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Drug Safety Regulations In The Us And Eu

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A comparison and contrast of Pharmacovigilance regulations in the EU and US

A comparison and contrast of Pharmacovigilance regulations in the EU and US

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    Drug Safety Regulations In The Us And Eu Drug Safety Regulations In The Us And Eu Presentation Transcript

    • Pharmacovigilance in the US & EU Angie Barfield, RN, BSN 20 January 2009
    • When the system fails….
      • Avandia ® (GSK)
      • Chantix ® (Pfizer)
      • Vioxx ® (Merck)
      • Baycol ® (Bayer)
      • Tysabri ® (Biogen Idec)
      • Ketek ® (Sanofi-Aventis)
      • Zelnorm ® (Novartis)
      • Lotronex ® (GSK)
    • Overview of Pharmacovigilance Literature Reports Spontaneous Reports Clinical Trial Data Regulatory Reports Licensing Partners Data Review Submission Amend Prescribing Information Review marketing status Licensing Partners World-wide Regulatory Reports (expedited and periodic) Enquiry Response Signal Generation Collect… Collate… Analyze… Communicate…
    • Risk Management Across the Lifecycle Product Life Cycle Capabilities Provided Approval Ph IV FIM PhI Ph II Ph III
      • Address any new emerging safety issues
      • Post approval studies and epidemiology
      • Signal Detection
      • Studies to better understand population, risks, etc
      • Promote high quality analysis
      • Determine appropriate label
      • Estimate potential benefit
      • Predict potential candidates
      • Disease and patient population
      • Mechanism of Action Studies
      Post Marketing Pharmacovigilance Clinical Development Drug Discovery/ Preclinical
    • Regulatory Oversight
      • National Authorities – each country’s CA is responsible for monitoring the safety profile of product in its territory and taking action when necessary
      • European Commission – Responsible for overall Community System of PV and for legal framework (authorization)
      • EMEA – evaluate and supervise medicinal products in the EU and provision of advice on measures to ensure safe and effective use.
      • CHMP - (Committee for Medicinal Products for Human Use) prepares the EMEA opinions/recommendations concerning medicinal products for human use
      US-FDA EU
    • Key Regulations Governing Pharmacovigilance
      • 2001/20/EC Clinical Trials Directive
      • 2005/28/EC Good Clinical Practice
      • Medicinal Products for human use in clinical trials – Volume 10-Clinical trials
      • Volume 9A Pharmacovigilance
      • US-IND Annual Reporting 21CFR 312.33
      • Post-marketing Reporting of ADRs 21CFR314.80
      • PDUFA Reenactment with U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007, FDAAA)
      • FDA Guidance Documents
        • Premarketing Risk Assessment
        • Development and Use of Risk Minimization Action Plans (RiskMAPs)
        • Good PVG Practices and Pharmacoepidemiologic Assessment
        • Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs — Improving Human Subject Protection
    • MAA Approval Procedures in the EU
      • Centralized Procedure
        • EMEA
        • Marketing authorization granted that cover all EU Member States and the EEA.
      • Mutual Recognition Procedure
      • – National Agencies + Mutual Recognition Facilitation Group
      • Reference Member State - RMS
      • Concerned Member State(s) –CMS
        • Pharmaceutical companies who already hold a marketing authorization in one EU Member State ask additional Member States to recognize the marketing authorization that has already been granted.
      • National Procedure
        • National Agencies
        • Marketing authorizations on a country-by-country basis by the competent authorities in each Member State.
      Different Labeling Requirements & Different Expedited Reporting Requirements/Timelines
    • Pre-Marketing Safety Reporting (EU)
      • Investigational medicinal product – not just study drug but also placebo and any active comparator
      • Electronic Reporting Mandatory!
      • Treatment un-blinding before SUSAR reporting to CA/EC
      • Information to EC
        • Expedited individual case reports may be limited to domestic cases only. All other foreign SUSARS may be provided in a bi-annual line listing
      • Information to investigators
        • Investigator Notifications on findings which might have implications to subject’s safety
        • Can be aggregated in a line listing of SUSARs + concise summary of safety profile
        • Blinded trials should have blinded treatment information of all SUSARs (placebo/comparator included)
      Investigator Reports all SAEs Sponsor Reports all SUSARs* CA EC EVCTM *S uspected U nexpected S erious A dverse R eaction
    • Pre-Marketing Safety Reporting (US)
      • Not required to send just expedited cases for placebo or active comparators
      • FDA does not currently support electronic reporting for expedited case reports for clinical trials
      • Treatment un-blinding prior to sending expedited report NOT required
      • Sending individual ESR reports to FDA and IRBs is the norm
      Investigator Reports all SAEs Sponsor Reports all ESRs* FDA IRB
    • Pre-marketing Periodic Reports Benefit-Risk Assessment Progress Report (focus on clinical development program) Purpose
      • Concise global analysis
      • Benefit-risk evaluation
      • Implications for trial subjects
      • Proposed measures to minimize risk
      • Supporting results of non-clinical studies
      • Tabular summary of most frequent and most serious AEs by body system
      • List of completed non-clinical studies and result summary
      • Summary of foreign marketing developments
      • General Investigational Plan for next year
      • Outstanding IND business
      • Description of IB revisions, Significant Phase 1 protocol modifications
      Format SUSARs; serious, associated, +/- expected Listings of all SAEs, deaths, ESRs, and withdrawals due to AEs for the reporting period Adverse Events Included Benefit-risk assessment; supporting tables Study data and summary information Content EMEA, MS, EC FDA Recipients Annual Safety Report (EU) IND Annual Report (US)
    • Pediatric Legislation
      • EU: Significant Therapeutic Benefit or Fulfilled Therapeutic need vs US Meaningful Therapeutic Benefit or Substantial number of pediatric patients.
      • Europe has a “centralized” procedure.
      • All appropriate applications are submitted for review by a Pediatric Committee which addresses the studies needed for the Pediatric Investigational Plan (PIP), waivers and deferrals. (Incentive linked to PIP)
      • European filing of a product for an adult indication can be denied if it does not have the required pediatric plan, waiver or deferral; not possible in US
      • European process is asking for more definitive information early in development process
      • EU: If the product is not marketed for pediatrics the safety review is not obligatory
      • US can ask for indication that does not exist in adults or not approved for marketing in adults
      • US has 2 separate triggering processes (incentive and requirement) that are only partially coordinated by a pediatric committee while Europe has 1 pediatric law
      • In the US only those studies in response to a Written Request are eligible for the incentive
      • US has required pediatric focused PM safety reviews with public presentation
      • US has mandated pediatric focused review of post marketing adverse events and a public review of the data, even if the product does not have a pediatric indication (not approved but labeled)
      EU US
    • Post-Marketing Safety Reporting
      • AERS
      • MedWatch Program (Voluntary and Mandatory)
      • Optional Electronic Reporting
      • NDA Annual Reports to FDA.
      • Consumer Reports
      • ‘ Dear HCP’ Letters
      • Expedited Reporting of all Class Action lawsuits
      • Clinicians are encouraged, but not required, to report drug-related adverse events either to drug manufacturers or directly to the FDA
      • NDA Periodic Reports quarterly during the first 3 years after the medicine is approved, and annual reports thereafter .
      • Eudravigilance
      • Mandatory electronic reporting
      • Only include Medically Confirmed Reports
      • Require QPPV
      • Rapid Alert System EU, there are no harmonized rules for post-marketing studies.
      • In the United Kingdom, reports of such events are actively solicited through the Prescription-Event Monitoring system, which surveys prescribers regarding any adverse experiences among the first 10,000 people who use a given drug.
      • The European Medicines Evaluation Agency (EMEA) requires PSURs every 6 months for 2 years, annually for the 3 following years, and then every 5 years (at the time of renewal of registration).
    • PADER vs. PSUR
      • Summary and analysis of the 15-day reports submitted during the reporting period.
      • Tables of frequency of occurrence of adverse events from the reporting period, organized by body system.
      • A MedWatch form for each adverse event not previously submitted as a 15-day report.
      • Actions taken for safety reasons since the last report.
      • NDA periodic reports do not include adverse events occurring outside the U.S. or those obtained from the scientific literature or from post-approval studies, except for 15-day reports.
      • Companies are also encouraged by FDA to seek a waiver to exclude MedWatch forms for non-serious listed adverse events from periodic reports.
      • Worldwide approval status
      • Update on regulatory agency or pharmaceutical company actions taken for safety reasons
      • Changes to ref. safety information
      • Data on patient exposure derived from an estimate of the number of patients exposed, along with the method used to calculate the estimate.
      • Individual case histories (from literature, spontaneous reports, clinical studies, or other sources)
      • Newly analyzed completed studies yielding safety data
      • Serious unlisted reactions, placing cumulative reports into perspective
      • Non-serious unlisted reactions
      • Increased reporting frequency of listed reactions
      PADER PSUR
    • Risk Management Plans
      • FDA may determine Risk Evaluation and Mitigation Strategy (REMS) but this is not a requirement (FDAAA)
      • Risk Minimization Action Plans (RiskMAPs) not mandatory in US but strongly advised at the time of filing, especially for NCE
      • Risk management plan is mandatory in the EU
      • A valid EU-RMP must Section 1: Product Information
      • Section 2: Safety Specifications
      • Section 3: PVG Plan
      • Section 4: Risk Minimisation Plan if needed
    • Pharmacovigilance Audits
      • Focus on reporting of data to FDA
      • Field investigators
      • 0 to 3 days notice for domestic inspections
      • No clear agenda/plan
      • Document/data review
      • 1-2 inspectors for 1-3 days
      • Focus on Systems ( Summary of Pharmacovigilance Systems)
      • Variable resources but includes PV inspectors
      • 4 months notice
      • Detailed agenda/plan in advance of the audit
      • Interview driven
      • 3-4 inspectors for 5 days
    • Questions ?