2.1 Contact person for pharmacovigilance

Sponsors must report to the TGA, the name and contact details of the person ('the nominated contact person') responsible for fulfilling the sponsor's reporting requirements for the ARTG entries they hold, described in this document. The sponsor must notify the TGA of this person within 15 calendar days of entering a product on the ARTG, and within 15 calendar days of any change in details of the nominated contact person¹⁸. This information should be submitted to the TGA using the Client Details form¹⁹.

Any pharmacovigilance information required by this document to be reported to the TGA should be submitted by the nominated contact person.

2.2 Adverse reactions (ARs)

For both registered and listed medicines, reports of suspected ARs received by the sponsor from all sources including healthcare professionals and consumers²⁰ must be reported as specified in this document. This includes spontaneous AR reports²¹, those reported in the world-wide literature and any suspected ARs from post-registration studies or post market initiatives. An AR is suspected if either the person reporting to the sponsor, or the sponsor, believes there is a possible causal relationship between it and the medicine in question. Spontaneous reports of suspected ARs must be reported in accordance with this document even if the sponsor does not agree with the reporter's assessment of a possible causal association, or if the reporter has not provided a causal assessment. Therefore all spontaneous reports notified by healthcare professionals, patients or consumers to the sponsor are considered suspected ARs and reportable in accordance with this document, since they convey the suspicions of the primary source²², unless the person reporting to the sponsor specifically states that they believe the events to be unrelated or that a causal relationship can be excluded, and the sponsor agrees with this assessment.

For reports of suspected ARs where the sponsor disagrees with the reasonable possibility of a causal relationship between the suspected medicine and the AR reported by the primary source, the opinions of both the primary source and the sponsor should be recorded in the AR report, including the criteria on which the sponsor has made their assessment. This information should also be included in reports submitted to the TGA.

For reports from post-registration studies²³ and other post marketing initiatives²⁴, all cases judged by either the reporting healthcare professional, the investigator or the sponsor as having a possible causal relationship to the medicine would qualify as suspected ARs.

Different methods may be applied for assessing the causal role of a medicine on the reported adverse event (AE)²⁵ (e.g., the World Health Organisation - Uppsala Monitoring Centre (WHO-UMC) system for standardised case causality assessment). In this situation, the level of causality that corresponds to a reasonable possibility of causal relationship should be established in order to determine if an AE is also considered an AR.

For AR cases reported in the worldwide literature, such as those in international multi-centre reports, the sponsor should endeavour to identify which cases occurred in Australia. In instances where sponsors cannot confirm whether the reaction occurred in Australia or overseas, they must keep records of such ARs and produce the report if requested by the TGA, within the requested timeframe, and should consider the AR report in any global analysis of adverse reports.

ARs are reportable in accordance with the requirements outlined in this document, regardless of whether the listed or registered medicine was used in accordance with the Product Information (PI) document (such as prescribed doses higher than those recommended), or with directions for use and indications on the medicine label. However, medicines supplied under the Special Access Scheme (SAS) are subject to separate reporting requirements²⁶. Section 2.5.7 includes information specific to reporting overdose, abuse, off-label use, misuse, medication error or occupational exposure.

If sponsors are aware that a person has reported a reaction to one of its products to the TGA, the sponsor must still report the reaction to the TGA if required by this document and inform the TGA at the time of making the report, that the report is likely to be a duplicate of a previous report. In this case the sponsor must provide all available details to aid identification of the duplicate, including the AR record number allocated to the initial report by the TGA if known.

2.3 Information that must be reported

2.3.1 Serious adverse reaction reports

Sponsors must report the following information in relation to any medicine for which they are the sponsor:

• all serious²⁷ unexpected and serious expected ARs occurring in Australia, that become known to the sponsor, and are associated with the use of the medicine or active substance in the medicine²⁸;
• all serious unexpected and serious expected ARs reported in the worldwide literature, that become known to the sponsor, occurred in Australia and are associated with the use of the medicine or active substance in the medicine, including a copy of the relevant published article in English or, if not published in English, accompanied by a summary or translation in English;
• all clinical and medically relevant information in relation to serious ARs occurring in Australia that becomes available to the sponsor as a result of follow-up activities; and
• a suspected increase in the frequency of serious ARs to the medicine, including the basis on which the frequency assessment has been made²⁹.

In order to meet mandatory reporting requirements and as a part of good practice, sponsors should validate³⁰ and follow up all serious ARs they report. The sponsor must give the TGA all clinical and medically relevant information that becomes available as a result of follow-up activities. Where possible, follow-up reports must include the AR record number allocated to the initial report by the TGA as recorded in the original acknowledgement from the TGA. The sponsor must also clearly identify the additional information provided.

In exceptional cases, when a reported AR impacts significantly on the established safety profile of the product, the sponsor must indicate this in the report. Examples might be where the report is one of a series of similar or linked cases simultaneously reported, or where there is evidence in favour of a causal relationship for a serious and unexpected reaction. Other situations include a suggestion of a change in the nature, severity or frequency of expected ARs or when new risk factors are identified³¹. Information on the frequency of ARs should also provide the basic data on which the estimate of the frequency has been made, including data on the total number of AR reports and number of patients exposed.

Sponsors are not required to routinely report to the TGA non-serious ARs that occurred in Australia, but must report such ARs as line listings³² in a PSUR if one is required, and must also report such ARs if requested by the TGA, in the requested format and within the requested timeframe.

Individual AR reports initially becoming known to the sponsor from the TGA must be included in the next PSUR, if one is required, and not routinely reported as individual ARs. This includes where a sponsor chooses to interrogate the TGA Database of Adverse Event Notifications (DAEN) for ARs to their medicine(s). However, if these TGA reports could lead to a change in the benefit/risk evaluation for the product, this possibility must be communicated to the TGA as a significant safety issue (see sections 2.3.2 and 2.4.2).

2.3.2 Significant safety issues

Sponsors must report the following information in relation to any medicine for which they are the sponsor:

• significant safety issues identified by the sponsor as a result of its ongoing review and analysis of all information that is pertinent to the safety or benefit-risk assessment of the product. This includes, but is not limited to, issues identified following review and analysis of reports of ARs that have occurred in a country other than Australia, or action taken by a foreign regulatory agency and the basis for such action.

Significant safety issues generally include, but are not limited to, any matter about the safety of the product which results, in a country other than Australia, in the:

• withdrawal or suspension of availability of the product;
• addition of a contraindication, warning or precaution statement to the PI or label;
• modification of an existing contraindication, warning or precaution statement in the PI or label for safety reasons; or
• modification or removal of an indication for safety reasons.

If requested by the TGA, a sponsor must be able to provide, within the requested timeframe, copies of foreign AR reports in its possession that formed the basis for such actions.

Examples of other significant safety issues that may be pertinent to the safety or benefit-risk assessment of the product include:

• safety issues arising from signal detection activity, or emerging from a new AR report, that impact on the risk-benefit balance of the medicine and/or have implications for public health;
• major safety findings from a newly completed non-clinical study, post-registration study or clinical trial;
• signal of a possible teratogenic effect or of significant hazard to public health;
• safety issues published in the scientific or medical literature;
• safety issues due to misinformation in the PI;
• safety issues related to use outside the terms of the PI or directions for use;
• safety issues in relation to any raw materials used in the medicine; or
• a change in the nature, severity or frequency of expected ARs, or when new risk factors are identified that impact on the safety or benefit-risk assessment of the product³³.

In situations where sponsors inform the TGA that reported ARs impact on the established safety profile, sponsors must also indicate to the TGA what action they propose to take. The outlined action might relate to conditions of registration or listing including amendments to the label or the PI, or any other change or action.

If requested by the TGA, a sponsor must be able to provide within the requested timeframe any additional information to assist with evaluation of the benefits and risks of a medicine, including the provision of information about the volume of sales or prescriptions of the product concerned.

2.4 Reporting timeframes

2.4.1 Reporting timeframes for serious adverse reactions

All serious ARs must be reported as soon as possible and in no case later than fifteen (15) calendar days from receipt by the sponsor. The clock for serious ARs starts (as day 0) on the day that the four minimum data elements,³⁴ in relation to the AR report, are received by one or more of the following:

• any personnel of the sponsor - including sales representatives;
• the person responsible for pharmacovigilance or persons working for or with this person; or
• where the sponsor has entered into a relationship with a second company for the marketing of, or research on, the suspected product, the clock starts as soon as any personnel of the primary sponsor receives the minimum information. Wherever possible, the timeframe for regulatory submission should be no longer than 15 days from first receipt by the second company and explicit procedures and detailed agreements should exist between the sponsor and the second company to facilitate achievement of this objective.

The reporting time clock is considered to begin again when a sponsor receives additional clinical or medically relevant information for a previously reported serious AR. This information must be reported as soon as possible and in no case later than fifteen (15) calendar days after receipt of the additional information.

If a sponsor receives additional information about a case initially classified as non-serious that indicates the case should be re-classified (e.g., from non-serious to serious), the sponsor must report the case as soon as possible, and in no case later that 15 calendar days after receipt of the information that led to the change in classification.

For suspected serious AR cases occurring in Australia that are identified through screening the worldwide literature, the clock starts (day zero) when the sponsor becomes aware of a publication containing the four minimum data elements. It is preferable that a copy of the relevant published article (in English or an English summary/translation) is provided to the TGA at the time the initial AR report is made. However if the article is not available at this time, it must be provided to the TGA within 15 calendar days of submission of the AR report to the TGA. Where difficulty is experienced in meeting the 15 calendar day requirement for submission of the article, the TGA must be notified in writing prior to the 15 day period ending.

2.4.2 Reporting timeframes for significant safety issues

Any significant safety issue³⁵ identified by the sponsor must be reported to the TGA within 72 hours. The 72-hour clock starts from the time of awareness of the issue by any personnel of the sponsor. This is considered to have occurred when the sponsor's review and analysis have been completed and a conclusion is drawn that a significant safety issue exists, or when the sponsor becomes aware of the actions of an overseas regulatory agency.

These situations are different from the reporting of individual ARs, where the sponsor is allowed up to 15 days to confirm and follow up details before submitting an individual serious AR report to the TGA.

2.5 Reporting requirements in special situations

2.5.1 Adverse reaction reports from post-registration studies

The TGA requires sponsors to report all known serious suspected ARs occurring in post-registration studies³⁶ undertaken in Australia, of which the sponsor is aware, in accordance with reporting time frames for serious ARs (Section 2.4.1). Sponsors should have mechanisms in place to collect full and comprehensive case information and to evaluate that information, in order to allow meaningful assessment of individual cases and reporting of valid ARs related to the studied (or supplied) medicine. Sponsors should therefore exercise due diligence in establishing such a system; in following up those reports; and in seeking the view of the primary source with regard to the causal role of the studied (or supplied) medicine in the notified AE. Where the primary source's opinion as to the causal role is missing, the sponsor should exercise its own judgement based on the information available in order to decide whether the report is a valid AR that must be reported to the TGA in accordance with the requirements described in this document.

In instances where the post-registration study is conducted or initiated by an investigator independent of the sponsor of the medicine, the responsibility for reporting ARs to the TGA rests with the investigator. However, if the sponsor is aware of the study, the sponsor should request that it is notified by the investigator of serious ARs that occur in the study. Where a sponsor becomes aware of such ARs, they must ensure that the ARs are reported in accordance with the requirements described in this document.

Sponsors are not required to report blinded cases and AEs not suspected of being due to the study product(s) as individual cases.

Section D of the ICH Guideline E2A Note for guidance on clinical safety data management: Definitions and standards for expedited reporting (CPMP/ICH/377/95 )³⁷ should be referred to for guidance on the management of blinded cases. Sponsors must report serious ARs only if the blind has been broken. Otherwise, sponsors are required to submit cases of serious ARs in blinded studies upon unblinding at the end of the study, in accordance with reporting timeframes for serious ARs (see section 2.4.1).

Records of non-serious ARs and AEs, of which the sponsor is aware, that occur during post-registration studies must be retained by the sponsor and provided if requested by the TGA within the requested time frame, and do not require routine submission as individual AR reports.

Sponsors should refer to the TGA's notes for guidance on clinical trials³⁸ for information about reporting ARs from ongoing clinical trials conducted outside the terms of the PI or label indications.

2.5.2 Reports from other post-marketing initiatives: surveys, registries etc.

Sponsors may be involved in post-marketing initiatives that result in the collection of information related to their products, such as patient support and disease management programs, surveys of patients or healthcare providers, information gathering on efficacy or patient compliance, market research programs and voluntary patient registries. These activities may involve the receipt of information on AEs.

Sponsors should have in place a system to collect full and comprehensive case information and to evaluate that information in order to determine whether the collected AEs are possibly related to the studied (or supplied) medicine. If so, they should be classified and processed as suspected ARs and are subject to the reporting requirements described in this document.

2.5.3 Reporting outcomes of use during pregnancy and breastfeeding

Sponsors should follow up all individual reports of pregnancies where the embryo or foetus could have been exposed to one of its products (either through maternal exposure or transmission of a medicine via semen following paternal exposure) in order to collect information on the outcome of the pregnancy and development of the child after birth. Where reports originate from consumers, reasonable attempts should be made to follow up via the patient's healthcare professional³⁹.

Sponsors should take into account when an active substance (or one of its metabolites) has a long half-life when considering whether an embryo or foetus could have been exposed. In other words, sponsors should consider whether a medicine may have been taken prior to conception or pregnancy.

Not infrequently, pregnant women or healthcare professionals will contact sponsors to request information on the teratogenicity of a medicine and/or experience of use during pregnancy. Reasonable attempts should be made to obtain information on any possible medicine exposure to an embryo or foetus and to follow up on the outcome of the pregnancy.

Reports of exposure to medicines during pregnancy should contain as many detailed elements as possible in order to assess the causal relationship between any reported AEs and the exposure to the suspected medicine.

If the sponsor becomes aware of cases where a pregnancy results in an abnormal outcome, which the reporting healthcare professional considers might be due to a listed or registered medicine, the sponsor must treat it as a serious AR and report in accordance with the timeframes in section 2.4.1. This especially refers to:

• reports of congenital anomalies or developmental delay, in the foetus or the child;
• reports of foetal death and spontaneous abortion; and
• reports of suspected ARs in the neonate that are classified as serious.

Other cases, such as reports of induced termination of pregnancy without information on congenital malformation, reports of pregnancy exposure without outcome data or reports that have a normal outcome, should not be reported since there is no suspected AR. These reports should however be collected by the sponsor and must be provided if requested by the TGA, in the requested format and within the requested timeframe. These reports must also be included in the next PSUR (if one is required) together with aggregated data of overall exposure and details of normal and abnormal outcomes. The TGA may also request reports from prospective registries to be included and evaluated in the PSUR.

If at any time the sponsor becomes aware of a signal of a possible teratogenic effect (e.g. a cluster of similar abnormal outcomes) then it must inform the TGA in accordance with reporting timeframes for significant safety issues (see section 2.4.2).

If the sponsor becomes aware of a suspected serious AR that occurs in an infant following exposure to a medicine from breast milk, it must report such cases to the TGA in accordance with timeframes for serious ARs (section 2.4.1).

2.5.4 Use of a medicine in a paediatric or elderly population

The collection of safety information in the paediatric or elderly population is important. Reasonable attempts should therefore be made to obtain and submit the age or age group of the patient when a serious case is reported by a healthcare professional or consumer, in order to be able to identify potential safety signals specific to a particular population.

2.5.5 Lack of efficacy

Reports of lack of therapeutic efficacy should be recorded and followed-up if incomplete. A single case reporting lack of efficacy does not generally constitute information requiring notification to the TGA. Most individual cases notified to the sponsor about a suspected lack of efficacy are not required to be routinely reported to the TGA, but must be provided if requested by the TGA within the requested timeframe. Such cases must also be discussed in the next PSUR if one is required.

However, in certain circumstances sponsors must treat reports of lack of efficacy as serious ARs for reporting purposes. Medicines used in critical conditions or for the treatment of life-threatening diseases, vaccines and contraceptives are examples of classes of products where lack of efficacy requires reporting in accordance with timeframes for serious ARs (section 2.4.1). This applies unless the person reporting to the sponsor has specifically stated that the outcome was due to disease progression and was not related to the medicine.

Clinical judgement should be used when considering if other cases of lack of therapeutic efficacy qualify for reporting. For example, sponsors are not required to report lack of efficacy of antibiotics used in life-threatening situations where the medicine was not appropriate for the infective agent. However, sponsors must report any cases of life threatening infection where the lack of efficacy seems to be due to the development of a newly resistant strain of a bacterium previously regarded as susceptible, in accordance with timeframes for serious ARs (section 2.4.1).

For vaccines, cases of lack of therapeutic efficacy should be reported to the TGA by the sponsor, in particular with the view to highlight potential signals of reduced immunogenicity in a sub-group of vaccinees, waning immunity, or strain replacement. With regard to the latter, it is considered that spontaneously reported cases of lack of therapeutic efficacy by a healthcare professional may constitute a signal of strain replacement. Such a signal may need prompt action and further investigation through post-authorisation safety studies as appropriate.

When reporting a case of suspected lack of therapeutic efficacy, the indication for which the suspected medicine was administered should not be included in the report as a reaction, unless modification of the existing condition occurred that was related to the suspected lack of efficacy. This includes aggravation, progression or recurrence of the medical condition. The report should include the applicable term to describe the modification of the medical condition.

2.5.6 Reports related to a quality defect, including adulterated or counterfeit medicines

Sponsors are required to report serious suspected ARs associated with a suspected or confirmed quality defect of a medicine for which they are the sponsor, including a suspected or confirmed adulterated or counterfeit medicine, in accordance with the timeframes for serious ARs (section 2.4.1). Sponsors are also required to report such incidences where they result in a significant safety issue, in accordance with the timeframes specified in section 2.4.2. Sponsors should also report any quality issue to the TGA as a medicine problem report^40,41.

In order to protect public health, it may also become necessary to implement urgent measures such as the recall of one or more defective batch(es) of a medicine from the market. Therefore, sponsors should have a system in place to ensure that reports of suspected ARs related to quality defects of a medicine or an adulterated or counterfeit medicine are investigated in a timely manner, and that confirmed quality defects or safety issues are notified separately to the TGA with the least possible delay in accordance with the Uniform Recall Procedure for Therapeutic Goods (URPTG)⁴².

2.5.7 Reports of overdose, abuse, off-label use, misuse, medication error or occupational exposure

Reports of overdose, abuse, off-label use, misuse, medication error or occupational exposure with no associated AR, or with an associated non-serious AR, should not be routinely reported to the TGA. Such reports should be recorded and included in the ongoing review and analysis of the medicine, and must be provided on request by the TGA within the requested timeframe. Sponsors should routinely follow up these cases to ensure that information is as complete as possible with regard to early symptoms, treatments, outcomes, context of occurrence (e.g., error in prescription, administration, dispensing, dosage, unauthorised indication or population, etc.). When such reports constitute safety issues impacting on the risk-benefit balance of the medicine, they must be reported in accordance with the timeframes for significant safety concerns (section 2.4.2).

Sponsors are required to report all cases of overdose, abuse, off-label use, misuse, medication error or occupational exposure associated with suspected serious ARs in Australia in accordance with the timeframes specified in section 2.4.1.

Sponsors must also report cases that indicate that the taking of the suspect medicine led to suicidal intention and a subsequent overdose of the suspect medicine or other medication (in accordance with the timeframes specified in section 2.4.1).

2.5.8 Non-serious adverse reactions occurring in Australia, and adverse reactions that occurred outside Australia

The TGA requires sponsors to report non-serious ARs that occurred in Australia as line listings⁴³ in a PSUR if one is required. Sponsors must also report such ARs if requested by the TGA, in the requested format and within the requested timeframe.

The TGA does not require sponsors to routinely submit individual reports of ARs that have occurred in a country other than Australia (whether serious or not). Sponsors should keep records of such ARs and produce the report if requested by the TGA, and should consider the AR report in any global analysis of adverse reports. In the event that such ARs impact on the benefit to risk balance or overall safety profile of the medicine, this information must be reported as a significant safety issue in accordance with the reporting timeframes specified in section 2.4.2.

2.6 Consumer reports

The TGA considers reports from consumers to be a valuable source of information. The TGA places emphasis on the quality and completeness of the report rather than its source. In recognition of the difficulties posed by the potential lack of medical detail and clinical confirmation of consumer reports, a sponsor's judgment in relation to how such reports are recorded, followed-up, clarified and analysed should be guided by the following:

• consumers should be encouraged to report ARs, and seek any required medical attention through their healthcare professional;
• sponsors should make every attempt to obtain sufficient information to ascertain the nature and seriousness of the reaction;
• sponsors should seek and document permission from consumers, allowing contact with the their primary healthcare professional to obtain confirmation and additional relevant medical information;
• sponsors must document all consumer AR reports as for ARs from any other source and take these into account when overall safety assessments are made; and
• additional follow-up or medical confirmation may not be necessary for an apparently non-serious AR.

If a consumer denies permission to access relevant additional medical material, the person responsible for pharmacovigilance and/or a medically qualified person may be able to judge from the consumer information whether the case is apparently serious or non-serious, and guide subsequent handling of the report on a case-by-case basis.

If the reaction is apparently serious, the sponsor should make reasonable additional efforts either to obtain voluntary informed consent to contact the treating doctor, or have the consumer provide the relevant medical documentation to allow a reasonable assessment of causality.

In situations where a consumer explicitly withholds consent to his/her identification as a reporter, the sponsor must indicate on the reporting form that it is a consumer report and that the name and contact details have been withheld at the request of the reporter.

The TGA's requirement for sponsors to provide information on an identifiable reporter does not override privacy principles⁴⁴. In accordance with privacy principles, the sponsor must seek explicit consent from the consumer for the disclosure of his or her identity to the TGA.

Sponsors are required to be familiar with and discharge their obligations in relation to the collection, use and disclosure of personal information of consumer reports in accordance with the National Privacy Principles, and the Privacy Act 1988⁴⁵.

2.7 How to report adverse reactions and content requirements

AR reports must be submitted to the TGA using either a CIOMs form⁴⁶, the AR 'blue card' or online reporting form⁴⁷, and can be submitted via mail, facsimile, email or directly online⁴⁸.

Taking into account the international dimension of AR reporting and the need to achieve harmonisation and high quality between all involved parties, ARs should be submitted electronically as structured data with the use of controlled vocabularies for the relevant data elements where applicable.

Reports submitted to the TGA must:

• be legible and easy to read (e.g., in Times or Arial fonts); and
• not be photo-reduced or condensed, allowing the submitted report to be scanned and photocopied.

It is preferable that font size be in ten point font or larger. Reports using a font size less than 10 points should be posted, rather than faxed.

Computer-generated forms are acceptable, provided they are legible and follow the accepted content and layout.

All reports must clearly identify the name and contact details of the person in Australia who is taking responsibility on behalf of the sponsor for the accuracy and veracity of the information in the report. It is preferable that AR reports are submitted by the nominated contact person for pharmacovigilance.

The TGA will advise a sponsor if it regards a report format to be unacceptable.

2.7.1 Content of adverse reaction reports

Annex 2 provides a full list of key data elements recommended for inclusion in individual AR reports.

When submitting AR reports it is essential for the sponsor to provide the TGA with as many data elements as possible to facilitate assessment, however the following minimum four data elements must be provided with the initial report:

• an identifiable patient⁴⁹;
• one or more identifiable reporter(s) (see below);
• one or more suspected reaction(s); and
• one or more suspected medicine(s).

Initial reports received by the sponsor that do not include the minimum four data elements should be followed-up as necessary to obtain the missing minimum information. Sponsors should also follow up cases to obtain detailed supplementary information significant to the scientific evaluation of the cases. This is particularly relevant for monitored events of special interest, prospective reports of pregnancy, cases notifying the death of a patient, cases reporting new risks or changes in the known risks. Any attempt to obtain follow-up information should be documented.

Follow-up methods should be tailored towards optimising the collection of missing information. This should be done in ways that encourage the primary source to submit new information relevant for the scientific evaluation of a particular safety concern.

When information is received directly from a consumer suggesting that an AR may have occurred, if the information is incomplete, attempts should be made to obtain consent to contact a nominated healthcare professional to obtain further follow-up information. When such a case, initially reported by a consumer, has been confirmed (totally or partially) by a healthcare professional, this information should be included in the report⁵⁰.

Once the sponsor has obtained the minimum four data elements for serious ARs, sponsors must forward the information to the TGA within 15 calendar days of receipt by the sponsor⁵¹.

If the sponsor chooses to report without the minimum information, every initial AR case reported to the TGA must list the medicinal substance or product name at the very least, as reported by the primary reporter.

In the interest of good case management and detection of duplicate reports, each report should include the following information about the person making the report to the sponsor:

• the name;
• for reports from a healthcare professional, the profession and the name of the professional association or other group of which he or she is a member, if available; and
• the address, including postcode.

Where the person making the report explicitly seeks to remain anonymous, the TGA still requires supplementary information about the person such as the profession, or the name of the professional association or other group of which he or she is a member (for reports from healthcare professionals), and location in Australia, for example the postcode.

If the reaction is suspected to be the result of a drug/drug, drug/food, or drug/alcohol interaction, this must be clearly stated in the report and the names of the suspected interacting products or substances provided.

For combination medicines that contain more than one active ingredient, each active ingredient should be listed in the report. If the primary source suspects a possible causal role of one of the ingredients in the medicine, this information should also be provided in the report.

The TGA requires the sponsor to provide the original words that were used by the reporter to describe the AR⁵². It is preferrable that the appropriate Lowest Level Terms from the Medical Dictionary for Regulatory Activities (MedDRA)⁵³ are also included in the AR report, however this is not a mandatory requirement.

Where possible, sponsors should provide a case narrative for all reported ARs⁵⁴. The information should be presented in a logical time sequence, in the chronology of the patient's experience including clinical course, therapeutic measures, outcome and follow-up information obtained. Any relevant autopsy or post-mortem findings should also be summarised. The information provided in the narrative should be consistent with the data in other parts of the report.

Sponsors may comment on whether they consider there is a causal association between the suspect product(s) and reaction(s) and provide the criteria on which they have made the assessment.

2.7.2 Validation of reports

Only serious ARs that include the minimum four data elements are considered valid and required to be reported. All reports of suspected serious ARs should therefore be validated before they are reported to the TGA to make sure that the minimum criteria for reporting are included. This is:

• One or more identifiable reporter(s) (primary source), characterised by qualification (e.g. physician, pharmacist, other healthcare professional, lawyer, consumer or other non-healthcare professional), name, initials or address⁵⁵. Whenever possible, contact details for the reporter should be recorded so that follow-up activities can be performed. However, if the reporter does not wish to provide contact details, the AR should still be considered as valid providing the sponsor is able to confirm the case directly with the reporter. All parties providing case information or approached for case information should be identifiable, not only the initial reporter.
• One single identifiable patient characterised by at least one of the following: initials, patient identification number, date of birth, age, age group or gender⁵⁶. The information should be as complete as possible.
• One or more suspected substance(s)/medicine(s).
• One or more suspected AR(s). If the primary source has made an explicit statement that a causal relationship between the medicine and the AE has been excluded and the sponsor agrees with this, the report does not qualify as a valid AR since the minimum information is incomplete⁵⁷. The report also does not qualify as a valid AR if it is reported that the patient experienced an unspecified AR and there is no information provided on the type of AR experienced. Similarly, the report is not valid if only an outcome (or consequence) is notified and (i) no further information about the clinical circumstances is provided to consider it as a suspected AR, or (ii) the primary source has not indicated a possible causal relationship between the outcome and the suspected medicine. For example, a sponsor is made aware that a patient was hospitalised or died, without any further information. In this particular situation, medical judgement should always be applied in deciding whether the notified information is an AR or an AE. A report of an unexpected sudden death would usually be considered as a suspected AR and reported.

Identification of the patient and reporter is important to avoid case duplication, detect fraud, and facilitate follow-up of appropriate cases. The term identification in this context refers to the verification of the existence of a patient and a reporter. In the event of second-hand reports, every reasonable effort should be made by the sponsor to verify the existence of an identifiable patient and reporter.

The lack of any of these four data elements means that the case is considered incomplete and does not qualify for reporting. Sponsors should exercise due diligence in following up the case to collect the missing data elements (see section 2.7.1). Reports for which the minimum information is incomplete should nevertheless be recorded within the pharmacovigilance system for use in on-going safety evaluation activities.

2.8 How to report significant safety issues

Reports of significant safety issues must be provided in writing to the OPR, in legible text, and preferably in Times or Arial font no less than 10 point font size. These reports should be submitted via facsimile or email to help ensure that sponsors meet reporting timeframes for significant safety issues. As set out in section 2.7, all reports must clearly identify the name and contact details of the person in Australia who is taking responsibility on behalf of the sponsor for the accuracy and veracity of the information in the report. It is preferable that reports of significant safety issues are submitted by the nominated contact person for pharmacovigilance.

Footnotes

18. Sponsors should nominate one pharmacovigilance contact person for all the medicines they sponsor. The TGA will direct requests for pharmacovigilance information to the nominated contact person. This provides the most efficient way for ensuring details remain current. The nominated contact person is responsible for coordinating pharmacovigilance information between the sponsor and the TGA.
19. Annex 1 lists relevant contact details.
20. Section 2.6 includes further information on consumer reports.
21. Annex 3 includes the definition of spontaneous reports.
22. Annex 3 includes the definition of primary source.
23. Section 2.5.1 includes further information about post-registration studies.
24. Section 2.5.2 includes further information about post marketing initiatives.
25. Annex 3 includes the definition of an AE.
26. Section 3.3 includes further information about the SAS and AR reporting.
27. Annex 3 includes the definition of serious ARs.
28. The TGA does not require sponsors to submit individual reports of serious unexpected or serious expected AR reports that have occurred in a country other than Australia. However, should such reports impact on the benefit to risk balance or overall safety profile of the medicine, this information must be reported as a significant safety issue (see section 2.3.2 and 2.4.2).
29. For significant safety issues identified through ongoing review and analysis of information that is pertinent to the safety or benefit-risk assessment of the product, reporting timeframes specified in section 2.4.2 also apply.
30. Section 2.7.2 includes further information about validation of AR reports.
31. For significant safety issues identified through ongoing review and analysis of information that is pertinent to the safety or benefit-risk assessment of the product, reporting timeframes specified in section 2.4.2 also apply.
32. For further guidance about information that should be included in line listings, sponsors should refer to the ICH document E2C (R1) Note for guidance on clinical safety data management: Periodic safety update reports for marketed drugs (CPMP/ICH/288/95), which can be viewed online at ICH: Efficacy.
33. As set out in section 2.3.1, notification to the TGA regarding a suspected change in the frequency of ARs must also include the basis on which the frequency assessment has been made, such as data on the total number of AR reports and the number of patients exposed.
34. Section 2.7.1 lists the four minimum data elements.
35. Section 2.3.2 includes further information about significant safety issues.
36. Annex 3 includes the definition of a post-registration study.
37. The ICH guideline E2A Note for guidance on clinical safety data management: Definitions and standards for expedited reporting (CPMP/ICH/377/95) can be viewed online at ICH: Efficacy.
38. Note for guidance on clinical safety data management: definitions and standards for expedited reporting
39. Section 2.6 includes further information about consumer reports.
40. Although not mandated as a part of this document, the requirement for sponsors to provide in writing any information that indicates that the quality of a medicine for which they are the sponsor is unacceptable, as soon as they become aware of such information, is specified in sections 29A and 29AA of the Act.
41. More information about reporting medicine problems can be found on the TGA Internet site at Report a medicine deficiency or defect.
42. More information about the URPTG can be found on the TGA Internet site at Uniform recall procedure for therapeutic goods (URPTG).
43. For further guidance about about information that should be included in line listings, sponsors should refer to the ICH document E2C (R1) Note for guidance on clinical safety data management: Periodic safety update reports for marketed drugs (CPMP/ICH/288/95),which can be viewed online at ICH: Efficacy.
44. Annex 3, Section 2 includes further discussion on privacy.
45. Privacy obligations are set out in the Guidelines on Privacy in the Private Health Sector, Office of the Australian Information Commissioner, November 2001, which can be viewed online at Privacy in the Private Health Sector (November 2001).
46. Council for International Organizations of Medical Sciences (CIOMS).
47. AR blue card or online reporting can be found on the TGA Internet site at Reporting problems.
48. Annex 1 lists relevant contact details.
49. Section 2.7.2 includes more information on patient identifiability.
50. Annex 2 Section 4 includes more information about medical confirmation of a case.
51. This requirement is in addition to the requirement to report any significant safety issues within the timeframe specified in section 2.4.2.
52. Data received from the primary source should be treated in an unbiased and unfiltered way. Inferences and imputations should be avoided during data entry or electronic transmission. The reports should include the verbatim text as used by the primary source or an accurate translation of it.
53. More information about MedDRA can be viewed online at MedDRA MSSO. Guidance on the use of MedDRA terminology can be viewed online at MedDRA Points to Consider.
54. 'Where possible' should be interpreted as having received sufficient information from the primary source to prepare a concise clinical summary of the individual case.
55. Data privacy laws regarding patient's and reporter's identifiability apply. Annex 3, Section 2 includes further discussion on privacy.
56. In the absence of qualifying descriptors, a report referring to a definite number of patients will not be regarded as a valid case. For example, "Two patients experienced..." or "a few patients experienced" should be followed up for patient-identifiable information before regulatory reporting.
57. There is no suspected AR.