Faculty of Health and Medical Sciences

The community pharmacy setting as platform for collection of Real World data

Ole. J. BjerrumProfessor emeritus

Department of Drug Design and Pharmacologyand

Copenhagen Center for Regulatory Sciences

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Minisymposium 14. March 2018

Where to find the Real World for medicines users?

In the community pharmacy!

• To pick up the physicians prescription is a normal procedure for the patient

• This meeting with the healthcare system opens a window of opportunity to perform Real World studies

Three such studies are presented:

• Pharmacovigilance of Liraglutide;

• Off-label prescription of 5 medicines

• Effectiveness study on the switch to Xultophy

15/03/2018

Study 1. Pharmacovigilance data on Liraglutide users col-lected by students in 19 Danish pharmacies April – July 2010

Liraglutide (Victosa) marketed in DK January 2010

• Participants: Total 62

• Users reporting ADR’s: Total 38

• Mean age: 57 years

• Reported ADR’s: Total 84

• Duration Liraglutide use:

< 4 weeks: 34%; 4<weeks <8: 11%; > 8 weeks: 34%

• Concomitant anti-diabetic medicines were registered

• Approx. 5 min were spend per user with ADR’s

15/03/2018 Christensen and Bjerrum, J.Patient Safety 2013, 9, 219 -23

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Major reported ADR symptoms by users of Liraglutide (1.2 – 1.8 mg/day) with concomitant anti-diabetic treatment (MET, GLI, SU)

Symptoms This study This study LEAD 1-3*No. of reports (%), N=62 (%), N= 5000

• ___________________________________________________________________________________________________________________________________

Nausea 25 40 28-29

Appetite 10 16 1-10

Diarrhoea 9 15 12-18

Fatigue 5 8 1-10

Abdominal pain 5 8 1-10

Constipation 4 6 5-11

Vomiting 3 5 6-12

Abdominal distension 3 5 -

Flushing 2 3 -

Other 15 25 -

15/03/2018*Marre, Diabet.Med. 2009; Nauch Diabetes Care 2009; Garber Lancet 2009

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Proposal for pharmacist conducted ADR monitoring of new medicines

Flow of report forms

Pharmacist at community pharmacies

Medicines Agency

General Practitioner

(GP)

No demand for any changes in current procedures for the GP

Additional ADR report

after patient consultation

Electronic report form for all customers questioned

Electronic report only in case the observed ADR need medical attention

Study 2. Off-label use. Definition and Challenges.

EMA: “This relates to situations where the medicinal product is intentionally used for a medical purpose not in accordance with the authorized product information”

The purpose includes: * Intended patient population (Age)

* Dosing

* Indication area

* Route of administration

Challenges:

To register if off-label use of medicines poses a safety problem,

But off-label prevalence is difficult to quantify, since reliable data are cumbersome to obtain: e.g. via F2F questionnaire

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Off-label Study. Aim and Methodology

1. By means of structured Query Language (SQL) to design a programming code for collection of prescription data on CITO pharmacy servers.

2. To apply this collection method for

diclofenac, desmopressin, quetiapine, mirtazapine and fucidine

to investigate if they were used off-label.

With permission from Datatilsynet two years prescription data from five representative community pharmacies was collected in Denmark May –June 2017

Andrulyte and Bjerrum: Basic & Clinical Pharmacology and Toxicology 2018, in press

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Off-label related to age. Paediatric population prescriptions of quetiapine, mirtazapine, and diclofenac.

Medicines

<1815-17

Total %

Quetiapine 61 16 45 73

Mirtazapine 9 2 7 66

Diclofenac 74 31 43 58

Total 145 50 95 66

15/03/20188

Off-label prescriptions prevalence: 2% (<18 years) and 0.7% (<14 years)

Andrulyte and Bjerrum BCPT 2018 in press

GP’s: Physiological age often differs from nominal age!

Off-label related to age. Prescriptions for desmopressin for patients over 65 years

15/03/2018 9

Patients >65 years(authorized prescriptions)Pharmacy

location

Number of prescriptions

Total For patients over 65 years

TotalAutho-rized*

Off-label

Off-label (%)

A 175 42 6 36 86

B 138 24 0 24 100

C 179 19 0 19 100

D 227 40 3 37 92

E 206 43 0 43 100

Total 925 168 9 159 95

* Only when the daily dosage of desmopressin is 25 ugfor women and 50 ug for men.

Indication: Nycturia. For patients < 65 years dosing is max 240 ug

When used >65 years the daily dose should be reduced to 25 ug/woman and 50 ug/men

Off-label by dosage. Prescriptions for quetiapine categorized by daily dosage

Pharmacy location

Eligible prescriptions,

(total no. )

Daily dosage, mgOff-label

prescriptions (daily dosage <=100 mg), %>100 ≤100

A 543, (574) 124 419 77

B 379, (435) 95 284 75

C 764, (813) 216 548 72

D 164, (177) 59 105 64

E 675, (713) 146 529 78

Total 2525 (2712) 640 1885 7515/03/2018

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Indication: Treatment of schizophrenia and moderate to severe manic episodes andmajor depressive episodes in bipolar disorder. Recommended dosage 100-900 mg

Andrulyte and Bjerrum BPCT 2018 in press

Off-label by dosage. Dose related to authorized indications for quetiapine

• Daily dose (mg) Correct indication text (%) • 500-1200 100• 300-500 87• 100-300 86• < 100 26The higher the dose - the more use of correct indication text.The box-label text for doses < 100 mg reveals that some physicians do not admit, that the prescription is for off-label use

Andrulyte and Bjerrum BPCT 2018

“A prescription should include information on the indication, dosage and any relevant usage mode.” “The instructions on the prescription must be easily understood” DMA

Physicians choice

Use of diagnosis or code within the authorized indication

Description of expected symptoms to:

-help the user to differentiate between the medicines prescribed

-avoid a “grim” diagnose on the container

Off-label use is present when:

The intended off-label indication is stated and may be when unclear wording is used,like : *Neutral or un-precise/non-pathological wording ,

* Unusual disease symptoms or

* Just a generalized drug category

Physician’s considerations when formulating the text for the indication on the box label

Slide 13

Off-label use by indication. Classification of box label text for individual quetiapine prescriptions

Authorized indication Medically approved indication (likely) Off-label indication (most likely)

English Danish No. of

prescriptions

English Danish No. of

prescriptions

English Danish No. of

prescription

s

Mental

disorder

Mod

sindslidelse

848 Stabilizing Stabiliserrende 30 Anxiety Mod angst 162

Depression Mod

depression

743 Against

hallucinations

(delusions)

Mod

hallucinationer

18 Sedative Beroligende 132

CNS

medicines

Nervemedicin 327 Bad thoughts Mod grimme

tanker

14 Sleep dis-

turbances

Mod

søvnbesvær

115

Treatment for

bipolar

disorder

Behandling af

bipolær lidelse

211 Depression and

insomnia

Mod depression

og søvnbesvær

9

Unrest Mod uro 20

Treatment for

schizophrenia

Behandling af

skizofreni

69 By aggression Ved

udadreagerende

adfærd

1 Against

Thought

swarming

Mod

tankemylder

22

Psychosis Psykose 33 Against psychotic

reactions (mania

and depression)

Mod

affektreaktioner

1 Post-

traumatic

stress

disorder

Mod ptsd 10

Mania Ved mani 30 Miscellaneou - 14

Off-label by indication. Prescriptions for mirtazapine and quetiapine grouped by box label indications

Medicine Prescriptions

Eligible

(total no.)

Authorized indication

Likely off-label Most likely

off-label

No. % No. % No. %

Mirtazapine 3128 (3188) 2415 77 280 8 430 15

Quetiapine 2654 (2712) 2276 85 124 5 254 10

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Box label text reveals less off-label use than dosis analysis!

Andrulyte and Bjerrum BPCT 2018

Off-label by route of administration. Application of fucidine ointment

Indication

For fucidine sensitive dermatological infections

Results

Out of 60 fucidine prescriptions for application on the nose, 48 was prescribed for use on mucosa inside the nose.

This corresponds to 80% off-label use

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Study 3. Post-authorisation effectiveness study of Xultophy through patient reported outcome

Xultophy is a new injectable Fixed Dose Combination product of GLP-1 and basal insulin

It is approved by EMA for treatment of Type 2 Diabetes mellitus (T2D) irrespectively of former treatment

It was marketed March 2017 in Denmark .

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Effectiveness study. Aim and methodology

Aim.

A. Via a patient questionnaire to get info on how the patient perceive the treatment with Xultophy in connection to former treatment

B. Pattern of prescription of Xultophy to T2D patients who are:

• Drug naïve

• On oral anti-diabetic treatment?

• On GLP-1 and insulin treatment?

• On free combination of GLP- and insulin

Methodology

Contact patients when they present their prescription at the counter

After informed consent initiate patient/pharmacist reported outcome of the users experience with the new treatment via a Questionnaire 1

Note down the previous T2D medication via the local prescription registry

Follow-up by Questionnaire 2 at next patient visit for prescription renewalL:\4. sal\Ojb\Science\Combination

therapy\Adressing the GAP from E2E

Patient Questionnaire 1 and 2

Domains

1. Daily life

2. Diabetes management

3. Compliance

4. Psychological health

5. Adverse events

For Xulthopy users (examples)

Do you have to limit your daily activities

Are you satisfied with the control of your diabetes

How often do you miss a dose?

Does the medicine intake depress me or make me sad?

How often did you experience low blood sugar events (hypoglycaemia)

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On-going effectiveness study (Spring 2018)

A pilot study conducted Spring 2017 showed that:

• Identification and follow up of patient is possible

• The interview procedure and reporting functions.

• The questions should be short and simple as many costumers often are in a hurry

Recruitment of student are in progress

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Characteristics of Real world data collection through Pharmacy Prescription Event monitoring• Randomisation.

The patients are included as they appear

• Inclusion/exclusion

Home living patients that appear with relevant prescription at the pharmacy

/Patient not being able to pick up the medicines

• Blinding

The patient are unaware and thereby unprepared for the interview

The pharmacist reporting is neutral regarding the patients medication

• Anonymity

With informed consent data can be handled directly, otherwise Datatilsynet

only allows aggregated data to leave the pharmacy

• Reliability

• The data base gives accurate access to medication data, history and consumption in a two years period

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Conclusion and outlookCommunity pharmacies represent a source to conduct Real World studies on medicines consumers regarding pharmacovigilance and effectivenes studies as well as on-line prescription analysis

Through Pharmacy Prescription Event Monitoring Danish pharmacies could be a Laboratory for systematic collection of early RWD on medicines consumers

On-line data analysis on off-label use on local pharmacy servers is possible

• Accurate off-label data regarding age and dose can easily be obtained

• Interpretation of the prescriptions box label text is possible but uncertain

Pharmacy students on internship deliver feasible data, thereby making it possible to include sufficient number of pharmacies allowing Nationwide extrapolation

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AcknowledgementsThanks is due to

Søren T. Christensen, cand. pharm. for organising the ADR collection

Monika Andrulyte, master, pharm. sci. for organising the the off-label prescription collection and data handling

Nada Alkis, master, pharm. sci. for collection of patient reporting outcomes

Asger Mortensen, pharmacist, Værløse, who draw the attention to the

data richness of the local pharmacy servers.

Lotte Stig Nørgaard, associate professor for establishing contact to the

pharmacy intern students.

Hans J. Bjerrum, MD for clinical input to off-label use

Apotekerforeningen for financing the publication costs

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