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Pharmacoepidemiology: What Happens After Approval

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Title: Pharmacoepidemiology: What Happens After Approval


1
PharmacoepidemiologyWhat Happens After Approval?
2
Outline
  • Background / Context
  • Definitions
  • The Scope of Pharmacoepidemiology
  • Interpreting pharmacoepi research
  • ADEs and Reporting
  • Risk Management

3
What is Pharmacoepidemiology?
  • The study of the use of and the effects of drugs
    in large numbers of people
  • -B. Strom
  • Pharmaco medications
  • Epidemiology
  • Epi among
  • demos people
  • logos doctrine

4
What is Pharmacoepidemiology?
  • Versus
  • Clinical Pharmacology
  • Study of the effects of drugs in humans
  • Patient focus Risk / Benefit
  • Informed by pharmacoepidemiology
  • particularly where information gaps exist
  • Epidemiology
  • Epidemics
  • Chronic disease
  • risk

5
Why is Pharmacoepidemiology Important?
  • Aging Population
  • More Disease
  • Chronic disease
  • More Drugs
  • Combination Tx
  • Complex
  • Inadequacy of Systems
  • Variation in practice
  • Monitoring / surveillance

6
Some Driving Factors
  • Improvements in Technology
  • Growing Emphasis on Patient Safety
  • Regulation / Accreditation
  • Quality Improvement
  • Managed Care
  • Formularies Drug Selection
  • Pharmacogenetics

7
The Scope of Pharmacoepidemiology
  • The study of the use of and the effects of drugs
    in large numbers of people
  • -B. Strom
  • Beneficial effects
  • Adverse effects

There is much that we do not know!
8
What do we know about a drug?
9
Pre-Approval Studies (RCTs)
  • Can drug produce at least one beneficial effect?
  • Efficacy versus placebo
  • Is the drug safe?
  • benefit /risk

10
Measurable Drug Effects
  • Anticipated beneficial effects
  • Efficacy versus effectiveness
  • Efficiency
  • Unanticipated beneficial effects
  • Unanticipated harmful effects
  • Anticipated harmful effects

11
Drug Development
?
12
Why the Need for Pharmacoepidemiology?
  • Studies required for FDA approval
  • Too few
  • Too simple
  • Too median aged
  • Too narrow
  • Too brief
  • Too indirect

13
Information Gap
  • What dont we know about a newly approved drug?

14
Information Gap What is the effect of the drug
  • In a large population
  • In the elderly
  • In children
  • In minorities
  • In patients with differing clinical parameters
  • Pharmacokinetics
  • LADME
  • In pregnancy
  • In combination with other drugs
  • As compared with other therapies
  • In presence of co-morbidities
  • Off-label prescribing

Risks AND Benefits
15
How Do We Fill in These Gaps?
  • Pharmacoepidemiology
  • Phase IV research
  • Benefits and Risks
  • PharmEpi Research
  • Pharmacovigilance / Surveillance
  • Safety / Risk Management

16
PharmEpi Research
  • As Generated by
  • Academic Researchers
  • Drug Industry
  • MCOs
  • Government
  • Health Care Providers

17
Hierarchy of Study Design
  • RCTs
  • Cohort Studies
  • Case-Control Studies
  • Cross-Sectional Studies
  • Case Series
  • Case Reports
  • Expert Opinion / Anecdote

18
Hierarchy of Study Design
  • RCTs
  • Cohort Studies
  • Case-Control Studies
  • Cross-Sectional Studies
  • Case Series
  • Case Reports
  • Expert Opinion / Anecdote
  • Experimental versus Observational
  • Setting
  • Bias
  • Measure of Effect
  • Group Differences
  • Relative Risk
  • Odds Ratio

19
Hierarchy of Study Design Roles
  • RCTs
  • Cohort Studies
  • Case-Control Studies
  • Cross-Sectional Studies
  • Case Series
  • Case Reports
  • Expert Opinion / Anecdote
  • Prospective
  • Strongest evidence that effect exists
  • Statistical significance versus clinical
    relevance
  • Only pre-approval?

20
Hierarchy of Study Design Roles
  • RCTs
  • Cohort Studies
  • Case-Control Studies
  • Cross-Sectional Studies
  • Case Series
  • Case Reports
  • Expert Opinion / Anecdote
  • Retrospective
  • Search for association (s)
  • Exposure ? risk
  • Bias
  • Hypothesis generating
  • Absolute versus relative risk

21
Cohort Studies
  • Two or more groups of individuals that are free
    of disease and that are defined on the basis of
    presence or absence of exposure to a suspected or
    potential cause of the disease of interest are
    followed over time to assess the occurrence of
    the disease.
  • A type of observational study

22
Cohort Studies
P R O S P E C T I V E
R E T R O S P E C T I V E
EXPOSED
Disease?
Time ?
Disease?
UNEXPOSED
Can be more than one exposure group (i.e. levels
of exposure)
23
Cohort Study
24
Example Dioxin and Cancer
25
Identifying Risk Factors for Rare Disease
  • When diseases are rare, a cohort study design may
    likely fail to include patients that develop the
    outcome
  • How many patients would you need to enroll to
    ensure that rare events are captured when the
    incidence of the outcome is 1 in 10,000 people?
  • e.g. risk factors for developing ALS

26
Identifying Risk Factors for Rare Disease
  • Instead of starting with exposure, we can start
    by identifying cases.
  • e.g. identify ALS patients through a specialist
    MD
  • Problem
  • Before we classified people as exposed or not
    exposed. What is the classification now?
  • We can instead classify patients by disease
    (outcome) status

27
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28
Cross-Sectional Studies
  • Data collected during a specified period
  • A snap shot in time
  • Survey data
  • Can be used for evaluating relationships between
    variables
  • e.g. What percentage of teenage smokers are
    female?
  • Cannot determine temporal relationships, or
    measure outcomes
  • For developing hypotheses

29
Measure of Effect
  • Group Differences
  • e.g. Drug versus placebo Drug versus non-drug
    therapy
  • Risk
  • Absolute Risk
  • Relative Risk
  • Odds Ratio
  • Precision
  • Magnitude
  • Number Needed to Treat (NNT) Harm (NNH)

30
WHAT IS RISK?
  • risk     (r sk)n.
  • The possibility of suffering harm or loss
    danger.
  • A factor, thing, element, or course involving
    uncertain danger a hazard.

31
Interpretation of Risk
  • Absolute Risk
  • The probability of having an outcome
  • Relative Risk
  • The change/difference in probability of having an
    outcome given an exposure/treatment

32
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33
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34
What is the absolute risk?What is the relative
risk?
35
What is the relative risk?
36
What is the absolute risk?What is the relative
risk?
37
Expression of Relative Risk A / B
  • No Difference in Risk 1.0
  • e.g. 3/10
  • 3/10 1
  • Increase in Risk
  • e.g. 4/10
  • 3/10 1.33
  • Decrease in Risk
  • e.g. 2/10
  • 3/10 0.67

interpretation
38
ExampleDoes Hair Spray Cause Brain Cancer?
  • Group A
  • Uses Hair Spray
  • Daily
  • Brain Cancer
  • 6/10,000 1/1667
  • Group B
  • No Hair Spray
  • Brain Cancer
  • 4/10,000 1/2500

39
Does Hair Spray Cause Brain Cancer?
  • A
  • Uses Hair Spray
  • Daily
  • Brain Cancer
  • 6/10,000 1/1667
  • RR 6/10,000
  • 4/10,000 1.5
  • B
  • No Hair Spray
  • Brain Cancer
  • 4/10,000 1/2500

40
Confidence Intervals
  • Range within true estimate of risk lies
  • Usually set at 95 confidence
  • 100 confident 95 confident 0.05 chance of
    error (p 0.05)
  • Width of the interval related to the size of the
    study population
  • standard error
  • When expressing a relative risk, the confidence
    interval must not include a value of 1.0 to be
    considered statistically significant.

41
Examples
  • RR 1.6 95 CI 1.5 1.8
  • RR 1.6 95 CI 0.8 2.4
  • RR 8.6 95 CI 1.4 35.7
  • RR 0.5 95 CI 0.3 0.8
  • RR 0.5 95 CI 0.2 1.2

42
ExampleNon-steroidal Anti-inflammatory Drugs
and the Risk of Alzheimers Disease
  • The long-term use of NSAIDs may protect against
    Alzheimer's disease

Non-steroidal Anti-inflammatory Drugs and the
Risk of Alzheimers Disease N Engl J Med. 2001 No
v 22345(21)1515-21

43
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44
1993
1999
Relative Risk
1.0 0.95 0.83 0.20
NO NSAID

1 23 months NSAID
24 months NSAID
45
for Alzheimer's
46
Example Relative Risk
RR 3/250 150/2500
1/5 0.20
47
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48
How Do We Fill in These Gaps?
  • Pharmacoepidemiology
  • Phase IV research
  • Benefits and Risks
  • PharmEpi Research
  • Pharmacovigilance / Surveillance ?
  • Safety / Risk Management

49
Taxonomy
  • Adverse Drug Reaction
  • Adverse Drug Event
  • Drug-related Problems

50
Adverse Drug Reaction
  • World Health Organization (WHO) definition
  • ..any noxious and unintended effect of a drug
    which occurs at doses used in humans
  • Excludes
  • Therapeutic failures
  • Intentional and accidental poisoning and drug
    abuse
  • Errors in administration or adherence to therapy

Example Aspirin and gastritis
51
ADRs
  • Type A
  • predictable
  • often dose-dependent
  • Type B
  • unpredictable
  • unrelated to drugs known action
  • allergic, immunologic, carcinogenic, teratogenic

52
Adverse Drug Event
  • World Health Organization (WHO) definition
  • Any injury resulting from administration of a
    drug
  • Includes
  • Intentional and accidental poisoning and drug
    abuse
  • Errors in administration or adherence to therapy
  • Events that are preventable

Example Aspirin OD and renal dysfunction
53
Drug-Related Problems
  • Definition
  • An event or circumstance involving a patients
    drug treatment that actually, or potentially
    interferes with the achievement of an optimal
    outcome.
  • Hepler and Strand DCIP AJHP 1990

54
Drug-Related Problems
  • Untreated Indications
  • Improper Drug Selection
  • Sub-therapeutic Dosage
  • Failure to Receive Drugs
  • Over-dosage
  • Adverse Drug Reactions
  • Drug Interactions
  • Drug Use Without Indication

55
Taxonomy
  • Adverse Drug Reaction
  • Adverse Drug Event
  • Drug-Related Problems

56
  • What happens after approval?
  • Does FDA care about risks?
  • Phase IV studies
  • Kefauver-Harris
  • MedWatch
  • Risk Management

Benefit Risk
57
Kefauver-Harris (1962)
  • Safety Efficacy
  • MFGs must report to the FDA all adverse
    experiences events that come to their attention
  • Held by FDA in computerized databank since 1969

58
1985 Updated Regulations
  • Main objective Provide signals about safety
    problems with marketed drugs especially newly
    marketed drugs
  • Reports due quarterly for first 3 years
  • Then annually
  • Information sources?
  • Providers - Patients
  • Clinical trials - Literature
  • Domestic and Foreign

59
Adverse Drug ExperienceAdverse outcome that
occurs during use of a drug in professional
practice
  • Includes overdose, abuse, withdrawal, failure of
    expected action
  • Unexpected Not in product labeling
  • Serious events not in labeling must be reported
    within 15 days
  • FDA Division of Epidemiology and Surveillance

60
Taxonomy
  • Adverse Drug Reaction
  • Adverse Drug Event
  • Drug-Related Problems

61
The FDAs MedWatch Program
  • FDA has the responsibility for assuring the
    safety and efficacy of all regulated marketed
    medical products.
  • MedWatch allows healthcare professionals and
    consumers to report serious problems that they
    suspect are associated with the drugs and medical
    devices they prescribe, dispense, or use.

62
MedWatch
  • Objectives
  • Make it easier to report ADEs
  • Make it clear what FDA wants
  • Disseminate more widely what FDA action resulting
    from reports
  • Increase understanding and awareness of
    drug-induced disease

63
MedWatch
  • Information Sought
  • Serious Adverse Event
  • Product Problems
  • Defective
  • Malfunctioning

64
MedWatch Serious Adverse Event
  • FDA An adverse event is any undesirable
    experience associated with the use of a medical
    product in a patient.

65
MedWatch Serious Adverse Event
  • The event is SERIOUS and should be reported when
    the patient outcome is
  • Death
  • Life-Threatening
  • Hospitalization (initial or prolonged)
  • Disability
  • Congenital Anomaly
  • Requires Intervention to Prevent Permanent
    Impairment or Damage

66
MedWatchMedical Product Reporting
  • Product problems (defective or malfunctioning)
    should be reported when there is a concern about
    the quality, performance, or safety of any
    medication or device.
  • product contamination
  • defective components
  • poor packaging or product mix-up
  • questionable stability
  • device malfunctions and
  • labeling concerns

67
MedWatch Reports
  • 3500
  • For providers patients
  • Submit online, or by telephone, fax, or US mail
  • 3500a
  • Mandatory reporting forms for manufacturers
  • LISTSERV

68
MedWatch
  • Issues
  • Causality
  • Liability

69
MedWatch
  • Strengths
  • Identify events as they occur
  • Throughout US
  • Pre-marketing trials limited in N
  • Good for rare ADEs
  • Signal / early warning

70
MedWatch
  • Weaknesses
  • Cannot provide incidence rates
  • Under-reporting
  • Detection bias
  • Severity of event

71
How Do We Fill in These Gaps?
  • Pharmacoepidemiology
  • Phase IV research
  • Benefits and Risks
  • PharmEpi Research
  • Pharmacovigilance / Surveillance
  • Safety / Risk Management ?

72
FDA and Risk Management
  • Not applied equally to all issues/drugs
  • What is it attempting to address?
  • Preventable adverse events due to the use/misuse
    of the product
  • Benefit / Risk
  • Maximizing the benefits
  • Maximizing the safe use
  • Minimizing the risks
  • drug safety equated with latter two

73
Risk Management Drivers
  • Focus on health care quality, patient safety,
    prevention of medical errors
  • Withdrawal of valuable drugs due to poor or
    ineffective management of known risks
  • interactions/co-prescribing
  • failure to monitor
  • inappropriate use

74
FDA and Risk Management
  • Expect continuing and dramatic shift in focus
  • Passive to active RM
  • Involvement of pharmacist
  • Role in RM for high risk drugs
  • Current examples
  • Accutane
  • Lotronex
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