Recent guidelines introduced within Australia have recommended a standardised format for reporting the frequency of AE’s for products with more extensive marketing experience. The preferred format is that defined by the CIOMS Working Group III and is often presented according to body systems. The CIOMS Working Group III has also recommended guidelines about what should not be included within the Adverse Drug Reaction section of a PI. Examples of adverse events that should not be incorporated in a PI include events that have no relationship to therapy, uncritically or unsubstantiated information (e.g. weak signals, over warnings) as well as clutter & extraneous information.
It should be noted that the adverse events contained within a PI are not necessarily an exhaustive list of all untoward effects that may occur as a result of drug treatment. Knowledge regarding all beneficial and adverse events associated with drug treatment are accrued with time and experience. For example, most studies conducted before a drug is first registered are not designed nor sufficiently powered to detect some adverse effects. Other unwanted effects associated with drug treatment may be rare, or occur when the agent is used in new populations in ways different compared to those in the original trials. Consequently, the PI may have to be changed to reflect updates in information. An example of a recent PI update was the change made to the Zyprexa PI regarding glucose abnormalities associated with olanzapine treatment.
Discuss How AE and ADR’s are reported to the TGA?
ADR reports should be submitted for any adverse events observed with prescription medications (including vaccines), over the counter medications, as well as complimentary medicines (e.g. nutritional supplements & vitamins).
The Role of the Sponsor/Manufacturer
It is a condition of marketing approval for companies to report suspected adverse drug reactions to the Therapeutic Goods Administration (TGA). As a requirement of the TGA, manufacturers and sponsors of pharmaceutical products will invariably have a qualified person responsible for pharmacovigilance to assure responsibility & liability for its products on the market. Notably, sponsors are expected to validate and follow up all serious reactions reported to the TGA by them.
Pharmaceutical representatives may play a pivotal role in the reporting process, as they are often the first point of contact when a healthcare practitioner observes an unusual effect. Suspected adverse drug reactions should also be reported to the drug manufacturer so that central databases within companies can be updated and international safety reporting obligations met. There is little risk of duplicating reports by notifying both the manufacturer and the TGA because the details contained within the reports are unique (e.g. patient initials, date etc).
The Role of ADRAC
The group responsible for compiling information regarding adverse drug effects reported to the TGA is the Adverse Drug Reaction Advisory Committee (ADRAC). ADRAC is a subcommittee of the Australian Drug Evaluation Committee (ADEC) of the TGA and is appointed by the Federal Minister of Health. Members of ADRAC are independent medical experts who have expertise in areas of importance to the evaluation of medicine safety.
Time Frame & Format for Reporting Adverse Events
The system underpinning the Australian ADR reporting process is the “blue card”. “Blue cards” are pre-paid mailers that are available to all health professionals and members of the general public. The details requested on a blue card include patient information (e.g. initials, sex, age etc), details of all medications being taken (including dose, duration of therapy), an asterisk to denote the suspect drug, a description of the reaction, as well as details from the person reporting the event.
The timeframe for reporting adverse drug reactions associated with registered drugs is tabled below. Generally, serious events (i.e. those that result in death, significant disability, require inpatient hospitalisation, or are life threatening) must be reported within 72 hours. Importantly, serious events associated with non-registered or non-listed drugs (e.g. SAS drugs) should also be reported to the TGA within 72 hours.
Table One: Time Frame & Format for Reporting Adverse Events Associated with a Registered Drug.
Adverse Event Reporting & ADRAC Actions
All reports received by ADRAC are entered onto the ADRAC database and then passed on to the WHO data bank for International Drug Monitoring.
Based on the receipt of an adverse event report, ADRAC may take any number of several actions. For example, ADRAC may:
- Take no further action because the AE is a well-known non-serious reaction.
- Take no further action until similar reports are received.
- Request further information from the reporter.
- Analyse the ADRAC database to investigate potential AE trends.
- Request information from the Sponsor or manufacturer.
- Publish the information in the Australian Adverse Reactions Bulletin which is distributed to all health professionals free of charge and can be found on the TGA website.
- Refer to other areas of the TGA for further investigation.
- Discuss the reaction with international regulatory bodies.
- Recommend an amendment to the products PI.
- Recommend a restriction to the drugs availability.
- Recommend removing the product from the market.
Discuss processes for changing the PI to present new information.
(This question has been addressed in relation to safety related notifications such as new Adverse Drug Reactions (not new indications, dosage instructions etc).
The PI is a summary of the technical, animal & clinical data evaluated by the TGA. Once approved, the PI cannot be changed except as stipulated by the Australian Guidelines for Registration of Drugs (ARTG), Volume One. However on occasion, changes may need to be made to the PI of a pharmaceutical relating to newly identified safety information. Section 32(4) of the Therapeutic Goods Act 1989 provides for safety related notifications to PI.
Advice regarding newly identified ADR’s & other safety related information is made through lodgement of a notice to the TGA. In such cases, the company would submit a copy of the modified PI within 5 days of implementation & comply with other administrative requirements. In some instances, the TGA may seek further details relating to the alteration before the ARTG entry is modified.
If the PI is amended in this way, the PI document must show the last date of TGA approval, in addition to the date of the most recent notification. Depending on the significance of the PI amendment, companies may in some instances be bound by obligations discussed in Section 2.3 of the APMA Code of Conduct.
