2. 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

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

4. 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.

6. 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

7. 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.

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

9. 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

10. 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.

11. 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 NS
0.4
0.1
333
Complicated ulcers
0.6
0.9
0.5
200
Serious adverse events
4.3
4.2 NR
Symptomatic ulcers
0.7
1.0
2.1
1.1 91
Withdrawals due to adv. events
18.4
20.6
2.2 44
16.4
16.1 *
* 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

12. 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).

13. 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

14. 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)

15. 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).

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

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

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

19. Major coronary event Overall Plac Drug RR CI ARR NNT
5.5% 3.5% ( ) 2% 50(5 yr)

20. Serious adverse events (SAE) (AFCAPS)
Outcome Drug Placebo RR CI
SAE % 34.1% ( )
Deaths % % ( )

21. 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.

22. Primary prevention All-cause mortality
Trial (drug) Drug Plac RR CI
WHO (clofib) % 2.4% ( )
Helsinki (gemf) 2.2% 2.1% ( )
WOSCOP(prav) 3.2% 4.1% ( )

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

24. Secondary prevention All-cause mortality
Trial (drug) Drug Plac RR CI
VA-HIT(gemf) % 17.4% ( )
BIP (bezafib) % % ( )
3 trials (statin) ( )
ARR = 2.6% NNT = 38 for 5 years

25. 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.

26. Can we use SAE analysis for psychotropic drugs?
Bupropion

27. 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.

28. 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).

29. 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.

30. 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.

31. 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.

32. 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
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