Title: Pharmacoepidemiology: What Happens After Approval
1PharmacoepidemiologyWhat Happens After Approval?
2Outline
- Background / Context
- Definitions
- The Scope of Pharmacoepidemiology
- Interpreting pharmacoepi research
- ADEs and Reporting
- Risk Management
3What 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
4What 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
5Why is Pharmacoepidemiology Important?
- Aging Population
- More Disease
- Chronic disease
- More Drugs
- Combination Tx
- Complex
- Inadequacy of Systems
- Variation in practice
- Monitoring / surveillance
6Some Driving Factors
- Improvements in Technology
- Growing Emphasis on Patient Safety
- Regulation / Accreditation
- Quality Improvement
- Managed Care
- Formularies Drug Selection
- Pharmacogenetics
7The 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!
8What do we know about a drug?
9Pre-Approval Studies (RCTs)
- Can drug produce at least one beneficial effect?
- Efficacy versus placebo
- Is the drug safe?
- benefit /risk
10Measurable Drug Effects
- Anticipated beneficial effects
- Efficacy versus effectiveness
- Efficiency
- Unanticipated beneficial effects
- Unanticipated harmful effects
- Anticipated harmful effects
11Drug Development
?
12Why the Need for Pharmacoepidemiology?
- Studies required for FDA approval
- Too few
- Too simple
- Too median aged
- Too narrow
- Too brief
- Too indirect
13Information Gap
- What dont we know about a newly approved drug?
14Information 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
15How Do We Fill in These Gaps?
- Pharmacoepidemiology
- Phase IV research
- Benefits and Risks
- PharmEpi Research
- Pharmacovigilance / Surveillance
- Safety / Risk Management
16PharmEpi Research
- As Generated by
- Academic Researchers
- Drug Industry
- MCOs
- Government
- Health Care Providers
17Hierarchy of Study Design
- RCTs
- Cohort Studies
- Case-Control Studies
- Cross-Sectional Studies
- Case Series
- Case Reports
- Expert Opinion / Anecdote
18Hierarchy 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
19Hierarchy 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?
20Hierarchy 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
21Cohort 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
22Cohort 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)
23Cohort Study
24Example Dioxin and Cancer
25Identifying 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
26Identifying 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
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28Cross-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
29Measure 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)
30WHAT 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.
31Interpretation 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
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34What is the absolute risk?What is the relative
risk?
35What is the relative risk?
36What is the absolute risk?What is the relative
risk?
37Expression 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
38ExampleDoes 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
39Does 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
40Confidence 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.
41Examples
- 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
42ExampleNon-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
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441993
1999
Relative Risk
1.0 0.95 0.83 0.20
NO NSAID
1 23 months NSAID
24 months NSAID
45 for Alzheimer's
46Example Relative Risk
RR 3/250 150/2500
1/5 0.20
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48How Do We Fill in These Gaps?
- Pharmacoepidemiology
- Phase IV research
- Benefits and Risks
- PharmEpi Research
- Pharmacovigilance / Surveillance ?
- Safety / Risk Management
49Taxonomy
- Adverse Drug Reaction
- Adverse Drug Event
- Drug-related Problems
50Adverse 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
51ADRs
- Type A
- predictable
- often dose-dependent
- Type B
- unpredictable
- unrelated to drugs known action
- allergic, immunologic, carcinogenic, teratogenic
52Adverse 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
53Drug-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
54Drug-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
55Taxonomy
- 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
57Kefauver-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
581985 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
59Adverse 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
60Taxonomy
- 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.
62MedWatch
- 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
63MedWatch
- Information Sought
- Serious Adverse Event
- Product Problems
- Defective
- Malfunctioning
64MedWatch Serious Adverse Event
- FDA An adverse event is any undesirable
experience associated with the use of a medical
product in a patient.
-
65MedWatch 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
66MedWatchMedical 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
67MedWatch Reports
- 3500
- For providers patients
- Submit online, or by telephone, fax, or US mail
- 3500a
- Mandatory reporting forms for manufacturers
- LISTSERV
68MedWatch
- Issues
- Causality
- Liability
69MedWatch
- Strengths
- Identify events as they occur
- Throughout US
- Pre-marketing trials limited in N
- Good for rare ADEs
- Signal / early warning
70MedWatch
- Weaknesses
- Cannot provide incidence rates
- Under-reporting
- Detection bias
- Severity of event
71How Do We Fill in These Gaps?
- Pharmacoepidemiology
- Phase IV research
- Benefits and Risks
- PharmEpi Research
- Pharmacovigilance / Surveillance
- Safety / Risk Management ?
72FDA 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
73Risk 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
74FDA 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