1.1 Introduction

The World Health Organization describes pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem.

The Australian Requirements and Recommendations for Pharmacovigilance Responsibilities of Sponsors of Medicines (this document) includes mandatory reporting requirements for sponsors in relation to adverse reactions to medicines in the Australian Register of Therapeutic Goods (ARTG), as well as guidance on pharmacovigilance systems. This document comprises:

• the legal basis of this document;
• the scope, including responsibilities of sponsors, guidance on pharmacovigilance systems and the role of the Therapeutic Goods Administration (TGA);
• reporting requirements for adverse reactions (ARs) and significant safety issues; and
• other requirements and recommendations not mandated by this document.

This document includes certain requirements and recommendations consistent with those described in the European Medicines Agency's (EMA) Guideline on Good Pharmacovigilance Practices (GVP) Module VI - Management and reporting of adverse reactions to medicinal products¹, however other requirements and recommendations specified in this document are unique to Australia.

Annex 1 lists contact details for reporting ARs. Annex 2 lists the recommended key data elements for inclusion when reporting ARs to the TGA, which are based on the ICH guideline E2D Post-approval safety data management (CPMP/ICH/3945/03)² and the ICH guideline E2B (R2) Data elements for transmission of individual case safety reports³. The definitions of relevant terms and guidance on data management are at Annex 3, and are based on the definitions and information provided in the Guideline on Good Pharmacovigilance Practices (GVP) Module VI - Management and reporting of adverse reactions to medicinal products, the ICH guideline E2A Clinical safety data management: Definitions and standards for expedited reporting (CPMP/ICH/377/95)⁴ and the ICH guideline E2D Post-approval safety data management (CPMP/ICH/3945/03). Annex 4 is the glossary of terms.

1.1.1 Legal basis - reporting requirements

Sponsors must ensure that all information relevant to the balance of benefits and risks of a registered or listed medicine is reported to the TGA in a timely manner. Sections 29A and 29AA of the Therapeutic Goods Act 1989 (the Act)⁵ specify circumstances in which a sponsor must give information in writing to the TGA as soon as they become aware of such information. These circumstances are where the sponsor becomes aware of information:

• that contradicts information already furnished by the sponsor under the Act;
• that indicates that the use of the registered or listed medicine in accordance with the recommendations for its use may have an unintended harmful effect;
• that the registered or listed medicine, when used in accordance with the recommendations for its use, may not be as effective as information submitted or relied upon at the time of listing or registration previously suggests;
• that indicates that the quality, safety or efficacy of the registered or listed medicine is unacceptable.

Note that these circumstances apply more broadly than just to ARs to the product. In addition to these obligations, sponsors are required to comply with the reporting requirements set out in section 2 of this document, which include requirements for reporting a contact person to the TGA, reporting ARs and other significant safety issues, the time frames for submitting these reports to the TGA, the content requirements and how reports must be submitted.

Subsection 28(5)(e) of the Act and Regulation 15A of the Therapeutic Goods Regulations 1990 (the Regulations)⁶ provide the legal basis for the reporting requirements outlined in this document. Subsection 28(5)(e) of the Act specifies that the registration or listing of therapeutic goods is subject to the condition that the sponsor of the goods will comply, in relation to the goods, with any reporting requirements that are prescribed. Regulation 15A of the Regulations prescribes the requirements to which sponsors of registered or listed medicines included in the ARTG must comply for the purposes of subsection 28(5)(e) of the Act. Requirements imposed as conditions of registration or listing under section 28 of the Act continue to apply for medicines that have been suspended from the ARTG, in accordance with section 29G of the Act.

This document also refers to Periodic Safety Update Reports (PSURs) which are required for certain registered medicines. Reference to PSURs includes Periodic Benefit-Risk Evaluation Reports, which are also known as PSURs. The requirement to submit PSURs is not mandated by this document, but rather is applied as a condition of registration when the medicine is included in the ARTG (section 28(2B) of the Act provides that conditions can be imposed on the registration or listing of therapeutic goods included in the ARTG). PSURs are not required for all medicines, only those to which this specific condition is imposed.

Specific conditions may be imposed on any listed or registered medicine under section 28(2B) of the Act at the time of entry into the ARTG, or new conditions may be imposed and existing conditions removed or varied under section 28(3) of the Act at any time while the medicine remains in the ARTG. Where such conditions specify additional AR monitoring or reporting requirements to those described in this document, sponsors must comply with the additional requirements specified in the condition of listing or registration.

1.1.2 Failure to comply with requirements

Sponsors should be aware that refusal or failure to comply with conditions of registration or listing is grounds for cancellation and suspension of a medicine from the ARTG in accordance with subsections 30(2)(c) and 29D(1)(b) of the Act, and is also grounds for prosecution for an offence in accordance with section 21A of the Act.

1.2 Scope

While the requirements for reporting specified in section 2 of this document are mandated under the legislation described above, this document includes additional recommendations that are not currently underpinned by therapeutic goods legislation. These inclusions are to assist sponsors to meet reporting requirements and aim to provide guidance on best practice in terms of pharmacovigilance. The use of the words must or required in this document means that something is a mandatory requirement, while the use of the word should (including when used in Section 2 of this document) means that something is suggested or recommended, but is not mandated by this document.

1.2.1 Responsibilities of sponsors

Sponsors must comply with the mandatory reporting requirements specified in section 2 of this document.

To summarise, sponsors must:

• notify the TGA of the person responsible for fulfilling the sponsor's obligations described in this document;
• submit AR reports to the TGA (as specified in this document);
• notify the TGA when they become aware of any significant safety issues; and
• ensure that any request from the TGA for the provision of additional information is answered fully and within the requested timeframe.

When two or more separately registered or listed medicines, which are identical in all respects apart from their trade names, are marketed in Australia by separate sponsors, each sponsor is legally responsible for meeting pharmacovigilance reporting requirements for its medicine.

Where sponsors share co-marketing arrangements, they may enter into practical arrangements to meet their obligations. However, each sponsor is legally responsible for meeting pharmacovigilance reporting requirements for its medicine.

1.2.2 Guidance on a system of pharmacovigilance

Although not a legislative requirement, sponsors of registered and listed medicines in Australia are encouraged to have an effective system of pharmacovigilance in place in order to assure responsibility and liability for their products on the market and to ensure that appropriate action can be taken, when necessary.

Sponsors should have permanently and continuously at their disposal a person in Australia responsible for pharmacovigilance. Ideally this person should be the nominated contact person responsible for reporting and record keeping requirements, as notified to the TGA⁷. The person responsible for pharmacovigilance should be experienced in pharmacovigilance, and if not medically qualified, they should have ready access to a medically qualified person. The medically qualified person should hold Australian (or equivalent overseas) qualifications as a medical practitioner. Preferably the medically qualified person should be registered and reside in Australia to address ARs, significant safety issues, and balance the benefits and risks of registered or listed medicines in an Australian context.

In order to meet reporting and record keeping requirements⁸, sponsors, through the person responsible for pharmacovigilance, should:

• establish and manage a system that ensures information about all suspected ARs reported to the sponsor or people who work for the sponsor (such as medical and sales representatives) is collected⁹, collated and held so that it may be accessed at a single point within Australia;
• coordinate the preparation of AR reports, including reports arising from company-sponsored Australian post-marketing studies.

The pharmacovigilance system should be developed to allow the acquisition of sufficient information for the scientific evaluation of AR reports and any other safety issues associated with the medicine.

The system should be designed so that it helps to ensure that the collected reports are authentic, legible, accurate, consistent, verifiable and as complete as possible for their clinical assessment. This includes reports of suspected ARs received electronically or by any other means. In this context, sponsors may consider utilising their websites to facilitate the collection of reports of suspected ARs by providing AR forms for reporting, or appropriate contact details for direct communication.

The pharmacovigilance system should also be structured in a way that allows for reports of suspected ARs to be validated¹⁰ in a timely manner and submitted to the TGA within the legal reporting time frame.

The sponsor should request that any information on ARs suspected to be related to at least one of the active substances of its medicine, is brought to its attention by any company outside Australia belonging to the same parent company (or group of companies). The same applies to the sponsor when a commercial agreement is in place with a company outside Australia for one of its medicines authorised in Australia. This is particularly relevant for the identification of significant safety issues¹¹.

Clear written standard operating procedures should guarantee that the roles and responsibilities and the required tasks are understood by all parties involved and that there is provision for proper control and, when needed, change to the pharmacovigilance system. This is equally applicable to activities that are contracted out to third parties, whose procedures should be reviewed to verify that they are adequate and compliant with applicable requirements.

Staff directly performing pharmacovigilance activities should be appropriately trained in applicable pharmacovigilance legislation and guidelines in addition to specific training in report processing activities for which they are responsible and/or undertake. Other personnel who may receive or process safety reports (e.g., clinical development, sales, medical information, legal, quality control) should be trained in AR collection and reporting in accordance with internal policies and procedures.

Sponsors should ensure that their pharmacovigilance system adequately meets record keeping¹² and reporting requirements that apply more broadly than just to ARs to the product.

Literature reviews

The scientific and medical literature is a significant source of information for the monitoring of the safety profile and risk-benefit balance of medicines, particularly in relation to the detection of new safety signals or emerging safety issues. Therefore sponsors should maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g., Medline, Excerpta Medica or Embase) no less frequently than once a week. Sponsors should ensure that the literature review includes the use of reference databases that contain the largest reference of articles in relation to the medicine and its properties. In addition, sponsors should have procedures in place to monitor scientific and medical publications in local journals both in Australia and other countries where the medicine is supplied, and to review and assess these publications appropriately.

Reports of suspected ARs from the scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, should be reviewed and assessed by sponsors to identify and record ARs and significant safety issues.

If multiple medicines are mentioned in the publication, only those that are identified by the publication's author(s) as having at least a possible causal relationship with the suspected AR should be considered by the sponsor. Valid ARs¹³ and significant safety issues must be reported in accordance with the requirements outlined in this document.

Where contractual arrangements are made with a person/organisation to perform literature searches, detailed agreements should exist to ensure that the sponsor can comply with all reporting obligations.

Monitoring the internet or digital media

Sponsors should regularly screen internet or digital media¹⁴ under their management or responsibility, for potential reports of suspected ARs. This includes digital media that is owned, paid for and/or controlled by the sponsor¹⁵. The frequency of the screening should allow for valid ARs to be reported within the appropriate reporting timeframe based on the date the information was posted on the internet site/digital medium. Sponsors may also consider utilising their websites to facilitate the collection of reports of suspected ARs.

If a sponsor becomes aware of a report of a suspected AR described in any non-company sponsored digital medium, the report should be assessed to determine whether it qualifies for reporting. If so, it should be reported according to the timeframes specified in this document.

In relation to cases from the internet or digital media, the identifiability of the reporter refers to the existence of a real person, that is, it is possible to verify the contact details of the reporter (e.g., an email address under a valid format has been provided).

Monitoring reports from other sources

If a sponsor becomes aware of a report of a suspected AR originating from a non-medical source, for example the lay press or other media, it should be handled as a spontaneous report¹⁶. Every attempt should be made to follow up the case to obtain the minimum information that constitutes a valid AR report, and to determine the seriousness of the AR¹⁷. The same reporting time frames apply as for other spontaneous AR reports.

1.2.3 The role of the TGA

Consistent with the legislation, the TGA has established a pharmacovigilance system for collecting and evaluating information relevant to the benefit to risk balance of listed and registered medicines. The TGA continually monitors the safety profile of the products available in Australia and takes appropriate action where necessary.

Footnotes

1. The EMA Guideline on Good Pharmacovigilance Practices (GVP) Module VI - Management and reporting of adverse reactions to medicinal products can be viewed online at Good pharmacovigilance practices.
2. The ICH guideline E2D Post-approval safety data management (CPMP/ICH/3945/03) can be viewed online at ICH: Efficacy.
3. The ICH guideline E2B (R2) Data elements for transmission of individual case safety reports can be viewed online at: ICH Harmonised Tripartite Guideline.
4. The ICH guideline E2A Clinical safety data management: Definitions and standards for expedited reporting (CPMP/ICH/377/95) can be viewed online at ICH: Efficacy.
5. The Act can be viewed online at Therapeutic Goods Act 1989.
6. The Regulations can be viewed online at Therapeutic Goods Regulations 1990.
7. Section 2.1 includes further information about the nominated contact person.
8. Section 3.1 includes further information about record keeping requirements.
9. Sponsors should not refuse to consider reports of suspected ARs received from consumers and healthcare professionals.
10. Section 2.7.2 includes further information about validation of AR reports.
11. Sections 2.3.2 and 2.4.2 include further information about significant safety issues and reporting timeframes.
12. Section 3.1 includes further information about reporting requirements.
13. Section 2.7.2 includes further information about validation of reports.
14. Although not exhaustive, the following list should be considered as digital media: web site, web page, blog, vlog, social network, internet forum, chat room, health portal. 
15. A donation (financial or otherwise) to an organisation/site by a sponsor does not constitute ownership, provided the sponsor does not control the final content of the site.
16. Annex 3 includes the definition of spontaneous reports.
17. Section 2.7.2 includes further information about validation of reports.

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.

Some situations are not covered directly by the reporting requirements detailed in section 2. The recommendations and requirements discussed below are not mandated as a part of this document, but may be mandated by other legislation, or recommended in guidelines.  

3.1 Record keeping requirements

Sponsors are required to retain records of all reports of ARs or similar experiences associated with the use or administration of their registered/listed drugs for a period of not less than 18 months from the day the TGA is notified of the report. This requirement is specified as a standard condition of listing or registration applied to all medicines at the time of entry onto the ARTG⁵⁸.

3.2 Reporting in the period between submission of a registration application and granting of the registration

In the period between the submission of a registration application, but before registration, sponsors are not required to routinely submit individual AR reports of which they become aware, except where the product is being used in Australia in a clinical trial. In these cases, sponsors should follow the reporting recommendations outlined in the separate guidelines for clinical trials⁵⁹.

In the pre-registration period, information that impacts on the benefit to risk evaluation may become available to the applicant from countries where the medicine is already in use on a compassionate basis, or from countries where the medicine is marketed. The applicant should submit this information in writing to the Office of Medicines Authorisation (OMA)⁶⁰, preferably in accordance with time frames for significant safety issues (section 2.4.2)⁶¹.

What constitutes a change to the benefit to risk balance is a matter of judgment for the applicant (although an applicant may be required to justify a decision not to report). For example, normally another report of a well-known AR would not be considered significant, but a report of an unexpected or new serious suspected reaction with good evidence of a causal relationship, or where there is suspicion of a change in the frequency or severity of a known effect, would be considered relevant to the evaluation. Similarly results from studies that impact on the assessment of efficacy would be considered significant.

When an application for registration for a prescription medicine is about to be considered by the Advisory Committee on Prescription Medicines (ACPM), sponsors should submit with their pre-ACPM response a tabulation of any serious unexpected ARs that are not mentioned in the proposed Australian PI and that have not already been submitted. This information should be submitted in writing to the OMA.

In the period after submission of the Pre-ACPM response, but prior to registration, sponsors are encouraged to report the following to the OMA in accordance with time frames for significant safety issues (section 2.4.2)⁶²:

• significant safety issues identified by the sponsor as a result of its ongoing review and analysis of all information. This information includes foreign reports of ARs, information about the safety or benefit to risk assessment of the product, or action taken by a foreign regulatory agency, and the basis for such action.

In instances where an application for registration of a medicine is withdrawn or lapses, section 29B of the Act provides that the Secretary of the Department of Health and Ageing may require a sponsor to disclose whether certain information about the product is known to the sponsor and, if that is the case, to provide that information to the Secretary.

3.3 Special Access Scheme (compassionate use/named patient) supplies

Reporting requirements for medicines supplied under the SAS are not mandated by this document, but are specified as either a condition of authorisation for the supply of the particular medicine, or through the requirement to prescribe the unapproved medicine in accordance with good medical practice.  

The use of the particular medicine for which authorisation has been granted in accordance with Section 19 of the Act is subject to conditions specified in the notice of approval, including AR reporting requirements (Section 19 of the Act provides that approval may be granted for the importation into, or the exportation from, Australia or the supply in Australia of specified therapeutic goods that are not registered goods, listed goods or exempt goods. This is also known as Category B of the SAS). The use of an unapproved medicine notified in accordance with Regulation 12A of the Regulations is subject to the condition that the medicine must be prescribed in accordance with good medical practice, which similarly encompasses AR reporting requirements (Regulation 12A of the Regulations provides that medicines are exempt from Part 3-2 of the Act, which includes the requirement to be included in the ARTG, subject to certain conditions. One of these conditions is that the patient meets the definition of a Category A patient. Such medicines are not exempt from section 31A and sections 31C to 31F of Part 3-2 of the Act).

The onus for reporting ARs from SAS usage lies primarily with the treating doctor. It is a condition of approval that the treating doctor reports the details of any actual or suspected ARs to the TGA. The sponsor of the medicine may also impose reporting requirements upon treating doctors if the sponsor chooses to do so. Sponsors should report to the TGA all those serious and unexpected ARs to medicines supplied under the SAS of which they have been informed. It is preferable that such reports are submitted to the OPR⁶³, who will forward them to the relevant area in the TGA.

Reporting timeframes and further information on reporting ARs under the SAS can be found in the guidance document Access to unapproved therapeutic goods - Special Access Scheme⁶⁴.

Footnotes

58. The TGA Internet site includes this condition in the document Conditions - standard and specific Applying to registered or listed therapeutic goods under Section 28 of the Therapeutic Goods Act 1989, which can be viewed online at DR4 - Appendix 4.
59. More information about clinical trials can be found on the TGA Internet site at Clinical trials.
60. Annex 1 lists relevant contact details.
61. Significant safety issues that become known to the sponsor prior to registration should be submitted to the OMA, whereas information that becomes known after registration must be provided to the OPR.
62. Significant safety issues that become known to the sponsor prior to registration should be submitted to the OMA, whereas significant safety issues that become known after registration must be provided to the OPR.
63. Annex 1 lists relevant contact details.
64. More information about access to unapproved therapeutic goods and the SAS can be found on the TGA Internet site at Access to unapproved therapeutic goods - Special Access Scheme.

Address for submitting individual case reports of suspected ARs occurring in Australia, for notifying the TGA of significant safety issues with a medicine (once the medicine is on the ARTG), or for notification to the TGA of the nominated contact person for pharmacovigilance:

Mail:

Office of Product Review
Therapeutic Goods Administration
PO Box 100
Woden ACT 2606

Fax:

Office of Product Review
02 6232 8392

Email:

adr.reports@tga.gov.au

Web:

Reporting problems

Notifying the TGA of the nominated contact person for pharmacovigilance, or updating those details, can be done by completing the Client Details form (sections 1, 3 & 4) available on the eBS website under the eBS Access Forms link (see section 2.1)

Address for submitting the completed Client Details form is:

Mail:

TGA eBS Help Desk
Therapeutic Goods Administration
PO Box 100
Woden ACT 2606

Fax:

TGA eBS Help Desk
02 6232 8581

If you require further assistance, please contact the eBS Help Desk.

Phone:

TGA eBS Help Desk
1800 010 624

Email:

ebs@tga.gov.au

Address for submitting information described in section 3.2 and for ARs from ongoing clinical trials conducted outside the terms of the PI or label indications (See section 2.5.1):

Mail:

The Head
Office of Medicines Authorisation
Therapeutic Goods Administration
PO Box 100
Woden ACT 2606

Fax:

Office of Medicines Authorisation
02 6232 8140

Some data elements might not be relevant, depending on the circumstances. Attempts should be made to obtain information on as many listed items as are pertinent to the case.

1. Patient details

• Initials
• Other relevant identifier (e.g., patient number)
• Gender
• Age, age category (e.g., adolescent, adult, elderly), or date of birth
• For a parent-child/foetus report the gestation period at time of exposure
• Concomitant conditions
• Medical history including relevant past drug history
• Relevant family history
• Weight of patient
• Height of patient
• For parent-child/foetus reports, information concerning the parent (e.g., parent identification, parent age/date of birth, last menstrual period date, weight, height, sex, relevant medical history and concurrent conditions, relevant past drug history)
• Ethnicity

2. Suspected medicine(s)

• Brand name as reported
• International Non-Proprietary Name (INN) or Australian Approved Name (AAN)
• The AUST R or AUST L number present on label
• Active ingredients
• Batch/lot number
• Indication(s) for which suspect medicine was prescribed or tested
• Dosage form and strength
• Daily dose (specify units e.g., mg, ml, mg/kg) and regimen
• Route of administration
• Parent route of administration (in cases of a parent-child/foetus report)
• Starting date and time
• Stopping date and time, or duration of treatment
• Actions taken with drug (e.g., drug withdrawn, dose reduced, dose increased, dose not changed, unknown, not applicable)
• Additional information on drug
• For suspected drug/drug, drug/food, or drug/alcohol interactions, the names and active ingredients of the suspected interacting products or substances

3. Other treatment(s)

The same information as in item 2 should be provided for the following:

• Concomitant medicines (including non-prescription, over-the-counter medicines, herbal remedies, dietary supplements, complementary and alternative therapies, etc.); and
• Relevant medical devices.

4. Details of adverse reaction(s)

• Full description of reaction(s), including body site and severity
• Reaction as reported by the primary source
• Reaction in MedDRA terminology (lowest level term)
• The criterion (or criteria) for regarding the report as serious
• Description of the reported signs and symptoms
• Specific diagnosis for the reaction
• Onset date (and time) of reaction
• Stop date (and time) or duration of reaction
• Time interval between suspect drug administration and start of reaction
• Dechallenge and rechallenge information
• Relevant diagnostic test results and laboratory data
• Setting (e.g., hospital, out-patient clinic, home, nursing home)
• Outcome of reaction at the time of last observation (e.g., recovered/resolved, recovering/resolving, not recovered/ not resolved, recovered/resolved with sequelae. Describe sequelae)
• Date of death
• Was autopsy done? Relevant autopsy or post-mortem findings, including coroner's report
• Stated cause of death for a fatal outcome
• Relatedness of product to reaction(s)/event(s)
• Assessment of reaction: Source of assessment (e.g., initial reporter, investigator, regulatory agency, company), method of assessment (global introspection, algorithm, Bayesian calculation) and result
• Case narrative including clinical course, therapeutic measures, outcome and additional relevant information
• Sponsor's comments (e.g., diagnosis/syndrome and/or reclassification of reaction/event)
• Whether the case was medically confirmed (medical documentations [e.g. laboratory or other test data] provided by a consumer that support the occurrence of the suspected AR, or which indicate that an identifiable healthcare professional suspects a reasonable possibility of causal relationship between a medicine and the reported AE, are sufficient to consider the spontaneous report as medically confirmed. If a consumer initially reports more than one reaction and at least one receives medical confirmation, the whole report should be documented as a spontaneous report that has been medically confirmed. Similarly, if a report is submitted by a medically qualified patient, friend, relative of the patient or carer, the case should also be considered as medically confirmed.)

5. Details about the person reporting the adverse reaction to the sponsor

• Name
• Mailing address
• Electronic mail address
• Telephone and/or facsimile number
• Reporter type (consumer, healthcare professional, etc.)
• Profession (specialty)

6. Administrative and sponsor details

• Source of report (spontaneous, epidemiological study, patient survey, literature, etc.)
• Date the event report was first received by manufacturer/company
• Country in which the event occurred
• Type (initial or follow-up) and sequence (first, second, etc.) of case information reported to authorities
• Name and address of sponsor
• Name, address, electronic mail address, telephone number, and facsimile number of contact person at the sponsor's Australian address
• Identifying regulatory code or AUST R/AUST L number
• Company/manufacturer's identification number for the case (the same number should be used for the initial and follow-up reports on the same case)
• The AR identification number (if known) of possible duplicate reports initially submitted to the TGA by a consumer, healthcare professional or other primary source

1. Definitions

1.1 Adverse event (AE)

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

1.2 Adverse reaction (AR)

ARs concern noxious and unintended responses to a medicine.

This includes ARs that arise from:

• the use of a medicine within the terms of the marketing authorisation;
• the use outside the terms of the marketing authorisation, including overdose, abuse, off-label use, misuse, and medication errors; or
• occupational exposure.

The phrase 'responses to a medicine' means that a causal relationship between a medicine and an AE is at least a reasonable possibility.

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

1.3 Serious adverse reactions

A serious AR 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; or
• 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. These should also be considered serious. Examples of such events include 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.

For reporting purposes, any transmission via a medicine of an infectious agent is also considered a serious AR and therefore must be reported in accordance with reporting timeframes for serious ARs.

Any organism, virus or infectious particle (e.g., prion protein transmitting Transmissible Spongiform Encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.

A transmission of an infectious agent may be suspected from clinical signs or symptoms, or laboratory findings indicating an infection in a patient exposed to a medicine. Emphasis should be on the detection of infections/infectious agents known to be potentially transmitted via a medicine, but the occurrence of unknown agents should also always be considered.

In the context of evaluating a suspected transmission of an infectious agent via a medicine, care should be taken to discriminate, whenever possible, between the cause (e.g., injection/ administration) and the source (e.g., contamination) of the infection and the clinical conditions of the patient at the time of the infection (immuno-suppressed /vaccinee).

If the infectious agent is specified, the MedDRA lowest level term code corresponding to the infectious agent should also be included in the report.

Confirmation of contamination (including inadequate inactivation/attenuation of infectious agents as active substances) of the concerned medicine increases the evidence for transmission of an infectious agent and may therefore be suggestive of a quality defect for which the procedures detailed in section 2.5.6 should also be applied.

1.4 Non-serious adverse reactions

All ARs that do not meet the definition of a serious AR are considered non-serious ARs.

1.5 Spontaneous reports

A spontaneous report is an unsolicited communication by a health professional or consumer to a company, regulatory authority or other organisation (e.g. WHO, Poisons Information Centre) that describes one or more suspected ARs in a patient who was given one or more medicine(s) and that does not derive from a study or any organised data collection system where AE reporting is actively sought. Stimulated reporting can occur in certain situations, such as notification by a 'Dear Healthcare Professional' letter, publication in the press, questioning of healthcare professionals by company representatives, communication from patients' organisations to their members, or class action lawsuits. These reports should be considered spontaneous.

1.6 Healthcare professional

A healthcare professional is a medically qualified person such as a medical doctor, dentist, pharmacist, or nurse.

1.7 Consumer

A consumer is a person who is not a healthcare professional such as a patient, lawyer, friend, or relative of a patient.

1.8 Post-registration study

A post-registration study is any study carried out in accordance with the conditions of registration or under normal conditions of use. This includes studies that may have commenced prior to registration that are ongoing after the product has been registered. In relation to AR reporting and PSUR requirements, reference to a post-registration study means any post-registration study (carried out in accordance with the conditions of registration or under normal conditions of use) of which the sponsor is aware.

1.9 Overdose

This refers to the administration of a quantity of a medicine given per administration or cumulatively, which is above the maximum recommended dose according to the authorised PI or the directions for use on the medicine label.

1.10 Off-label use

This relates to situations where the medicine is intentionally used for a medical purpose not in accordance with the authorised PI or the directions for use on the medicine label.

1.11 Misuse

This refers to situations where the medicine is intentionally and inappropriately used not in accordance with the authorised PI or the directions for use on the medicine label.

1.12 Abuse

This corresponds to the persistent or sporadic, intentional excessive use of a medicine, which is accompanied by harmful physical or psychological effects.

1.13 Medication error

This refers to any unintentional error in the prescribing, dispensing, or administration of a medicine while in the control of the healthcare professional, patient or consumer.

1.14 Occupational exposure

This refers to exposure to a medicine as a result of one's professional or non-professional occupation.

1.15 Primary source

The primary source of the information on a suspected AR(s) is the person who reports the facts to the sponsor. Several primary sources, such as healthcare professionals and/or a consumer, may provide information on the same case. In this situation, the details of all primary sources, including the qualifications, should be provided in the case report.

2. Guidance on data management

Sponsors must be familiar with and discharge their obligations in relation to the collection, use and disclosure of personal information in accordance with the National Privacy Principles based on the Privacy Act 1988. These obligations are set out in the Guidelines on Privacy in the Private Health Sector, Office of the Federal Privacy Commissioner, November 2001⁶⁵. This is particularly important where the consumer is the reporter. In these cases the TGA's requirement for sponsors to provide information on an identifiable reporter does not override these privacy principles and explicit consent to the disclosure of the consumer's identity to the TGA must be sought⁶⁶.

Electronic data and paper reports of suspected ARs should be stored and treated in the same way as other medical records with appropriate respect for confidentiality regarding patients' and reporters' identifiability and in accordance with data privacy laws.

In order to ensure pharmacovigilance data security and confidentiality, strict access controls to authorised personnel only should be applied to documents and to databases. This security extends to the complete data path. In this aspect, procedures should be implemented to ensure security and non-corruption of data during data transfer. When transfer of pharmacovigilance data occurs within an organisation or between organisations having concluded contractual agreements, the mechanism should be such that there is confidence that all notifications are received. A confirmation and/or reconciliation process should therefore be undertaken.

Correct data entry, including the appropriate use of terminologies, should be verified by quality assurance auditing, either systematically or by regular random evaluation. Data entry staff should be instructed in the use of the terminologies, and their proficiency confirmed.

Electronic data storage should allow traceability (an audit trail) of all data entered or modified, including dates and sources of received data, as well as dates and destinations of transmitted data.

A procedure should be in place to account for identification and management of duplicate cases at data entry and during the generation of aggregated reports.

Conformity of stored data with initial and follow-up reports should be verified by quality control procedures, which permit for the validation against the original data or images thereof. In this aspect, the source data (e.g., letters, emails, records of telephone calls that include details of an event) or an image of the source data should be easily accessible.

Footnotes

65. The Guidelines on Privacy in the Private Health Sector, Office of the Federal Privacy Commissioner, November 2001 can be viewed online at Privacy in the Private Health Sector (November 2001).
66. Section 2.6 includes further information about consumer reports.