MIGRAINE IN PRIMARY CARE ADVISORS Guildford, 1 May 2003, 2-6 pm Understanding the evidence in...

MIGRAINE IN PRIMARY CARE ADVISORS

Guildford, 1 May 2003, 2-6 pm

Understanding the evidence in evaluating acute migraine medications in clinical

practice

Introduction and objectives

Dr Andrew Dowson

Kings’ Headache Service, London

Programme

• Dr Andrew Dowson: Introduction and objectives

Discussion: • Comparing acute medications: clinical trials

experience• Comparing acute medications: experience

from clinical practice• Practical advice for general use in the clinic • Dr Andrew Dowson: Conclusions

Objectives

• Review clinical trial evidence for the clinical profiles of triptans and other acute medications for migraine

• Compare these data with the situation in primary care

• Provide the practising clinician with rational methods of evaluating clinical trial data– Publications– Detail aids– Integrating clinical trial data into the real world

setting

Outputs

• MIPCA newsletter for GPs– How to evaluate detail aids and trial data

• Slide set for educational use

• Article on understanding the evidence for GPs– Critical review of the evidence

Comparing acute medications: clinical trials experience

Overview

• Clinical trial endpoints

• Post hoc endpoints

• Clinical trial data on the triptans and other acute medications

• Misunderstandings and pitfalls

• Understanding the evidence

Clinical trial endpoints

Primary endpoint for clinical trials

• Headache relief: Improvement from severe or moderate headache to mild or no headache at 2 hours– ‘Glaxo’ endpoint

• Improvement from severe or moderate to no headache at 2 hours– ‘IHS’ recommended endpoint

Pilgrim AJ. Eur Neurol 1991;31:295-9.

IHS Clinical Trials Subcommittee. Cephalalgia 2000;20:765–86.

Efficacy outcome

Pain-free (‘IHS’)

Pain relief (‘Glaxo’)

33SevereSevere

22ModerateModerate

11MildMild

00NoneNone

Pilgrim AJ. Eur Neurol. 1991;31:295-299.

Secondary endpoints for clinical trials

• Headache relief at other time points• Headache free at various time points• ‘Meaningful’ relief• Return to normal functioning• Relief of nausea, vomiting and photophobia /

phonophobia• Sustained pain relief• Headache recurrence• Adverse events

Pilgrim AJ. Eur Neurol 1991;31:295-9.

Discussion: perspective on endpoints

• In general, pain relief parallels that reported for other symptoms– Headache relief as a proxy for migraine relief?

• Stopwatch endpoints are used in pain studies, but not in migraine studies

• If the patient treats the headache when mild, non-headache symptoms may not have developed– Potential problems with IHS diagnostic criteria

• Adverse events vs safety– Tolerability (AEs) variable between patients– Drug-related AEs – tolerability vs safety– Side effects cloud use of drugs

• Patients may not differentiate migraine from other headaches– Spectrum study indicates migraine may present with symptoms of

TTH

Discussion: study design

• Data need to be accurate– Demonstrating reliability, power and validity

• Large study size increases power and clinical relevance of the results

• Placebo responses may be different in different settings– Hospital vs primary care

• Manipulation of patient populations may be used to obtain desired effects– Relative numbers of patients and centres

• Different study designs may lead to differences in results– cf ‘Glaxo’ type sumatriptan studies with those used in

comparators with domperamol and tolfenamic acid

Post hoc endpoints

Post hoc endpoints

• Meta-analyses

• Therapeutic gain (TG)

• Number needed to treat (NNT)

• Number needed to harm (NNH)

• Ad hoc analyses– e.g. nausea

Goadsby PJ. Can J Neurol Sci 1999;26(Suppl 3):S20-6.

Efficacy: Therapeutic Gain (TG)

Therapeutic gain =

Proportion of patients benefiting

on treatment

Proportion of patients

benefitingon placebo

—

Goadsby PJ. Can J Neurol Sci. 1999;26(Suppl 3):S20-S26.

Efficacy: Number Needed to Treat (NNT)

Number Needed to Treat =

Proportion of patients benefiting

on treatment


benefitingon placebo

—

100

Goadsby PJ. Can J Neurol Sci. 1999;26(Suppl 3):S20-S26.

Tolerability: Number Needed to Harm (NNH)

NumberNeeded toHarm =


with adverse events

on treatment

Proportion of patients with

adverse eventson placebo

—

100

Goadsby PJ. Can J Neurol Sci .1999;26(Suppl 3):S20-S26.

Dr Shaun [email protected]

GCPL Pharmacology : Royal Surrey County Hospital

Pain clinic : Royal Surrey County Hospital

Lawrencian Clinical: 1) Short Pain Inventory 2) objective marker of pain

Society of Pharmaceutical Medicine. Chairman

Insights into endpoints

Headache measures vary in accuracy

• Accuracy = Reliability x Power x Validity– Outcome measures need to exhibit these

features• Importance on coefficient of variance

Face analogue scale

0 1 2 3 4

•Five-point scale favoured in most therapy areas

•cf migraine 4-point scales

Visual analogue & Likerts

NONEEXTREME PAIN

•Difficult to deduce clinical significance from changes observed

•Need for simple, intuitive measures

NNT based upon

% of patients achieving a criterion

e.g.

% of patients with 50% reduction in pain or no pain

Placebo response & NNT

PLACEBO RESPONSE

Mean plot

NNT55%

NNT25%

NNT75%

.5.4.3.2.1

25

15

5

-5

-15

-25

NNT

•NNT varies with the placebo response

•Problematic in areas where a variable placebo rate is likely, e.g. migraine

Discussion: post hoc endpoints

• Post hoc endpoints (TG, NNT, NNH) may not provide clinically relevant information

• Placebo response affects NNT• High therapeutic response → little effect• Low therapeutic response → significant

effect

Discussion: 7 points for the critical appraisal of clinical trial data and detail aids

What to look out for• At least 50 patients per treatment group• Patient numbers equal in active and placebo arms• NNT must have 95% confidence interval• Drop-outs from trial ≤ 10%• Drop-outs from trial must be same in active and

placebo arms• Outcome measures use Likert, not visual analogue

scales• Speed of onset, duration of analgesia and normal

coping / functioning well are needed for clinical relevance.

Clinical trial data on the triptans and other acute medications

Quality of clinical evidence

• Grade A: Consistent evidence from multiple, well-designed, randomised clinical trials, systematic meta-analyses

• Grade B: Poorer quality clinical trial evidence; non-systematic meta-analyses

• Grade C: Opinion and practice in the absence of objective evidence

Matchar DB et al. Neurology 2000;54.

Comparing the oral triptans: headache relief (Grade A)

0

1020

30

4050

60

7080

90

Suma100mg

Suma50 mg

Zolmi2.5 mg

Riza10 mg

Ele 40mg

Almo12.5mg

Nara2.5 mg

Frova2.5 mg

Lowest

Highest

Pat

ien

ts (

%)

Dowson AJ et al. Curr Med Res Opin 2002;18:414-39

Comparing the ODT and oral triptans: headache relief (Grade A)

0

10

20

30

40

50

60

70

80

90

Zolmi 2.5 mgoral

Zolmi 2.5 mgODT

Riza 10 mgoral

Riza 10 mgODT

Lowest

Highest

Pat

ien

ts (

%)


Comparing the non-oral triptans: headache relief (Grade A)

0

10

20

30

40

50

60

70

80

90

Suma 6 mg SC Suma 20 mg NS Zolmi 5 mg NS

Lowest

Highest

Pat

ien

ts (

%)


Head-to-head comparator trials with oral triptans (Grade A)

Zolmitriptan versus sumatriptan

0

10

20

30

40

50

60

70

Zolmi 2.5 mgn = 500

Zolmi 5 mgn = 514

Suma 50 mgn = 508

Hea

dac

he

resp

on

se a

t 2

h (

% p

atie

nts

)

Gruffydd-Jones K et al. Eur J Neurol 2001;8:237-45.

NSNS

NS


Rizatriptan versus sumatriptan (n = 1,268)

Hea

dac

he

resp

on

se a

t 1

h (

% p

atie

nts

)

0

5

10

15

20

25

30

35

40

Riza 10 mg Suma 100 mg

**

** p=0.01

Tfelt-Hansen P et al. Headache 2000;40:748-55.


Rizatriptan versus naratriptan (n = 522)

Pai

n f

ree

at 2

h (

% p

atie

nts

)

0

5

10

15

20

25

30

35

40

45

50

Riza 10 mg Nara 2.5 mg

***

*** p<0.001

Bomhof M et al. Eur Neurol 1999;42:173-9.


Almotriptan versus sumatriptan

Hea

dac

he

reli

ef a

t 2

h (

% p

atie

nts

)

0

10

20

30

40

50

60

70

Almo 12.5 mgn = 591

Suma 50 mgn = 582

NS

Spierings EL et al. Arch Neurol 2001;58:944-50.


Eletriptan versus sumatriptan

Hea

dac

he

reli

ef a

t 2

h (

% p

atie

nts

)

0

10

20

30

40

50

60

70

80

Ele 40 mg Suma 100 mg Ele 40 mg Suma 100 mg

NS ***

*** p<0.001

a. (n = 692) b. (n = 2.113)

a. Goadsby PJ et al. Neurology 2000;54:156-63.

b. Mathew NT et al. Headache 2003;43:214-22.

Perspective on eletriptan comparator studies

• Sumatriptan encapsulated in these studies– But marketed as film-coated tablet

• Studies show that sumatriptan absorption is compromised on encapsulation1

• Because of this, ABPI does not allow Pfizer to use these comparative data in its UK detail aids

1. Fuseau E et al. Clin Ther 2001;23:242-51.


Triptans versus ergotamine plus caffeine

0

10

20

30

40

50

60

70

Suma 100 mg Erg 2 mg Ele 40 mg Erg 2mg

Hea

dac

he

reli

ef a

t 2

h (

% p

atie

nts

)

***

***a. (n = 580) b. (n = 733)

*** p<0.001

a. Study Group. Eur Neurol 1991;31:314-22.

b. Diener HC et al. Eur Neurol 2002;47:99-107.

Perspective on triptan-Cafergot comparator studies

• Oral ergotamine formulations have poor bioavailability and suboptimal efficacy

• Parenteral formulations of ergotamine are superior to oral– Rectal– Injection

Matchar DB et al. Neurology 2000;54.


Triptans versus aspirin plus metoclopramide

Hea

dac

he

reli

ef a

t 2

h (

% p

atie

nts

)

0

10

20

30

40

50

60

Suma 100 mg A+M 900+10mg

Zolmi 2.5 mg A+M 900+10mg

NS

NS

a. (n = 358) b. (n = 666)

a. Study Group. Eur Neurol 1992;32:177-84.

b. Geraud G et al. Eur Neurol 2002;47:88-98.

Conclusions from Grade A clinical data - 1

• All oral triptans are effective and well tolerated– Naratriptan and frovatriptan seem to be less

effective than the other triptans– Sumatriptan, zolmitriptan, rizatriptan, almotriptan

and eletriptan have similar efficacy profiles• Differences are numerically small and of uncertain

clinical significance

• Subcutaneous and nasal spray formulations are more effective and faster-acting than the oral formulations

Conclusions from Grade A clinical data - 2

Conventional clinical trial endpoints:

• Do not effectively distinguish triptans from some other acute medications– e.g. Aspirin plus metoclopramide

• Use artificial criteria that may not be applicable in clinical practice– Should / will patients wait till the headache

is moderate to severe before treating?

Caveats from Grade A evidence

• Suppressing of data– Only positive studies published

• Manipulation of formulations– Encapsulation issues in eletriptan studies

• Dose-response effects– Naratriptan and frovatriptan not used at doses equivalent to

other triptans– Some patients take up to 4 naratriptan tablets per attack to

achieve a satisfactory response• Suboptimal dosing schedules• Suboptimal endpoints• Diagnosis issues (migraine or CDH?)• Idiosyncratic responses

– Different results with rizatriptan in eastern and western Europe

Post hoc comparisons between the triptans (Grade B)

Meta-analyses

• Tfelt-Hansen et al

• Belsey

• Ferrari et al

• Economic analyses (Williams et al)

Comparing the triptans: Therapeutic gain (Grade B)

0

10

20

30

40

50

60

Suma6 mgSC

Suma50 mg

po

Zolmi2.5 mg

po

Riza10 mg

po

Almo12.5

mg po

Ele 40mg po

Nara2.5 mg

po

Frova2.5 mg

po

Tfelt-Hansen P et al. Drugs 2000;60:1259-87.

Pat

ien

ts (

%)

Efficacy: Therapeutic Gain for pain-free 2 hours post-dose (Grade B)

0% 5% 10% 15% 20% 25% 30% 35%

Eletriptan 20 mg

Naratriptan 2.5 mg

Zolmitriptan 2.5 mg

Sumatriptan 50 mg

Sumatriptan 100 mg

Almotriptan 12.5 mg

Rizatriptan 5 mg

Eletriptan 40 mg

Zolmitriptan 5 mg

Eletriptan 80 mg

Rizatriptan 10 mg

Therapeutic gain

Belsey JD. J Clin Res. 2001;4:105-27.

Efficacy: Number Needed to Treat for pain-free response (Grade B)

1 2 3 4 5 6 7 8 9 10

Eletriptan 20 mg

Naratriptan 2.5 mg

Zolmitriptan 2.5 mg

Sumatriptan 50 mg

Sumatriptan 100 mg

Almotriptan 12.5 mg

Rizatriptan 5 mg

Eletriptan 40 mg

Zolmitriptan 5 mg

Eletriptan 80 mg

Rizatriptan 10 mg

NNT


Tolerability: Number Needed to Harm for any adverse event (Grade B)

1 11 21 31 41 51 61 71

Naratriptan 2.5 mg

Almotriptan 12.5 mg

Eletriptan 20 mg

Sumatriptan 50 mg

Eletriptan 40 mg

Rizatriptan 5 mg

Zolmitriptan 2.5 mg

Rizatriptan 10 mg

Sumatriptan 100 mg

Eletriptan 80 mg

Zolmitriptan 5 mg

NNH

Belsey JD. J Clin Res.2001;4:105-27.

Integrating efficacy and tolerability data (Grade B)

0%

5%

10%

15%

20%

25%

30%

35%

10% 15% 20% 25% 30% 35%

Sumatriptan 100 mg

Rizatriptan 10 mg

Eletriptan 80 mg

Zolmitriptan 5 mg

Zolmitriptan 2.5 mg

Almotriptan 12.5 mg

Sumatriptan 50 mg

Tolerability(Therapeutic penalty)

Eletriptan 40 mg +Rizatriptan 5 mg

Naratriptan 2.5 mg

Eletriptan 20 mg

Efficacy (Therapeutic gain)


Headache relief at 2 hours (Grade B)

40

50

60

70

80

25 50 100 2.5 5 2.5 5 10 20 40 80 12.5

Hea

dach

e re

lief

at 2

h (

%)

Suma Zolmi Nara Riza Ele Almo

Ferrari MD, et al. Lancet. 2001;358:1668-75.

Pain-free at 2 hours (Grade B)

0

10

20

30

40

50

25 50 100 2.5 5 2.5 5 10 20 40 80 12.5

Pai

n-fr

ee a

t 2

h (%

)



Sustained pain-free (Grade B)

0

5

10

15

20

25

30

25 50 100 2.5 5 2.5 5 10 20 40 80 12.5

Sus

tain

ed p

ain-

free

(%

)



Incidence of any adverse event: Placebo subtracted data (Grade B)

-20

-10

0

10

20

30

40

25 50 100 2.5 5 2.5 5 10 20 40 80 12.5

An

y ad

vers

e ev

ent

(%)

- P

lace

bo



24-Hour Consistency Drug Studied vs Sustained AcrossSumatriptan 2-Hour Pain Pain-Free Migraine100 mg Relief (1 pill only) Attacks Tolerability

Suma 50 mg = = =/- =Suma 25 mg - =/- - +Zolmi 2.5 mg = = = =Zolmi 5 mg = = = =Nara 2.5 mg - - - ++Riza 5 mg = = = =Riza 10 mg + + ++ =Ele 20 mg - - - =Ele 40 mg =/+ =/+ = =Ele 80 mg +(+) + = -Almo 12.5 mg = + + ++

Overall comparison (Grade B)

Based on the results of the present meta-analysis and the direct comparator trials. = indicates no difference when compared with sumatriptan. + indicates better when compared with sumatriptan. - indicates inferior when compared with sumatriptan


Cost-effectiveness analysis

0

20

40

60

80

100

120

140

160

180

Almo 12.5 mg Riza 10 mg Suma 50 mg Suma 100 mg

Co

st-e

ffec

tive

nes

s ra

tio

($U

S)

Cost-effectiveness ratio per attack for sustained pain relief and no adverse events

Williams P, Reeder CE. Am J Manag Care 2003; in press.

Williams P, Reeder CE. Clin Ther 2003; in press.

Overview of meta-analyses of the oral triptans (Grade B)

• All oral triptans were effective and well tolerated– More similarities than differences between

the drugs

• Rizatriptan 10 mg exhibited the best efficacy

• Naratriptan 2.5 mg and almotriptan 12.5 mg exhibited the best tolerability

Discussion: perspective on the meta-analyses

• The different meta-analyses do not provide consistent data– Selection of studies, patient populations and

endpoints differ– Bandolier could not repeat results from Ferrari et

al meta-analysis

• Timing of dosing important• Power and timing of endpoints important

– Data dredging?

• ‘Economy with the truth’?

Acute treatments in clinical practice versus clinical trials

Overview

• Efficacy in clinical practice

• Early treatment

• Dose optimisation

• Sensitivity of endpoints

Efficacy in clinical practice

• In general, triptans seem to be more effective in clinical practice than in clinical trials– Different populations of patients

• Greater proportion of women• CDH patients may be included in trials

– Country differences– Primary care versus secondary care

• Need for long-term naturalistic studies conducted with prescription formulations and doses

Sumatriptan in clinical practice

0

10

20

30

40

50

60

70

80

90

Suma 25 mgn = 285

Suma 50 mgn = 2,053

Suma 100 mgn = 1,522

4-h

res

po

nse

(%

Att

acks

)

Dowson AJ et al. IJCP 1999;Suppl 105:25-33.

No. of patients = 338

Zolmitriptan in clinical practice

0

10

20

30

40

50

60

70

80

90

Zolmi 2.5 mg Zolmi 5 mg

Pain-free

Headache relief

2-h

res

po

nse

(%

Att

acks

)

Tepper SJ et al. Curr Med Res Opin 1999;15:254-71.

No. of patients = 2,499

Rizatriptan in clinical practice

0

10

20

30

40

50

60

70

80

Riza 10 mg tab Riza 10 mgMLT

Usual therapy

Symptom-free

Headache relief

2-h

res

po

nse

(%

Att

acks

)

Jamieson D et al. Headache 2003;43:223-30.


Early treatment: Optimising timing of dosing

• Recent evidence indicates that triptans work optimally if taken when the headache is mild early in the attack– Sumatriptan– Zolmitriptan– Rizatriptan– Almotriptan

• Clinical and cost-effectiveness data

Zolmitriptan: Pain-free response at 2 hours treating mild headache

43

18

n=136 n=141

Pa

in-f

ree

res

po

nse

(%

pa

tien

ts) ***

*** p<0.0001 versus placebo

n=no. of patients evaluated

0

20

40

60Zolmitriptan 2.5 mg Placebo

Dose optimisation

• Patients may require lower or higher than recommended doses to achieve an optimal response– Sumatriptan– Zolmitriptan– Naratriptan / frovatriptan

• Marketed doses may not be comparable due to dose-response effects

Patient selection of optimal dose:Sumatriptan

0

10

20

30

40

50

60

70

Suma 25 mg Suma 50 mg Suma 100 mg

Patient preference after treating 6 attacks (n = 338)

Pat

ien

ts (

%)

Dowson AJ et al. IJCP 1999;Suppl 105:25-33.

Patient selection of optimal dose:Zolmitriptan

Patient choice of 2.5 mg and 5 mg doses (n = 2,499)

0

10

20

30

40

50

60

70

Zolmi 2.5 mg Zolmi 5 mg

Att

acks

(%

)

Tepper SJ et al. Curr Med Res Opin 1999;15:254-71.

Sensitivity of endpoints

• For regulatory purposes, clinical trial endpoints are designed to show significant differences between active drug and placebo– They may be relatively insensitive in

distinguishing between two active drugs

• They are probably not appropriate for use in clinical practice, where more sensitive endpoints may be required

Alternative endpoints

• Patient preference

• Impact questionnaires

• Cost effectiveness

• Qualitative endpoints

Patient preference

• Global measure of efficacy and tolerability

• In studies, patients consistently prefer oral triptans over non-triptan acute medications

• Patients also prefer individual oral triptans over other oral triptans– But responses may be idiosyncratic

Sumatriptan versus ‘usual’ non-triptan therapies

0

10

20

30

40

50

60

70

80

Sumatriptan 50 mg Non-triptan No preference

Kwong WJ et al. Cephalalgia 2001;21:411.

Pat

ien

ts (

%)


‘Triptans’ versus ‘usual’ non-triptan therapies

0

10

20

30

40

50

60

Triptans Non-triptans Both No preference

Pat

ien

ts (

%)

Robbins L. Cephalalgia 2001;21:406.


Sumatriptan 50 mg versus zolmitriptan 2.5 mg tablets

Pat

ien

ts (

%)

0

5

10

15

20

25

30

35

40

45

50

Suma 50 mg Zolmi 2.5 mg No preference

Pascual J et al. Cephalalgia 2001;21:680-4.


Sumatriptan 50 mg tablets versus rizatriptan 10 mg ODT

Pat

ien

ts (

%)

0

10

20

30

40

50

60

Suma 50 mg Riza 10 mg

**

** p<0.01

Loder E et al. Headache 2001;41:745-53.


Zomitriptan ODT versus sumatriptan tablet

*

* p<0.05 versus sumatriptan tablet

60.1

39.9

0

10

20

30

40

50

60

70

Pat

ien

ts (

%)

Zolmitriptan 2.5 mg ODT

Sumatriptan 50 mg tablet

Zolmitriptan ODT versus rizatriptan ODT

Source: CIMA Patient Preference Study 2001 (West Pharmaceutical Services)

Re

sp

on

de

nts

(%

)

Prefer Zomig Rapimelt

Prefer Rizatriptan MLT

No preference27%

3%

70%

0%

20%

40%

60%

80%

Overall reasons for preference

• Rapid relief

• Effective relief

Discussion: patient preference

• May not be sensitive to subtleties of pain

• Some lapsed consulters said they preferred OTC drugs to triptans

Impact questionnaires

• MIDAS

• HIT

• Only MIDAS has so far shown sensitivity to change

• SPI

Efficacy of zolmitriptan 2.5 mg tablet assessed with MIDAS

0

5

10

15

20

25

30

35

40

Baseline After treatment

MID

AS

sc

ore

Torres G et al. Poster at 53rd AAN, 2001.


Change in MIDAS following primary care interventions

0

2

4

6

8

10

12

14

16

Baseline 6-mo care

MID

AS

sc

ore

Main A et al. Curr Med Res Opin 2002;18:471-8.

*

* p<0.05


Short Pain Inventory©

• Developed by Dr Shaun Kilminster

• A 17-item self rating questionnaire

• ‘measuring the whole pain disturbance’

• Potential new endpoint for headache studies

SPI© subscales

• Pain severity • Social interaction • Anxiety • Anger • Sadness• Sedation

• TOTAL PAIN DISTURBANCE 17 items

• TOTAL MOOD DISTURBANCE 14 items

SPI© subscales that correlate directly with level of headache severity

Mood changes

• Social interaction

• Sedation

• Sadness

• Anger

• Anxiety

• Total mood disturbance (TMD)

SPI©: correlation of Total Mood Disturbance and Headache Pain (n = 75)

SPI: TOTAL MOOD DISTURBANCE (TMD)

HEADACHE SEVERITY

-1.96*SE

-SE

Mean

+SE

+1.96*SE

43210

55

50

45

40

35

30

25

20

15

10

SPI©: Conclusions

• How the patient feels about their headache impacts on mood and vice versa

• SPI is a reliable, valid and discriminatory measure of headache severity

• SPI has high potential utility in headache research– Likely to be a highly-sensitive endpoint for clinical

trials– Naturalistic studies in clinical practice underway

Cost-effectiveness

• Compared to placebo and non-triptan acute medications, triptans:– Improve quality of life– Increase workplace productivity– Reduce healthcare costs

Rizatriptan versus usual therapies: improvements in QOL

0

2

4

6

8

10

12

14

16

Workfunct

Energy Symptoms

Rizatriptan 10 mg

Usual medications

Social funct Feelings

Gerth WC et al. Clin Drug Invest 2001;21:853-60.

24-h Migraine-Specific QOL Questionnaire (n = 265)

* * ** *****

* p≤0.05

** p<0.01

*** p<0.001

Workplace productivity loss following treatment of migraine with sumatriptan or

placebo

0

10

20

30

40

50

60

70

80

Sumatriptan 6 mg sc(n = 76)

Placebo(n = 40)

Tim

e/d

ay

(m

in)

***

*** p<0.001

Schulman EA et al. Mayo Clin Proc 2000;75:782-9.

Cost-effectiveness analysis in Canada

• Sumatriptan tablets versus ergotamine plus caffeine tablets

• Economic benefit in favour of sumatripan– $98 saved per attack aborted– Cost-utility ratio = $29,366 per QALY

Evans KW et al. Pharmacoeconomics 1997;12:565-77.

Qualitative endpoints

Michele PetersUniversity of Surrey, Guildford

Qualitative research

• Objective: to increase the understanding of patients and physicians

• Processes through interviews– Decision trees– Working through attacks– Patient-doctor behaviour and its evolution

over time– Explaining the variations in patient

responses

Qualitative research in clinical trials programmes

• MRC advises the use of qualitative research in clinical trials

• Phase I (modelling, not preclinical)

• Pre- classic Phase II, III and IV clinical trials

• Study of behaviours:– Doctor-nurse– Doctor-patient

MRC. A framework for development and evaluation of RCTs for complex interventions to improve health; 2000.

What can qualitative research investigate?

• Why does an intervention have therapeutic benefit?– Testing underlying assumptions– Effect of inappropriate beliefs– Active and non-active elements of

intervention– Groups of patients likely or not likely to

respond• Mitigates against no effect results


Qualitative research: methodology

• Group interviews (focus groups)

• Individual in-depth interviews

• Observational research

• Organisational case studies

• Quantitative surveys may also be used



• Pilot studies with small numbers of people can increase understanding of issues

• Interviews can give insight into validity of likely trial results– Patient compliance– Importance of placebo response

• Cf:– Interviews are qualitative– Factor analysis is quantitative


• New way of analysing headache issues

• Investigating patient feelings

• Studies needed on how to deliver care– PCT clinics– GPs with a special interest in headache

(GPWSIH)1

1. Department of Health. www.doh.gov.uk/pricare/gp-specialinterests/headache.pdf

Summary

• Clinical trials may not reflect clinical practice due to different:– Populations of patients– Treatment modalities used– Timings of treatment– Primary versus secondary care sites

• Clinical trial endpoints often do not differentiate between treatments

Future needs

• Qualitative research to set the agenda– Patient-doctor behaviour– Doctor-nurse behaviour

• Study the whole range of management options– Pharmacological and non-pharmacological

• Conduct naturalistic studies• Develop more sensitive endpoints• Develop an objective test for pain

– Blood test?

MIGRAINE IN PRIMARY CARE ADVISORS Guildford, 1 May 2003, 2-6 pm Understanding the evidence in...

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