Pharmacovigilance responsibilities of medicine sponsors

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Australian recommendations and requirements

1 September 2017

Introduction

Pharmacovigilance is defined by the World Health Organization as the science and activity related to detecting, assessing, understanding and preventing adverse effects and other medicine-related problems. The Therapeutic Goods Administration (TGA) collects and evaluates information related to the benefit-risk balance of medicines in Australia to monitor their safety and, where necessary, take appropriate action.

This guidance sets out the pharmacovigilance responsibilities of sponsors of medicines included on the Australian Register of Therapeutic Goods (ARTG) and regulated by the TGA. It outlines the mandatory reporting requirements and offers recommendations on pharmacovigilance best practice.

In this guidance, we use 'must' or 'required' to describe something you are legally obliged to do. We use 'should' to recommend an action that will assist you to meet your legal requirements. We refer to the TGA as 'we' or 'us', and to sponsors as 'you'.

Scope

This guidance:

  • applies to all sponsors who have medicines registered or listed on the Australian Register of Therapeutic Goods (ARTG)
  • describes your reporting and record-keeping requirements
  • offers recommendations on the monitoring, collection and management of safety data to help you achieve best practice pharmacovigilance
  • outlines the legal basis for pharmacovigilance requirements associated with medicines on the ARTG.

This guidance is mostly consistent with the European Medicines Agency's EMA Guideline on Good Pharmacovigilance Practices (GVP) Module VI - Management and reporting of adverse reactions to medicines. Some requirements and recommendations, however, are specific to Australia.

Responsibilities

You MUST meet your pharmacovigilance reporting responsibilities for all the medicines you have registered or listed on the Australian Register of Therapeutic Goods (ARTG). This is regardless of their Australian marketing status - that is, whether they are currently available for purchase, withdrawn from sale or otherwise supplied e.g. in a company-sponsored post-registration study.

Unapproved medicines used in Clinical trials or supplied under the Special Access Scheme (SAS) or Authorised Prescriber are subject to separate reporting requirements and are not covered by these guidelines.

You, as a sponsor of medicines approved for supply in Australia, are legally responsible for meeting pharmacovigilance reporting requirements for your medicine. You MUST:

This includes situations where:

  • separate sponsors market two or more separately registered or listed medicines that are considered identical in all respects apart from their trade names
  • sponsors share or outsource marketing or distribution arrangements
  • pharmacovigilance activities are contracted to external organisations.

We expect you to have an effective pharmacovigilance system in place in order to:

  • monitor and take responsibility for the safety of your medicine
  • meet legislative requirements for reporting serious adverse reactions and significant safety issues
  • identify any changes to the benefit–risk balance of your medicine
  • take appropriate action in a timely manner when necessary
  • update product labels and product information (PI) with new safety information in a timely way.

Adverse events and adverse reactions

Pharmacovigilance distinguishes between adverse events and adverse reactions.

Adverse events

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

Adverse reactions

An adverse reaction is a noxious and unintended response to a medicine. The phrase 'response to a medicine' means there is at least a reasonable possibility that the medicine caused the adverse event. A reaction, in contrast to an event, is characterised by the fact that a sponsor, investigator or reporter suspects there is a causal relationship between the medicine and the occurrence.

This guidance describes the reporting requirements that apply to adverse reactions (as opposed to adverse events) identified from all sources, including adverse reactions that arise from:

  • the use of a medicine within the terms of approved indications as per the product information or ARTG
  • the use of a medicine outside the terms of the approved indications - including overdose, abuse, misuse, off-label use and medication errors
  • occupational exposure.

Note: synonyms of adverse reactions include adverse drug reaction (ADR), suspected adverse (drug) reaction, adverse effect, and undesirable effect.

For regulatory reporting purposes, if an adverse event is spontaneously reported, even if the causal relationship is unknown or unstated, it meets the definition of an adverse reaction. Therefore all spontaneous reports notified by healthcare professionals or consumers are considered suspected adverse reactions, since they convey the suspicions of the primary sources, unless the reporter specifically state they believe the events to be unrelated or that a causal relationship can be excluded.

You should make reasonable attempts to obtain additional information so you can assess causality.

Expected and unexpected adverse reactions

An expected adverse reaction is an adverse reaction known to be associated with the use of the medicine, as reflected in the product information document or label warning statement.

An unexpected adverse reaction is an adverse reaction in which its nature (that is, its specificity or outcome), severity or frequency is either not identified, or not consistent with the term or description used, in the product information document or label warning statement.

Regulatory reporting requirements apply to both expected and unexpected adverse reactions.

Serious adverse reactions

A serious adverse reaction is any medical occurrence that in relation to a medicine, at any dose:

  • results in death
  • is life-threatening
  • results in inpatient hospitalisation or prolonged hospitalisation
  • results in persistent or significant disability or incapacity
  • is associated with a congenital anomaly or birth defect (see Reports in pregnancy and breastfeeding)
  • is a medically important event or reaction.

Non-serious adverse reactions

Non-serious adverse reactions are adverse reactions that do not meet the definition of a serious adverse reaction.

Significant safety issues

A significant safety issue is a new safety issue or validated signal considered by you in relation to your medicines that requires urgent attention of the TGA. This may be because of the seriousness and potential major impact on the benefit-risk balance of the medicine and/or on patient or public health, which could warrant prompt regulatory action and/or communication to patients and healthcare professionals.

You can identify significant safety issues as a result of ongoing review and analysis of all information that is pertinent to the safety or benefit-risk balance of the medicine.

Examples of significant safety issues include:

  • safety-related actions by comparable international regulatory agencies such as
    • the withdrawal or suspension of the medicine's availability
    • the addition or modification, for safety reasons, of a contraindication, warning or precaution statement to the product information or label
    • the modification or removal, for safety reasons, of an indication.
  • changes in the nature, severity or frequency of known serious adverse reactions which are medically significant
  • detection of new risk factors for the development of a known adverse reaction or a new serious adverse reaction that may impact on the safety or benefit-risk balance of the medicine
  • series of reports of similar or linked adverse reactions reported at the same time (that is, a cluster) assessed to suggest a quality defect issue that may have implications for public health
  • an unusual and significant lack of efficacy occurring in or outside Australia that may have implications for public health
  • major safety findings from a newly completed non-clinical study, post-registration study or clinical trial that may impact the benefit-risk balance of the medicine on the ARTG
  • a signal of a possible teratogenic effect or of significant hazard to public health
  • safety issues related to any raw materials used in the medicine that may impact the safety of the medicine and/or have implications for public health
  • safety issues due to misinformation in the product information or label that may impact the safety of the medicine
  • safety issues related to use outside the approved indication or intended use that may impact the safety or benefit-risk balance of the medicine

We use the information you report to take appropriate action, if deemed necessary. We may provide further safety information to the public, request updates to product information documents and labels, impose additional risk management interventions or pharmacovigilance activities, or (rarely) remove a medicine from the market.

We expect you to use your professional judgement in determining whether a safety issue is significant. The examples above are not intended to be an exhaustive list of significant safety issues, and it is up to you to assess safety issues on a case-by-case basis and evaluate whether this has an impact on the medicine's safety or benefit-risk balance and/or implications for public health.

All pertinent factors should be taken into account when assessing a safety issue. Issues to consider include the medicine, the risks involved and the regulatory context. Further, a safety issue leading to international regulatory action is considered to be significant and hence reportable regardless of whether you agree with the recommendations and conclusions of the international regulator.

If you determine after appropriate assessment that a safety issue is not significant and do not report it, you should document a justification for this decision. We may ask you to provide this documentation at any time. If in doubt about a safety issue, treat it as significant (or contact us for advice).

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