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ACRP CPI® > ICH E2A Safety Monitoring > Flashcards

ICH E2A Safety Monitoring Flashcards

1
Q

Adverse Event, or Adverse Experience (AE)

A

Any untoward (unfavorable and unintended) laboratory or clinical abnormality associated with, not necessarily caused by, the intervention.

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2
Q

Adverse Drug Reaction (ADR)

A

Any noxious and unintended response to a pre-approval stage drug given at any doses, or to a post-marketing drug given at normal doses in human.

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3
Q

Side Effect

A

SE can be both favorable and unfavorable, and thus is no longer recommended in practice due to ambiguity.

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4
Q

Unexpected ADR determined by Source Documents

A

Any adverse reaction not included in the product information from the source documents (i.e., Investigator’s Brochure of an investigational drug, or the Safety Labeling of a post-marketing drug).

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5
Q

Serious AE/ADR (5+1)

A

Any untoward medical occurrence that at any does:

  1. results in death,
  2. is life-threatening.
  3. requires inpatient hospitalization or prolongation of existing hospitalization
  4. results in persistent or signifaicant disability/incapacity, or
  5. is a congenital anomaly/birth defect.
  6. Other medical events that require intervention to prevent one of the other outcomes above.
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6
Q

Life-threatening Event Definition

A

An event in which the patient was at risk of death at the time of the event, but not in which the patient might have died hypothetically if it were more severe.

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7
Q

Medical Events that Require Intervention to Prevent a Serieous Events, Examples (3)

A
  1. Intensive teratment for allergic bronchospasm at ER/home
  2. Blood dyscrasias or convulsions that do not result in hospitalization
  3. Development of drug dependency or drug abuse
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8
Q

Severity vs Seriousness

A

Severity (leading event)
Seriousness (resulting outcome)

“Mild myocardial infarction (severity) did not affect survival or cardiac function (seriousness).”

Regulatory reporting obligations are defined by serious outcome, but not on severe event.

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9
Q

Expedited Reporting Obligations for Unexpected AE

A

Once an unexpected AE occurs, expedited reporting is required for additional occurrences of the AE, until source documents are amended (from unexpected to expected).

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10
Q

Unexpected AEs Criteria (2)

A

Either:
1. Not documented in Investigators’s Brochure or product Safety Label, or
2. Documented but lacks specificity or severity.

Example:
Acute renal failure / interstitial nephritis
Hepatitis / fulminant hepatitis

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11
Q

Expedited Reporting Requirements (2)

A

Both:
1. Serious, and
2. Unexpected

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12
Q

Ordinarily Inappropriate Circumstances for Expedited Reporting (4)

A
  1. Serious but not unexpected
  2. Expected but not serious
  3. Not serious, and not expected
  4. Serious AE but not related to the study
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13
Q

Expedited Report Source Information Examples (3)

A

Any one of the following:

  1. Spontaneous reports (for marketed drugs)
  2. Clinical/epidemiological investigations
  3. Others (registries or publications)
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14
Q

Valid ADR Causality Assessment

A

Reasonable suspected causal relationship judged by either:

  1. Reporting health care professional
  2. Sponsor

For marketed drugs, Spontaneous Reports on ADR also imply causality.

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15
Q

Description for Causality Examples (1+3)

A

Other than “cause”, the following also qualify:

  1. “Plausible relationship”
  2. “Suspected causality”
  3. “Causal relationship cannot be ruled out”
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16
Q

Degree of Causality (5)

A

Certainly, definitely, probably, possibly or likely related, or not related

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17
Q

Non-single-case for Expedited Reporting Scenarios (3)

A

Population based situations:

  1. Serious ADR, but unexpected for its rate of occurrence, which reaches over a significant clinical threshold.
  2. Lack of efficacy in treating life-threatening disease, posing a significant hazard to patient population.
  3. Major safety finding from newly completed animal studies, which translates to human.
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18
Q

Reporting Time Frames for Fatal or Life-threatening Unexpected ADRs

A

Very rapid reporting to regulatory agencies:

Initial report: ASAP but within no later than 7 calendar days, after case qualification acknowledgement by sponsor.

Complete report: within no later than 15 calendar days, after case qualification acknowledgement by sponsor (8 additional days).

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19
Q

Reporting Time Frames for other Serious (Non-fatal, Non-life-threatening) Unexpected ADRs

A

Initial report: ASAP but within no later than 15 calendar days after case qualification acknowledgement by sponsor.

20
Q

Case Qualification: Minimum Criteria for Initial Report (5+1)

A
  1. An identifiable patient,
  2. A suspect medicinal product,
  3. An identifiable reporting source,
  4. An event or outcome identified as serious AND unexpected,
  5. Reasonable suspected causal relationship, and
  6. Other follow-up information if available.
21
Q

Key Elements for Inclusion in Completed Expedited Report of Serious ADRs (6)

A
  1. Patient details
  2. Suspected medicinal product(s)
  3. Other concomitant treatment(s)
  4. Details of suspected ADRs
  5. Details on Reporter of Event
  6. Administrative and Sponsor details
22
Q

Patient Details for Expedited Report (6)

A
  1. Initials
  2. Clinical investigation ID
  3. Gender
  4. Age/DOB
  5. Weight
  6. Hight
23
Q

Suspected Medicinal Products(s) Details for Expedited Report (10)

Drug (3)
Usage (7)

A

Drug:
1. Brand name
2. International non-proprietary name (INN)
3. Batch number

Usage:

  1. Indications for which the drug was prescribed or tested
  2. Dosage form and strength
  3. Daily dose and regimen
  4. Route of administration
  5. Starting date and time
  6. Stopping date and time
  7. Duration of treatment
24
Q

Examples of Concomitant Treatment for Expedited Report (2)

A

Information on the same level of details is required for concomitant treatment:

  1. Medicinal products (prescription and non-prescription/OTC drugs)
  2. Non-medicinal product therapies
25
Q

Details of Suspected ADRs for Expedited Report (9)

Description (5)
Intervention (4)

A

Description
1. Body site,
2. Severity,
3. Seriousness (criteria for the report),
4. Description of the reported signs and symptoms, and
5. Specific diagnosis for the reaction when possible

Intervention
6. Start/stop date and time
7. Dechallenge and rechallenge information
8. Setting (e.g., hospital, out-patient clinic, nursing home, home)
9. Case outcome

26
Q

Non-fatal Outcome Description for Expedited Report (4)

A

Non-fatal ADR:

  1. Recovery or sequelae information
  2. Clinical test results
  3. Required treatment
  4. Medical history
27
Q

Fatal Outcome Description for Expedited Report (4)

A

Fatal ADR:

  1. Cause of death
  2. Autopsy, or other post-mortem findings
  3. Comments on causality relationship between ADR and death
  4. Medical history
28
Q

Examples of Medical History supporting Outcome Assessment for Expedited Report (4)

A

Examples:

  1. Allergy
  2. Drug or alcohol abuse
  3. Family history
  4. Special investigation findings
29
Q

Details on Reporter of Event for Expedited Report (4)

A
  1. Name
  2. Address
  3. Telephone number
  4. Profession (speciality)
30
Q

Administrative Details for Expedited Report (6)

A
  1. Source of report (spontaneous, investigation, or literature)
  2. Date and location of the event
  3. Initial vs follow-up report
  4. Sponsor information
  5. Reporter information
  6. Identifying regulatory code for the suspected product
31
Q

Recommendations for sponsors on Blinded Cases for Expedited Report (2+1)

A

Recommendations when a serious ADR qualifies for expedited reporting:

  1. Blind broken by sponsor for the specific patient.
  2. Blind maintained for the investigator, if possible (if not already broken).
  3. Blind maintained for persons responsible for analysis and interpretation.
32
Q

Assumptions on Blinded Cases for Expedited Report

A

If investigator has broken the blind, the sponsor is assumed to be unblinded.

33
Q

Disadvantage to Maintaining the Blind

A
  1. Unnecessarily filing for placebo/comparator controls
  2. Delayed revision/update of safety database
  3. Inappropriate post-hoc update of the Investigators Brochure
  4. Insignificant of impact of single cases to the overall study
34
Q

Blinding Exceptions for Expedited Reporting for Serious Outcome as the Primary Efficacy Endpoint

A

If agreement is reached with regulatory authorities in advance, fatal or other serious events may be not subject to routine expedited reporting, and blind can be maintained to avoid compromising the integrity of the clinical investigation.

35
Q

Reactions Associated with Controls: Comparator or Placebo

A

Active Comparator: ADR must be reported by sponsor to manufacture or to regulatory agencies.

Placebo Controls: usually do not meet ADR and thus do not meet the expedited reporting criteria.

36
Q

Cross-referencing ADRs for Drugs with Multiple Presentation or Use

A

Specific product presentations and use, warrant separate Investigators Brochures for their specific “expectedness”, however,

other product presentations and uses need to be discussed in separate sections in the same document, to avoid ambiguities and uncertainties.

37
Q

Examples for Multiple Medicinal Product Presentations (3)

A
  1. Dosage form
  2. Formulation
  3. Delivery system
38
Q

Examples for Multiple Medicinal Product Uses (3)

A
  1. Different disease indications
  2. Different patient populations
  3. Different regimens (i.e., acute vs chronic administration)
39
Q

Principles in Cross-referencing ADRs for Drugs with Multiple Presentation or Use

A

Cross-referencing to all product presentation or use, which may lead to over-reporting, is needed to completely avoid underreporting.

Example:
A report of phlebitis on IV injection sent to authorities in a country where only an oral dosage form is studied or marketed, is needed despite some redundancy.

40
Q

Post-study Serious AE

A

Post-study serious adverse events, such as during any protocol-required post-treatment follow-up, should be regarded for expedited reporting purpose as though they were study reports.

Causality and expectedness needs to be determined to decide whether expedited reporting is required.

41
Q

Informing Investigators and IRB of New Safety Information

A

Sponsor should amend the Investigator’s Brochure to keep the description of safety information updated.

42
Q

Suspected Medicinal Products(s) Details for Expedited Report (10)

Drug (3)

A

Drug:

  1. Brand name
  2. International non-proprietary name (INN)
  3. Batch number
43
Q

Suspected Medicinal Products(s) Details for Expedited Report (10)

Usage (7)

A

Usage:

  1. Indications for which the drug was prescribed or tested
  2. Dosage form and strength
  3. Daily dose and regimen
  4. Route of administration
  5. Starting date and time
  6. Stopping date and time
  7. Duration of treatment
44
Q

Details of Suspected ADRs for Expedited Report (9)

Description (5)

A

Description
1. Body site,
2. Severity,
3. Seriousness (criteria for the report),
4. Description of the reported signs and symptoms, and
5. Specific diagnosis for the reaction when possible

45
Q

Details of Suspected ADRs for Expedited Report (9)

Intervention (4)

A

Intervention
6. Start/stop date and time
7. Dechallenge and rechallenge information
8. Setting (e.g., hospital, out-patient clinic, nursing home, home)
9. Case outcome

ACRP CPI® (7 decks)

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