Pharmacovigilance Overview

1
Pharmacovigilance Overview

• UK Trial Managers Network
• EU directive workshop
• 18 November 2004

2
Pharmacovigilance in its broadest terms

• Monitoring medicines to determine unrecognised
  adverse effects or changes in the patterns of
  their adverse effects
• yellow cards, signals from clinical trials
• Continuously assessing the risks and benefits of
  medicines, taking action if necessary to improve
  their safe use
• adding information to the SPC, restricting use of
  a drug, withdrawing a drug

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Pharmacovigilance regulations

• Medicines for Human Use Clinical Trials
  Regulations 2004 - legal requirements
• EU directive and detailed guidance required
  harmonisation of laws- some flexibility
• Internationally accepted principles of good
  clinical/trial practice, data management,
  reporting E3, E6, E8, E2A

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Key components of the regulations

• Notification of adverse events to sponsors
• Immediate reporting of SUSARs
• Annual reporting of serious adverse reactions

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Pharmacovigilance responsibilities

• Timely collection of data recording and
  notification
• Appropriate assessments (data completeness,
  seriousness, relatedness, expectedness)
• Expedited and periodic reporting

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Pharmacovigilance in practice

• All protocols must have a PV section
• Risk to patients varies in the range of clinical
  trials. Extent of recording and notification of
  adverse events may vary depending on knowledge of
  the risks and benefits of drugs under study and
  aims of the trial.
• Responsibilities and systems to deal with
  recording, assessment and reporting must be
  clearly stated.
• Time frames for notification, assessment and
  reporting are critical
• As are SOPs

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Important definitions

• SAE Serious Adverse event
• not the same as clinically severe
• headache can be severe but not serious
• CVA can be serious but not severe
• Adverse events and adverse reactions
• Expected and unexpected adverse reactions
• SUSAR serious unexpected suspected adverse
  reaction
• SAR serious adverse reaction

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Serious Adverse Event

• Death
• life-threatening
• requires hospitalisation or prolongation of
  existing hospitalisation
• persistent or significant disability or
  incapacity
• congenital anomaly

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SAEs that may not need to be recorded on an SAE
form

• Deaths due to disease in a study where death is a
  primary endpoint
• death from stroke in a stroke trial
• Hospitalisation for an event that is an endpoint
• MI, AIDS event, cancer recurrence

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Adverse events and Adverse reactions

• An adverse event is any untoward event which
  happens in a patient in a clinical trial
• An adverse reaction is one in which a causal
  association is suspected between the trial drug
  and the event

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Expected and unexpected adverse reactions

• Not included (or more severe than) reactions
  listed in the applicable product information
• Investigators brochure for an unapproved drug,
  you will need company to help
• Summary of product characteristics (SPC, data
  sheet) for an authorised product

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Data recording

• Ask about occurrence of adverse events in all
  trial arms at each visit
• Information recorded in patients notes and/or
  CRFs (routine or AE forms)
• Ensure that frequency of follow up is appropriate
  for level of surveillance required
• none in a trial of timing of antibiotic therapy
• 3-6 monthly in a trial of commonly used drug
• monthly in a trial of a new drug

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Data recording and notification

• Local clinical investigators need to understand
  their responsibilities with respect to SAE
  recording and notification
• Report SAEs to the sponsor immediately (in
  practice 24 to 48 hours).
• Other forms with safety information also
  important
• state maximum time for submitting forms with
  other AE information, timing will depend on phase
  of development, shorter for early phase studies

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Assessment of Adverse eventsseriousness

• Best done by clinician responsible for patient
• If a follow up form suggests that a patient may
  have had an SAE, request an SAE form from
  investigator

15
Assessment of Adverse eventsrelatedness/causalit
y

• An assessment of whether the adverse event is
  related to the drug
• 5 categories, not mandatory to use them
• not related, unlikely, possibly, probably,
  definitely
• Possibly, probably and definitely adverse
  reactions
• Best done by clinicians closest to patient
• If TM feels that the event may be related can
  give their own assessment in addition to
  clinicians

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Assessment of Adverse events expectedness (I)

• Can you use SPC or must you have an investigator
  brochure?
• Try and use the SPC
• Is trial being done exactly within licensed
  indications (same disease, same dose/schedule,
  same age group)
• If not, can you argue that drug is already widely
  used in this group?

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Assessment of Adverse events expectedness (II)

• Who does assessment?
• Trial Management staff
• difficult to judge if event is more severe than
  mentioned in SPC
• specificity of reporting requires judgement e.g
  rash v dermatitis, angina v ischaemic heart
  disease
• Clinicians
• less administrative work by trials staff
• may not be consistently interpreted

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Non Serious Adverse Events (I)

• Under discussion, single most contentious area
• Discuss and justify in protocol and to MHRA
• Extent of data collection should depend on what
  is known about the risks/benefit of a particular
  drug
• trials of very new drugs or drugs used in new
  combinations
• trials of drugs widely used in clinical practice
• trials of drugs which cause non-serious reactions
  in a high proportion of patients e.g cytotoxic
  chemotherapy

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Non Serious Adverse Events (II)

• Collect all
• Collect only non-serious reactions of a
  particular clinical severity
• Collect only non-serious reactions critical to
  the evaluation of safety
• abnormal liver enzymes if worried about liver
  toxicity
• Collect none

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Blinded trials

• Try to protect blinding as much as possible,
  important to the integrity of the trial
• For placebo controlled trial, investigator can
  assess causality as if patient was on active
  treatment
• Trial centre can assess expectedness
• Only need to unblind those assessed as possible
  SUSARs for expedited reporting
• Ideally, unblinding performed by individuals not
  directly involved in trial e.g. a trial manager
  of another trial

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Blinded trials with active comparator

• More complicated
• Clinician can assess causality for 2 drugs
• Trial centre can assess expectedness for 2 drugs
• Person charged with unblinding can make final
  classification of whether SAE is a SUSAR or not

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Expedited reporting (I)

• Who should report
• Person responsible for PV
• chief investigator
• drug safety office of a trust
• co-ordinating centre
• pharmaceutical company

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Expedited reporting(II)

• Strict time frames
• Fatal or life threatening SUSAR Not later than 7
  days after sponsor had information that the case
  fulfilled the criteria, any follow up information
  within a further 8 days
• All other SUSARs not later than 15 days after
  receiving information that the case fulfilled the
  criteria

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Expedited reporting (III)

• How to report
• paper copies of SAE form
• short clinical summary, information on whether
  follow up is being sought
• cover sheet to explain if a report is late
• Meddra coding not required

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Expedited reporting (IV)

• Electronic reporting will be mandatory at some
  time in the future
• At that stage Meddra coding will be required
• For the moment there are issues of access to the
  Eudravigilance database

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Expedited reporting (V)

• Who to report to
• MHRA Pharmacovigilance Unit UK reports
• Overseas reports to the Clinical Trials Unit
• Other European competent authorities if trial is
  being conducted in more than one European country
• Relevant Ethics Committee (the one that approved
  the trial, not LRECs)

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Reporting to investigators

• SUSARs occurring in the UK and international
  SUSARs in an international trial need to be
  reported to investigators
• Time frame and format of reports is not
  specified, state in protocol gain approval from
  main REC
• Expedited, monthly, annually are up for
  discussion. copies of SAE form, copy of MHRA
  report

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Annual reporting (I)

• What is required
• line listing of all SARs, including SUSARs
  already reported
• international and UK reports
• Summary of safety of the subjects in the trial
• Summary of published literature relevant to safety

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Annual Reports (II)

• Timing
• As soon as practicable after the end of the
  reporting year, defined as one year after the
  date when the CTA was obtained.
• Protocol should specify this date, unless
  otherwise agreed within 60 days
• May be able to tie in with annual DMEC report

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Summary

• Overall there is a desire to reach a pragmatic
  solution
• It is do-able
• Define roles, responsibilities and time frames in
  protocol and SOPs
• if agreed by ethics and MHRA in CTA application
  you are ok