1. © Crown copyright 2007 Safeguarding public health Common Inspection Findings May 2008

2. Slide 2 May 2008 Common Inspection Findings Crown copyright 2008 The materials featured within this MHRA presentation are subject to Crown copyright protection. Any other copy or use of Crown copyright materials featured in this presentation, in any form or medium, is subject to prior approval of the MHRA which has Delegated Authority from Her Majesty's Stationery Office (HMSO) to administer Crown copyright for MHRA originated material. Applications should be in writing, clearly stating the proposed use/reuse of the information, and should be sent to the MHRA at the following address: Conference and Education Function, 16 th Floor, MHRA, 1 Nine Elms Lane, London SW8 5NQ. Fax 020 7084 3522 or e-mail speakers@mhra.gsi.gov.uk. You may not sell or resell any information reproduced to any third party without prior agreement. The permission to reproduce Crown copyright protected material does not extend to any material in this pack which is subject to a separate licence or is the copyright of a third party. Authorisation to reproduce such material must be obtained from the copyright holders concerned.

3. Slide 3 May 2008 Common Inspection Findings Examples of areas of concern and common inspection findings are provided within this presentation. This is not an exhaustive list, but serves to summarise some key points and highlights areas that can be problematic. It is anticipated that examples will prove useful to help Marketing Authorisation Holders to address such issues.

4. Slide 4 May 2008 Common Inspection Findings System Failures “Multiple serious deficiencies in all areas of pharmacovigilance system taken together” or no system in place (less common) Example No global pharmacovigilance system due to: -inadequate safety data exchange with affiliates/subsidiaries -no timescales or formal arrangements for the transfer of individual case safety reports (ICSRs) or other safety information. -no quality assurance auditing of the affiliate companies Resulting in…either lack of or late expedited reporting of ICSRs and periodic safety update reports (PSURs) containing incomplete safety data.

5. Slide 5 May 2008 Common Inspection Findings Qualified Person for Pharmacovigilance (QPPV) No QPPV or interim measures (change of QPPV, back-up procedures for absence etc.) Failure to notify Competent Authorities of QPPV details Inadequate oversight of the pharmacovigilance system (ICSRs, PSURs, PASS, Safety profile of products, audits, SOPs, database) Lack of training and/or experience Roles and responsibilities not formally defined (especially important if parts of role are delegated) Inadequate access to medically qualified personnel

6. Slide 6 May 2008 Common Inspection Findings Signalling & Updating Reference Safety Information No signal detection other than at time of PSUR production Procedures did not reflect actual practice Documentation regarding signal evaluation not produced / retained Delays in reporting significant new safety findings from post authorisation clinical trials and studies:  Delays in completing final study reports (sometimes 2 years or more since last patient, last visit).  Failure to adequately discuss trial and study results in PSURs.  Lack of awareness by drug safety staff/QPPV of trials sponsored by the MAH.  Failure to discuss in PSURs significant safety findings from academic studies reported in published literature.

7. Slide 7 May 2008 Common Inspection Findings Signalling & Updating Reference Safety Information continued A variety of concerns have been identified relating to the control and updating of reference safety information (CCDS, SPC, IB):  Following identification of a new safety signal & MAH decision to update the CCDS, delays in submitting variation(s) to update the SPC(s). Delays of over a year have been observed.  Delays in implementing SPC and PIL changes following approval of safety variations.  Poor processes for ensuring that the minimum core safety information contained in the CCDS is consistently represented, as appropriate, in local product information.  Unwarranted inconsistencies in safety information between reference documents e.g. CCDS, SPC(s) and IB.  Use of inappropriate reference safety document for the determination of expectedness.  Wrong version of the SPC made available to health care professionals e.g. on the eMC web site.

8. Slide 8 May 2008 Common Inspection Findings Processing of ICSRs All information about suspected ADRs not accessible from at least one point within the Community (e.g. consumer reports not captured on database and held at local affiliates) Lack of reconciliation -Internal (medical information, product quality) -External (distributors, manufacturers, licensing partners) Lack of follow up e.g. HCP confirmation for consumer cases, pregnancy outcome. Late reporting of expeditable cases Lack of QC check (Data entry, expedited reporting decision)

9. Slide 9 May 2008 Common Inspection Findings Literature Searching Inadequacies in the construction of, or process used for, literature searching -sources used -adequacy of scope of search with respect to search objective (how will information on non-clinical data be identified?) -local literature scanning -language restrictions -lack of QC

10. Slide 10 May 2008 Common Inspection Findings Quality Management System Procedural documentation -None exist / insufficiently detailed to ensure consistency -Do not reflect practice -Training not done or even lack of awareness by staff of existence of procedure Training -Inadequate or absent -Lack of refresher training -Restricted to PV department Quality Assurance Auditing -Lack of PV audits (conducted and future plans) -Extent of audits (affiliates, contractors) -Scope of audits - key functions (signal detection process, SPC updates) Record retention -No definition of how long documents (and which documents) should be stored and what the minimum requirements are to ensure documentation remains in a readable and understandable state.

11. Slide 11 May 2008 Common Inspection Findings PSURs Production – No procedure, not in desired format, not a consistent standard Standard searches not validated (no impact assessment of database changes on queries generated) Lack of Quality control Incomplete – missing cases, no summary tabulation, does not address Competent Authority requests Submissions – No mechanism to track (QPPV oversight), late submissions, no submission No simultaneous submission (or deadline to submit included in cover letter) of a Type II variation where proposed changes to SPC have been included in PSUR

12. Slide 12 May 2008 Common Inspection Findings Contracts and agreements Lack of contracts with third parties, or contracts still in draft Insufficiently detailed -Responsibilities of each party -Exchange of ADRs (and other special situation cases) and product complaints -Exchange of changes to Reference Safety Information -Timelines -Reconciliation Review period (changing regulations will likely change the agreement)

13. Slide 13 May 2008 Common Inspection Findings IT systems and Business Continuity Validation (not a one off exercise) Inadequate disaster recovery / business continuity plans Product Quality Recall procedures not tested, or testing not documented No input from Product Quality into Pharmacovigilance Medical Information Out of hours service inadequate / not tested Lack of due diligence Detailed Description of Pharmacovigilance System Inconsistent with current system in place