Hot Topics in Safety in the EU

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Hot Topics in Safety in the EU

• Dr Brian Edwards
• Scientific Adviser
• Pharmacovigilance Drug Safety
• NDA Regulatory Science Ltd
• BADSA meeting,
• Actelion Pharmaceuticals US, Inc.
• 5000 Shoreline Court, Suite 200,
• South San Francisco
• August 13th 2009

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Presentation overview

• Advanced therapies
• EudraVigilance
• Risk management plan
• The QPPV role
• Inspections
• Human Factor the secret to Safety

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Advanced therapies

• First advanced therapy authorised by CHMP June
  2009..Chondrocelect
• Traceability MAH responsible for product
  hospital responsible for tracing patients aided
  by MAH
• Efficacy follow-up system (analogous to
  paediatric guideline)
• Procedural AEs are recordable and reportable
• Communication right product, right patient,
  right site
• System still under development by EMEA how CAT
  and CHMP will interact
• Guideline on safety efficacy follow up
  Risk management of advanced therapy medicinal
  products EMEA/149995/2008

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New version QA from EV-EWG

• New set of QA expected soon to address
  frequently answered questions consensus between
  EV-EWG and PhVWG
• Literature articles reporting ADRs in a group of
  patients such as PE studies
• Only one ICSR per article with a summary with
  information in ICHE2B(R2) B.5.1 )as described in
  Chapter I.4 and still discuss in PSUR

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EudraVigilance ICH E2B

• ICH E2B working group have revised the current
  E2B(R2) specifications
• - around Drug Section
• - identification of Medicinal Products (IDMP/M5)
• - seriousness at event level only (not case)
• - better provision for Studies repeatable
  section for study numbers
• ICH M2 transferred messaging standard
  responsibility to ISO who have formed WG 6 (ISO
  TC215) linked to HL7 CEN CDISC and
  vocabularies such as SNOWMED
• HL7 required for interoperability with healthcare
  systems to allow ADR reporting
• ICHE2B and M2 working groups working on
  Implementation guide (can produce messages
  regardless of whether understand HL7 or not)
  reference message instance sample messages
  backwards/forwards conversion between e2B(R2) and
  ISO ICSR (E2B(R3)
• ICH testing will be completed in August and
  report to national standards body and ISO
• Implementation guide Step 3 ideally end Oct 2009
  ..maybe up to May 2010

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EudraVigilance Data Elements and standards for
Drug Dictionaries

• ICH M5 guideline switched to ISO standards from
  February 2007
• prEN ISO 11615 11616 11238 11239 11240 with
  different project leads and editors
• Drafts released May 12th 2009
• Joint initiative with HL7 CDISC IHTSDO CEN
  health informatics to exchange regulated
  medicinal product information
• Conceptual testing by all ICH regions and Health
  Canada with comments by Aug 12 2009
• Gap analysis of HL7 Common Product Model

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EudraVigilance Data Elements and standards for
Drug Dictionaries- best case scenario

• ISO Identification of MP Draft International
  Standard (DIS) sometime between Nov 2009 and May
  20101 depending on extent of ISO ballot comments
• ICH Step 2 for testing will be initiated in
  October 2009 with testing implementation guide
  out for consultation November 2009
• Joint implementation with ICSR E2B(3) standard in
  the EU
• New EU PV legislation will require MAH to provide
  these data

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Duplicate detection good practice

• EV Duplicate detection algorithm based on patient
  details AND similarity in ADR data AND similarity
  in drug data
• Look for similarities for potential groupings
• Look for differences in MedDRA coding
• If no match broaden search
• Manual confirmation important with checking of
  narrative
• Merging cases either by creating one Master case
  or single new case linked to the duplicates

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Duplicate detection good practice

• MAH should manage duplicate reports in their own
  system
• IF MAH aware a duplicate report has been
  submitted then should be placed in A.1.11.12 or
  add in senders comments (B.5.4)
• For co-marketing agreements follow chapter 1,1
  section 3 of Volume 9A
• Care in worldwide ref. no. and duplicate no.
  fields
• Parallel reporting should now stop
• Literature main source of duplicates

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Duplicate detection good practice

• EV duplicate detection and a management tool
  currently planned to be deployed for October 2009
• EudraVigilance Data Quality Management tender
  under finalisation looking for a vendor
• I would expect further guidance about regulatory
  expectations in future version Volume 9A

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Regulatory feedback on RMPs Key assessment
issues

• Too much emphasis on routine PV not product
  specific measures
• Too much emphasis on what is already known rather
  than identifying areas
• which are lacking
• Lack of read across between the key risks and
  the PV plan
• Information poorly presented with long and
  complicated tables

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Regulatory feedback on RMPs Key assessment
issues

• Relevance of the epidemiology of the disease to
  the target indication is not sufficiently
  considered
• Discrepancies between DDPS and the
  pharmacovigilance plan

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Regulatory feedback on RMPs

• Some measures cannot be uniform across all member
  states
• Need flexibility to ensure that adequate risk
  minimization is possible in all MS where the
  product is marketed

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Assessment conclusions following EMEA
commissioned assessment of RMPs

• Risk management plans have become routine
  practice
• Safety specifications generally complete
  important risks are sometimes lacking
• Overreliance on routine pharmacovigilance
• Limited availability of study protocols
  precludes proper scientific assessment sometimes
  difficult to assess whether study will answer
  question
• Studies in non-EU population might lead to
  differences in patient characteristics and health
  care systems compared to the EU
• Registries seem to be a valuable tool to obtain
  safety data of biological products
• Need for individualised PASS depending on the
  type of product
• Assessment by
  Bert Leufkens et al.
• University of
  Utrecht, Faculty of Science,
  Pharmaceutical Sciences

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• Pharmacovigilance Inspection Metrics Report
• July 2008 to December 2008

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• Pharmacovigilance Inspection Metrics Report
• July 2008 to December 2008

Miscellaneous Reg. affairs, QA, med.info.
Clinical)
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• Pharmacovigilance Inspection Metrics Report
• July 2008 to December 2008

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Where are we going with the QPPV?

• Organisation for the QPPV officially launched
  April 2009 if you are a DIA member and a QPPV or
  a deputy you are eligible
• Working group to establish the organisation
• Working group to look at training education

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By this stage how do you feel?
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Next some local news..
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Human Factor Elements
Academic Researchers Regulatory
Authorities Industry
Human - Machine. Switches Info
presentation Instrument Layout.
MA
S
E
HU
Humans - Environment Organisational
hierarchy Organisational climate Working
Environment.
Humans - Software Procedures Digital
printouts Regulations
HU
Humans - Humans. Team performance Prof.culture. Tr
aining.
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How to set up a process?
Decisionmaking. Leadership Cooperation. Situation
awareness.
Human Function.
Fluid.
PROCESS
Solid.
Regulations. SOPs Quality systems Rules. Methods.
System Function.
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Why Do Errors OccurSome Obstacles

• Workload fluctuations
• Interruptions
• Fatigue
• Multi-tasking
• Failure to follow up
• Poor handoffs
• Ineffective communication
• Not following protocol

• Excessive professional courtesy
• Halo effect
• Passenger syndrome
• Hidden agenda
• Complacency
• High-risk phase
• Strength of an idea
• Task fixation

Source TeamSTEPPS at
http//www.ahrq.gov/teamstepps/index.htm
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Secret of High Reliability Safety

• 1. Preoccupied with Failure Focused on ways
  systems can fail and courageous about acting on
  their concerns.
• 2. Resistant to Oversimplification Inclined to
  question conventional or convenient
  interpretations for failures.
• 3. Sensitive to Operations Constantly
  integrating broad-ranging
• information and the actions of others into a big
  picture.
• 4. Committed to Resilience and Self-Examination
  Mindful of past errors and planning ahead to
  prevent future errors.
• 5. Deferential to the Best Expertise Responsive
  to the knowledge of those closest to the action,
  regardless of their rank or organizational power.
  
• Adapted from Henriksen, K., E. Dayton, M. Keyes,
  P. Carayon, and R. G. Hughes. 2007.
• Understanding adverse events A human factors
  framework. In Patient safety and quality An
  evidence-based handbook for nurses (prepared with
  support from the Robert Wood Johnson Foundation),
  ed. R. G. Hughes, 167-85, 08-0043. Rockville,
  MD Agency for Healthcare Research and Quality.
  For the original five tenets, see Weick, K., and
  K. Sutcliffe. 2001.
• Managing the unexpected Assuring high
  performance in an age of complexity. San
  Francisco Jossey-Bass.

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Team working to improve System Effectiveness
Safety
PLEASE LOOK AT http//teamstepps.ahrq.gov/
DECISION MAKING SITUATIONAL AWARENESS LEADERSHI
P COMMUNICATION ERROR MANAGEMENT PERSONALITY
AND BEHAVIOUR
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For the pharmaceutical sector what does it all
mean?
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How has International Society of
Pharmacovigilance responded?

• 1. Application of Human Factor in core processes
  such spontaneous reporting process and the PSUR
• 2. Application of the Human Factor in Clinical
  trial safety starting with training of sites and
  investigators
• 3. Application of the Human Factor in training
  especially developing games and workshops to show
  how applying teamwork can improve compliance and
  efficiency.
• 4. Develop and appropriate checklist to help
  ensure safe use of the product.
• 5. Develop PV competency based curriculum in the
  U.S. aligned with objectives of TeamSTEPPS
• 5. Safety climate survey first version is on it
  way
• 6. Application in PV quality management and
  inspections
• 7. Application of HF in risk communication (New
  Erice Statement due)
• 8. Develop The Safety Case for safe outsourcing
• 9. Input of all of the above into the QPPV
  curriculum
• 10. These topics to features in theses in MSc
  pharmacovigilance courses

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Hot Topics In Summary

• Advanced therapies are truly all about thinking
  out of the box
• Changes in EudraVigilance expected more complex
  with resource implications and national awareness
  still required
• Expectations about duplicate process
• Do not underestimate the amount of effort to
  produce a RMP keep to the template
• Inspections are routine plenty of evidence now
  available about what to expect
• The QPPV role will become more prominent
• Do not forget Safety is the end game and prime
  purpose of why we are here need to apply the
  evidence of what make a Safe System
• Urgent need to align the pharma sector with
  system changes in healthcare modernisation
• Do not forget the fundamental priorities of
  signal detection and managing risk

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Questions?
Please contact brian.edwards_at_ndareg.com