Annexes to Chapter 5: Preliminary Results
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Annexes to 5.4
Preliminary Results
15 September 2004
Table of ContentsAnnex 5.4A: Drug to Drug Comparisons
Annex 5.4B: Balancing Risks and Benefit: A preliminary attempt at quantification
Annex 5.4A: Drug to Drug Comparisons
We found 187 drug to drug comparisons in Clinical Evidence that dealt with interventions for diseases on the preliminary “priority” list. Twenty four (12.8%) of these were multiple comparisons (e.g., drugs A,B,C, wherein A v. B, A v C, B v. C). Of the total comparisons, forty eight (48/187= 25.6%) showed significant differences ( at the 95% confidence level) in clinical efficacy between one intervention and another (i.e., between drug A v. B or all combinations of several drugs compared two at a time). A full 75% of these 187 comparisons revealed no significant difference in clinical efficacy between all of the drugs tested. A table showing the comparisons that showed NO statistically significant differences is found in Table 5.4A1 and a table showing the remaining significant comparisons is in Table 5.4A2.
Clinical Evidence itself performed a related analysis and found that a “quick scan” of the 1851 treatments in volume 10 revealed that 270 treatments (15%) were beneficial and 1050 (56%) were either unlikely to be beneficial, likely to be ineffective or of unknown effectiveness.
Annex Table 5.4.A1 Comparative Trials- NO Difference between Interventions
Intervention 1 / Intervention 2 / OutcomeAcute/ Chronic
Conditions
Acute otitis media / Cephalosporins / among each other / Middle ear effusion at 30 days
Acute otitis media / Erythromycin / among each other
Acute otitis media / Penicillin / among each other
Acute otitis media / Cotrimoxazole / among each other
Acute otitis media / Penicillin / ampicillin or amoxycillin / Clinical failure rate 7-14 days
Acute otitis media / Cefaclor / ampicillin or amoxycillin / Clinical failure rate 7-14 days
Chronic otitis media / gentamicin / trimethoprim/polymyxin
Chronic otitis media / gentamicin / colistin/neomycin/hydrocortisone
Chronic otitis media / ciprofloxacin / gentamicin
Chronic otitis media / ciprofloxacin / tobramycin
Chronic otitis media / nebulized adrenaline / nebulized salbutamol / Clinical scores
Acute sinusitis / newer non penicillins / amoxicillin / Clinical resolution rate
Acute sinusitis / azithromycin / cefaclor / Clinical resolution rate
Acute sinusitis / TMP/SMX / pentamidine / toxoplasmosis
Acute sinusitis / TMP/SMX / dapsone / PCP incidence
Acute sinusitis / TMP/SMX / dapsone / toxoplasmosis
Acute sinusitis / atovaquone / dapsone / PCP incidence
Acute sinusitis / atovaquone / aerolsolized pentamidine / PCP incidence
Acute sinusitis
Malaria / chloroquine / quinine / Mortality
Malaria / Artemether / quinine / Mortality
Malaria / Artemether / quinine / Mortality
bipolar / Lithium / haloperidol / Remission of symptoms-3 wks
bipolar / Llithium / olanzapine / Rating score at 28 days
bipolar / Lithium / valproate / Failure to respond
bipolar / Lithium / carbamazepine / Responders
bipolar / Lithium / carbamazepine / Global severity
bipolar / Lithium / lamotrigine / Rating score at 28 days
bipolar / Lithium / clonazepam / Symptom severity at 4 wks
Pre eclampsia and HBP / any hypertensive / any other hypertensive / Risk of HBP or pre eclampsia
Acute bronchitis / cefuroxime / amoxicillin / Clinical cure-10-14 days
Acute bronchitis / cefuroxime / amoxicillin/clavulinic acid / Clinical cure-10-14 days
Acute bronchitis / cefuroxime / amoxicillin/clavulinic acid / Clinical cure-1-3 days
Acute bronchitis / cefuroxime / cefixime / Clinical cure-14 days
Acute bronchitis / cefuroxime / cefpodoxime / Clinical cure-10 days
Acute bronchitis / azithromycin / clarithromycin / Clinical cure- 7 days
Acute bronchitis / Roxithromycin / amoxicillin / Clinical cure
Acute bronchitis / ipratropium / salmeterol / FEV
Bronchiolotis / nebulized adrenaline / nebulized salbutamol / "Clinical score"
inhaled adrenaline / nebulized salbutamol / Oxygen saturation
P. carinii pneumonia / TMP/SMX / pentamidine / PCP incidence
TMP/SMX / dapsone / PCP incidence
Invasive fungal infections / itraconazole / fluconazole / cryptococcal meningitis relapse
Malaria / chloroquine / quinine / Fever clearance time
Malaria / Fansidar / quinine / Mortality
Fansidar / quinine / Parasite clearance
Eclampsia / magnesium sulfate / phenytoin / Prevention of eclampsia
Pre term labor / calcium channel blockers / beta agonists / Delayed delivery
beta agonists / oral erythromycin / Reduce cough
Chronic Conditions
Acute Myocardial Infarction / Streptokinase / tPA / Any stroke or death
Acute Myocardial Infarction / recombinant PA / tPA / Total 30 day mortality
Acute Myocardial Infarction / variant of tPA / tPA / Total 30 day mortality
Acute Myocardial Infarction / tPA / tPA + mab / All cause 30 day mortality
Acute Myocardial Infarction / tPA + heparin / tPA + mab / All cause 30 day mortality
Ischaemic heart disease- Secondary prevention / ticlopidine / aspirin / Serious vascular event
Ischaemic heart disease- Secondary prevention / oral anticoagulants / aspirin / Mortality, stroke, MI
clopidogrel / aspirin / Serious vascular event
ticlopidine or clopidogrel / aspirin / Serious vascular event
Ischaemic heart disease- Primary prevention(HBP) / diuretics / beta blockers / death, stroke,
Ischaemic heart disease- Primary prevention(HBP) / ACE inhibitors / diuretics or beta blockers / death, stroke,
Ischaemic heart disease- Primary prevention(HBP) / Ca channel blockers / diuretics or beta blockers / death, stroke,
Ischaemic heart disease- Primary prevention(HBP) / ACE inhibitors / Ca channel blockers / death, stroke,
Cardiovascular events / dipyridamole + aspirin / aspirin / Serious vascular event
Cardiovascular events / ticlopidine / aspirin / Serious vascular event
Cardiovascular events / clopidogrel / aspirin / Serious vascular event
Bipolar disorder / Valproate / haloperidol / Failure to respond
Bipolar disorder / Valproate / carbamazepine / Failure to respond
Bipolar disorder / SSRIs / TCAs / # Responders at end of trial
Bipolar disorder / MAOI / TCAs / # Responders at end of trial
Bipolar disorder / Lithium / valproate / RELAPSE-12 mos
Bipolar disorder / Lithium / carbamazepine / RELAPSE-12-36 mos
Bipolar disorder / Lithium / lamotrignine / RELAPSE- 6 mos
Dementia / Donepezil / rivastigmine / Cognition in Alzheimer
Dementia / Haloperidol / rivastigmine / Efficacy
Dementia / diazepam / among each other / Efficacy
Dementia / thioridazene / among each other / Efficacy
Dementia / loxapine / among each other / Efficacy
Dementia / oxazepam / among each other / Efficacy
Depression- mild to moderate / TCAs / SSRIs / Overall efficacy
TCAs / SSRIs / Overall efficacy
Generalized anxiety disorder
benzodiazepines / alprazolam / bromazepam / Anxiety scores
alprazolam / mexazolam / Anxiety scores
buspirone / diazepam / Reduction in anxiety scores
hydroxyzine / buspirone / Reduction in anxiety scores
antidepressants / imipramine / trazodone / Global improvement-8 weeks
opipramol (TCA) / alprazolam / Response rate- 28 days
imipramine / diazepam / Global improvement- 8 weeks
trazodone / diazepam / Global improvement- 8 weeks
venlafaxine / buspirone / Response rate-8 weeks
venlafaxine / haloperidol / Response rate
Schizophrenia / depot bromperidol / haloperidol / Needing additional meds
Schizophrenia / depot bromperidol / fluphenazine … / Needing additional meds
Schizophrenia / depot haloperidol / oral haloperidol / % not improving
Schizophrenia / Amisulpride / olanzapine / Symptoms
Schizophrenia / Amisulpride / risperidone / Symptoms
Schizophrenia / Loxapine / chlorpromazine / Global improvement
Schizophrenia / Molindone / haloperidol OR chlorprom.. / Global improvement
Schizophrenia / Olanzapine / haloperidol / Symptom reduction
Schizophrenia / Olanzapine / risperidone / Scores at 54 weeks
Schizophrenia / Perazine / haloperidol / % Improving at 28 days
Schizophrenia / Pimozide / standard antipsychotics / Global impression- 30-90 days
Schizophrenia / pimozide / standard antipsychotics / Global impression-120-180 days
Schizophrenia / quetiapine / haloperidol / Improvement score
Schizophrenia / sulpride / halo OR chlor or perphenazine / Improvement score
Schizophrenia / ziprasidone / haloperidol / Improvement score
Schizophrenia- relapse rates / oral fluphenazine / depot fluphenazine / Relapse
Schizophrenia- relapse rates / depot haloperidol / other depots / Relapse
Schizophrenia- relapse rates / flupenthixol / other depots / Relapse
Schizophrenia- relapse rates / pipotiazine / other depots / Relapse
Schizophrenia- relapse rates / pipotiazine / oral antipsychotics / Relapse
Schizophrenia- relapse rates / fluspirilene / oral chlorpromazine / Relapse
Schizophrenia- relapse rates / pimozide / standard antipsychotics / Relapse
Schizophrenia- relapse rates
Schizophrenia- relapse rates / Lithium / chlorpromazine / Remission of symptoms-3 wks
Schizophrenia- relapse rates / Llithium / risperidone / Severity score-4 wks
Schizophrenia- relapse rates / Lithium / clonazepam / Motor activity
Schizophrenia- relapse rates / Valproate / olanzapine / Symptom reductions
Schizophrenia- relapse rates / Lithium / haloperidol / Remission of symptoms-3 wks
Schizophrenia- relapse rates / Llithium / olanzapine / Rating score at 28 days
Schizophrenia- relapse rates / Lithium / valproate / Failure to respond
Schizophrenia- relapse rates / Lithium / carbamazepine / Responders
Schizophrenia- relapse rates / Lithium / carbamazepine / Global severity
Schizophrenia- relapse rates / Lithium / lamotrigine / Rating score at 28 days
Schizophrenia- relapse rates / Lithium / clonazepam / Symptom severity at 4 wks
olanzapine / risperidone / Scores at 28 weeks
perazine / zotepine / % Improving at 28 days
risperidone / haloperidol / Improvement score
risperidone / haloperidol / Improvement score
zotepine / haloperidol / Improvement score
zuclopenthixol / other depots / Relapse
clozapine / standard antipsychotics / Relapse
bromperidol / haloperidol / Relapse
COPD / tiotropium / ipratropium / FEV
(inhaled anticholinergics) / tiotropium / ipratropium / QOL at 1 year
ipratropium / beta agonists / FEV
ipratropium / salmeterol / FEV
ipratropium / formoterol / FEV
tiotropium / salmeterol / FEV
gemcitabine+vinorelbine / vinorelbine alone / Survival 14 months
gemcitabine+cisplatin / cisplatin alone / Survival
cisplatin+vinorelbine / cisplatin alone / Survival
gemcitabine / cisplatin+vindesine / Clinical benefit
Small cell LC / oral etoposide / combination chemo / Survival
oral etoposide / combination chemo / Survival
anastrozole / tamoxifen / Disease progression
letrozole / tamoxifen / Disease progression
anastrazole / megestrol / Survival 31 months
exemestane / megestrol / Survival time
letrozole / megestrol / Time to Tx failure
letrozole / aminoglutethimide / Time to Tx failure
azathioprine, D penicillamine
Stage 4 NSCLC / Pt analog + vinorelbine / either Tx alone / Survival 1 year
Stage 4 NSCLC / cisplatin+etoposide / gemcitabine / Survival
Stage 4 NSCLC / docetaxel+cisplatin / docetaxel+gemcitabine / Survival
Stage 4 NSCLC / paclitaxel+carboplatin / paclitaxel+gemcitabine / Survival
Stage 4 NSCLC / paclitaxel+carboplatin / paclitaxel+gemcitabine / Survival
Colorectal cancer / FU + levamisole / FU alone / Recurrence or death
Metastatic breast cancer / methoxyprogesterone / tamoxifen / Survival
Metastatic breast cancer / methoxyprogesterone / tamoxifen / Survival
Metastatic breast cancer / anastrozole / tamoxifen / Survival
Metastatic breast cancer / anastrazole / fulvestrant / Disease progression
Metastatic breast cancer / anastrazole / fulvestrant / Disease progression
Metastatic breast cancer / doxorubicin+paclitaxel / doxorubicin+cyclophosphamide / Survival
Metastatic breast cancer / docetaxel / 5FU+ vinorelbine / Survival
Metastatic breast cancer / capecitabine / paclitaxel / Survival
Osteoarthritis / paracetamol / oral NSAIDS / Pain relief
Osteoarthritis / topical NSAID (piroxicam) / oral NSAID (ibuprofen) / Pain relief
Rheumatoid Arthritis / methotrexate / leflunomide / Reducing joint inflammation
Rheumatoid Arthritis / methotrexate / parenteral gold / Reducing joint inflammation
Rheumatoid Arthritis / methotrexate / parenteral gold / joint scores
Rheumatoid Arthritis / antimalarials / methotrexate, auranofin, sulfasalazine / Efficacy/harm trade offs
Rheumatoid Arthritis / sulfasalazine / hydroxychloroquine / # swollen joints
Rheumatoid Arthritis / sulfasalazine / penicillamine / functional status- 12 years!!
Rheumatoid Arthritis / parenteral gold / antimalarials, methotrexate, auranofin / Efficacy/harm tradeoffs
Rheumatoid Arthritis / parenteral gold / methotrexate / Assessment scores
Rheumatoid Arthritis / parenteral gold / cyclosporin / Assessment scores
Rheumatoid Arthritis / auranofin / antimalarials, methotrexate, sulfasalazine / Efficacy/harm tradeoffs
Rheumatoid Arthritis / auranofin / sufasalazine / Continuing with treatment
Rheumatoid Arthritis / leflunomide / methotrexate / # tender joints
Rheumatoid Arthritis / leflunomide / methotrexate / ACR20 criteria reached-12 mos
Rheumatoid Arthritis / TNF mAb- etanercept / methotrexate / ACR scores
Rheumatoid Arthritis / TNF mAb- etanercept / oral methotrexate / SF 36 QOL
Table 5.4A2: Comparative Trials
Intervention 1 / Intervention 2 / OutcomeAcute Conditions / ITALIC/UNDERLINE = intervention 1 superior
Bronchiolotis / nebulized adrenaline / nebulized salbutamol / "Clinical score"
inhaled adrenaline / nebulized salbutamol / Oxygen saturation
P. carinii pneumonia / TMP/SMX / pentamidine / PCP incidence
TMP/SMX / dapsone / PCP incidence
Malaria / chloroquine / quinine / Fever clearance time
Fansidar / quinine / Parasite clearance
Eclampsia / magnesium sulfate / phenytoin / Prevention of eclampsia
Pre term labor / calcium channel blockers / beta agonists / Delayed delivery
beta agonists / oral erythromycin / Reduce cough
Chronic Conditions
Ischaemic heart disease- Secondary prevention / clopidogrel / aspirin / Serious vascular event
Ischaemic heart disease- Secondary prevention / ticlopidine or clopidogrel / aspirin / Serious vascular event
Ischaemic heart disease- Primary prevention among hypertensives / Ca channel blockers / diuretics or beta blockers / death, stroke,
Bipolar disorder / Lithium / chlorpromazine / Remission of symptoms-3 wks
olanzapine / risperidone / Scores at 28 weeks
risperidone / haloperidol / Improvement score
risperidone / haloperidol / Improvement score
zotepine / haloperidol / Improvement score
zuclopenthixol / other depots / Relapse
clozapine / standard antipsychotics / Relapse
COPD
(inhaled anticholinergics) / tiotropium / ipratropium / FEV
tiotropium / ipratropium / QOL at 1 year
ipratropium / beta agonists / FEV
ipratropium / salmeterol / FEV
tiotropium / salmeterol / FEV
gemcitabine+vinorelbine / vinorelbine alone / Survival 14 months
gemcitabine+cisplatin / cisplatin alone / Survival
cisplatin+vinorelbine / cisplatin alone / Survival
gemcitabine / cisplatin+vindesine / Clinical benefit
Small cell LC / oral etoposide / combination chemo / Survival
anastrozole / tamoxifen / Disease progression
letrozole / tamoxifen / Disease progression
anastrazole / megestrol / Survival 31 months
exemestane / megestrol / Survival time
letrozole / megestrol / Time to Tx failure
letrozole / aminoglutethimide / Time to Tx failure
azathioprine, D penicillamine
Rheumatoid Arthritis / sulfasalazine / penicillamine / functional status- after 12 years!!
Rheumatoid Arthritis / TNF mAb- etanercept / methotrexate / ACR scores
Acute Conditions / ITALIC/UNDERLINE = intervention 2 superior
Invasive fungal infections / itraconazole / fluconazole / cryptococcal meningitis relapse
Chronic Conditions
Bipolar disorder / Llithium / risperidone / Severity score-4 wks
Bipolar disorder / Lithium / clonazepam / Motor activity
Bipolar disorder / Valproate / olanzapine / Symptom reductions
Bipolar disorder / perazine / zotepine / % Improving at 28 days
Bipolar disorder / bromperidol / haloperidol / Relapse
COPD / ipratropium / formoterol / FEV
Small cell LC / oral etoposide / combination chemo / Survival
Rheumatoid Arthritis / auranofin / antimalarials, methotrexate, sulfasalazine / Efficacy/harm tradeoffs
Rheumatoid Arthritis / auranofin / sufasalazine / Continuing with treatment
Rheumatoid Arthritis / leflunomide / methotrexate / # tender joints
Annex 5.4B: Balancing Risks and Benefit: A preliminary attempt at quantification
There is limited available data on side effect profiles of most pharmacological interventions in the Cochrane Database. The data, we believe, is not sufficient to determine which side effects are clinically important. For policy analyses, we have quantified the relative risk of side effects with the limited data available to use. We find that certain interventions, even though they are clinically efficacious have side effect profiles that suggest an unfavourable benefit/risk balance.
There are two key limitations, however, to this "balancing" analysis. First, many clinical trials found in the Cochrane database do not even report adverse events so our dataset is weak. Second, measuring the clinical effectiveness of a “harm” in a clinical trial is difficult, particularly since the more rare, but important side effects, will not be seen in a trial with few patients and run over a relatively short time period.
Figure 5.4B1 is a schematic diagram of a risk/benefit relationship for a host of interventions and a variety of diseases. Relative risk numbers on the X axis greater than 1 denote benefit (as per our convention). Adverse event relative risks on the Y axis are usually, but not always, less than 1 (as per our convention). Figure 5.4B2 presents actual data for those chronic conditions where both "adverse events" and efficacy were recorded via meta-analysis. The vast majority of these are for interventions for treating mental conditions.
From a public health viewpoint, beneficial interventions with risky side effect profiles should be investigated further. The present Project raises questions about the public health definition of “innovative R&D”. We suggest that “innovation” does not necessarily mean creating new products but might mean taking a renewed look at existing medicines- in part to improve their side effect profiles.
Figure 5.4.B1 Schematic Risk Benefit matrix
Figure 5.4B2
For each meta-analysis that has both sets of data, we have tried to estimate the balance between adverse events and clinical effectiveness. An example of a dataset is shown below in Figure 5.4B3 which shows the balance of risk and benefit for selected interventions used in treating infectious diseases.
Just as we have looked at the lower confidence interval of the relative risk ratio to count the number of times this interval falls in the zone of “no benefit” and the zone of “benefit” (see Chapter 4 of Report), we have looked at the lower confidence intervals of the adverse event relative risk ratios. For all the adverse event data that we have for a given intervention (which is admittedly sparse) we took the average lower confidence interval score as an estimator of adverse events. Since we are looking at adverse events, this interval is almost always less than 1 (as we have defined it) and we are asking, “how far away from 1 (i.e., no harm) is it?.” The further below 1 the number, the more people were affected by the particular adverse event in the clinical trial. We arbitrarily have made three zones of “adverse event” based on the average of the lower confidence interval:
Low Risk: Average lower confidence interval between 0.99 and 0.6
Medium Risk: Average lower confidence interval between 0.59 and 0.3
High Risk: Average lower confidence interval less than 0.29
Similarly, for outcomes designed to measure benefit, we took the average lower confidence interval of the relative risk ratio as a measure of a beneficial event measure. Since we are looking at purported beneficial events, this lower confidence interval should be greater than 1 for many analyses and we are also asking, “how far away from 1 (no benefit) is it?” The higher the number, the more people are positively benefited in the clinical trial. We arbitrarily have made three zones of “benefit” based on the average of the lower confidence interval:
Marginal Benefit: Average lower confidence interval between 1.01 and 1.2
Medium Benefit: Average lower confidence interval between 1.21 and 1.39
High Benefit: Average lower confidence interval greater than 1.4
We have used data generated in this way to summarize the average adverse and beneficial event measures for a variety of acute and chronic conditions, as presented below in raw data form in Tables 5.4B1 and Table 5.4B2. The benefit/ risk “index” is simply the difference of these two averages. For those interventions with "high risk" as we have defined it, small differences (column 3 in the Tables) mean that these interventions that might be marginally beneficial, but also carry the weight of potentially risky side effects.
Figure 5.4B3 Adverse Event and Benefit Measures for Acute Conditions