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Pharmacovigilance in CancerAre we doing enough?

Bruce Burnett

Senior Lecturer in Pharmacy Practice, University of Central Lancashire

Acknowledgements and Declarations

• With thanks to ISOPP committee for inviting me to speak

• University of Central Lancashire for supporting my attendance

• I have previously received honoraria from Roche UK in respect of presentations on pharmacovigilance.

Learning Outcomes

• Identify areas of improvement in ADR reporting

• Critically appraise strategies employed to improve ADR reporting

• Understand the impact of reporting failures on patient care

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Alemtuzumab

Bevacizumab

Cetuximab

Denosumab

Filgrastim

Ibritumomab tiuxetan

Ipilimumab

Ofatumumab

Panitumumab

Pegfilgrastim

Rituximab

Trastuzumab

%

Dru

g% ADR with BN completed

MHRA Data Analysed 2013 – personal communication.

Definition (Pharmacoepidemiology 5th Edition Strom et al.)

“The principal difference between an adverse event and an adverse drug reaction is that a causal relationship is suspected for the latter, but is not required for the former.

In this framework, adverse drug reactions are a subset of adverse event reports.”

How do we assess how we are doing?

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So we can measure “completeness” Okay but we’ve been improving, haven’t we?

It’s those pesky medics fault……..

Top of the League Table(Number of complete reports)

https://www.sps.nhs.uk/wp-content/uploads/2017/09/MiDatabank-ADR-reporting-2017-PDS-flier-final.pdf

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But do we know?

• No (at least not reliably)

• ? 10% (0.5 – 12.8%) of all ADRs reported…… (late 90’s)

• But we can improve reporting rates…………

Key problems

• Completeness

• Reliability (patient versus HCP)

• Lack of reporting

Completeness is still an issuehttp://www.scopejointaction.eu/downloads/scope-wp4-adr-reporting/

Patients reports are not as reliable as HCP

• Well, no that is not entirely true

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Reporting rates

• It is generally accepted that reporting rates are low.

• We don’t know how low (reported range is very wide)

But we are so much better in oncology……….Adapted from Supportive Care Cancer

(2004) 12:626-633

Cont’d

• May 2014 to April 2015 (no pharmacist) – 5 ADR reports

• May 2015 to April 2016 (pharmacist) - ?

What have we found from our reporting

How much data do we actually have?

• Dose reductions / dose delays

• Quality of life / performance status

• ADR reports (all sources)

• Social media / blogs

• Hospital admission / readmission data

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Can we have too much data?

• Duplication

• “noise”• Weber effect

• Ripple effect

• Analysis

Challenges in Oncology

• Immunotherapy

• Combination therapies versus suspect medicine

• Multiple courses of treatment

• Supportive care medicines

• Focus on grade III / IV toxicity

• Biologics and biosimilars

• (Pharmacogenetics)

• “Personalised medicine” = personalised ADR?

Journal der Deutschen Dermatologischen Gesellschaft 8(6):411-26

Challenges in Oncology

• Multiple therapies (including for co-morbidities) and impact on causality assessment

• Multiple drugs for complex regimens, existing co-morbidity, tumour effects (including from progression)

• Off-label / unlicensed use

• Good traceability on aseptically prepared items but what about dispensed items (oral and others)?• Batch number / manufacturer information

• Location of toxicity / ADR identification or assessment

So it’s easy then?

• Can we do it efficiently

– Drug manufacturer, competent authority, academic organisationsoften “uncoordinated, inefficient and under-regulated” in analysis etc1

– ICER of requiring Periodic Safety Update Reports (PSURs), compared with not requiring PSURs was €342,110 per QALY gained2

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What can oncology pharmacists do?

• Report / record ADRs

• Report / record grade III / IV toxicity

• Report / record grade I / II toxicity

• Report / record timelines for ADR

• Report / record duration of ADR

• Encourage reporting by other HCPs

• Encourage reporting by patients

• Ensure feedback on ADRs and clinical implications shared

Reporting changes

As adverse events might be interrelated and accumulative, it is important that also moderate side effects are reported and treated as possible. Future studies should not only focus on the CTCAE-grades, but also on the total burden of adverse events and the impact of these adverse events on patients’ QoL.

What do I suggest?

• Regimen versus individual medicines

• Use existing data (e.g. SACT data UK)

• Combine with existing data (e.g. VigiBase)

• Incorporate patient / carer reporting (apps, paper, forums)

• ALL toxicity data (to include all grades AND cumulative effect)

• Improve identification – admissions, delays, dose reductions, test results

• Compare with registration data initially, then monitor variance

• Disseminate clinical implications and QoL / PROM impact

Real world data“The average onset of different toxicities may guide physicians; however, given the variability between patients in the time to onset of toxicities (of any kind), this cannot be relied upon.”

Real World Data

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Why?

• Better understand which patients a regimen is most appropriate for

• Reduce costs (toxicity / response)

• Improve patient QoL

• Avoidance better than managing sequelae

What do I want / need?

• Proof of concept that regimen versus individual medicine reporting adds value

• Better data quality• (completeness)

• Better data access• Database access is generally good but inconsistent

• Better feedback to improve patient outcomes and improve reporting• If we know why we are doing something……

But think of all those medicines and events!

Training• Do we know how to identify an ADR?

• Should we be able to assess, even if just an initial assessment, the probability of causality?

• How to recognise and deal with reactions consistent with SmPC which alter in frequency from that expected……

• Training programmes already available• http://www.nes.scot.nhs.uk/education-and-training/by-discipline/pharmacy/about-nes-

pharmacy/educational-resources/resources-by-topic/clinical-governance/patient-safety-adverse-drug-reactions.aspx

• http://learning.bmj.com/learning/module-intro/pharmacovigilance-adverse-drug-reactions.html?moduleId=10042344&locale=en_GB

• http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/TheYellowCardScheme/Informationforhealthcareprofessionals/TrainingandCPD/#l3

• Training can improve ADR reporting11 Drug Saf. 2009;32:77–83

Training

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Feedback• What should we expect from competent authority?

• Individual (personal) vs community• How frequently are reports monitored / analysed?

• Two weekly or monthly• MHRA decide UK list of drugs

• What do we want?• Time course of the reported ADR (? Including duration)• Pharmacological mechanism

• Netherlands study1

• Preference for personal feedback• Very unsatisfied if just got an acknowledgement• 80.3% felt personalised feedback improved their knowledge• Of those receiving personal feedback only 0.6% DID NOT READ IT• Caution: responders tended to be more frequent reporters

1 Drug Saf 2012; 35: 221 – 232

Feedback

Questions?