October - December 2017

Waiver of IRB Requirements for Drug and Biological Product Studies Final: October, 2017 Summary: The purpose of this guidance is to explain the process of requesting a waiver of Institutional Review Board (IRB) requirements for drug and biological product studies regulated by the Food and Drug Administration (FDA). As noted by FDA, the following updates were made to the guidance.

• “The last paragraph of Section V was deleted to clarify that a sponsor does not need to apply for a waiver of local IRB review when a centralized IRB review process is used.” • “New Section VIII When Is An IRB Waiver for Individual Patient Expanded Access Use Of An Investigational Drug Appropriate? was added.”

https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126500.pdf

Expanded Access to Investigational Drugs for Treatment Use — Questions and Answers Final: October, 2017 Summary: The purpose of this guidance is to provide information about the Expanded Access program in a question and answer format that addresses the most frequently asked questions received by FDA. As noted by FDA, the updates to this guidance document include the following. “• Questions 6 and 9 have been updated to clarify the IRB review requirements for individual patient expanded access treatment use of investigational drugs. The updates discuss revisions to Form 3926 that are intended to allow for a waiver of the requirement for review and approval at a convened IRB meeting if the physician obtains concurrence by the IRB chairperson (or designated IRB member) before the treatment use begins.

• Question 25 has been revised and a new Question 26 has been added to address how the Agency reviews adverse event data in the expanded access context.

• Question 31 (previous Question 30) now also references the 21st Century Cures Act requirement that expanded access policies be publicly posted.”

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm351261.pdf

M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use Final: October 2017 Summary: The purpose of this document is to provide “recommendations on the organization of the CTD and the electronic common technical document (eCTD) for Modules 2 through 5 providing direction on the location and hierarchy of headings within modules, document pagination and segregation, section numbering within documents, and the formatting of the table of contents.” This guidance replaces two other guidances, M4 Organization of the CTD which was issued in 2001 and the 2005 Granularity Document Annex to M4 Organization of the CTD which was issued in 2005. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073257.pdf?elqTrackId=f94f864e0d3b4206a8a3dff85bbfde54&elq=451014240c1547a1a8254954c15c674f&elqaid=753&elqat=1&elqCampaignId=352

E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials Draft: October 2017 Summary: The purpose of this guidance is as follows. “This addendum presents a structured framework to link trial objectives to a suitable trial design and tools for estimation and hypothesis testing. This framework introduces the concept of an estimand (see Glossary), translating the trial objective into a precise definition of the treatment effect that is to be estimated (Section A.3). It aims to facilitate the dialogue between disciplines involved in clinical trial planning, conduct, analysis and interpretation, as well as between sponsor and regulator, regarding the treatment effects of interest that a clinical trial should address.

www.cromsource.com

Page 29 of 33Regulatory Newsletter Issue 20 October - December 2017

The statistical analysis, aligned to the estimand, will be associated with assumptions and data limitations, the impact of which can be investigated through sensitivity analysis (see Glossary). This addendum clarifies the definition and the role of sensitivity analysis. References to the original ICH E9 are made using x.y. References within this addendum are made using A.x.y. This addendum clarifies and extends ICH E9 in a number of respects. Firstly, ICH E9 introduced the Intention-To-Treat (ITT) principle in connection with the effect of a treatment policy, i.e. the effect of treatment initially assigned at baseline, regardless of adherence to the planned course of treatment, indicating that preservation of randomisation provides a secure foundation for statistical tests. It remains undisputed that randomisation is a cornerstone of controlled clinical trials and that analysis should aim at exploiting the advantages of randomisation to the greatest extent possible. However, the question remains whether understanding the effect of a treatment policy always targets the treatment effect of greatest relevance to regulatory and clinical decision making. The framework outlined in this addendum gives a basis for discussing other treatment effects and some points to consider for the design and analysis of trials to give estimates of these treatment effects that are reliable for decision making. Secondly, issues considered generally under data handling and missing data (see Glossary) are re-visited. On one hand, intercurrent events such as discontinuation or switching of treatment, or use of rescue medication, may in some circumstances render the later measurements of the variable irrelevant or difficult to interpret even when it can be collected. In the case of death, measurements after a subject dies do not exist. On the other hand, ICH E9 noted the difficulty of fulfilling the ITT principle when clinical trial subjects discontinuing treatment were lost to follow up. This addendum invites consideration of the important distinction between non-adherence with, or withdrawal from, randomised treatment and discontinuation from the trial; also between measurements that exist but have not been collected, and measurements that do not, or cannot, exist. Having clarity in the estimand gives a basis for planning which data need to be collected and hence which data, when not collected, present a missing data problem to be addressed. In turn methods to address the problem presented by missing data can be selected to align with the chosen estimand. Thirdly, the concept of analysis sets is considered in the proposed framework. Section 5.2 strongly recommends that analysis of superiority trials be based on the full analysis set, defined to be as close as possible to including all randomised subjects. However, trials often include repeated measurements on the same subject. Elimination of some planned measurements on some subjects, perhaps because the measurement is considered irrelevant or difficult to interpret, can have similar consequences to excluding subjects altogether from the full analysis set, i.e. that the initial randomisation is not fully preserved. In addition, a meaningful value of the outcome variable might not exist, as when the subject has died. Section 5.2 does not directly address these issues. Clarity is introduced by carefully defining the treatment effect of interest in a way that determines the population of subjects to be included in the estimation of that treatment effect and the observations from each subject to be included in the analysis considering the occurrence of intercurrent events. The meaning and role of the per-protocol analysis is also re-visited in this addendum; in particular whether the need to explore the impact of protocol violations and deviations can be addressed in a way that is less biased and more interpretable than naïve analysis of the per protocol set. Finally, the concept of robustness is given expanded discussion under the heading of sensitivity analysis. In particular, a distinction is made between the sensitivity of inference to the particular assumptions of a particular analysis and the sensitivity to the choice of analytic approach more broadly. With precise specification of an agreed estimand and a statistical analysis that is both aligned to the estimand and pre-specified to a level of detail that it can be replicated precisely by a third party, regulatory interest can focus on sensitivity to deviations from assumptions and limitations in the data in respect of a particular analysis.”https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM582738.pdf

www.cromsource.com

Page 30 of 33Regulatory Newsletter Issue 20 October - December 2017

Statistical Approaches to Evaluate Analytical Similarity Draft: September 2017 Summary: The purpose of this guidance is as follows:

“This guidance is intended to provide advice on the evaluation of analytical similarity to sponsors interested in developing biosimilar products for licensure under section 351(k) of the Public Health Service Act (PHS Act) (42 U.S.C. 262(k)). This evaluation is to support the demonstration that a proposed biosimilar product (hereinafter proposed biosimilar or biosimilar) is highly similar to a reference product licensed under section 351(a) of the PHS Act. Specifically, this guidance describes the type of information a sponsor of a proposed biosimilar product should obtain about the structural/physicochemical and functional attributes of the reference product, how that information is used in the development of an analytical similarity assessment plan for the proposed biosimilar, and the statistical approaches recommended for evaluating analytical similarity.

The objective of this guidance is to assist sponsors in demonstrating, through an evaluation of the analytical similarity of the proposed biosimilar and reference product, that the proposed biosimilar and reference product are highly similar to support licensure under section 351(k) of the PHS Act. In general, an analytical similarity assessment involves a comparison of structural/physicochemical and functional attributes using multiple lots of the proposed biosimilar product and the reference product.

Conducting appropriate statistical analyses in the evaluation of analytical similarity can provide a high degree of confidence in the results and reduce the potential for bias. However, there are many challenges in designing the statistical analyses to be performed. First, there may be a limited number of reference product lots, and those obtained may be the result of biased sampling, leading to imprecise and possibly inaccurate estimates of the distributions of important quality attributes for the reference product. Second, there may also be a limited number of proposed biosimilar lots, and the available lots may not reflect the true variability of biosimilar product manufacturing. Third, there are a large number of potential quality attributes that can be compared in an evaluation of analytical similarity, and subjecting all of these attributes to formal statistical tests in the context of limited lots could lead to concluding incorrectly that a large number of truly highly similar products are not highly similar.

To address these challenges, the Agency recommends using a risk-based approach in the analytical similarity assessment of quality attributes. This approach to the evaluation of analytical similarity consists of several steps. The first step is a determination of the quality attributes that characterize the reference product in terms of its structural/physicochemical and functional properties. In the second step, these quality attributes are then ranked according to their risk of potential clinical impact. Third, these attributes/assays are evaluated according to one of three tiers of statistical approaches based on a consideration of risk ranking as well as other factors. It should be noted, however, that some attributes may be important but not amenable to quantitative evaluation.”

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm576786.pdf

www.cromsource.com

Page 31 of 33Regulatory Newsletter Issue 20 October - December 2017

NEWS FROM THE UNITED STATES OF AMERICA: MEDICAL DEVICES News from the FDA Breakthrough Device Program

On October 25, 2017, FDA published a draft guidance titled Breakthrough Devices Program. “The Breakthrough Devices Program is a voluntary program for certain medical devices that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. This program is intended to help patients have more timely access to these medical devices by expediting their development, assessment, and review, while preserving the statutory standards for premarket approval, clearance of a premarket notification (510(k)), and marketing authorization via the De Novo classification process, consistent with the Agency’s statutory mission to protect and promote public health.” The Breakthrough Devices Program replaces the Expedited Access Pathway (EAP), the Innovation Pathway and the Priority Review Program. However, some features remain from all programs as can be seen by the seven principles of the program.

1. Interactive and timely communication between the program’s sponsor and FDA during device development and the review process.

2. Balancing Pre and Postmarket Data Collection for Breakthrough Devices requiring Premarket Approval (PMA). “ a) .“FDA may accept a greater degree of uncertainty of the benefit-risk profile for these devices if the uncertainty is sufficiently balanced by other factors, including the probable benefits for patients to have earlier access to the device (e.g., a device that treats a life threatening disease when no alternative treatments are available) and adequate postmarket controls to support premarket approval” 3. Efficient and Flexible Clinical Study Design 4. Review Team Support 5. Senior Management Engagement 6. Priority Review status for all submissions designated as a Breakthrough Device. 7. Manufacturing Considerations for PMA Submissions such as expedited preapproval inspections.

Additional details and program features can be found in the draft guidance. Guidance for Industry: https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM581664.pdf

Federal Register Notice: https://www.federalregister.gov/documents/2017/10/25/2017-23195/breakthrough-devices-program-draft-guidance-for-industry-and-food-and-drug-administration-staff

FDA Website: https://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/ucm441467.htm

Medical Device Innovation Program FDA qualified the first Medical Device Development Tool (MDDT) in October 2017. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a clinical outcome assessment that measures patient-reported outcomes (PRO) from patients with congestive heart failure or weakened heart muscle due to prior heart attacks, heart valve problems, viral infections, or other causes. According to the FDA, “Use of this tool could expedite the regulatory submission and review process by reducing the number of subjects in clinical trials, saving money, increasing confidence in data quality, and improving review speed and consistency, while maintaining the same level of safety and effectiveness for patients”

www.cromsource.com

Page 32 of 33Regulatory Newsletter Issue 20 October - December 2017

MDDTs qualified by FDA can be used in clinical trials by the medical device industry to support both device submissions and post-approval studies.

Decision Summary https://www.fda.gov/downloads/MedicalDevices/ScienceandResearch/MedicalDeviceDevelopmentToolsMDDT/UCM581761.pdf

Blog - Medical Device Development Tools: Helping to Speed Medical Device Evaluation and Approval. https://blogs.fda.gov/fdavoice/index.php/2017/10/medical-device-development-tools-helping-to-speed-medical-device-evaluation-and-approval/

Website: https://www.fda.gov/medicaldevices/scienceandresearch/medicaldevicedevelopmenttoolsmddt/default.htm

Guidance Document Update Between September 16, 2017 and December 15, 2017, FDA published over 100 guidances on a variety of subjects. Brief summaries of the guidance documents most applicable to CROMSOURCE and its customers are presented below. A link to all FDA guidance documents is included at the end of this section.

Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff Final: September 29, 2017 Summary: The purpose of this guidance is to describe the process through which feedback on planned or potential medical device can be requested. This guidance replaces the previous 2014 version. The updates are mostly administrative. Figure 2 (below) summarizes the changes.

https://www.fda.gov/downloads/Training/CDRHLearn/UCM578386.pdf Figure 2 - Overview of the new Pre-Submission Process https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm311176.pdf

www.cromsource.com

Page 33 of 33Regulatory Newsletter Issue 20 October - December 2017

Classification of Products as Drugs and Devices & Additional Product Classification Issues Final: September 2017 Summary: The purpose of this guidance is to describe the process for obtaining a formal determination of a product’s classification from FDA and to describe the decision-making process FDA uses to make the determination. https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM258957.pdf

Deciding When to submit a 510k for a Change to an Existing Device Final: October 2017 Summary: This guidance replaces the previous guidance (K97-1) Deciding When to Submit a 510(k) for a Change to an Existing Device which was issued on January 10, 1997. The purpose of this guidance is to provide clarity of when a change to a medical device may trigger the submission of a new premarket notification [510(k)] to FDA. Changes made that affect the safety or effectiveness of a device may warrant a new 510(k) submission. https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/documents/document/ucm514771.pdf

Deciding When to Submit a 510(k) for a Software Change to an Existing Device Final: October 2017 Summary: This guidance is intended as a companion to the guidance Deciding When to Submit a 510(k) for a Change to an Existing Device. The purpose of this guidance is to describe circumstances when a software (including firmware) change to a medical device may require the submission of a new 510(k). A flowchart is included to help ascertain the impact of any changes. Appendix A provides several examples of software modifications. Some require a new 510(k) and some do not. https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm514737.pdf

Software as a Medical Device (SAMD): Clinical Evaluation Draft: December 2017 Summary: The purpose of this guidance is to describe the activities to be conducted to clinically evaluate SAMD.

Guidance: https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM524904.pdf Website: https://www.fda.gov/MedicalDevices/DigitalHealth/SoftwareasaMedicalDevice/ucm587925.htm

Clinical and Patient Decision Support Software Draft: December 2017 Summary: The purpose of this guidance is “to identify the types of decision support software functionalities that: (1) do not meet the definition of a device as amended by the Cures Act; (2) may meet the definition of a device but for which FDA does not intend to enforce compliance with applicable requirements of the FD&C Act, including, but not limited to, premarket clearance and premarket approval requirements; and (3) FDA intends to focus its regulatory oversight on.” https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM587819.pdf

Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act Draft: December 2017

Summary: The purpose of this guidance is to describe the four instances when software is not considered a medical device. https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM587820.pdf Link to all FDA guidance documents https://www.fda.gov/RegulatoryInformation/Guidances/default.htm

North American Headquarters 309 Waverley Oaks Road, Suite 101Waltham, MA 02452 - USA Direct: +1 617.871.1128 Fax: +1 617.871.1129

European HeadquartersVia Giorgio De Sandre, 337135 Verona - ItalyDirect: +39 045 8222811Fax: +39 045 8222812

CROMSOURCE Quality ISO 9001:2015 multi-site certified quality management system.

ISO 14155:2011 conformity confirmed.

www.cromsource.com

CROMSOURCE is an international provider of outsourced services to the Pharmaceutical, Biotechnology and Medical Device industries, specialized in

clinical development and staffing solutions