STANDARDS FOR EXPEDITED REPORTING
A. What Should be Reported?
1. Single Cases of Serious, Unexpected ADRs
All adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited reporting. This applies to reports from spontaneous sources and from any type of clinical or epidemiological investigation, independent of design or purpose. It also applies to cases not reported directly to a sponsor or manufacturer (for example, those found in regulatory authority-generated ADR registries or in publications). The source of a report (investigation, spontaneous, other) should always be specified.
Expedited reporting of reactions which are serious but expected will ordinarily be inappropriate.
Expedited reporting is also inappropriate for serious events from clinical investigations that are considered not related to study product, whether the event is expected
or not. Similarly, non-serious adverse reactions, whether expected or not, will ordinarily not be subject to expedited reporting. Information obtained by a sponsor or manufacturer on serious, unexpected reports from any source should be submitted on an expedited basis to appropriate regulatory authorities if the
minimum criteria for expedited reporting can be met.
Causality assessment is required for clinical investigation cases. All cases judged by either the reporting health care professional or the sponsor as having a reasonable suspected causal relationship to the medicinal product qualify as ADRs. For purposes of reporting, adverse event reports associated with marketed drugs (spontaneous reports) usually imply causality.
Many terms and scales are in use to describe the degree of causality (attributability) between a medicinal product and an event, such as certainly, definitely, probably, possibly or likely related or not related. Phrases such as “plausible relationship,” “suspected causality,” or “causal relationship cannot be ruled out” are also invoked to describe cause and effect. However, there is currently no standard international nomenclature. The expression “reasonable causal relationship” is meant to convey in general that there are facts (evidence) or arguments to suggest a causal relationship.
2. Other Observations
There are situations in addition to single case reports of “serious” adverse events or reactions that may necessitate rapid communication to regulatory authorities; appropriate medical and scientific judgement should be applied for each situation. 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.
a) For an “expected,” serious ADR, an increase in the rate of occurrence which is judged to be clinically important.
b) A significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating life-threatening disease.
c) A major safety finding from a newly completed animal study (such as carcinogenicity).
B. Reporting Time Frames
1. Fatal or Life-Threatening Unexpected ADRs
Certain ADRs may be sufficiently alarming so as to require very rapid notification to regulators in countries where the medicinal product or indication, formulation, or population for the medicinal product are still not approved for marketing, because such reports may lead to consideration of suspension of, or other limitations to, a clinical investigations program.
Fatal or life-threatening, unexpected ADRs occurring in clinical investigations qualify for very rapid reporting. Regulatory agencies should be notified (e.g., by telephone, facsimile transmission, or in writing) as soon as possible but no later than 7 calendar days after first knowledge by the sponsor that a case qualifies, followed by as complete a report as possible within 8 additional calendar days. This report must include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar medicinal products.
2. All Other Serious, Unexpected ADRs
Serious, unexpected reactions (ADRs) that are not fatal or life-threatening must be filed as soon as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting.
3. Minimum criteria for reporting
Information for final description and evaluation of a case report may not be available within the required time frames for reporting outlined above. Nevertheless, for regulatory purposes, initial reports should be submitted within the prescribed time as long as the following minimum criteria are met: an identifiable patient; a suspect medicinal product; an identifiable reporting source; and 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. Follow-up information should be actively sought and submitted as it becomes available.
C. How to Report
The CIOMS-I form has been a widely accepted standard for expedited adverse event reporting. However, no matter what the form or format used, it is important that certain basic information/data elements, when available, be included with any expedited report, whether in a tabular or narrative presentation. The listing in Attachment 1 addresses those data elements regarded as desirable; if all are not available at the time of expedited reporting, efforts should be made to obtain them.
All reports must be sent to those regulators or other official parties requiring them (as appropriate for the local situation) in countries where the drug is under development.
D. Managing Blinded Therapy Cases
When the sponsor and investigator are blinded to individual patient treatment (as in a double blind study), the occurrence of a serious event requires a decision on whether to open (break) the code for the specific patient. If the investigator breaks the blind, then it is assumed the sponsor will also know the assigned treatment for that patient.
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 the sponsor even if the investigator has not broken the blind. It is also recommended that, when possible and appropriate, the blind be maintained for those persons, such as biometrics personnel, responsible for analysis and interpretation of results at the
There are several disadvantages to maintaining the blind under the circumstances described which outweigh the advantages. By retaining the blind, placebo and comparator (usually a marketed product) cases are filed unnecessarily. When the blind is eventually opened, which may be many weeks or months after reporting to regulators, it must be ensured that company and regulatory data bases are revised. If the event is serious, new, and possibly related to the medicinal product, then if the Investigator’s Brochure is updated, notifying relevant parties of the new information in a blinded fashion is inappropriate and possibly misleading.
Moreover, breaking the blind for a single patient usually has little or no significant implications for the conduct of the clinical investigation or on the analysis of the final clinical investigation data.
However, when a fatal or other “serious” outcome is the primary efficacy endpoint in a clinical investigation, the integrity of the clinical investigation may be compromised if the blind is broken. Under these and similar circumstances, it may be appropriate 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.
E. Miscellaneous Issues
1. Reactions Associated with Active Comparator or Placebo Treatment
It is the sponsor’s responsibility to decide whether active comparator drug reactions should be reported to the other manufacturer and/or directly to appropriate regulatory agencies. Sponsors must report such events to either the manufacturer of the active control or to appropriate regulatory agencies. Events associated with placebo will usually not satisfy the criteria for an ADR and, therefore, for expedited reporting.
2. Products with More than one Presentation or Use
To avoid ambiguities and uncertainties, an ADR that qualifies for expedited reporting with one presentation of a product (e.g., a dosage form, formulation, delivery system) or product use (e.g., for an indication or population), should be reported or referenced to regulatory filings across other product presentations and uses.
It is not uncommon that more than one dosage form, formulation, or delivery system (oral, IM, IV, topical, etc.) of the pharmacologically active compound(s) 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 (single dose vs. chronic administration, for example). Thus, “expectedness” may be product or product-use specific, and separate Investigator’s Brochures may be used accordingly.
However, such documents 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.
It is recommended that any adverse drug reactions that qualify for expedited reporting observed with one product dosage form or use be cross referenced to regulatory records for all other dosage forms and uses for that product. This may result in a certain amount of overreporting or unnecessary reporting in obvious situations (for example, a report of phlebitis on IV injection sent to authorities in a country where only an oral dosage form is studied or marketed). However, underreporting is completely avoided.
3. Post-study Events Although such information is not routinely sought or collected by the sponsor, serious adverse events that occurred after the patient had completed a clinical study (including any protocol required post-treatment follow-up) will possibly be reported by an investigator to the sponsor.
Such cases should be regarded for expedited reporting purposes as though they were study reports. Therefore, a causality assessment and determination of expectedness are needed for a decision on whether or not expedited reporting is required
F. Informing Investigators and Ethics Committees/Institutional Review Boards of New Safety Information
International standards regarding such communication are discussed within the ICH GCP Guidelines, including the addendum on “Guideline for the Investigator’s Brochure.” In general, the sponsor of a study should amend the Investigator’s Brochure as needed, and in accord with any local regulatory requirements, so as to keep the description of safety information updated.
KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED REPORTS OF SERIOUS ADVERSE DRUG REACTIONS
1. Patient Details
- Other relevant identifier (clinical investigation number, for example)
- Age and/or date of birth
2. Suspected Medicinal Product(s)
- 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 (specify units – e.g., mg, ml, mg/kg)
- Route of administration
- Starting date and time of day
- Stopping date and time, or duration of treatment
3. Other Treatment(s)
For concomitant medicinal products (including non-prescription/OTC medicinal products) and non-medicinal product therapies, provide the same information as for the
4. Details of Suspected Adverse Drug Reaction(s)
- Full description of reaction(s) including body site and severity, as well as the criterion (or criteria) for regarding the report as serious should be given. In addition to a
description of the reported signs and symptoms, whenever possible, attempts should be made to establish 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 (e.g., hospital, out-patient clinic, home, nursing home)
5. Details on Reporter of Event (Suspected ADR)
- Telephone number
- Profession (speciality)
6. Administrative and Sponsor/Company Details
- Source of report: was it spontaneous, from a clinical investigation (provide details), from the literature (provide copy), 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 (first, second, etc.)
- Name and address of sponsor/manufacturer/company
- Name, address, telephone number, and FAX number of contact person in reporting company or institution
- Identifying regulatory code or number for marketing authorisation dossier or clinical investigation process for the suspected product (for example IND or CTX number,NDA number)
- Sponsor/manufacturer’s identification number for the case (this number must be the same for the initial and follow-up reports on the same case)