ICH Guideline E2A. Clinical Safety Data Mgmt

Adverse Drug Reaction (ADR) (Post Approval)

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

What is the timeframe for reporting fatal or life-threatening unexpected ADRs?

ASAP by telephone, fax, or in writing, but no later than 7 calendar days after first knowledge by the sponsor that a case qualifies.

Non-life-threatening or fatal unexpected ADRs need to be reported in what timeframe?

ASAP, but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting.

Adverse Drug Reaction (ADR) (Pre-Approval)

All noxious and unintended responses to a medicinal product related to any dose.

Unexpected Adverse Drug Reaction

An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product).

Life-threatening

An event in which a patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

Adverse Event (AE)

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

What must a fatal or life-threatening unexpected ADR report contain?

Assessment of the importance and implications of the findings including relevant previous experience with the same or similar product.

How to report ADRs?

CIOMS-I or another source and they should be sent to regulators or other official parties requiring them in the country where the IP is under investigation.

Adverse events suspected IP related may be significant enough to:

Changes it is developed ie. dosing, population, monitoring, consenting, etc. Prompt reporting is necessary to regulators.

How long do you have to complete a report for a fatal or life-threatening unexpected ADR?

Eight days following first report.

How should information obtained by a sponsor or manufacturer on serious, unexpected reports be reported?

Expedited

Expedited reporting should be applied to each of the following situations:

For an "expected", serious ADR an increase in the rate of occurrence, a significant hazard to the patient, and a major safety finding from a newly completed animal study i.e. carcingenicity.

Minimal reporting criteria for ADRs should contain:

Identifiable patient, suspect IP, identifiable source; and an event or outcome that can be identified as serious and unexpected along with a causal relationship. Updates should be sent as they are obtained.

What items are the minimal required data for ADR expedited reporting?

Identifiable patient, the name of the suspect drug, identifiable reporting source, identifiable event or outcome that is identified as a serious and unexpected.

Severe

Intensity of an event.

How are blinded cases managed in the event of unexpected ADRs?

It may need to be unblinded for the patient, but may keep blinding for analysts, etc. and only unblind investigator, or sponsor.

Sponsors must report ADRs for a comparator drug to whom?

Manufacturer of drug and any other regulatory agencies.

What are other items that should be included on expedited reporting?

Patient Details: Initials, DOB, Age, gender, ht, and wt. Suspected Medicinal Products: Brand name, International non-proprietary name, batch number indication, dosage, strength, daily dose, route of admin, start date and time, stopping date and time. Other medicines as provided for the suspected med., Adverse event reaction, start and stop of the event, setting i.e. hosp. or clinic, dechallenge info. Outcome and patient history., Reporter of event information. Admin and sponsor company details. date event received, demographics of the company, country, type of report initial, f/u, etc., regulatory codes, sponsor id/mfr number.

Serious

Patient/event outcome or action criteria usually asssociated with events that pose a threat to a patient's life.

Other times to report ADRs include

Products with more than one presentation and involving post study events.

Source documentation for the serious adverse event is contained in what?

The IB which determines whether or not an event is expected.

How should updates in regards to ADRs to investigators, IRBs, and IECs?

They need to maintain an up to date IB.

What is the purpose of expedited reporting?

To make appropriate regulators, investigators and others aware of new important information on serious reactions i.e. ones that have not been previously observed or documented.

An event that is more severe or specific than listed in the IB is considered to be:

Unexpected.

Serious Adverse Event

Untoward medical occurrence that at any dose: results in death or is life-threatening. Requires hospitalization or prolongation of such, results in persistent or significant disability or capacity, is a congenital anomaly/birth defect.