Regulatory Aspects of Pharmacovigilance

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1 Regulatory Aspects of Pharmacovigilance Deirdre Mc Carthy Pia Caduff-Janosa Training Course Uppsala 2012

2 Agenda Risk based approach to spontaneous reporting (incl clinical trials) -> Pia Caduff-Janosa Principles of REMS/RMP -> Deirdre McCarthy Handling of RMPs by Reg Authorities > Pia Caduff-Janosa Changes to EU PV legislation -> Deirdre McCarthy PSURs -> Pia Caduff-Janosa Discussion 30 min

3 Requirements by Drug Regulatory Authority (DRA): MAH Marketing Authorisation Holders (MAH) must submit: AE from clinical trials PV Master File, PV/Risk Management Plans Spontaneously reported ADR ADR reports from Post Authorisation Studies (PASS) Periodic Update Safety Reports (PSUR) Ad hoc reporting (emerging signals, quality defects, supply bottle necks etc

4 Requirements by DRA: Health Care Professionals (HCP) Spontaneous ADR reports Suspected quality defects Not a legal obligation in every country

5 Patient/Consumer reporting A right, not a legal obligation

6 Requirements by DRA Principles and content are harmonized (ICH Guidelines, reports by CIOMS Working Groups) Format and timelines can differ between geographical areas consult the applicable legislation

7 Useful Links cacy-guidelines.html Home_Page.jsp ulation/general/general_content_ jsp&mid=wc0b0 1ac058033e8ad Information/default.htm

8 Individual Case Safety Reports (ICSR) Same risk based approached for pre- and postauthorisation reporting: serious reactions first and documented as completely as possible

9 Seriousness (ICH E2A) ADR Results in death Is life-threatening Requires or prolongs hospitalization Results in persistent or significant disability Is a congenital anomaly/birth defect

10 Medically Important Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately lifethreatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious.

11 Severe Serious Severe is a clinical term that describes the intensity of a clinical event Serious is a regulatory term that defines reorting obligations and is related to the outcome

12 Clinical trials Interventional clinical trials must be authorized by ethical committee and DRA changes to protocol etc must be submitted to DRA for approval Ethical committe and all investigators must be informed on findings that may adversely affect study participants

13 Reporting from Clinical Studies ICSRs: SUSAR (serious, unexpected, suspected adverse reactions) only Development Safety Update Report DSUR: comprehensive safety evaluation of the clinical studies (all study centres!)

14 Spontaneous Reporting Minimal reporting criteria: Identifiable reporter Identifiable patient Adverse reaction Suspected drug No hearsays

15 Good PV Practice Complete narrative Chronology Medical history Investigations performed Differential diagnosis Action taken with drugs (dechallenge/rechallenge) Outcome

16 Good PV Practice Suspected drugs Substance and trade name Formulation Dosage Route of application Concomitant drugs

17 Recommended Reading

18 Principles of EU-RMPs & US REMS

19 Basic Components of EU Risk Management Plan Risk Management Plan Safety Specification Summary of important identified risks, important potential risks and missing information (ICH E2E) Pharmacovigilance Plan b Based on safety specification; Routine PV practices and action plan to investigate specific safety concerns (ICH E2E) Risk Minimization Activities to be taken to minimize the impact of specific safety concerns on the benefit-risk balance 19

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21 Under the new legislation Previously, risk management guidance was based solely on managing risks. However, when considering how to maximise, or indeed assess, the riskbenefit balance, risks need to be understood in the context of benefit. In assessing the risk-benefit balance at the time of authorisation, the assumption is made that these benefits and risks apply to the whole target population. However, there may be subsets of patients for whom the risk is greater than that for the target population as a whole or in whom the benefit may not be as great.

22 Under the new legislation In addition, efficacy in the clinical trial setting may not reflect the true efficacy of the medicinal product in everyday medical practice and so the risk-benefit balance of a medicinal product as assessed at the time of authorisation will inevitably change postauthorisation. Regulation (EU) No 1235/2010 amending Regulation (EC) No 726/2004 and Directive 2010/84/EU 128 amending Directive 2001/83/EC include provisions for both post-authorisation safety studies and post authorisation efficacy studies to be a condition of the marketing authorisation in certain circumstances and for these studies to be included in the risk management plan (RMP)

23 Risk Evaluation and Mitigation Strategies (REMS) Regulatory History September 27, 2007 FDAAA signed March FDA Guidance Format and content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications Key FDA powers: FDA has authority to require a REMS REMS requires timetable for assessments FDA can impose monetary penalties under REMS

24 Possible Components of REMS Medication Guides Patients Communication Plan Letters to HCPs Provide information for professional societies to disseminate Elements to Assure Safe Use (ETASU) Training of HCPs and pharmacists Restrict setting for use and/or dispensing Proper patient selection Monitoring Registry

25 Possible Components of REMS (cont d) Implementation system Database Used to assess REMS elements Timetable for Assessments No less than every 18 months, 3 years, and 7 years FDA may specify shorter or longer frequencies

26 Medication Guide Updated requirements February 2011 Draft Guidance for Industry: Medication Guides Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies If MGs can assure safety per 21 CFR part 208, a REMS is not required Manufacturers may request elimination of previously approved REMS Enforcement discretion when a product with a MG is dispensed inpatient or outpatient to a healthcare professional

27 Analysis of Approved REMS Type Total M 123 MEIC 10 MEI 15 EIC 3 MC 29 C 11 ME M=Medication Guide E= Elements to Assure Safe Use I = Implementation System C = Communication Plan

28 Risk Management DRA Integral part of marketing authorization submission in most countries reviewed at authorisation increasingly made public replacing PSURs?

29 Key differences in regulations Insert EU flag Insert US flag

30 Single case reports Key differences US EU Classification Report serious unexpected (all countries) Report all serious Source HCP and consumer HCP only (usually) Aggregate Reports Causality Report irrespective of causality Timelines Quarterly for 3 years Only report at least possibly related cases Six-monthly for 2 years Annually thereafter Annually for 2 years, 3 yearly thereafter

31 Key differences US EU Literature searching Frequency Monthly Weekly Search for Case reports only Case reports and other safety data Report forms MedWatch (3500) CIOMS 1 Risk Management Programs VAERs REMS (RiskMAPs) QPPV No Yes EU-RMPs

32 Changes to the EU PV legislation

33 Why change the pharmaceutical legislation? >10 year since last (major) change EU-enlargement Appraisal of the existing pharmacovigilance system Fraunhofer-Report Industry s interests Broad consensus: the existing system and rules are complex and difficult Simplification! 33

34 Assessment of the Community System of PV Frauenhofer Institute for Systems and Innovation Research; 2006 General aim: To analyse how the European central and EU Member States medicines agencies collaborate with each other, the Marketing Authorisation Holders and other stakeholders, in monitoring the adverse effects of pharmaceuticals and to put forward recommendations Main components of PV systems: Data collection Data management Signal Detection Safety issue assessment Decision making Communication and action

35 Why the need for change? European Commission Assessment Report estimated that: - 5% of all hospital admissions are due to adverse drug reactions - 5% of all hospital patients experience an adverse drug reaction - Adverse drug reactions are the 5th most common cause of hospital death - The legislation will save 5910 lives per year across the EU

36 Context Critical assessment of scandals (?) New active substances monoclonal antibodies, gene therapeutics etc. Huge data bases ADRs, epidemiological databases etc. Increased interest of the public Globalisation of drug markets 36

37 EU legislation New PV legislation was adopted by the European Parliament on 22 September 2010 and will come into force in July The legislation takes the form of a new Directive amending the requirements of 2001/83/EC and a Regulation that amends Regulation (EC) No.726/2004. Together these will bring about a number of changes to strengthen the way in which the safety of medicines for human use is monitored in the EU. Three main areas of change: enhanced monitoring of the benefits and risks of medicines postauthorisation replacement of the Pharmacovigilance Working Party with a Committee an increased level of transparency of safety information.

38 EMA Plan for Implementation Collection of key information on medicines Better analysis and understanding of data and information Regulatory action to safeguard public health Communication with stakeholders

39 Principles of Periodic Safety Update Reports (PSURs)

40 PSURs Periodic evaluation of the safety profile of a product signals should be detected during PSUR compilation, not at review by DRA! Format according to ICH E2C (1996/2003) Resources and time consuming both for industry and DRA Obsolete with RMPs?

41 PSURs Periodic safety evaluation of authorized products reporting with varying timelines in different countries Adverse reactions reported spontaneously worldwide in the period (+ cumulative data), usage data, registration status, new regulatory actions, findings from studies, literature, active surveillance etc Any changes the prescribing information (CCSI)?

42 From PSUR to PBRER PBRER??? Periodic Benefit-Risk Evaluation Report, as described in ICH Guideline E2C(R2) currently under revision in Step 2

43 Why? Progress in PV -> more attention to benefitrisk evaluation Shift towards proactive risk management Focus on risk in the context of benefit Overlap in Guidelines (E2C, E2E, E2F)

44 So, what s new? Focus on benefit-risk balance Modular approach identical sections in different documents, i.e. safety specification as in E2E submissions or DSURs

45 Content Worldwide marketing approval status Action taken for safety reasons Exposure dta Findings from clinical trials, literaure, non clinical data, PASS and other sources incl. lack of efficacy Signal and Risk Evaluation Benefit evaluation Benefit-risk analysis for approved indications Conclusions and actions

46 Questions?

47 Thank you