Drug Evaluation and Drug Safety: A Clinical and PharmacoEpidemiology Perspective

1
Drug Evaluation and Drug Safety A Clinical and
Pharmaco-Epidemiology Perspective

• Mitchell Levine, MD MSc FRCPC FISPE
• Professor, Clinical Epidemiology Biostatistics
• McMaster University
• Director, Centre for Evaluation of Medicines
• Hamilton, Canada

2
Drug Evaluation and Drug Safety

• I. Relative and dynamic issues of drug safety
• II. Clinical determinants of drug safety
• III. Evidence-based medicine in evaluating drug
  safety

3
Drug Evaluation and Drug Safety

• Part I
• Drug Safety is a Relative and Dynamic Issue

4
Benefit
Perspective
Risk
Value
5
Drugs with Substantial Benefits Despite Potential
Risks
6
Drug safety is a relative issue that is also
influenced by temporal factors.
7
A new drug is developed for treating patients
with acute myocardial infarction. The drug is
associated with a 1 increase in mortality
compared to the current standard therapy.Should
this drug be approved?
8
If it should not be approved, this is an example
of birth order bias.Drugs that are first to
the market are held to a different standard than
similar drugs that are marketed later.
9
Overall 1-year mortality in the Global
Utilization of Streptokinase and t-PA for
Occluded Coronary Arteries (GUSTO-I) trial by
treatment assignment
Califf, R. M. et al. Circulation 1996941233-1238
10
Benefit
Perspective
Risk
Value
11
Benefit
Perspective
Perspective
Risk
Value
time
12
Drug Evaluation and Drug Safety

• Part II
• Clinical Determinants of
• Drug Safety

13
Post Marketing Evaluation
Benefit
Rational Use?
Risk
Value
14
HOW a DRUG is USED is a CRITICAL DETERMINANT
of RELATIVE DRUG SAFETY
15
Cisapride Dangerous Drug or Misused Drug?
16
Cisapride

• Prokinetic GI motility drug
• 341 reports of heart rhythm abnormalities 80
  reports of death
• Manufacturer discontinued marketing July 2004
• Available through investigational limited access
  program

17
Cisapride

• No signal from RCTs
• 1 AE per 111,000 prescriptions and 1 fatality
  per 428,000 prescriptions
• Modest QT prolongation
• CYP 3A4 substrate
• Clarithromycin 3X increase in concentration

18
Cisapride Use Study

• To describe the impact of cummulative labeling
  changes
• Cisapride contraindicated with
• CYP 3A4 inhibitors
• QT prolonging drugs
• Co-morbidities

19
Cisapride UsePre and Post Labeling Change
20
(No Transcript)
21
Spironolactone Dangerous Drug or Misused Drug?
22
Rate of prescriptions for spironolactone among
patients recently hospitalized for CHF who were
receiving ACE inhibitors.
23
Rate of hospitalization admission for
hyperkalemia among patients recently hospitalized
for CHF who were receiving ACE inhibitors.
24
Rate of readmission for CHF among patients
recently hospitalized for CHF who were receiving
ACE inhibitors.
25
Anorexigens Dangerous Drugs or Misused Drugs?
26
Primary Pulmonary Hypertension
27
Aortic Regurgitation

• Exposure gt90 days
• OR 2.5 (1.9 3.3)
• Exposure lt90 days
• OR 1.4 (0.8 2.6)

28
Selective Cox-2 inhibitors Dangerous Drugs or
Misused Drugs?
29
APPROVeAPTC Events Time to Event Plot
30
VIGOR Confirmed CV/ Thrombotic Events Time to
Event Plot
31
VioxxGastrointestinal Benefits

• Rofecoxib versus naproxen, median follow-up of
  9.0 months
• Confirmed gastrointestinal events
• relative risk 0.5 (0.3 to 0.6)
• Complicated events (perforation, obstruction, and
  severe upper gastrointestinal bleeding)
• relative risk 0.4 (0.2 to 0.8)

32
Selective Cox-2 InhibitorRisk Benefit
Assessment

• Absolute risk difference RR ? Baseline Risk
• RR for CV events approximately 2.0
• RR for GI events approximately 0.5
• Therefore, it is the patients BASELINE RISK for
  each of these events that determines whether a
  selective Cox-2 inhibitor would produce an
  acceptable riskbenefit ratio.

33
Natural Health Products Dangerous Drugs or
Misused Drugs?
34
Natural Health Product Use in Adults gt 60
year-olds in Ontario, Canada

• 51 use natural health products products
• 19 of users are taking a prescription drug to
  manage the same health problem
• 32 of users do not disclose their natural health
  product use to their physicians

35
Drug NHP Potential Interactions

• 11,424 adults in 2000-2001 Canadian National
  Population Health Survey (NPHS)
• 9.3 of survey participants reported the use of
  at least one NHP in the prior two days.
• Among NHP users, 57 also used a conventional
  medicine with systemic exposure in the same time
  period.
• A minimum of one potential drug-NHP interaction
  was identified in 28.4 of combination users.

36
St Johns Wort and TSH elevation?

• 4/37 cases and 2/37 controls exposed to St Johns
  Wort in 3-6 month period preceding TSH
  measurement
• OR 2.12 (95 CI 0.36 12.36)

37
Patients with Elevated TSH
38
Bisphosphonates Dangerous Drugs or Misused
Drugs?
39
Alendronate

• Associated with esophagitis, some cases being
  quite severe and requiring hospitalization
• Frequency of the problem was much higher in
  clinical practice that in the pre-marketing RCTs
• RCTs were subject to inclusion and exclusion
  criteria involving three associated risk factors
  
• adherence with special dosing instructions
• exclude pre-existing gastro-esophageal disorders
• exclude concomitant use of NSAIDs or
  ASA-containing compounds

40
Bisphosphonate Use Study

• The purpose of the study was to determine the
  proportion of post-menopausal osteoporotic women
  using a bisphosphonate in a Canadian province who
  are also being treated for concurrent
  gastro-esophageal disorders or whoare receiving
  NSAID therapy.

41
GI drug and NSAID use in 5400 postmenopausal
women using a bisphosphonate to treat
osteoporosis, (95 CI)
42
Beta Agonist Inhalers Dangerous Drugs or
Misused Drugs?
43
Asthma Mortality

• Mortality has been increasing despite the
  availability of more effective and less toxic
  drugs
• Death has been associated with the use of inhaled
  beta-agonist therapy
• Risk for death per canister per month
• OR 2.6 (1.7 3.9)

44
Inhaled Medication Use by Asthma
Patients(patient based survey)

• 9 of patients used beta-agonist daily without
  daily use of inhaled steroids
• 25 of patients use steroids on a prn basis
• 6 of patients use inhaled medications at a
  different frequency than had been prescribed by
  their physician

45
Medication Problems
46
HOW a DRUG is USED is a CRITICAL DETERMINANT
of RELATIVE DRUG SAFETY
47
Post Marketing Evaluation
Benefit
Rational Use!
Risk
Value
48
Drug Evaluation and Drug Safety

• Part III
• Evidence-Based Medicine in Evaluating Drug Safety

49
(No Transcript)
50
Validity Issues

• Clinical Evidence
• RCT
• Cohort Study
• Case-Control Study
• Case Reports

• Legal Evidence
• DNA
• Eye Witness
• Circumstantial Evidence
• Hearsay

51
Adverse Event Reporting

• Essential for signal detection and hypothesis
  generation
• Inappropriate inferences can lead to undesirable
  actions

52
(No Transcript)
53
(No Transcript)
54
Duplicate Inhaler Study

• Designed to evaluate the impact that changing a
  patients medication can have on perceptions of
  efficacy and adverse effects.
• Patients received the same medications but were
  lead to believe that their medication had been
  changed.
• Efficacy and adverse effects were evaluated.

55

56
Duplicate Inhaler Study
57
Adderall XR

• Removed from the Canadian market in February 2005
• case reports of sudden/cardiac death and/or
  stroke in individuals receiving Adderall.
• Reinstated in August 2005
• after review of data by a special advisory
  committee and additional analyses conducted.

58
Adderall XR

• Problem with using Adverse Event Reporting Ratios
• In epidemiological studies it is imperative that
  the two cohorts (defined by their exposure
  status) have similar opportunities for the
  outcome of interest, which in this analysis is
  the generation of a case report.

59
CASE REPORTS
Outcome
-

?
DATA

Exposure
-
?
?
60
Confounding and Biasin Cohort and Case-Control
Studies

• Did the cohorts have EQUAL OPPORTUNITY for the
  OUTCOME?
• Did the cases and the controls have EQUAL
  OPPORTUNITY for EXPOSURE?

61
Statistical vs. Clinical Significance

• Results that may be statistically significant but
  clinically insignificant include
• Small relative risk increases involving large
  sample sizes
• Large relative risks involving rare events

62
Study Subjects ? Future Patients?

• Could the patient have been in the study?
• Inclusion and exclusion criteria?
• Similar exposure? Similar outcome?

63
Subgroup AnalysesPatient Characteristics

• Rationale
• Limited number of analyses
• A priori
• Within a positive study
• Consistent between studies

64
Population ? Patient?

• Attributable risk percent, (RR-1) / RR
• In a patient with the outcome of interest and a
  history of exposure, a RR gt 2 is required for the
  etiology of the outcome to be more likely than
  not secondary to the exposure (AR gt 50)

65
Risk vs. Benefit

• Clinical decision making individual patient
• Policy decision making patient population
• ? Evidence (objective) and Values (subjective)

66
Benefit
Perspective, Rational Use, Evaluation
Risk
Value
67
(No Transcript)