Prescription Event Monitoring

Transcription

1 Prescription Event Monitoring David Coulter NZ Intensive Medicines Monitoring Programme 27 March 2003 Lusaka 1

2 PEM worldwide NZ Intensive Medicines Monitoring Programme (IMMP), Dunedin, 1977 Drug Safety Research Unit, Southampton, UK, 1980 J-PEM, Tokyo, Japan 27 March 2003 Lusaka 2

3 David Coulter 27 March 2003 Lusaka 3

4 A method of pro-active safety surveillance 27 March 2003 Lusaka 4

5 The Reason Post-marketing surveillance is essential because the safety database on newly licensed drugs is limited by both the number and characteristics of the patients involved. In the UK for example, successful applications for product licenses for medicines containing new active substances include, as a safety database, information on a median number of 1480 patients. Most of these patients will have been carefully chosen to have only one disease being treated with one drug. Few, if any of them, will be typical of the patients likely to receive the drug once it has been marketed. The identification of uncommon, even if serious or lethal, reactions from such a small number of highly selected patients is unlikely. Mann RD. Prescription-event monitoring -recent progress and future horizons. Br J Clin Pharmacol 1998; 46: March 2003 Lusaka 5

6 Randomised clinical trials Cannot provide adequate safety profile Study cohort is highly selected to exclude confounders in study of efficacy -excludes: comorbidity co-prescription pregnant elderly or young self medication 27 March 2003 Lusaka 6

7 Randomised clinical trials Cannot provide adequate safety profile Short term delayed reactions withdrawal effects changes in death rates Dose variations Women Unlabelled use 27 March 2003 Lusaka 7

8 Spontaneous Reporting The advantages Easy to implement Cheap Covers all medicines Rare reactions identifiable 27 March 2003 Lusaka 8

9 Spontaneous Reporting The disadvantages Incomplete (<3%) No denominator Markedly subject to biases Delayed effects unnoticed Common clinical problems not linked to drug 27 March 2003 Lusaka 9

10 Practolol the Model The oculomucocutaneous syndrome Early symptoms delayed until 2 years dry eyes popping ears Caused blindness, retroperitoneal fibrosis, death Syndrome unrecognised for 4 years with spontaneous reporting even though symptoms common 27 March 2003 Lusaka 10

11 Monitoring requirements Adverse events - the numerator as complete as possible Patients exposed (cohort) - the denominator as complete as possible 27 March 2003 Lusaka 11

12 Events definition The term event designates a desirable or undesirable manifestation, without presuming that it is or not related to the use of a drug 27 March 2003 Lusaka 12

13 Events Reporting requirements All new events even if common & minor Change in a pre-existing condition Abnormal changes in laboratory tests Accidents All deaths with date & cause Possible interactions NB alcohol, OCs, CAMs 27 March 2003 Lusaka 13

14 Basic methodology 1 Observational cohort studies on selected new drugs prospective longitudinal non-interventional inceptional dynamic descriptive 27 March 2003 Lusaka 14

15 Basic methodology 2 Cohorts established from prescription data supplied by community & hospital pharmacisits on request 93% compliance rate Events data obtained by Prescription event monitoring (PEM) & Spontaneous reporting 27 March 2003 Lusaka 15

16 Basic methodology 3 Event collection Spontaneous reporting Questionnaires (PEM) computer generated patient & drug data entered minimal recording - events since date given return envelope compliance 80% + Reasons for cessation of therapy 27 March 2003 Lusaka 16

17 Data elements - patient Name Title Gender Address National Patient Number Date of Birth 27 March 2003 Lusaka 17

18 Data elements - doctor Name Type Specific worksite address Doctor database (Pharmacy) 27 March 2003 Lusaka 18

19 Data elements - drug Name & formulation Dose Date of dispensing Quantity dispensed 27 March 2003 Lusaka 19

20 How many patients? The magic figure is 10,000 IMMP mean 10, March 2003 Lusaka 20

21 Events = reactions + incidents Reactions definite probable possible Incidents (background noise) unlikely 27 March 2003 Lusaka 21

22 COULTER F Celecoxib 400mg OA Melena Hypotension Myocardial infarction URTI m 3m 3m 3m H 1 2, 3 4 ALI CIR RES 27 March 2003 Lusaka 22

23 Incidents Should represent background morbidity May contain unrecognised signals unexpected profiles Useful for assessing reporting bias as within-drug controls as between-drug controls Unmasking 27 March 2003 Lusaka 23

24 Profile of Incidents Acci Alim Card Emd/Met Hepa Musc Neop Neur Psyc Resp Skin Urog 24 Rates/1000 Bez Gem

25 Angina with bezafibrate Bezafibrate Gemfibrozil Odds Ratio 21 / / ( ) 27 March 2003 Lusaka 25

26 Angina & bezafibrate Evaluation Detailed survey of cohort Excess angina confirmed Diabetes mellitus 25% (gem 7%) Hypertension 60% (gem 47%) Confounding by indication 27 March 2003 Lusaka 26

27 Incidents: within-drug control Gender Differences Relative Risk F:M (95% C.I.) Reactions Incidents Moclobemide 1.7 ( ) 1.0 ( ) Fluoxetine 1.7 ( ) 1.0 ( ) 27 March 2003 Lusaka 27

28 The purpose Signal identification Measurement of risk (rates) Characterisation of reactions features, onset, outcome, seriousness Identifying risk factors M/F, age, dose, kidney, morbidity, other drugs Validation of signals 27 March 2003 Lusaka 28

29 Signal definition Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. WHO 27 March 2003 Lusaka 29

30 Development of a signal Omeprazole and polymyositis 27 March 2003 Lusaka 30

31 Omeprazole Polymyositis Increase in expected incidence No reports with other monitored drugs Increase in expected rate of falls Compared with ranitidine (WHO) more muscle weakness more CPK elevation 27 March 2003 Lusaka 31

32 Other adverse events possibly related FALLS No Cohort Omeprazole 7 (3.5) 2014 Other drugs * 9(1.5) 5390 Figures are numbers (rates per 1000 > 60 yrs) Relative Risk for omeprazole 2.3 (CI ) * moclobemide, fluoxetine, bezafibrate, gemfibrozil, simvastatin 27 March 2003 Lusaka 32

33 WHO data omeprazole ranitidine CPK increased 19 (0.15) 16 (0.08) RR 1.9 (95% CI ) Muscle weakness 26 (0.21) 18 (0.09) RR 2.3 ( ) 27 March 2003 Lusaka 33

34 Sumatriptan An example of a monitoring study and demonstration of methodology 27 March 2003 Lusaka 34

35 Use Acute treatment of migraine and cluster headache Injections (pre-filled) 6mg; tablets 100mg (& 50mg) Usage restrictions maximum of 6 doses prescribed maximum of 2 doses dispensed 27 March 2003 Lusaka 35

36 Basic data Patients 14,964 Prescriptions 107,654 Questionnaires 26,309 Spontaneous events 348 PEM events 3631 Total events March 2003 Lusaka 36

37 Questionnaires Completed by: doctor from records (35%) nurse by telephone interview (50%) patient (15%) 83% return (n=21,836) 27 March 2003 Lusaka 37

38 Sumatriptan Signals 1 Event No. 1 st alert Publ Angioedema 4 Yes 0 Chest pain 296 Yes >2 Depression 19 Yes 2 Panic 17 Yes 2 Rebound 93 No 2 27 March 2003 Lusaka 38

39 Sumatriptan Signals 2 Event No. 1 st Alert Publ Sensory 254 Yes 1 disturbance Tolerance 50 Yes 1 Throat 119 Yes 1 tightness Pain activation 22 Yes 2 27 March 2003 Lusaka 39

40 Sumatriptan signals 3 Event No. 1 st Alert Publ Amnesia 9 Yes 1 Anxiety 25 Yes 1 Apnoea 5 Yes 1 Confusion 15 Yes 1 Deperson -alisation 103 Yes 1 27 March 2003 Lusaka 40

41 Sumatriptan signals 4 Event No. 1 st alert Publ Dry mouth 30 Yes 1 Hallucinations 5 Yes 1 Weakness 30 Yes 1 Myalgia/ arthralgia 31 Yes 1 27 March 2003 Lusaka 41

42 Sumatriptan signals 5 Event No. 1 st Alert Publ Rigors 41 Yes 1 Sweating 26 Yes 1 Tachycardia 146 Yes 1 27 March 2003 Lusaka 42

43 Sumatriptan & autonomic response Fight or flight reaction Tachycardia Cold sweat Dry mouth Anxiety / panic Pallor Paraesthesia Piloerection 27 March 2003 Lusaka 43

44 Sumatriptan Pain activation syndrome Pain trauma activated skin scratches sunburn bruising recent surgery Pain inflammation activated rheumatoid arthritis colitis sinus pain toothache backache 27 March 2003 Lusaka 44

45 Sumatriptan & tolerance 1 50 reports from PEM of increased number of doses required per attack treatment becoming ineffective Doesn t work as well as it used to 27 March 2003 Lusaka 45

46 Tolerance to Sumatriptan Mean number of items dispensed per patient per 6 month period (tablets and/or injections) Interval Patients Total Dispensed Mean no per patient 1st nd rd th th th th th March 2003 Lusaka 46

47 Sumatriptan Injections Only: mean numbers of items dispensed per patient per six month intervals of treatment Injections Only Interval Patients Mean March 2003 Lusaka 47

48 27 March 2003 Lusaka 48

49 Sumatriptan Pregnancy & lactation 31 pregnancy exposures 25 pregnancy outcomes 11% of world-wide experience (Glaxo) 29 lactation exposures 27 March 2003 Lusaka 49

50 Sumatriptan & chest pain Analysis of age & gender duration of event (n=295) other possibly related events eg tachycardia control events 27 March 2003 Lusaka 50

51 Sumatriptan and chest pain Suggested mechanisms Coronary artery spasm Oesophageal dysfunction Muscle pain chest wall Bronchospasm 27 March 2003 Lusaka 51

52 Sumatriptan & chest pain Analyses showed no relationship with cardiovascular events oesophageal problems musculoskeletal events bronchospasm strong relationship with throat tightness 27 March 2003 Lusaka 52

53 Sumatriptan & chest pain Acute changes in pulmonary circulation Increase in pressure Pulmonary systolic 40-50% Pulmonary diastolic 40-50% Capillary wedge 90% 27 March 2003 Lusaka 53

54 Media scare Sudden death of woman in 40 s from?cardiac arryhthmia Legal proceedings 80 deaths linked to sumatriptan (USA) Media interest in NZ 27 March 2003 Lusaka 54

55 Reassurance No deaths in NZ (cohort 7,500) No reports of MI Cardiac dysrythmias tachycardia 23 palpitations 35 bradycardia 2 multiple VPBs with Cafergot 27 March 2003 Lusaka 55

56 Multiple dosing Multiple dosing within a short period of time, but within the recommended guidelines, is a risk factor for arterial occlusion This may affect cerebral or peripheral arteries It may occur well after the normal pharmacological action The mechanism is likely to be due to receptor changes 27 March 2003 Lusaka 56

57 Standard reports 1 Monitoring summary Reporting rates by gender total, reactions, incidents Age & sex distribution of cohort Regional distribution Indications for use (Historical morbidity) Dose distribution 27 March 2003 Lusaka 57

58 Standard reports 2 Monitoring summary Duration of therapy Frequency of events by SOC (profile) Most frequent events with rates Reasons for withdrawal of therapy Listing of events in clinically related groupings with sex, age, dose, duration to onset, relationship Reports listing 27 March 2003 Lusaka 58

59 Doctors role Privacy requirements leaflets Event reporting spontaneous questionnaires duplicate prescriptions events yes/no, dob, (record event) 27 March 2003 Lusaka 59

60 Pharmacists role Privacy Code requirement leaflets Provision of prescription data include duplicates Provision of events data annotate printout spontaneous reports duplicates 27 March 2003 Lusaka 60