Safety reporting requirements in the post marketing phase. Pharmacovigilance Specialty Committee SQA Conference March 2017 Washington

Transcription

1 Safety reporting requirements in the post marketing phase Pharmacovigilance Specialty Committee SQA Conference March 2017 Washington

2 DISCLAIMER These materials have been prepared solely for educational purposes and does not reflect the views of the author (s) employers. 2

3 Agenda Setting the stage Overview EU/Japan/USA Regulatory Requirements/Authorities PV Quality Management Systems (QMS) Audit/Self Inspection Qualified Person for Pharmacovigilance (QPPV) Unique requirements EU/Japan/USA Expedited Reporting Requirements EU/Japan/USA Aggregate Reporting Requirements EU/Japan/USA Additional Post Marketing Requirements Risk Management Post Marketing Studies

4 Setting the stage Pharmacovigilance has differing levels of importance in different parts of the world Most countries understand the concept of monitoring drug safety even though their legislation may not be mature (134 countries are part of the WHO Pharmacovigilance programme) The three most regulated markets with respect to pharmacovigilance are the EU, Japan and the USA The objectives of the requirements in these territories are similar in that they require licence holders to: Submit individual case reports Submit aggregate periodic reports Review safety data in order to manage risks

5 OVERVIEW EU/JAPAN/USA REGULATORY REQUIREMENTS/AUTHORITIES

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7 Overview Regulations EU/Japan/USA Regulatory environment is the most complex Regs are less detailed than EU/Japan. Traditionally main concern has been on AE reporting so that FDA can perform signal detection (aggregate review of safety data), however it is shifting to also include quality systems (to ensure sponsors have appropriate processes to support safety activities The principles of the pharmacovigilance legislation and guidance in Japan is similar to that in Europe but there are some differences in the detail. FDA EMA and local Pharmaceuticals and Medical Devices Agency (PMDA) Ministry of Health Labour and Welfare (MHLW)

8 EU PV Requirements Hierarchy Regulation 1235/2010 and Directive 2010/84/EU: high level requirements. Directives and Regulations are available on the EMA website Implementing Measures Regulation (IMR) (520/2012): detailed requirements for MAHs (not in the Regulation or Directive) in relation to PSMF, QMS, monitoring of data in Eudravigilance, transmission of ICSRs, RMPs, PSURs and post authorisation safety studies (PASS) The Good Vigilance Practices (GVPs) contain the fine details Current Modules and their status are available on the EMA website Regulation & Directive Implementing Regulation Good Vigilance Practices

9 GVP Modules Key for QA Quality Systems PSMF PV Inspections PV Audits Risk Management Systems Management and Reporting of ADRs PSURs PASS Signal Management Additional Monitoring Safety Communication Risk Minimisation Measures Public Participation in PV Continuous PV, ongoing benefit risk evaluation, regulatory action International co operation

10 PV Quality Management Systems (QMS) Audit/self inspection EU JAPAN USA Risk based audits: Strategic: (long term approach) endorsed by upper management; Tactical: audit programme Operational: audit planning Mandatory Self Inspection (e.g., safety department performing periodic reviews & inspections of their key activities)

11 PV Quality Management Systems (QMS) Training and Procedures EU JAPAN USA Initial and ongoing training is expected for all personnel involved in PV tasks and MAHs are expected to have processes in place to check that training is effective. Education/ training requirements for PV staff Critical processes (as identified in GVPs) should be documented in written procedures Records retention requirements for PV records. Requirements on how to collect, classify and review safety information

12 Qualified Person for Pharmacovigilance (QPPV) EU JAPAN USA A named (QPPV) who has oversight of all aspects of The PV system and takes Overall responsibility for That system. (EU resident, trained/experienced in PV, a physician or access to one). Single person responsible for pharmacovigilance: Safety Management Supervisor (SNS) The SNS must be independent of the sales and marketing departments so that decisions about the product are based purely on protecting patient safety. Similar to the QPPV requirements in the EU, the SNS must have relevant experience

13 Unique requirements EU Pharmacovigilance System Master File (PSMF) 2012: New and describes the PV system in place and is a living document Company PV system and processes Sources of data Key roles (QPPV) Metrics to assess PV system performance Description of QMS Audits/CAPAs, plus various appendices (licensing partners, EU authorized product listings, computerised systems, log book of changes) Must be maintained in a current manner typically updated quarterly unless requested by regulatory authority (company then has 7 days to product current version)

14 Japan Regulatory bodies The Ministry of Health Labour and Welfare (MHLW) are ultimately responsible for the approval of medicines in Japan although the PMDA may carry out the review work. The Pharmaceuticals and Medical Devices Agency (PMDA) are responsible for implementing MHLW policy and day to day PV activities.

15 USA FDA FDA s requirements for postmarketing safety reporting for human drugs and biological products under 21 CFR , , , , and Section 760 of the Food Drug and Cosmetic Act (FDCA).

16 EU/JAPAN/USA EXPEDITED REPORTING REQUIREMENTS

17 Overview expedited reporting of Individual Case Safety Reports (ICSRs) Spontaneous source (days) Region/ Country Serious valid ICSRs (Domestic/ Foreign) calendar days Serious unexpecte dadr (Domestic/ Foreign) Death/oth er serious Serious expecte dadr (Domest ic ) Death/ other serious Serious & unexpected drug experiences (Domestic/ Foreign) NS valid ICSRs Domestic NS unexpected ADRs/infectio n reports Foreign NS Infection reports (Unexpect ed /expected Comment EU 15 (initial & follow up) 90 Japan /30 Aggregate/15 15/15 USA 15 (after initial receipt) Serious and unexpected drug experiences should be investigated and follow up reported in 15 calendar days.

18 EU/JAPAN/USA AGGREGATE REPORTING REQUIREMENTS

19 Aggregate reporting requirements EU JAPAN USA PSURs/PBRERs (Periodic Safety Update Reports / Periodic Benefit Risk Evaluation reports): evaluation riskbenefit balance of a medicinal product for submission by MAHs at defined time points during the post authorisation phase legislation: greater focus on benefit risk evaluation Data: AEs, where product is authorised, signals, labelling Periodic Safety Reports (PSR) Similar to PBRERs in the EU and produced after a product launch (domestic & foreign data). PBERS attached to PSR or data incorporated into PSR. NDA Annual Reports: Annual CMC, labelling, status updates of post marketing commitments or other postmarketing studies performed by, or on behalf of, the applicant Periodic reporting (PADER Periodic Adverse Drug Experience Report): 3 monthly for 3 yrs/then annually : Adverse drug experiences not previously expedited (e.g., serious expected AEs and non serious AEs), labeling changes, studies initiated With approved waiver from NDA requirements may submit PSUR in lieu (with line listings)

20 EU/JAPAN/USA ADDITIONAL POST MARKETING REQUIREMENTS

21 Additional Post Marketing Requirements: Risk Management EU USA JAPAN Risk Management Plan (RMP) All new product licences to have RMP to describe risks identified in relation to the product, measures implemented to manage risks and effectiveness of the measures RMPs do not all contain risk minimisation measures beyond conducting routine pharmacovigilance. Examples risk minimisation measures: Targeted Follow up questionnaires which need to be sent when a specific event occurs in association with a specific product Distribution of educational materials to HCP Specific training to be given to company staff (most commonly training for sales representatives) Post authorisation safety studies (PASS) by a specific deadline Risk Evaluation & Mitigation Strategies (REMS) Required when product label is not sufficient to manage the risks associated with the product e.g. products that are teratogenic if used by pregnant woman (Isotretinoin), products with a high abuse/misuse potential etc HCPs follow specific safety procedures prior to prescribing and dispensing the product e.g., lab/pregnancy monitoring, restricted distribution etc. MAH may need to prepare communication plans to inform HCPs of risks

22 Additional Post Marketing Requirements: Post Marketing Studies EU JAPAN USA Post Authorisation Safety Studies (PASS) 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. Early Post Marketing Phase Vigilance (EPPV) Post marketing surveillance studies after product launch at medical institutions who are visited by Medical Reps at the required frequency and EPPV Report is prepared and submitted at the end of EPPV period. Post marketing surveillance (PMS) For a period of time after product launch. Japanese Regulatory Agencies are likely to receive more safety data on the product vs spontaneous reporting Post Marketing Commitment (PMC) / Post Marketing Requirement (PMR) FDA can mandate additional studies to be conducted to further investigate safety profile (conditional approval)

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