1 US Investigator Meeting DIAS-4, San Diego, January 2011 Pharmacovigilance & Adverse Event Reporting 15-JUL-2011 Frida Bushnell Scientific Safety Advisor.

1 US Investigator Meeting DIAS-4, San Diego, January 2011

Pharmacovigilance &Adverse Event Reporting

15-JUL-2011 Frida BushnellScientific Safety AdvisorGlobal Pharmacovigilance HQ

US Investigator Meeting DIAS-4, San Diego, January 2011 2

Agenda

Context What will you get from this session? Safety and Pharmacovigilance at Lundbeck Working in partnership

Getting it ‘right first time’ Definitions of Adverse Events and Serious Adverse Events Ensuring correct diagnosis From diagnosis to coding Identifying causality Using the study reporting tools


Voting pads


Context


Your patients, our reputation

Why we are here: A new medicine that may help doctors and patients So far, so good, but this is still ‘something new’ Our first duty: the safety of trial participants You are our eyes and ears What we do will affect how this medicine benefits patients


60 minutes, to safeguard study participants

What you will get from this presentation:

How we will work togetherHow to save time and avoidreworkHow to reportHow to use the reporting toolsOpportunity to ask questions

How many safety/ pharmacovigilance presentations have you been to?

7

Interactive question

0%

0%

0%

0%

0% 1. This is my first

2. A few

3. A lot

4. Far more than you can imagine

5. I could probably give this presentation myself

10


Please give us yourundivided attention


Pharmacovigilance: The science of safety

Understanding and preventing adverse events by:Monitoring and reporting the use of the drugDetecting and assessing any adverse effectsAssessing frequency, riskfactors, levels of riskAssessing risk versus benefit


Working together

First point: the patient comes first Partners in an investigative process Simplicity, accuracy and ‘right first

time’ Unclear or incomplete data will be

followed up Every report is followed up

appropriately


Getting it‘right first time’


Adverse events

What is an Adverse Event? Untoward, or out of place, medical event during the clinical trial Patients included when they sign the consent form Events before first administration ARE included Does not need to be caused by the drug Unchanged pre-existing conditions are not AEs

Which of the events shown should you report as an Adverse Event or Serious Adverse Event?

14


0%

0%

0%

10


Laboratory abnormalities can also indicate an Adverse EventIf the investigator believes they are clinically significantIf they lead to a change or discontinuation of treatmentIf they fulfil a seriousness criteriaIf they indicate a potential safety risk to the patient

Other things to note



Overdose At minimum, should be reported as an AE, stating whether intentional

or accidental If intentional, please add the reason Any symptoms resulting from the overdose should also be declared as

AEs Medication errors, drug abuse, drug interactions, quality issues with the

drug Medical or surgical procedures

The reason for the procedure should be reported as an AE



Pregnancy Should be reported as an AE within 24

hours using the ‘Pregnancy’ form and entered as an ‘AE’ in the eCRF

Any untoward event, such as spontaneous abortion, congenital anomaly or foetal death should be reported as a Serious Adverse Event

Report the outcome to Lundbeck, even if study has ended


What is a serious adverse event?

Death Life-threatening Results in persistent or permanent

disability or incapacity Results in birth defect/

congenital anomaly Requires

hospitalisation Medically important


Serious adverse events

All SAEs should be reported immediately, then tracked and updated until there is an outcome:

“Recovering”

“Recovered”

“Recovered with sequelae”

“Died”

“Did not recover”(for chronic conditions)

Which of the following are serious adverse events?

21


0%

0%

0%

0%

0% 1. Patient died after being stabbed with a knife

2. Patient broke leg and was admitted to hospital

3. Patient suffered anaphylactic shock

4. Patient gave birth to a healthy baby

5. Patient admitted for scheduled surgery to remove gall bladder

10


Reporting AEs and SAEs

Reports should include:Symptoms and/or diagnosisTheir intensityCause (if known)Causality assessmentAction takenOutcome

Be specific about cause and sequence: “Patient took an extra tablet because he forgot the previous dose”Patient presented with an arm fracture after falling over due to dizziness”


Symptoms and diagnosis


Symptoms and diagnosis

Ensure that cumulative symptoms are reported correctly:Together, chest pain, dyspnoea, diaphoresis and ECG changes can indicate a myocardial infarctionThe symptoms should be reported as AEs or SAEs as they occur but should be connected when the link becomes clear


Coding and why we do it


Causality

Is the AE or SAE linked to the study drug? Probably: There is a reasonable time relationship between the AE/SAE and

drug administration, or the AE/SAE recurs when the drug is taken again. Is unlikely to be caused by disease or other drugs.

Possibly: There is a suggested time relationship between the AE/SAE and drug administration, however, it could also be caused by disease or other drugs.

Not related: There is no time relationship between the AE/SAE and drug administration, or AE/SAE is caused by disease or other drugs.

How many different CRF systems have you been trained in over the years?

28


0%

0%

0%

0%

0% 1. None

2. 1-3

3. 4 or 5

4. 6-10

5. More than 10

10


Recording using the eCRF


Recording using the eCRF

Our goals: Simple to use Necessary, but not excessive, data Clear purpose and subsequent outcomes

Your goals: Devote adequate time CRF completion as a priority task Consistent and, where appropriate, report diagnosis instead of signs and

symptoms


Sample entry: reporting an AE








Sample entry: reporting a sequence of linked AEs

If possible combine signs and symptoms into a single diagnosis

Ensure the initially reported AEs (symptoms) are inactivated

Note whether the adverse event is serious



If possible combine signs and symptoms into a single diagnosis

Ensure the initially reported AEs (symptoms) are inactivated

Note whether the adverse event is serious





What should you report when a patient presents with a series of symptoms which are later linked?

40


0%

0%

0% 1. Report each symptom as an adverse event

2. Report each symptom as an adverse event and the diagnosis as a serious adverse event

3. Report each symptom as an adverse event but inactivate the initial reports when you realise that the previously reported symptoms are covered by one diagnosis

10


Sample entry: narrative reports


Sample entry: narrative reports

Narrative reports can be pasted into a free text field Give detail about the events leading to the AE Describe investigations and treatments Ensure the outcome is included

A good example:

On 12 October the patient was shovelling snow. The path was slippery and he fell and hit his head. He had not ingested alcohol and was not dizzy. He was hospitalised to be investigated (CT scan) and monitored for neurological injury. None was found and, on 14 October he was discharged with only a mild headache.






Back-up procedure

If it is not possible to use the eCRF, record SAEs on emergency worksheets

If necessary, continue to use these for follow-up assessments and reports

Send them to the contact details shown at the end

Update the eCRF at the earliest opportunity


Summary


Summary

You are our eyes and ears -- we, and the study participants, are in your hands

Familiarise yourselves with the definitions of AEs and SAEs

Familiarise yourselves with the reporting tools

Getting it right, first time, will prevent follow-up contact and save you time

There is a support network to help answer any queries


For further information

All information in this presentation is summarised in the study protocol:

Section 9, pages 47-73 Ask your CRA or international/regional study manager Ask your Safety Advisor: [email protected]

Contact Details: For reporting, always use the eCRF Backup options: Fax +45 36 30 99 67 or email [email protected]



Data Monitoring Committee(DMC)

28-JAN-2011 Frida BushnellScientific Safety AdvisorGlobal Pharmacovigilance HQ


DMC

The Data Monitoring Committee (DMC) is an independent expert advisory group

Combined DMC for 12402A (DIAS-3) study and 12649A (DIAS 4)

Purpose and functions: Monitoring the safety of patients Conduct a predefined interim futility analysis when

half of the patients have been evaluated in either one of the studies.


DMC

Members:3 external experts Chairman Deputy Chairman Third member

MeetingsThroughout the studies when a predefined number of patients have been enrolled and followed up for 90 days. First meeting: Feb 2010, 50 patients Second Meeting: 09 Feb 2011, 150 patients Thereafter for 250, 400, 550 and 700 patients


DMC members

Prof. Kennedy R. Lees, MDDMC Chair and Stroke SpecialistDepartment of Medicine Western InfirmaryGlasgow, UK

Dr Lawrence R. Wechsler, MDDeputy DMC Chair and Stroke SpecialistUniversity of Pittsburgh, Stroke InstitutePittsburgh, USA

Dr Michael Eliasziw, PhDDMC member and Biostatistics SpecialistDavLar BiostatsCalgary, Canada

Lundbeck personnel involved: Meredin Stoltenberg MD, PhD, DMScDMC secretaryH. Lundbeck A/S, Denmark


1 US Investigator Meeting DIAS-4, San Diego, January 2011 Pharmacovigilance & Adverse Event Reporting 15-JUL-2011 Frida Bushnell Scientific Safety Advisor.

Documents

us investigator meeting

san diego

ae slide

time slide

aes slide

context slide

important slide

benefit slide