Pharmacovigilance Overview

UK Trial Managers Network EU directive workshop 18 November 2004 Clinical Trials Unit

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

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

Key components of the regulations

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

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

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

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

Serious Adverse Event

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

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

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

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

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

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

Assessment of Adverse events: seriousness

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

Assessment of Adverse events: relatedness/causality

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

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?

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

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

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

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

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

Expedited reporting (I)

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

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

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

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

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)

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

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

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

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