Guidelines on the reporting of adverse drug reactions by drug sponsors

1. Foreword

These guidelines describe the administrative procedures to be followed by drug sponsors in submitting Australian reports of adverse drug reactions to the Therapeutic Goods Administration (TGA).

All adverse drug reaction reports should be forwarded to the Office of Medicines Safety Monitoring (OMSM), for appropriate action within the Office and other relevant areas of the TGA. Foreign reports are not to be forwarded to the TGA on a routine basis, but in the context of a specific safety issue or on specific request (see Section 4.1.3).

Under current arrangements, and for the purposes of these guidelines, the Office of Medicines Safety Monitoring <http://www.tga.gov.au/adr/index.htm> can be considered synonymous with the Adverse Drug Reactions Advisory Committee (ADRAC) Secretariat <http://www.tga.gov.au/adr/adrac.htm>.

Although these are guidelines, and certain stipulations are not obligatory, sponsors are encouraged to comply in a spirit of cooperation. If the guidelines are found to be unclear or there are difficulties in complying with them, please direct any comments or enquiries to:

Further copies of the guidelines and other relevant documentation can be obtained from:

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2. General principles

The Office of Medicines Safety Monitoring has a preferred format for the presentation of clinical details concerning adverse reactions to drugs. The preferred format is embodied in the "blue card" prepaid mailer form which is sent out to individual Australian health professionals.

It has been the TGA's experience that the "blue card" <http://www.tga.gov.au/adr/bluecard.htm>, although relatively small in size, allows for the provision of sufficient clinical information to permit an efficient initial assessment of the significance of the adverse reaction and of the suspected drug's role in causing the adverse reaction. The brevity and succinctness of the "blue card" also permits the review of relatively large numbers of suspected adverse reaction reports on a daily basis by OMSM. Although further details are occasionally asked for sponsors are requested, when notifying a reaction involving a drug, in the first instance to provide to the TGA only those details which are requested in its "blue card" reporting form.

A copy of the "blue card" form is available from the Office of Medicines Safety Monitoring on request or can be downloaded from the TGA website. Sponsors are also encouraged to use this form as a template or to devise a similar form for submitting data on adverse reactions to drugs to the TGA. Further relevant individual patient clinical or laboratory data should be held by the sponsor and made available to the TGA on request.

All reports, except in cases of perceived extreme urgency, should be mailed and not faxed. After the initial notification, further correspondence relating to the same case submitted to the TGA should be cross-referenced, wherever possible, to an "ADR" (database) number (if one has been advised) or to an appropriate unique sponsor number (which relates specifically to the initial notification). This is the only reliable means by which duplication of reports submitted by sponsors will be minimised.

Please note that if the data submitted by a sponsor lack essential individual clinical information and cannot be assessed objectively, the report(s) will not be entered into the database and no ADR number(s) will be allocated.

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3. Definitions

Adverse Event (AE)

An adverse event is any untoward medical occurrence in a patient administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product.

Adverse Drug Reaction (ADR)

Adverse drug reactions concern noxious and unintended responses to a medicinal product.

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.

A reaction, in contrast to an event, is characterised by the fact that a causal relationship between the drug and the occurrence is suspected. For regulatory reporting purposes, if an event is spontaneously reported, even if the relationship is unknown or unstated, it meets the definition of an adverse drug reaction.

Serious AE/ADR

A serious adverse event or reaction is any untoward medical occurrence that at any dose:

• results in death
• is life-threatening
  (NOTE: The term "life-threatening" in the definition of "serious" refers to an event/reaction in which the patient was at risk of death at the time of the event/reaction; it does not refer to an event/ reaction which hypothetically might have caused death if it were more severe),
• requires inpatient hospitalisation or results in prolongation of existing hospitalisation,
• results in persistent or significant disability/incapacity,
• is a congenital anomaly/birth defect,
• is a medically important event or reaction.

Medical and scientific judgment should be exercised in deciding whether other situations should be considered serious such as important medical events that might not be immediately life-threatening or result in death or hospitalisation but might jeopardise the patient or might require intervention to prevent one of the other outcomes listed in the definition above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse.

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4. Specific procedures

4.1 Registered (prescription) drugs

(Note: The Australian pharmacovigilance guideline introduced on 1 July 2002 has been amended. This document applies only to medicines regulated by the Office of Prescription Medicines (OPM) of the TGA.)

4.1.1 Australian spontaneous reports

It is a condition of registration/listing that a sponsor must forward all spontaneous Australian reports it receives, of suspected adverse reactions to drugs for which it is responsible, to the TGA. The format and timeframe for submission of reports to the TGA is:

1. Serious reactions whether expected or unexpected occurring in Australia should be notified to the TGA immediately and in no case later than 15 calendar days from receipt in the form of a detailed "blue card" format case summary; even if initial information is scanty, these details should be forwarded to the TGA pending receipt and provision of further data.
2. Other reactions (non-serious unexpected reactions and non-serious expected reactions) occurring in Australia should not be notified immediately but should be reported on request or as line listings in a Periodic Safety Update Report.

4.1.2 Company-sponsored Australian postmarketing studies

Company-sponsored post-marketing surveillance studies carried out in Australia potentially generate a large volume of adverse drug reaction reports. The format and timeframe for submission to the TGA of such company generated reports, which should be identified as such, is:

1. Serious reactions whether expected or unexpected occurring in Australia should be notified to the TGA immediately and in no case later than 15 calendar days from receipt in the form of a detailed "blue card" format case summary with provisos as in 4.1.1 (a) above concerning scanty initial data.
2. Other reactions should be provided as a tabulation at the end of the study;
3. When the study has been completed, a comprehensive in-depth analysis of all the final results, with discussion of the implications of any new findings, should be provided to the TGA.

4.1.3 Foreign reports

Sponsors are not required to routinely submit foreign reports of suspected adverse drug reactions. The TGA requires, instead, that sponsors advise the TGA, within 72 hours, of any significant safety issue or action which has arisen from any analysis of foreign reports, or which has been taken by a foreign regulatory agency, including the basis for such action.

The TGA also requires that sponsors be able to provide promptly to the TGA clinical details of any foreign adverse drug reactions reports.

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4.2 Registered (OTC) and listed drugs

It is a condition of registration/listing that a sponsor must forward all spontaneous Australian reports it receives, of suspected adverse reactions to drugs for which it is responsible, to the TGA. The format and timeframe for submission of reports to the TGA is:

1. Serious unexpected reactions should be notified "immediately" to the TGA (ie within 72 hours of the sponsor becoming aware of the report) in the form of a detailed "blue card" format case summary; even if initial information is scanty, these details should be forwarded to the TGA pending receipt and provision of further data.
2. Other reactions, although not warranting the same urgency, should also be reported regularly to the TGA using the "blue card" format, as the sponsor becomes aware of the report(s)

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4.3 Drugs not registered or listed

In general, reports of adverse drug reactions generated during clinical trials should be handled according to the advice issued by the Drug Safety and Evaluation Branch, in July 2000 entitled Notes for Guidance on Clinical Safety Management: Definitions and Standards for Expedited Reporting (CPMP/ICH/377/95). Annotated with TGA Comments <http://www.tga.gov.au/docs/html/ich37795.htm>.

Reports in accordance with this guideline for clinical trials should be sent to the Experimental Drugs Section of the Office of Prescription Medicines. Further information can be obtained by calling 02 6232 8046.

Summary

Summary of information concerning Guidelines on the reporting of Australian adverse drug reactions by drug sponsors

Drug status		Format	Timeframe
REGISTERED (PRESCRIPTION) DRUGS
Spontaneous report
	Serious	Blue card	< 15 days
	Other	Line listing	in PSUR
Company-sponsored post-marketing surveillance study
	Serious	Blue card	< 15 days
	Other	Tabulation	At end of study
REGISTERED (OTC) OR LISTED DRUGS
Spontaneous report
	Serious/unexpected	Blue card	< 72 hours
	Other	Blue card	Regularly

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