1. „Ensuring Regulatory and Pharmacovigilance Compliance“ „Ensuring Regulatory and Pharmacovigilance Compliance“

2. „Ensuring Regulatory and Pharmacovigilance Compliance“ Team of specialised experts All in one - Full services for whole Europe in one place EU regulatory knowledge and strategies MA holding and support EU/local RA and PHV contact Complex innovation support Who we are?

3. „Ensuring Regulatory and Pharmacovigilance Compliance“ Regulatory Patterns of the EU The EU regulatory area is, in many aspects, despite of harmonization effort of EC still fragmented and national authorities play important role. This result in: –Different requirements in MSs –Different regulatory bodies for medicinal products, medical devices, blood derivatives, tissues and cells as well as for clinical trials, clinical trials for medical devices etc –Differentness in legal obligation in MSs (reg. requirements, responsibility, leaflet texts, assessment of products) –As usual the legislation lay back of the science reality – it creates increasing problems in passing through the regulatory barriers

4. „Ensuring Regulatory and Pharmacovigilance Compliance“ Registration in EU – Is it so simple? Medicinal products Positioning - Rx, OTC, others - Borderline products (on the edge, differ per country/NCA) Procedures - CP, DCP, MRP, national - Repeat use, duplicated - Different legal backgrounds Different - Timelines - Risks - Conditions in countries (indication, contraindication, use, dosage) - Local packages/leaflets The registration strategy is the key to success.

5. „Ensuring Regulatory and Pharmacovigilance Compliance“ Medicines – Post-approval PHV - Master file EU - Registration in EU database - Continual reporting on countries/EU level - Local QPPV Maintenance – changes - Assesment of clasification - Complicated/Strategy needed MAH responsibilities - Local, very wide – full for everything - Well set distribution/technical agreements (local requirements) - Regulation of promotion - Patient service (PIS)

6. „Ensuring Regulatory and Pharmacovigilance Compliance“ Borderline products - assessment Needs to be done – different view in countries Marketing strategy important - Time to launch - Conditions of launch - Reimbursement - Promotion Other categories to be evaluated - Medicinal view - Consultation with local authorities

7. „Ensuring Regulatory and Pharmacovigilance Compliance“ Other Categories Veterinary - Similar situation - In some countries different CA Medical Devices - Different regulatory system - Vigilance - Clinical trials regulation - Quick development towards medicines Cosmetics - Notification - Cosmetovigilance

8. „Ensuring Regulatory and Pharmacovigilance Compliance“ Our Services Continuous support and updates depending on EU legislation Regulatory services - Medicinal products, medical devices - Cosmetics, food supplements - Veterinary products Education + trainings Clinical trials PASS - Post-Authorisation Safety Studies Marketing + sales - Import/Distribution - Marketing

9. „Ensuring Regulatory and Pharmacovigilance Compliance“ Our Services – Key Features Partner/Products/Concept analysis - Identification of key issues and risks of market entry - Elaborating of possible scenarios and strategy alternatives Quantification of the alternatives - Value, Time, Risks Evaluation of the influence on - Product definition - Registration strategy - Pricing - Reimbursement - Follow up procedures

10. „Ensuring Regulatory and Pharmacovigilance Compliance“ GMP Setup of EU GMP for manufacturers from 3rd countries - Initial assessment of current state of GMP - GMP training for employees - Setup of GMP documentation - Implementation of GMP requirements - Internal GMP audits - GMP audits of API manufacturers - Control audits to assess corrective and preventive actions, final control of the project - Support in GMP certification process

11. „Ensuring Regulatory and Pharmacovigilance Compliance“ Scope of The Services in Regulatory Affairs Consultation and registration services in the territories - EU countries - Croatia - Russia - Ukraine Strategy, Registration, Maintenance Services in - Human and veterinary medicinal products - All alternatives of registration procedures (National, CP, MRP, DCP) - Food supplements and novel foods - Medical equipments/devices - „Health“ Cosmetics

12. „Ensuring Regulatory and Pharmacovigilance Compliance“ Registration Files - Submissions –Compilation and evaluation –Completeness and quality check: pre-submission –Preparation of CTD files –Support in creating Module 1 for all procedures according national/EU requirements –Negotiations with authorities –DCP slots blocking and management –Transforming/ creating of e-CTD format

13. „Ensuring Regulatory and Pharmacovigilance Compliance“ e - CTD The electronic Common Technical Document (e-CTD) is an interface for the pharmaceutical industry to agency transfer of regulatory information. The content is based on the Common Technical Document (CTD) format. The e-CTD was developed by the ICH as a standard format for regulatory submissions in the Europe, the USA and Japan.

14. „Ensuring Regulatory and Pharmacovigilance Compliance“ Registration Files - Text Management Compliant in each country Insert leaflet, summary of product characteristic (PIL), packaging material (mock-ups) Harmonization of texts according to: –Actual QRD format –Local requirements –EU reference product (generics) Mock-up creation Translation of texts to all languages Braille requirements The smooth pass of the texts → fundamental part of instant national phase of registration → fundamental part of instant national phase of registration

15. „Ensuring Regulatory and Pharmacovigilance Compliance“ Complex Regulatory Maintenance Management Variations Communication with authorities Renewals of MAs Sunset clause monitoring and solving Professional maintenance management → saved time, stress, money … Professional maintenance management → saved time, stress, money …

16. „Ensuring Regulatory and Pharmacovigilance Compliance“ Pharmacovigilance Pharmacovigilance monitoring of the products 24/7/365 - Non-stop services for receipt of adverse events signals - Proprietary PHV database - Literature search service - Safety studies /clinical trials support Complex services of QPPV: - Creation and run of the PHV system according to current EU requirements - Electronic submission of ADRs/AEs to EMA/NA (MedDRA, EudraVig) - Compulsory regular PHV training of the stuff - Electronic submission of a product information to EMA database (XEVMPD)

17. „Ensuring Regulatory and Pharmacovigilance Compliance“ Other Services Public information service - 24/7/365 patient service - Disabled people Consultation services for - Patients - Health care professionals - Companies The role of Pharmacovigilance becomes extremely important part of the daily business

18. „Ensuring Regulatory and Pharmacovigilance Compliance“ Translation Support

19. „Ensuring Regulatory and Pharmacovigilance Compliance“ Translational Evaluation/Support Process The aim of the process is to support early biomedical discoveries for novel preventive, diagnostic or therapeutic products to first in human application and clinical proof of concept. The entire process is designed to adopt step by step approach to identify the needs and the best way of providing the value for investigators. Gathering the information - Structured template is provided to collect the basic information valuable for translational assessment and strategy set up. - The output is an assessment report Analysis and recommendations - In depth analysis, collecting additional information - Recommendation of the effective way ahead - Providing the key milestones Translation strategy - To elaborate on all aspects of translational process - Detail project planning and project management to eliminate the risks and orchestrate the all aspects to reach the goal

20. „Ensuring Regulatory and Pharmacovigilance Compliance“ Clinical Trials

21. „Ensuring Regulatory and Pharmacovigilance Compliance“ Clinical Trial Preparation Feasibility studies, start-up support Selection of qualified investigators and trial sites Preparation of study documents (Protocol, Investigator´s Brochures, Informed Consent Form, Questionnaires, Manuals etc.) Protocol and medical writing Statistical support, clinical trial designing Submission to regulatory authorities and ethics committees Co-ordination of preparation works, investigator´s meeting

22. „Ensuring Regulatory and Pharmacovigilance Compliance“ Monitoring and CT Management Site management, communication with investigators, on- site activities Trial monitoring in compliance with Good Clinical Practice (GCP) Data management and statistical data processing Identification of changes and evaluation of regulatory aspects Supervision of the progress of a clinical trial Support for fast recruitment Ensuring protocol compliance Applying SOPs, GCP and applicable regulatory requirements Set up of adequate procedures for quality control and quality assurance

23. „Ensuring Regulatory and Pharmacovigilance Compliance“ Medical Services Support of the investigators Preparation of Standard Operating Procedures Good Clinical Practice trainings Good Laboratory Practice trainings Good Manufacturing Practice for Advanced Therapies Legal aspects of CT, data protection, insurance Medical Services Medical support of project teams 24/7 medical support, ongoing medical safety review Medical review of clinical study reports Medical expert opinion Medical reporting (Interim, final reports, safety reports)

24. „Ensuring Regulatory and Pharmacovigilance Compliance“ Pharmacovigilance, Risk Management QPPV service Immediate report of serious adverse events to the sponsor Reporting of SUSARS and all safety issues to the authorities and ethics committee Submission of annual safety reports to the competent authority and the ethics committee Transmission of safety reports to the investigators Immediate hazard management Risk management plan Continuous follow-up and evaluation of risks Quality assurance and Quality Control, QA/QC Audits

25. „Ensuring Regulatory and Pharmacovigilance Compliance“ PASS

26. „Ensuring Regulatory and Pharmacovigilance Compliance“ Post-Authorisation Safety Studies (PASS) A post-authorisation safety study (PASS) is defined in Article 1(15) of Directive 2001/83/EC as any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk-management measures. PASS are designed to ensure that medicinal products are monitored for long-term safety and effectiveness in Routine Clinical Practice and may be initiated, managed or financed by MAH voluntarily, or pursuant to an obligation imposed by a competent authority. PASS – Critical New Tool in searching for „Missing Information“

27. „Ensuring Regulatory and Pharmacovigilance Compliance“ PASS - Services PASS Management Definition of scientific format of protocols, abstracts and final study report for non-interventional PASS Identification of the Requirements and Key elements for PASS Creating Guidance on Effectiveness of Risk Minimisation Establishing monitoring system – GVP (Good Pharmacovigilance Practice) E-register of non-interventional PASS maintained by the Agency Publication of Final Study Report PASS On-site services ON-SITE preparation of PASS (including on-site training, contract issue etc.) ON-SITE Data Management and Data Collection of PASS e-CRFs services, Statistical analysis Preparing FINAL Study Report

28. „Ensuring Regulatory and Pharmacovigilance Compliance“ Education & Training

29. „Ensuring Regulatory and Pharmacovigilance Compliance“ Education & Training Regulatory affairs excellence is mainly driven by knowledge – let´s be up to date and learn effectively Life Cycle of Medicinal Products Biostatistics GCP course Coordination of the clinical trials All courses are provided in co-operation with PharmAround education platform www.pharmaround.com

30. „Ensuring Regulatory and Pharmacovigilance Compliance“ Marketing & Sales

31. „Ensuring Regulatory and Pharmacovigilance Compliance“ Market Access Market analysis and market environment Market Access strategy – reflecting actual and upcoming legislation development and „current“ practices Pharmacoeconomic analysis - Budget impact - Cost effectiveness - Cost containment Preparation and submission of application for - Maximum price - Reimbursement Organisation of „patient registries“ Management of „life cycle“ of the reimbursement/price

32. „Ensuring Regulatory and Pharmacovigilance Compliance“ Regulatory House – „All you need“

33. „Ensuring Regulatory and Pharmacovigilance Compliance“ www.regulatoryhouse.com e- mail: office@regulatoryhouse.com Skype: regulatory.house