Therapeutics Initiative Drug Assessment Working Group Jim Wright Ken Bassett Vijaya Musini Ciprian Jauca Lorri Puil Tom Perry, Jr Keith Chambers Barbara Mintzes Maud van Breemen Benji Heran Michelle Wong Marco Perez Cremona Ticea Gurdial Mattu

A person who is deluded or deceived by another. Dupe (definition) A person who is deluded or deceived by another.

TI Objectives To attempt not to be DUPED in our assessment of the evidence. To attempt to establish the benefit/harm relationship for drug interventions in particular clinical settings.

Cox 2 inhibitors Lipid lowering drugs Bupropion Deficient reporting of Serious Adverse Events in Clinical Trials Jim Wright MD, PhD, FRCP(C) Cox 2 inhibitors Lipid lowering drugs Bupropion

Outline How to measure the benefit/harm relationship? A tool: serious adverse events. Setting where harm exceeds the benefit. Setting where benefit exceeds the harm. Setting where benefit equals harm. Settings where we don’t know.

Serious Adverse Events Deaths. Life threatening events (e.g. cancer). Hospitalizations. Events leading to prolongation of hospitalization. Events leading to permanent disability.

Serious Adverse Events Must be carefully documented and reported to regulatory authorities in all clinical trials. Total serious adverse events (SAEs) are a measure of both benefit and harm. If a particular intervention is beneficial the relative ratio (RR) of SAEs for the intervention/comparator will be <1.0

COX 2 selective inhibitors: celecoxib and rofecoxib Designed to reduce GI toxicity of non-selective NSAIDs. To be beneficial must be equally effective and have less complicated ulcers (safer than NSAIDs). Successfully marketed worldwide, therefore they must be better.

Major outcomes in order of most to least serious CLASS trial VIGOR trial Outcome Celecoxib % Other % RR 95%CI ARR % NNT 4 mo Rofecoxib % Naproxen % ARR ARI % NNT NNH 9 mo Myocardial infarction 0.3 0.9 0.4-2.1 NS 0.4 0.1 4.0 1.3-12 333 Complicated ulcers 0.6 0.6 0.3-1.2 0.9 0.4 0.2-0.8 0.5 200 Serious adverse events 4.3 4.2 1.02 0.8-1.3 NR   Symptomatic ulcers 0.7 0.65 0.4-1.2 1.0 2.1 0.5 0.3-0.7 1.1 91 Withdrawals due to adv. events 18.4 20.6 0.89 0.8-0.97 2.2 44 16.4 16.1 1.02 0.9-1.1 * * Half ibuprofen and half diclofenac RR=Risk Reduction CI=confidence Interval ARR=Absolute Risk Reduction NNT=Number Needed to Treat to prevent one event ARI=Absolute Risk Increase NNH=Number Needed to cause one Harmful event NS=Non-Significant, NR=Not Reported

FDA review of CLASS and VIGOR studies No change in labeling. Data made available on FDA website. CLASS study in JAMA; one trial, 6 months. FDA trial protocols: 2 trials, one 12-month (diclofenac) and one 15 month (ibuprofen).

Diclofenac + Ibuprofen FDA review of CLASS trials Outcome Celecoxib (n=3987) % Diclofenac + Ibuprofen (n=3981) RR (95% CI) Serious adverse events 6.8 5.8 1.17 (0.99, 1.39) Complicated ulcers 0.50 0.60 0.83 Other serious adverse events 6.3 5.2 1.21 (1.01, 1.45) Mortality 0.48 0.43 1.12 Myocardial infarction 0.33 1.45

FDA review of VIGOR trial Outcome Rofecoxib (n=4047) % Naproxen (n=4029) RR (95% CI) Serious adverse events 9.3 7.8 1.21 (1.04, 1.40) Complicated ulcers 0.40 0.92 0.43 (0.24, 0.78) Other serious adverse events 8.9 6.9 1.29 (1.11, 1.50) Mortality 0.54 0.37 1.46 Myocardial infarction 0.49 0.10 4.9 (1.7, 14.3)

COX 2 selective inhibitors Conclusions COX 2’s are equieffective to non-selective NSAIDs. Rofecoxib causes less complicated ulcers than naproxen. Celecoxib and rofecoxib are overall more dangerous than non-selective NSAIDs (harm exceeds the benefit).

Does lipid lowering therapy cause more benefit than harm? In people without evidence of cardiovascular disease (primary prevention)

Lovastatin versus placebo for primary prevention JAMA,1998;279:1615-22 AFCAPS/TexCAPS Lovastatin versus placebo for primary prevention JAMA,1998;279:1615-22

Primary Outcome First major coronary event Includes: Fatal or non-fatal MI Unstable angina Sudden death

Major coronary event Overall Plac Drug RR CI ARR NNT 5.5% 3.5% 0.63 (0.5-0.8) 2% 50(5 yr)

Serious adverse events (SAE) (AFCAPS) Outcome Drug Placebo RR CI SAE 34.2% 34.1% 1.00 (0.9-1.1) Deaths 4.6% 4.4% 1.04 (0.8-1.4)

SAE / Mortality analysis Serious adverse events were searched for in the other nine major trials. SAEs were not reported. Total mortality, one component of SAEs, was reported.

Primary prevention All-cause mortality Trial (drug) Drug Plac RR CI WHO (clofib) 3.0% 2.4% 1.27 (1.01-1.6) Helsinki (gemf) 2.2% 2.1% 1.06 (0.7-1.6) WOSCOP(prav) 3.2% 4.1% 0.78 (0.6-1.01)

Does lipid lowering therapy cause more benefit than harm? In people with cardiovascular disease (secondary prevention)

Secondary prevention All-cause mortality Trial (drug) Drug Plac RR CI VA-HIT(gemf) 15.7% 17.4% 0.9 (0.8-1.1) BIP (bezafib) 10.4% 9.9% 1.06 (0.9-1.3) 3 trials (statin) 0.79 (0.7-0.9) ARR = 2.6% NNT = 38 for 5 years

Serious adverse event (mortality) analysis Supports the use of statins alone in moderate doses for secondary prevention. Does not support the use of fibrates alone or in combination for primary or secondary prevention. Does not support the use of statins alone for primary prevention.

Can we use SAE analysis for psychotropic drugs? Bupropion

Bupropion is associated with significant risks and harms Product monograph says so. Post marketing surveillance has triggered warnings in Canada and elsewhere. Seizures, agitation, hallucinations, mania, insomnia, serum sickness, rash etc. Increased blood pressure, anorexia, weight loss, etc.

How can we estimate the magnitude of the harm? SAE meta-analysis of all placebo controlled RCTs. SAE meta-analysis of all RCTs comparing bupropion to other antidepressants. Limitations: published RCTs often don’t fully report SAEs. RCTs are mostly short (8 weeks).

What can be done? Demand an independent audit and publication of SAE data from company. Design and run large simple long-term RCTs comparing bupropion with other anti-depressants.

SAE (mortality) analysis Benefit to harm balance Confirms the benefit of some drugs in some settings. Suggests a lack of overall benefit in some clinical settings. Demonstrates overall harm in some clinical settings. Is unknown in most drug intervention settings.

Conclusions Accept the fact that we have been and will be duped. Demand reporting of SAEs in RCTs, past present and future. Demand reduction in SAEs before claiming a health benefit with any intervention. When an overall health benefit has not been demonstrated or is uncertain do not prescribe or take a drug.

Website http://www.ti.ubc.ca Includes organization and objectives of the Therapeutics Initiative Includes all 42 Therapeutics Letters Includes links to other evidence based web sites Accessed on average over 2,000 times/day