Definitions and Standards for Expedited Reporting E2A

Question 1

What does ICH stand for?

Answer 1

The International Council of Harmonization of Technical Requirements for Pharmaceuticals for Human Use

Question 2

Adverse Event (or Adverse Experience)

Answer 2

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Question 3

Adverse Drug Reaction (in the pre-approval clinical experience)

Answer 3

All noxious and unintended responses to a medicinal product related to any dose.
The phrase “responses to a medicinal product” means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, the relationship cannot be ruled out.

Question 4

Adverse Drug Reaction (regarding marketed medicinal products)

Answer 4

A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function.

Question 5

What old term should no longer be used and particularly should not be regarded as synonymous with adverse event or adverse reaction?

Answer 5

Side effect

Question 6

Unexpected Adverse Drug Reaction

Answer 6

An adverse reaction, the nature or severity of which is not consistent with the applicable product information.

Question 7

True/False:
An unexpected adverse drug reaction is an adverse reaction, the nature and severity of which is not consistent with the applicable product information.

Answer 7

False.
An unexpected adverse reaction is an adverse reaction, the nature OR severity of which is not consistent with the applicable product information.

Question 8

True/False:
The terms “serious” and “severe” are synonymous.

Answer 8

False.
The term “severe” is often used to describe the intensity (severity) of a specific event.
The term “serious” is based on the patient/event outcome or action criteria and is usually associated with events that pose a threat to a patient’s life or functioning.

Question 9

True/False:
Severity serves as a guide for defining regulatory reporting obligations.

Answer 9

False.
SERIOUSNESS serves as a guide for defining regulatory reporting obligations.

Question 10

Serious

Answer 10

Based on the patient/event outcome or action criteria and is usually associated with events that pose a threat to a patient’s life or functioning.

Question 11

Severe

Answer 11

Used to describe the intensity (severity) of a specific event.
The event itself may be of relatively minor medical significance.

Question 12

Serious Adverse Event (Experience) or Reaction

Answer 12

Any untoward medical occurrence that at any dose:
- Results in death
- Is life-threatening
- Requires inpatient hospitalization or prolongation of existing hospitalization
- Results in persistent or significant disability/incapacity
- Is a congenital anomaly/birth defect

Question 13

True/False:
There are other important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the SAE definitions that should be considered serious and should be reported as such.

Answer 13

True

Question 14

What documents or circumstances are used to determine whether an adverse event/reaction is expected?

Answer 14

1. For a medicinal product not yet approved for marketing in a country, a company’s IB will serve as the source document in that country.
2. Reports which add significant information on specificity or severity of a known, already documented serious ADR constitute unexpected events.

Question 15

All adverse drug reactions that are both serious and unexpected are subject to what?

Answer 15

Expedited reporting

Question 16

True/False:
Expedited reporting of reactions which are serious but expected will ordinarily be appropriate.

Answer 16

False.
Expedited reporting of reactions which are serious but expected will ordinarily be INAPPROPRIATE.

Question 17

True/False:
Expedited reporting is inappropriate for serious events from clinical investigations that are considered not related to study product, whether the event is expected or not.

Answer 17

True

Question 18

True/False:
Non-serious adverse reactions, whether expected or not, will ordinarily be subject to expedited reporting.

Answer 18

False.
Non-serios adverse reactions, whether expected or not, will ordinarily NOT be subject to expedited reporting.

Question 19

Information obtained by a sponsor or manufacturer on serious, unexpected reports from any should be submitted on an expedited bases to who if the minimum criteria for expedited reporting can be met?

Answer 19

Appropriate regulatory authorities

Question 20

There is currently no standard international nomenclature, but what are some examples of terms used to describe the degree of causality between a medicinal product and an event?

Answer 20

• Certainly
• Definitely
• Probably
• Possibly
• Likely related
• Likely not related
• Plausible relationship
• Suspected causality
• Causal relationship cannot be ruled out
• Reasonable causal relationship

Question 21

There are situations in addition to single case reports of “serious” adverse events or reactions that may necessitate rapid communication to regulatory authorities. In general, information that might materially influence the benefit-risk assessment of a medicinal product or that would be sufficient to consider changes in medicinal product administration or in the overall conduct of a clinical investigation represents such situations. What are some examples?

Answer 21

• For an expected, serious ADR, an increase in the rate of occurrence which is judged to be clinically important.
• A significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating life-threatening disease.
• A major safety finding from a newly completed animal study.

Question 22

What is the reporting time frame for fatal or life-threatening unexpected ADRs occurring in clinical investigations?

Answer 22

Notification as soon as possible but no later than 7 calendar days after first knowledge by the sponsor.
The complete report should be sent as soon as possible within 8 calendar days.

Question 23

What must a report of a fatal or life-threatening event sent to the regulatory authorities include?

Answer 23

An assessment of the importance and implication of the findings, including relevant previous experience with the same or similar medicinal products.

Question 24

What is the reporting time frame for serious, unexpected reactions that are not fatal or life-threatening?

Answer 24

As soon as possible but no later than 15 calendar days after the fist knowledge by the sponsor.

Question 25

Information for final description and evaluation of a case report may not be available within the required time frames for reporting. Nevertheless, for regulatory purposes, initial reports should be submitted within the prescribed time as long as what minimum criteria is met?

Answer 25

- An identifiable patient - A suspect medicinal product - An identifiable reporting source - An event or outcome that can be identified as serious and unexpected, and for which, in clinical investigation cases, there is a reasonable suspected causal relationship

Question 26

Although it is advantageous to retain the blind for all patients prior to final study analysis, when a serious adverse reaction is judged reportable on an expedited basis, it is recommended that the blind be broken only for that specific patient by who?

Answer 26

The sponsor (even if the investigator has not broken the blind)

Question 27

If the blind is broken for a patient that has experienced a serious adverse reaction, when possible and appropriate, who should the blind be maintained for?

Answer 27

Those persons, such as biometrics personnel, responsible for analysis and interpretation of results at the study's conclusion

Question 28

Under what circumstances would it be appropriate to not break the blind when a patient experiences a serious adverse reaction and to reach agreement with regulatory authorities in advance concerning serious events that would be treated as disease-related and not subject to routine expedited reporting?

Answer 28

When a fatal or other "serious" outcome is the primary efficacy endpoint in a clinical investigation and the integrity of the clinical investigation may be compromised if the blind is broken.

Question 29

Who decides whether active comparator drug reactions should be reported to the other manufacturer and/or directly to appropriate regulatory agencies?

Answer 29

The sponsor

Question 30

True/False: To avoid ambiguities and uncertainties, an ADR that qualifies for expedited reporting with one presentation or a product or product use, should be reported or referenced to regulatory filings across other product presentations and uses.

Answer 30

True

Question 31

It is not uncommon that more than one dosage form, formulation, or delivery system of the pharmacologically active compound is under study or marketed; for these different presentations there may be some marked differences in the clinical safety profile. The same may apply for a given product used in different indications or populations. This, expectedness may be product or product-use specific, and separate IBs may be used accordingly. With this in mind, are IBs expected to cover ADR information that applies to all affected product presentations and uses or only those for the presentation and use outlined in that specific IB?

Answer 31

IBs are expected to cover ADR information that applies to all affected product presentations and uses. When relevant, separate discussions of pertinent product-specific or use-specific safety information will also be included.

Question 32

What are the key data elements for inclusion in expedited reports of serious adverse drug reactions?

Answer 32

- Patient Details - Suspected Medicinal Product(s) - Other Treatment(s) - Details of Suspected Adverse Drug Reaction(s) - Details on Reporter of Event (Suspected ADR) - Administrative and Sponsor/Company Details

Question 33

What patient details should be included in expedited reports of serious adverse drug reactions?

Answer 33

- Initials - Other relevant identifier (clinical investigation number) - Gender - Age and/or date of birth - Weight - Height

Question 34

What information regarding the suspected medicinal product(s) should be included in expedited reports of serious adverse drug reactions?

Answer 34

- Brand name as reported - International Non-Proprietary Name (INN) - Batch Number - Indication(s) for which suspect medicinal product was prescribed or tested - Dosage form and strength - Daily dose and regimen - Route of administration - Starting date and time of day - Stopping date and time, or duration of treatment

Question 35

INN

Answer 35

International Non-Proprietary Name

Question 36

What information regarding other treatments should be included in expedited reports of serious adverse drug reactions?

Answer 36

For concomitant medicinal products and non-medicinal product therapies, the same information as for the suspected product should be provided: - Brand name as reported - International Non-Proprietary Name (INN) - Batch Number - Indication(s) for which suspect medicinal product was prescribed or tested - Dosage form and strength - Daily dose and regimen - Route of administration - Starting date and time of day - Stopping date and time, or duration of treatment

Question 37

What suspected adverse drug reaction(s) details should be included in expedited reports of serious adverse drug reactions?

Answer 37

- Full description of reaction(s) including body sit and severity, as well as the criterion for regarding the report as serious. - When possible, a specific diagnosis for the reaction - Start date (and time) of onset of reaction - Stop date (and time) or duration of reaction - Dechallenge and rechallenge information - Setting - Outcome - Information on recovery and any sequelae - Specific tests and/or treatment that may have been required and their results - Anything relevant to facilitate assessment of the case - For a Fatal Outcome: - Cause of death and a comment on its possible relationship to the suspected reaction - Any autopsy or other post-mortem findings

Question 38

What reporter of event details should be included in expedited reports of serious adverse drug reactions?

Answer 38

- Name - Address - Telephone number - Profession (specialty)

Question 39

What administrative and sponsor/company details should be included in expedited reports of serious adverse drug reactions?

Answer 39

- Source of report (spontaneous, clinical investigation, literature, other) - Date event report was first received by sponsor/manufacturer - Country in which event occurred - Type of report filed to authorities: initial or follow-up - Name and address of sponsor/manufacturer/company - Name, address, and telephone number for marketing authorization dossier or clinical investigation process for the suspected product - Sponsor/manufacturer's identification number for the case