Pharmacoepidemiology: What Happens After Approval

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PharmacoepidemiologyWhat Happens After Approval?
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Outline

• Background / Context
• Definitions
• The Scope of Pharmacoepidemiology
• Interpreting pharmacoepi research
• ADEs and Reporting
• Risk Management

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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

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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

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Why is Pharmacoepidemiology Important?

• Aging Population
• More Disease
• Chronic disease
• More Drugs
• Combination Tx
• Complex
• Inadequacy of Systems
• Variation in practice
• Monitoring / surveillance

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Some Driving Factors

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

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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!
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What do we know about a drug?
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Pre-Approval Studies (RCTs)

• Can drug produce at least one beneficial effect?
• Efficacy versus placebo
• Is the drug safe?
• benefit /risk

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Measurable Drug Effects

• Anticipated beneficial effects
• Efficacy versus effectiveness
• Efficiency
• Unanticipated beneficial effects
• Unanticipated harmful effects
• Anticipated harmful effects

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Drug Development
?
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Why the Need for Pharmacoepidemiology?

• Studies required for FDA approval
• Too few
• Too simple
• Too median aged
• Too narrow
• Too brief
• Too indirect

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Information Gap

• What dont we know about a newly approved drug?

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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
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How Do We Fill in These Gaps?

• Pharmacoepidemiology
• Phase IV research
• Benefits and Risks
• PharmEpi Research
• Pharmacovigilance / Surveillance
• Safety / Risk Management

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PharmEpi Research

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

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Hierarchy of Study Design

• RCTs
• Cohort Studies
• Case-Control Studies
• Cross-Sectional Studies
• Case Series
• Case Reports
• Expert Opinion / Anecdote

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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

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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?

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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

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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

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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)
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Cohort Study
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Example Dioxin and Cancer
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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

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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

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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

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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)

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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.

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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

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What is the absolute risk?What is the relative
risk?
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What is the relative risk?
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What is the absolute risk?What is the relative
risk?
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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
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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

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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

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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.

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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

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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

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1993
1999
Relative Risk
1.0 0.95 0.83 0.20
NO NSAID

1 23 months NSAID
24 months NSAID
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for Alzheimer's
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Example Relative Risk
RR 3/250 150/2500
1/5 0.20
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How Do We Fill in These Gaps?

• Pharmacoepidemiology
• Phase IV research
• Benefits and Risks
• PharmEpi Research
• Pharmacovigilance / Surveillance ?
• Safety / Risk Management

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Taxonomy

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

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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
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ADRs

• Type A
• predictable
• often dose-dependent
• Type B
• unpredictable
• unrelated to drugs known action
• allergic, immunologic, carcinogenic, teratogenic

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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
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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

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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

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Taxonomy

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

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

Benefit Risk
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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

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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

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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

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Taxonomy

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

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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.

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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

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MedWatch

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

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MedWatch Serious Adverse Event

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

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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

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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

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MedWatch Reports

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

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MedWatch

• Issues
• Causality
• Liability

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MedWatch

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

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MedWatch

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

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How Do We Fill in These Gaps?

• Pharmacoepidemiology
• Phase IV research
• Benefits and Risks
• PharmEpi Research
• Pharmacovigilance / Surveillance
• Safety / Risk Management ?

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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

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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

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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