Drug Safety and PV Revision - PowerPoint Presentation

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Drug Safety and PVRevision

PGCPM Revision Module July 2019With thanks to Tina Strutt

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Syllabus Drug Safety, PV and Pharmacoepidemiology

The role of the pharmaceutical professional in drug safety and pharmacovigilance

Assessment and classification of Adverse Events, Adverse Drug Reactions, Serious Adverse Events and Suspected Unexpected Serious Adverse Reactions (SUSARs); evidence for association and causality

The concept of benefit-risk balance assessment

Collection of adverse events in clinical trialsThe role of investigators, clinicians, study monitors, sponsors and manufacturers in the pre- and post-marketing phases to detect, assess and report adverse events and suspected adverse drug reactions; regulatory reporting requirements in the pre- and post-marketing phases; medical literature reportsPredisposing factors and the impact of pre-existing disease on the susceptibility for and severity of adverse events and how to minimise riskPost-marketing spontaneous reportingReportable events: overdose, medication errors, off-label use, misuse and abuse, experience during pregnancyDrug interactionsPharmacoepidemiologyMain sources of epidemiological pharmacovigilance informationSignal detection, interpretation and managementPost-authorisation risk management including issue and crisis managementRisk communication

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11.1 The role of the pharmaceutical professional in drug safety and pharmacovigilance

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Pharmacovigilance/Patient Risk Management - Aims

Further clarification of important risks and potential risks

Identification and quantification of new ADRs

Identification of ‘at risk’ sub-populations

Ongoing benefit-risk evaluation – includes safety monitoring following newly approved indicationsComparative ADR profile within the therapeutic classDetection of inappropriate prescription and administrationFurther elucidation of pharmacological/toxicological properties and mechanisms of ADRsDetection of drug-drug interactionsRefutation of false-positive ADR signalsImplementation of appropriate communication and risk mitigation 5

11.1

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The role of the EU QPPV

Each pharmacovigilance system can have only one QPPV

A QPPV may be employed by more than one MAH, for a shared or for separate pharmacovigilance systems or may fulfil the role of QPPV for more than one PV of the same MAH, provided that the QPPV is able to fulfil all obligations.

The marketing

authorisation holder shall ensure that the QPPV has sufficient authority to influence the performance of the quality system and the PV activities of the MAH (should allow the QPPV to implement changes to the system and to provide input into risk management plans as well as into the preparation of regulatory action in response to emerging safety concerns)The QPPV has to be able to access all information they consider relevant, in particular on: emerging safety concerns and any other information relating to the benefit-risk evaluation of the medicinal products covered by the PV system; ongoing or completed clinical trials and other studies the MAH is aware of and which may be relevant to the safety of the medicinal products; information from sources other than from the specific marketing authorisation holder, e.g. from those with whom the MAH has contractual arrangements; and the procedures relevant to PV which the MAH has in place at every level in order to ensure consistency and compliance across the organisation. 6

11.1

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The role of the EU QPPV

The QPPV is a natural person (!) – ie

a real human being, as distinguished from a corporation which is often treated in law as a fictitious person

Appropriately qualified

At the MAH’s disposal ‘permanently and continuously’Shall reside and operate in the EU (EEA)Back-up procedures for absence should be in place (QPPV should ensure that the back-up has all the necessary information)Shall be responsible for the establishment and maintenance of the MAH’s PV SystemShall have sufficient authority to influence the performance of the quality system and the PV activities Should have access to the pharmacovigilance system master file (PSMF) and be in a position of authority to ensure and to verify that the information contained in the PSMF is an accurate and up-to-date reflection of the pharmacovigilance system May delegate specific tasks, under supervision, to appropriately qualified and trained individuals, eg safety experts for certain products, provided that the QPPV maintains system oversight and overview of the safety profiles of all products; such delegation should be documented. 711.1

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The role of the EU QPPV – products

Having an overview of medicinal product safety profiles and any emerging safety concerns, with awareness of:

any conditions or obligations adopted as part of the marketing

authorisations

and other commitments relating to safety or the safe use of the products; risk minimisation measures; risk management plans, with sufficient authority over the content; post-authorisation safety studies requested by a competent authority including the results of such studies – involved in the review and sign-off of protocols of PASS conducted in the EU or pursuant to a risk management plan agreed in the EU; Ensuring; conduct of PV and submission of all PV-related documents in accordance with the legal requirements and GVP; the necessary quality, including the correctness and completeness, of PV data submitted to the competent authorities in Members States and the Agency; a full and prompt response to any request from the competent authorities in Members States and from the Agency for the provision of additional information necessary for the benefit-risk evaluation of a medicinal product; Providing: any other information relevant to the benefit-risk evaluation to the competent authorities in Members States and the Agency; input into the preparation of regulatory action in response to emerging safety concerns (e.g. variations, urgent safety restrictions, and communication to patients and healthcare professionals); Acting as a single pharmacovigilance contact point for the competent authorities in Member States and the Agency on a 24-hour basis and also as a contact point for pharmacovigilance inspections. 8

11.1

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The role of the EU QPPV – PV System

This responsibility for the

pharmacovigilance

system means that the QPPV has oversight over the functioning of the system in all relevant aspects, including

its quality system, egstandard operating procedurescontractual arrangementsdatabase operationscompliance data regarding quality, completeness and timeliness of expedited reporting and submission of periodic update reportsaudit reportstraining of personnel in relation to pharmacovigilanceSpecifically for the adverse reaction database, if applicable, the QPPV should be aware of the validation status of the database, including any failures that occurred during validation and the corrective actions that have been taken to address the failures. The QPPV should also be informed of significant changes that are made to the database (e.g. changes that could have an impact on pharmacovigilance activities). GVP Module I – Pharmacovigilance systems and their quality systems 911.1

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Adverse event & other PV datum reporting timelines

Reporting timelines start as soon as

ANY COMPANY EMPLOYEE/CONTRACTOR

is aware of the adverse event

Every member of staff

has a responsibility

to report adverse events

to the PV department

immediately

or within

1 working day

Safety reporting obligations

11.1

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11.2 Assessment and classification of AEs, ADRs, SAEs, and SUSARs; evidence for association and causality

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ICH definitions

Adverse Event

‘

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment

’ICH E2A, and E6(R1)ICH E2D confirms this definition for adverse events on marketed products1211.2

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ICH definitions

Adverse Drug Reaction

ICH E2A (clinical investigations)

‘

All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions’Questions:A causal relationship is at least a reasonable possibility..........or ‘cannot be ruled out’All cases judged by either the reporting HCP or the sponsor as having a reasonable suspected causal relationship; there are facts (evidence) or arguments to suggest a causal relationship‘at doses normally used in man’ (ICH E2A and E6(R1)For marketed products, ICH E2D does not repeat ‘cannot be ruled out’, and does not include any reference to a requirement for normal doses. Spontaneous (unsolicited) reports imply a causal relationship.1311.2

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Causality assessments

ICH E2A – clinical investigationsFormal causality assessments are required for all cases that arise from clinical investigations

All cases considered by either the reporting investigator or the sponsor as having a reasonable possibility of a causal relationship to the study drug qualify as suspected ADRs

No standard international nomenclature to describe causal relationships

Consider an AE as either ‘suspected’ or ‘not suspected’ (ie causal relationship suggested by facts, evidence or other reasons)Therefore ask investigators a simple ‘yes’ or ‘no’ question1411.2

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Causality assessment

Temporal association

De-challenge

Dose-response

Re-challengeMechanism (biological plausibility)Class effectAbsence of alternativesConsistency of effectFrequency (vs placebo, or comparator?)NB: some of these are obviously more applicable to case series (or safety signals) than to individual casesBradford Hill 1511.2

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ICH definitions

Serious AEs/ADRs

ICH E2A, E6 and E2D

An AE or ADR is serious if (at any dose) it:

Results in deathIs life-threatening*Requires in-patient hospitalisation or prolongation of hospitalisationResults in persistent or significant disability or incapacityIs a congenital anomaly or birth defectMedical judgment should be exercised in deciding whether other situations should be considered as serious reactions; Important Medical Events that may jeopardise the patient or may require intervention to prevent one of the above (NB: EudraVigilance Expert Working Group IME terms list, based on MedDRA – intended for guidance)Any suspected transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction (EU GVP Module VI, June 2012)*Life-threatening refers to a reaction in which the patient was at risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might have caused death if more severe.16

11.2

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ICH definitions

Unexpected/Unlisted AEs and ADRs

ICH E2A, E6 and E2D

Expectedness

applies to expedited reporting, and is therefore based on the relevant local product information (local prescribing information texts, or the IB for investigational products)Listedness applies for periodic safety reporting purposes, and is therefore based on the company position (the company core safety information)Based on previous knowledge about that medicinal product, not on the basis of what might be anticipated from the product’s pharmacological properties*Unexpected/unlisted if the nature, severity, specificity or outcome is not consistent with the applicable information*Therefore class-related reactions which are mentioned in the SmPC but which are not specifically described as occurring with this product are considered unexpected17

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Timing of expedited reporting

ICH E2A – clinical investigations

Fatal/life-threatening unexpected ADRs – 7 calendar days

Other serious unexpected ADRs – 15 calendar days

Significant safety findings – 15 calendar daysICH E2D – Post-marketingAll serious and unexpected – 15 calendar daysNB in Europe, new legislation (July 2012)  All serious ICSRs must be reported (whether or not they are unexpected

) –

within

15

calendar

days

Non-

serious

ICSRs

originating

in the EU must

also

be

reported

–

within

90

calendar

days

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NB: terminology =

SUSARs

11.2

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Expedited reports – minimum criteria for reporting

ICH E2A – clinical investigations

An identifiable patient

A suspected medicinal product

An identifiable reporting sourceAn event or outcome that can be identified as serious and unexpectedA reasonable suspected causal relationship (for cases arising from clinical investigations)ICH E2D – post-marketingAn identifiable patient, a suspect product, an identifiable reporter and an ADRNB – follow-up information should be sought1911.2

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Minimum information required for a valid case report:

At least one identifiable reporter*Name, initials, address or qualificationOne single identifiable patient

Initials, patient number, date of birth, age, age group, gender

Suspected active substance/medicinal product

Suspected adverse reaction*** Preferably with contact details, although these are not essential; all parties providing case information should be identifiable, not only the initial reporter** If the reporter explicitly states that causality has been excluded, and the MAH (or Competent Authority) agrees, the report is not valid because there is no suspected ADRMinimum information for a reportable ADR20

From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.2

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11.3 The concept of benefit / risk assessment

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Principles for evaluation of benefit-risk

Benefit-risk evaluation should be carried out throughout the lifecycle of the medicinal product, to:

Promote and protect public health

Enhance patient safety through effective risk minimisation

Post-approval, need to evaluate benefit-risk inActual useLong-term use (if applicable)Risk evaluation should be based on all uses of the medicinal productScope of benefit information should be limited to authorised indicationsGVP Module VII.B.22211.3

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Conclusion

and

Dissemination

Exploration

Analysis

Evidence

Gathering

and

Data

Preparation

Problem Statement & Planning

From: IMI-PROTECT Benefit-Risk Group

RECOMMENDATIONS REPORT

2014

Key Steps in B-RA Process

Defined Triggers

New information on B/R (studies, signals)

Application for market authorization / renewal

Request from Health Authorities

Aggregate Reports (PBRER/PSUR/DSUR)

Regular review

Output:

B-R Assessment Core Document

Context / trigger

Evaluation and summary of benefit

Evaluation and summary of risks

Assessment of benefit versus risk

Conclusions on the BR profile

Recommendation of action plan,

A Benefit-Risk method is not an algorithm to be fed with data and which would provide an automatic answer; it is a support to human decision making

Benefit-Risk balance assessment is not based only on objective data but also on subjective judgments made by the decision maker

Expressing B-R as a ratio is one out of many other methods. Benefit-Risk balance assessment may be expressed by many other methods and tools, and have various graphical/visual representation

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11.3

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11.4 Collection of adverse events in clinical trials

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Routine safety monitoring

Adverse events

Laboratory safety data (routine)

Vital signs and physical findings

Specific safety assessment (specific question)

Adverse events of special interest (AESI)

Specific questions, questionnaire/checklist

Specific tests – laboratory, or ECGs (QT/

QTc

)

Targeted safety assessments

eg

. cognitive function, developmental growth assessments in children etc.

Specific safety studies (drug-drug interaction)

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11.4

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Methods for collecting AEs in Clinical Trials

Wait for the patient to volunteer information

Observation/examination

Standard open question

Checklist of symptomsSelf-administered questionnaireDiary cardQuality of Life assessment2611.4

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Laboratory Data

Normal ranges

Extended reference ranges

Threshold limits

Specific toxicity – eg renal, hepatic, haematologicalConsider factors that could influence data2711.4

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Data Monitoring Committees

Purpose is to protect the:safety of study participants

credibility of the study

validity of the study results

Generally for:-Randomised blinded studies that address major health outcomes, eg mortality, disease progression or life-threatening eventsNot for:-Open (non-randomised) studiesPhase I (may require an internal ‘Safety Monitoring Committee’) studiesStudies with a very rapid recruitment and short-term end-pointsStudies of drugs intended to provide short-term symptom reliefDrugs for which only minimal safety concerns have been identified2811.4

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Setting up a Data Monitoring Committee

DMC Charter (tasks, responsibilities)

Composition of the committee

Independence and avoiding conflict of interest

Confidentiality and review of unblinded dataStatistical methods and interim analysesCommunication procedures and data flowFrequency and format of data reviews, meetings and minutesInteractions with stakeholders (sponsors, principal investigator, ethics committees, regulatory authorities)Ultimate decision-making2911.4

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Pre-marketing studies Routine clinical experienceNumbers of patients Relatively small Large

Type of patients Restricted Guided by Prescribing Information

Duration of treatment Limited Guided by Prescribing Information

Populations exposed Can be restricted Guided by Prescribing Information (children, elderly, by exclusion pregnant women etc) criteriaConcomitant medications, Can be specifically Guided by Prescribing Informationillnesses etc excluded Type of doctors Specialists May be non-specialistsLevel of patient High Lowmonitoring Pre-marketing clinical studies compared with post-marketing clinical experience3011.4

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11.5 Role of investigators, clinicians, study monitors, sponsors and manufacturers in the pre- and post-marketing phases to detect, assess and report adverse events and suspected adverse drug reactions; regulatory reporting requirements in the pre- and post-marketing phases; medical literature reports

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EU CTD (Directive 2001/20/EC) and ‘CT-3’

‘sponsor’: an individual, company, institution or organization which takes responsibility for the initiation, management and/or financing of a clinical trialInvestigator’s

responsibilities

: reporting of serious adverse events to the sponsor (‘immediately’ and in no case later than 24 hours); except for those that the protocol or investigator's brochure identifies as not requiring immediate reporting. The immediate report shall be followed by detailed, written reports. reporting of certain non-serious adverse events and/or laboratory abnormalities to the sponsor (identified in the protocol as critical to safety evaluations) to the sponsor according to the reporting requirements and within the time periods specified in the protocol.Investigators’ responsibilties3211.5

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Sponsor’s

responsibilities:

Recording of adverse events (detailed records of all adverse events which are reported by the investigator(s); these records shall be submitted to the Member States in whose territory the clinical trial is being conducted

on

request.Reporting of suspected unexpected serious adverse reactions (‘SUSARs’) as soon as possible to the competent authorities in all the Member States concerned, and to the Ethics Committee(s)*:fatal or life-threatening – no later than 7 days after knowledge by the sponsor of such a case, with relevant follow-up information subsequently communicated within a further 8 daysAll other SUSARs – within a maximum of fifteen days of first knowledge by the sponsor* all SUSARs occurring in the clinical trial concerned, if the SUSARs occurred in the territory of that Member StateSponsors’ responsibilities3311.5

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Sponsor’s responsibilities (cont.):

Informing the investigators** Annual safety reporting to the national competent authority and the Ethics Committee (DSUR)The sponsor should arrange for systems and written standard operating procedures to ensure compliance with the necessary quality standards at every stage of case documentation, data collection, validation, evaluation, archiving, reporting and following-up.

** The information should be concise and practical – whenever practicable use aggregated line listing of SUSARs in periods as warranted by the nature of the research project/clinical development project and the volume of SUSARs generated; with a concise summary of the evolving safety profile of the IMP

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Sponsors’ responsibilities, cont.11.5

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11.6 Predisposing factors in health and disease/AEs/risk …

Related to the patient (intrinsic),

eg

Age

GenderEthnicityBMICo-morbiditiesRelated to the environment (extrinsic), egGeographical regionTime of year (seasonal?)Important to understand for:Assessing causality of drug-event relationshipAssessing risk factors for particular ADRs (and thereby associated risk mitigation measures)Context of a patient-centric holistic healthcare approachSo how would you minimize risk?3511.6

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11.7 Spontaneous reporting post-marketing

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Spontaneous Reporting

Advantages

Operates as soon as drug is marketed

Covers entire population(s) exposed

Involves all doctors, other Healthcare Professionals (HCPs) and patientsGood at generating signalsContinues indefinitely and relatively inexpensiveLimitationsUnder-reporting and variable quality dataInfluenced by external factorsNo control group and cannot calculate incidenceNot good at detecting events that also occur in the background population3711.7

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ICH E2D – Sources of ICSRs

Spontaneous reports

Unsolicited; does not derive from any organised data collection system

Stimulated reports are considered spontaneous (

eg notification in response to a ‘Dear Dr’ letter)LiteratureInternetMAH should regularly screen internet or digital media* under their management or responsibility for potential ADR reportsSolicited sourcesContractual agreementsRegulatory authoritiesOther sources38*web site, web page, blog, vlog, social network, internet forum, chat room, health portal; considered to be company sponsored if it is owned, paid for and/or controlled by the company11.7

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Spontaneous reports

Unsolicited communication by a healthcare professional or consumer describing one or more ADRs

does not derive from a study or any organised data collection scheme

Stimulated reports to be considered ‘spontaneous’

e.g.: notification in response to a ‘Dear Dr’ letter, publication in the press, or questioning of healthcare professionals by company representativesConsumer reports to be handled as spontaneous reportsEU now accept consumer reports3911.7

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ICH E2D – Literature searching

Companies should regularly screen worldwide scientific literature

access widely used systematic literature reviews or reference databases

frequency: according to local requirements or at least every two weeks (EU – ‘at least once a week’)

Companies to regularly screen websites under their management/responsibility for potential case reportsnot expected to screen external websites[EU legislation  MAH should assume that the publication refers to his product if the medicinal product source and/or the invented name are not specified, and ownership cannot be excluded on the basis of active substance(s), formulation or route of administration]4011.7

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EU legislation – definitions 1

Off-label use

‘…the

medicinal

product is intentionally used for a medical purpose not in accordance with the authorised product information.’Misuse‘…the medicinal product is intentionally and inappropriately used

not in accordance

with

the

authorised

product

information.’

Abuse

‘…the persistent or

sporadic

,

intentional

excessive

use of a

medicinal

product

,

which

is

accompanied

by

harmful

physical or psychological effects.’

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From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.7

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EU legislation – definitions 2

Overdose

‘…administration of a quantity of a medicinal product….which is

above the maximal recommended dose

according to the authorised product information.’Occupational exposure‘…exposure to a medicinal product as a result of one’s professional or non-professional occupation.’Medication error‘…refers to any unintentional error in the prescribing, dispensing, or administration of a medicinal product while in the control of the healthcare professional, patient or consumer.’42

From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.7

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(11.8 Reportable events: overdose, medication error off-label use, abuse, misuse, (occupational exposure), pregnancy)

Such reports should be routinely followed-up to ensure that the information is as complete as possible with regards to the symptoms, treatments, outcomes, context of occurrence (e.g., error in prescription, administration, dispensing, dosage,

unauthorised

indication or population, etc.).

Expedited reports are required for cases that lead to ADRs, in accordance with usual requirementsIf no associated adverse reaction should not be reported as ICSRs. They should be considered in periodic safety update reports as applicable. When those reports constitute safety issues impacting on the risk-benefit balance of the medicinal product, they should be notified to the competent authorities in accordance with the usual recommendations. 43

From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.7

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Key Points – EU Legislation

A reporter for a ‘valid case’ could be a ‘

physician, pharmacist, other healthcare professional, lawyer, consumer or other non-healthcare professional

’

The reporting of valid ICSRs electronically, by competent authorities in Member States and marketing authorisation holders, is mandatory for all products authorised in the EU. Non-adherence to this requirement constitutes a non-compliance with EU legislation.’*In accordance with the ICH-E2D guideline, a healthcare professional is defined as a medically-qualified person such as a physician, dentist, pharmacist, nurse, coroner or as otherwise specified by local regulations 44

From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.7

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Adverse Reactions from the Internet

MAH should regularly screen internet or digital media* under their management or responsibility for potential ADR reports

Frequency of screening should allow for potential valid ICSRs to be expedited in the appropriate timeframe from the date the information was posted

If MAH becomes aware of an ADR on any non-Company sponsored digital medium, it should be assessed to determine whether it qualifies for reporting

MAH should consider utilising his websites to facilitate ADR collection*web site, web page, blog, vlog, social network, internet forum, chat room, health portal; considered to be company sponsored if it is owned, paid for and/or controlled by the company 45

From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.7

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Organised Data Collection Systems

ICSRs for marketed products

Includes clinical trials, non-interventional studies, registries, post-approval named-patient use programmes, other patient support and disease management programmes, surveys of patients or healthcare providers, and information gathering on efficacy or patient compliance

Adverse reactions reports obtained from any of these data collection systems should

not be considered spontaneous (except for suspected adverse reactions originating from certain compassionate use or named patient use where adverse events are not actively sought) Solicited reports – should be classified as study reports, and should have an appropriate causality assessment, to consider whether they refer to suspected adverse reactions and therefore meet the criteria for reporting 46

From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.7

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Use of a medicinal product during pregnancy

MAH to follow up all reports of pregnancy for outcome and development of child after birth

Take long half-life of product/metabolites into account (ie medicinal products taken before conception)

Abnormal outcomes are subject to usual expedited and periodic reporting requirements

Congenital anomaliesFoetal death and spontaneous abortionNeonatal serious ADRsDo not need to provide expedited reports for:Termination of pregnancy lacking information on congenital malformationPregnancies with normal outcomeReports lacking outcomeAll signals of a possible teratogenic effect must be notified on an expedited basis e.g. a cluster of similar abnormal outcomesMAH may be required to notify all pregnancies on expedited basis eg if relating to a product with high teratogenic potential 47

From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.7

Slide47

Lack of therapeutic efficacy

Reports of lack of therapeutic efficacy should be recorded and followed-up if incomplete

Should not normally be reported, but should be discussed in PSURs as applicable

Expedited reports required if lack of efficacy relates to:

Products for treatment of life-threatening diseasesVaccinesContraceptivesUnless the reporter has specifically stated outcome due to disease progressionJudgement often required, egNo need to report if antibiotic used in a life-threatening situation where the product was not appropriate for the infective agentShould report if life-threatening infection results from development of newly resistant strain of a bacterium previously regarded as susceptible For vaccines, should report, particularly to highlight potential signals of reduced immunogenicity in a sub-group of vaccinees, waning immunity, or strain replacement 48

From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.7

Slide48

Suspected Transmission of an Infectious Agent

For the purposes of reporting, any suspected transmission of an infectious agent via a medicinal product should be considered as a

serious adverse reaction

and such cases should be reported within 15 days……

A transmission of an infectious agent may be suspected from clinical signs or symptoms or laboratory findings indicating an infection in a patient exposed to a medicinal productConfirmation of contamination of the concerned medicinal product (including inadequate inactivation/attenuation of infectious agents as active substances) increases the evidence for transmission of an infectious agentAny organism, virus or infectious particle (e.g. prion protein transmitting TSE), pathogenic or non-pathogenic, is considered an infectious agentCases should be considered for reporting as product defects if appropriate 49

From GVP Guideline, Module VI (Rev 2), 02 Aug 2017

11.7

Slide49

Dosage, accumulation, medication errors and interactions

Dosage: importance of a dose-response in assessing causality

Accumulation: likely to manifest as later-onset time-dependent reactions;

N.B. always consider the t

½Medication errors: important in the context of risk management; may be difficult to distinguish from deliberate off-label use or misuse, but this is important as medication errors should be preventableInteractions:Drug-drug (N.B. always consider the possibly of OTC and eg herbal remedies)Drug-food5011.8

Slide50

Periodic Safety Update Reports

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Slide51

PBRERs

A Periodic Benefit-risk Evaluation Report (PBRER) provides:

a comprehensive, concise, and critical analysis of new or emerging information on the risks of the medicinal product, and on its benefit in approved indications, to enable an appraisal of the product’s overall benefit-risk profile

Submitted to the health authorities at defined time points post-marketing authorisation5511.10

Slide52

PSURs

ICH E2C (R1)Interval data

Line listings of data

Includes narratives

No assessment of benefitIf benefit-risk analysis has been conducted separately, include summarySubmission time from data-lock = 60 calendar daysPBRERs ICH E2C (R2)Interval data, but greater cumulative contextNo line listings of dataNo narrativesFormal evaluation of benefitIntegrated benefit-risk evaluationSubmission time from data-lock = 70 (6-12 month interval) or 90 (>12 month interval) calendar days Modular approachNo Summary Bridging, or Addendum ReportsWhat is different?Periodic Safety Update Reports → Periodic Benefit-risk Evaluation Reports

56

11.10

Slide53

Format and contents of the PBRER

Executive Summary

Table of Contents

Introduction

Worldwide marketing approval statusActions taken in the reporting interval for safety reasonsChanges to reference safety informationEstimated exposure and use patternsData in summary tabulations

Summaries of significant findings from clinical trials during the reporting period

Findings from non-interventional studies

Information from other clinical trials and sources

Non-clinical data

Literature

Other periodic reports

Lack of efficacy in controlled

clinical trials

Late-breaking information

Overview of signals: new,

ongoing

or closed

Signal and risk evaluation

Benefit evaluation

Integrated benefit risk analysis for

approved indications

Conclusions and actions

Appendices to PBRER

57

11.10

Slide54

Format and Contents of DSUR

Executive Summary

Table of Contents

Introduction

Worldwide marketing approval statusActions taken in the reporting period for safety reasonsChanges to RSI

Inventory of clinical trials ongoing and completed during the reporting period

Estimated cumulative exposure

Data in Line Listings and Summary Tabulations

Significant findings from clinical trials during the reporting period

Relevant findings from non-interventional studies

Other Clinical Trial / Study Safety Information

Safety findings from marketing experiences

Non-clinical data

Literature

Other DSUR

Lack of Efficacy

Region Specific information

Late-breaking information

Overall safety evaluation

Summary of important risks

Conclusions

Appendices to DSUR

58

11.10

Slide55

11.9 Drug-drug interactions

Pharmaceutical

eg sodium bicarbonate + calcium gluconate

 precipitation of insoluble calcium carbonate

PharmacodynamicDirect antagonismeg opiates and naloxone  reversal of opiate effectsDirect potentiationeg alcohol and antidepressants  increased sedationIndirect potentiationeg antiarrhythmic drugs (eg digoxin) and diuretics  cardiac arrhythmias (hypokalaemia) 5111.8

Slide56

Drug-drug interactions – pharmacokinetic

‘Victim drug’

‘Perpetrator

drug’

Result1.  absorptiontetracyclinescalcium, aluminium, magnesium salts tetracycline absorption2.  protein bindingphenytoinaspirin

 phenytoin plasma concentration

3.  metabolism

a) CYP3A4

terfenadine

grapefruit

juice

prolonged QT

 arrhythmias

b) CYP2C19

phenytoin

ticlopidine

phenytoin

toxicity

c) CYP2D6

clozapine

paroxetine

clozapine

toxicity

d) other

enzymes

- xanthine oxidase

azathioprine

allopurinol

azathioprine

toxicity

- monoamine oxidase

catecholamines

monoamine

oxidase

inhibitorsmonoamine toxicity  hypertensive crisis4.  metabolism (induction)cyclosporinSt John’s wortloss of immunosuppression

oral contraceptives

phenytoin

,

rifampicin

pregnancy

5.  renal elimination

lithium

diuretics

lithium toxicity

52

11.8

Slide57

Drug adherence / compliance

In the context of benefit-risk

How do we encourage/support compliance?

Education

Convenience of administrationImpact of presentation, packaging etcHealthcare professional support for patients and carersTechnology? – apps etcWhat factors lead to non-compliance? Adverse reactionsLack of perceived benefitOther benefits of non-compliance – attention, support etcDifficulty in obtaining the product – repeat prescriptions etcPhysical problems – arthritis, dysphagia, blindness etc5311.9

Slide58

11.10 Pharmacoepidemiology

59

Slide59

The Two Main Types of Observational Study Design

Cohort Studies

A cohort study is a prospective observational study, following groups of people (cohorts) who have or have not been exposed to the drug in question, over time, to see whether they do or do not develop the particular adverse effect in question. The patients are not randomized to the cohort groups.

Case-Control StudiesA case-control study is retrospective observational study, in which a group of people with the condition (adverse reaction) in question (‘cases’) are matched with a group without but who are similar in all other relevant aspects (‘controls’), and compared on the basis of some supposed causal attribute (exposure to the drug in question). 6011.11

Slide60

Cohort Studies: Basic Outline

Population

Study

population

without

the ADR

Exposed

Not

Exposed

ADR occurs

ADR occurs

ADR absent

ADR absent

Time

Direction of enquiry

61

11.11

Slide61

Cohort Studies - Summary

Start with a group of exposed and unexposed patients, then follow them over time (N.B. patients are

not

randomised)

Cohort studies are essentially ‘prospective’ (go forward with time) but the method can be used to look at historic dataHypothesis generating and hypothesis testingIssues associated with ‘bias’ & ‘confounding’6211.11

Slide62

Cohort Studies

Advantages

Ability to study

multiple outcomes

Ability to study rare exposures (e.g. people given unusual cancer treatments, people living near nuclear power stations, etc)Ability to study a temporal sequence of eventsCalculation of both absolute risks & relative risksTheoretically less prone to bias than the case-control design6311.11

Slide63

Cohort Studies

Disadvantages

Susceptible to bias (especially

attrition bias

& selection bias)Time taken Unfeasibly large studies could be required to study rare outcomesCan be expensive6411.11

Slide64

Case-Control Studies

Population

Cases

(People with ADR)

Time

Direction of enquiry

Controls

(People without

ADR)

Exposed

Exposed

Not exposed

Not exposed

65

11.11

Slide65

Case-Control Studies

Select ‘

cases

’ with the ADR

Match to ‘controls’ without the ADRCompare exposure to “risk factors” (e.g. drugs, etc)Usually an odds ratio is calculated (i.e. “the odds of exposure in ‘cases’ divided by the odds of exposure in ‘controls’), which is a measure of relative risk6611.11

Slide66

Case-Control Studies

Advantages

Ability to study

rare outcomes

(or where there is a long latency)Ability to study multiple exposuresCan give a quick answer if a suitable database is availableRelatively low costDisadvantagesRequires a prior hypothesis (i.e. can only be hypothesis testing)A suitable database is not always availableOften more susceptible to bias than cohort studies (e.g. especially measurement bias)Only allows calculations of relative risk6711.11

Slide67

11.11 Main sources of epidemiological pharmacovigilance information

Databases, egClinical Practice Research Datalink

Studies

Registries

PublicationsNational statistics6811.12

Slide68

11.12 Signal detection, interpretation and management

69

Slide69

What is a signal?

‘

Information that arises from one or multiple sources (including observations and experiments), that suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify further action to verify.

’

ICH Guideline E2C (R2): Appendix A – Glossary 7011.13

Slide70

Clinical development

Precise numerator and denominator data  comparison of AE incidence rates between carefully selected populations

Blinding helps reduce bias

Additional data more readily available, eg lab data

Post-marketingMore diverse sources of dataGreater volume of dataMay involve off-label useSpontaneous reporting carries biasesQuality of ICSRs?Clinical development vs post-marketing7111.13

Slide71

Signal Management

Action

Assessment

Analysis and prioritisation

Validation

Detection

Signal detection needs to include data from all sources

Validation is a key step

Triage and prioritisation is essential

Assessment to determine risk (identified or potential) or not

Further assessment or mitigation actions

Communication

Quality assurance of the process

72

11.13

Slide72

Outcomes of signal management

Signal refutedNew identified risk

 risk mitigation

New potential risk

 risk assessmentNew ADRNew Contraindication, or Warning and PrecautionNew risk assessment actionsNew risk mitigation actions7311.13

Slide73

Patient Risk Mitigation Activities

Routine risk minimisation measures

Product label (

SmPC

) (and/or IB)Patient package insert PackagingLegal status of the productAdditional risk minimisation measuresEnhanced communicationDHCP letter (Dear investigator letter)Amend protocol(s), ICF(s), advise Ethics CommitteesEducational programmesRestricted accessMandatory registration in order to prescribe/dispenseControlled distributionRestricted accessSuspension or withdrawal (batch(es) or product)………and measure the effectiveness of these…………

74

11.13

Slide74

Post-authorisation safety studies

75

Slide75

“….

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.”

A

post-authorisation study should be classified as a PASS when

the main aim for initiating the study includes any of the following objectives: to quantify potential or identified risks, e.g. to characterise the incidence rate, estimate the rate ratio or rate difference in comparison to a non-exposed population or a population exposed to another drug or class of drugs, and investigate risk factors and effect modifiers; to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (e.g. pregnant women, specific age groups, patients with renal or hepatic impairment); to evaluate the risks of a medicinal product after long-term use; to provide evidence about the absence of risks; to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (e.g. indication, dosage, co-medication, medication errors); to measure the effectiveness of a risk minimisation activity. Post-Authorisation Safety Studies (PASS)

76

GVP Guideline, Module VIII (Rev 3), 12 Oct 2017

11.14

Slide76

Post-Authorisation Safety Studies

Interventional Clinical trial

or

Non-interventional trial - product prescribed according to the terms of the MA - assignment of therapy within current practice, and not decided by a trial protocol - no additional diagnostic or monitoring procedures - data analysis by epidemiological methodsRun-inRandomise

Treatment A

Treatment B

Treatment C

Data cut-off

Analyse

77

11.14

Slide77

11.13 Post-

authorisation risk management including issue and crisis management

78

Slide78

A risk management system is a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of those interventions

The aim of a risk management system is to ensure that the benefits of a particular medicine (or a series of medicines) exceed the risks by the greatest achievable margin for the individual patient and for the target population as a whole.

Q & A EMEA

Risk

Management

System

79

11.15

Slide79

Risk Management Plans (RMPs)

EU PV

Legislation

When

do we need a RMP or RMP update?For all new marketing applicationsFull RMPReduced RMP may be possible for genericsWith an application involving a significant

change

to

an

existing

marketing

authorisation

eg

new

dosage

form

,

route

of

administration

, new

manufacturing

process

of a

biotechnologically-derived

product, paediatric indication or other significant change in indicationAt the request of the EMA, or NCA when

there is concern about a risk impacting the RMP

With the submission of final study results impacting the RMPWith

a PSUR for a single centrally authorised medicinal product, when the changes to the RMP are a direct result of data presented in the PSURIf there is a significant change to the risk-benefit balance of one or more medicinal products

included

in

the

RMP

80

11.15

Slide80

RMP format and contents

NB:

Module SVIII – ‘Safety

concerns

’ = Important identified risks, Important potential risks, Missing InformationPart VI – Summary in lay local languages, available to the public81

11.15

Slide81

11.14 Risk communication

GVP Module XVI

Objectives

of safety communication Safety communication aims at: providing timely, evidence-based information on the safe and effective use of medicines; facilitating changes to healthcare practices (including self-medication practices) where necessary; changing attitudes, decisions and behaviours in relation to the use of medicines; supporting risk minimisation behaviour; facilitating informed decisions on the rational use of medicines. 8211.16

Slide82

Safety communication should contain:

Important emerging information on any authorised medicinal product which has an impact on the medicine’s benefit-risk balance under any conditions of use; The reason for initiating safety communication clearly explained to the target audience; Any recommendations to healthcare professionals and patients on how to deal with a safety concern;

When applicable, a statement on the agreement between the MAH and the competent authority on the safety information provided;

Information on any proposed change to the product information (e.g. the summary of product characteristics (

SmPC) or package leaflet (PL)); A list of literature references, when relevant or a reference to where more detailed information can be found Risk communication cont‘d8311.16

Slide83

11.13 again- Issue and Crisis Management

84

An issue

:

A manageable situation that presents a potential threat to patients, resulting from new information which might influence the evaluation of the benefits and risks of a medicinal product; might arise from: clinical trials pharmacovigilance (individual cases, or signal detection)scientific publicationstoxicological findingshealth authorities, or ethics committees/institutional review boardspatient action groupsmedia attentionproduct quality issuesproduct litigationWhen does an issue become a crisis?When the company does not have full control11.16

Slide84

Issue- exam coming up

84

Slide85

85

Crisis- exam today -no revision

Slide86

11.13 more

Issue and Crisis Management

85

Managing an issue

:Recognise the issueAssess the level of urgencyDo I need to act fast to protect a patient/group of patients?How many patients are at risk?How is the communication/information flow?How easily can I get the information I might need?What are the regulatory timelines?Ask the right questionsGather information and engage the appropriate cross-functional colleagues to answer themTell the right people, in the right timeframe (need to know!)InternallyExternallyFollow-up and next steps11.16

Slide87

SAQ

87

Do

do this at home! Remember: bulleted lists

Slide88

88