Embed Size (px)
Citation preview
Risk analysis applied to post-marketing regulatory changes related to safety and efficacy of medicines (pharmacovigilance/clinical trials) – European perspective
*Date: 28/06/2017 *Author: Sini Eskola, Executive Committee member in Industrial Pharmacy Section 2011-now, FIP & Director Regulatory Affairs, EFPIA *Version: FINAL draft
Presentation
2 www.efpia.eu
A few words on FIP – Industrial Pharmacy Section and EFPIA
Industrial Pharmacy Section (IPS) of International Pharmaceutical Federation (FIP) represents individual members of FIP who work or are interested in working in the pharmaceutical industry. We unite and bring forward the expertise of industrial pharmacists a global level. We put a strong emphasis in planning and delivering high quality industrial pharmacy related programs in FIP Annual Conference and participate in and organise other congresses and webinars (e.g. ANVISA/Sindusfarma/FIP/IPS Symposium) among other activities aim at supporting our members in networking and personal development.
The European Federation of Pharmaceutical Industries and Associations (EFPIA) represents the pharmaceutical industry operating in Europe. Through its direct membership of 33 national associations and 40 leading pharmaceutical companies, EFPIA is the voice on the EU scene of 1,900 companies committed to researching, developing and bringing to patients new medicines that will improve health and the quality of life around the world.
FIP Industrial Pharmacy Section ExCo 2016
3 www.efpia.eu
The views expressed in this presentation are the personal views of the
presenter and may not be understood or quoted as being made on
behalf of or reflecting the position of EFPIA nor Industrial Pharmacy
section in FIP.
Disclaimer
4 www.efpia.eu
Managing risks of an investigational and marketed medicinal product in the European context, focus on
Introduction to European framework
Risk-Management Plan (RMP)
Post-Authorisation Studies (PAS)
Post-authorisation safety study (PASS)
Post-authorisation efficacy study (PAES)
Routine reporting (SUSAR/PSUR-PBRER) Risk-focused analyses to post-marketing regulatory changes
Change in mindset and application of risk-based thinking
Streamlining the pharmacovigilance legislative framework
Example on Digitalisation
What is still needed for efficient management of post-marketing regulatory (safety/efficacy) changes?
Today’s presentation
5 www.efpia.eu
New Pharmacovigilance Legislation in EU
adopted in 2010
entered into force 2012: Establishment of PRAC and NEW PSUR procedure
ICH E2C(R2): periodic benefit risk evaluation report (PBRER)
Concept paper 2010
Finalised Guideline November 2012
What happened next?
Establishment of PRAC
Implementation of the ‘new’ PSUR procedure
Finalisation of GVP VII
Expansion to NAPs only PSUR single assessment
Focus on implementation/change management
Experience was starting to be gained
Feedback from Industry received..
Intro
6 www.efpia.eu
Intro: The risk management cycle
7 www.efpia.eu
Intro: Managing risks
European Commission report: Results for period mid-2012 to mid-2015.
The safety of patients is increasingly being managed proactively through risk management plans.
Every medicine approved for marketing in the EU is required to include a Risk Management Plan (RMP) as part of the dossier submitted by the company.
The PRAC is now assessing around 600 RMPs each year for centrally authorized medicines, while over the period of the report some 20,000 RMPs have been submitted to the Member States for nationally authorized medicines.
8 www.efpia.eu
RMPs include information on:
a medicine's safety profile;
how its risks will be prevented or minimised in patients;
plans for studies and other activities to gain more knowledge about the safety and efficacy of the medicine;
measuring the effectiveness of risk-minimisation measures
Good Pharmacovigilance Practice, Module V rev.2 on RMP
Concise and clear description of risk management and how safety risks evolve through a product’s lifecycle based on evidence from a variety of sources
Acknowledgement of important risk vs risk
Risk Management Plan (RMP)
Post-authorisation studies – PASS and PAES
9 Phase 4 studies using registries/PERSPECTIVES FROM PHARMA
Post-authorisation study (PAS)
Post-authorisation safety study (PASS)
Interventional PASS=clinical
Non-interventional (NI-
PASS)=observational
Postauthorisation efficacy study (PAES)
Interventional PAES=clinical
Non-interventional (NI-
PAES)=observational
10 www.efpia.eu
Post-authorisation study (PAS) may be requested by competent authorities in EU Member States or the EMA in accordance with DIR 2001/83/EC or REG (EC) 726/2004, or conducted voluntarily by MAHs, and could either be
Clinical trial
Requirements of DIR 2001/20/EC apply
Non-interventional post-authorisation study
Requirements of DIR 2001/83/EC and REG (EC) 726/2004 apply
Post-Authorisation Study (PAS)
Clinical trial Non-interventional post-authorisation
study
Post-authorisation Study (PAS)
Post-authorisation
Pre-authorisation
Source: EMA
11 www.efpia.eu
Post-authorisation Safety Study (PASS)
Legal definition DIR 2001/83/EC Article 1(15):
‘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’
May cover clinical trials and non-interventional studies;
May be imposed as an obligation of marketing authorisation or conducted voluntarily;
Covered by a specific chapter of the pharmacovigilance legislation, Implementing Regulation (EC) 520/2012 chapter VIII and GVP (Good Pharmacovigilance) Module VIII on PASS;
Post-Authorisation Safety Study
Source: EMA
12 www.efpia.eu
Post-authorisation Safety Study (PASS) A study is non-interventional if the following requirements are cumulatively fulfilled:
the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation;
the assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study; and
no additional diagnostic or monitoring procedures are applied to the patients and epidemiological methods are used for the analysis of collected data.
Definition revised in new EU Clinical Trials Regulation (EC) 536/2014
Whether a study with an authorised medicinal product is non-interventional or a clinical trial is further explained in GVP VIII introduction and in DIR 2001/20/EC; * Volume 10 of The Rules Governing Medicinal Products in the European Union, Q7A, Version 9.0, August 2011, Question 1.9
Post-Authorisation Safety Study
Source: EMA
13 www.efpia.eu
A Post-Authorisation Efficacy Study (PAES) may be imposed for
Conditional marketing authorisations [REG (EC) 726/2004 Article 14(7)]
Marketing authorisation under exceptional circumstances [REG (EC) 726/2004 Article 14(8) or DIR 2001/83/EC Article 22]
Marketing authorisation for ATMP [REG (EC) 1394/2007 Article 14]
Paediatric use of medicinal product [REG (EC) 1901/2006 Article 34(2)]
Pharmacovigilance referral procedure for safety reasons [Articles 31 or 107i of DIR 2001/83/EC; Article 20 of REG (EC) 726/2004 ]
Covers clinical trials and observational (non-interventional) study designs;
Post-Authorisation Efficacy Studies
Source: EMA
14 www.efpia.eu
In addition, PAES may be imposed as an obligation of MA within the scope of Delegated Regulation (EU) 357/2014 which lays down the specific situations
when it may be necessary to complement the data available at the time of
authorisation with additional information concerning the efficacy of a medicinal
product;
when post-authorisation information may require significant revision of previous
efficacy evaluations and call for additional, confirmatory efficacy data, while the
marketing authorisation is maintained.
EMA scientific guidance on post-authorisation efficacy studiesEMA/PDCO/CAT/CMDh/PRAC/CHMP/261500/2015) includes a ‘working’ definition of PAES (no legal definition);
Since June 2014, 29 PAES have been imposed by CHMP, all are clinical trials;
Post-Authorisation Efficacy Studies
Source: EMA
15 www.efpia.eu
The PSUR /PBRER is a scientific critical analysis of benefit risk; neither intended nor designed to be:
A compliance tracking tool
A monitoring tool
The PSUR/PBRER is a global document
Importance of maintaining consistency with ICH E2C(R2)/GVP Module VII for core document
Legitimate regional requirements should be confined (In EU: specific appendices)
Routine reporting (PSUR-PBRER)
16
Risk-focused analyses to post-marketing
regulatory changes
Pharmacovigilance in the Future A Complete Shift in Emphasis/mindset ?
Risk Management
Risk Management
Signal Detection
Signal Detection
Periodic Reporting
Periodic Reporting
AE Handling
AE Handling
2007 2011
Fast forward to 2015 post new legislation Implementation
17
Benefit Risk Management
Signal Detection
Periodic Reporting
AE Handling
Streamlining the framework - Example on Complexity- Post Authorisation Safety Studies in
Europe (PASS)
Requirements detailed in: PV Legislation
Guidance GVP Modules
Variations Regulation
Post-authorisation Q&As
RMP and other templates
PV Fees Legislation
Against backdrop of increased costs: IDMP (Identification of
Medicinal Products)
EudraVigilance CT Regulation (depending
on implementation)
Falsified Medicines Directive (depending on implementation)
Confusing legislation has led to inconsistent implementation Inconsistent processes for centralised and national / MRP products Inconsistent application of the requirements by regulators
The system has become too complex and provides a detraction from scientific focus and a potential source for additional compliance risk for involved operators
Streamlining the framework - Example of Individual Case Safety Reports (ICSR) Target
• Risk minimisation:
• Risk-proportionate data collection and focus
Focus data
collection
here!
19 Quality of safety information received
Streamlining the framework - Benefit-Risk Holistic View
Assessment of data-generated pre-approval in clearly defined patient population
Assessment of data-generated post-approval in real-world context
Risk Management Plan (RMP)-PASS-PAES
Registry strategy
B/R methodolgy
A framework with the patient at its centre, which supports an informed
benefit-risk decision in the context of the relevant disease
Streamlining the framework - Benefit-Risk Assessment Framework in Europe
MAH Regulators
Patient
Other stakeholders
e.g. Healthcare Professionals,
academia
22 www.efpia.eu
Streamlining the framework – benefit of digitalisation
Link to Web-RADR project: https://web-radr.eu/
23 www.efpia.eu
Focus on what is most likely to impact patient safety and public health
For data collection concentrate on sources most likely to generate quality information
In Periodic Safety Update Reports and Risk Management Plans focus on important risks
Convergence to allow compliance with legislation and guidance on a global basis
Consistent with international consensus Proportionate and pragmatic approach for all players (MAHs,
Regulators, Health Care Professsionals and patients)
Based a on common understanding e.g for PASS and PAES,
registries and utilisation of Real World Evidence (RWE)
What is still needed for efficient management of post-marketing regulatory (safety/efficacy) changes?
Optimised utilisation of modern technology (electronic reporting etc)
24 www.efpia.eu
Thank You For Your Attention!
MORE INFORMATION: Link to FIP Industrial Pharmacy Section: http://www.fip.org/industrial_pharmacy Link to EFPIA: https://www.efpia.eu/
25 www.efpia.eu
EFPIA Pharmacovigilance Expert Group (PVEG) & Emma DuFour (Abbvie) FIP Industrial Pharmacy Section Dr Thomas Goedecke and Irene Rager (EMA) for references
Acknowledgements
