Biovigilance responsibilities of sponsors of biologicals
Australian requirements and recommendations
Identifying adverse events and serious threats to public health
This guidance concerns proposed amendments to the Therapeutic Goods Act 1989. The proposed amendments have not yet become law and may be subject to change. The purpose of this guidance is to make you aware of these proposed changes if/when they take effect.
The Therapeutic Goods Amendment (2017 Measures No. 1) Bill 2017 proposes amendments to the Therapeutic Goods Act 1989 (Act). The proposed amendments have not yet been passed by Parliament and may be subject to change. A link to the Bill can be found at: Therapeutic Goods Amendment (2017 Measures No. 1) Bill 2017.
Amendment regulations to support a number of measures in this Bill are proposed, but have also not yet become law as they rely on the Bill first being in place and on the Governor General's approval of the regulations. The purpose of this guidance is to inform stakeholders about these proposed changes. While reasonable care is taken to ensure that the information is an accurate description of the proposed changes, TGA does not guarantee or warrant the accuracy, reliability, completeness or currency of the information or its usefulness in achieving any purpose. To the fullest extent permitted by law, including but not limited to under s 61A of the Act, TGA will not be liable for any loss, damage, expense or cost incurred or arising as a result of any use or reliance on this information.
An adverse event is any undesirable medical event that occurs during or after the administration or use of a biological. It is a harmful and unintended response and can be any unfavourable and unintended symptom, sign (for example, an abnormal laboratory finding), disease or injury that occurs related to the use of a biological.
For biovigilance, the TGA uses the term adverse event to mean an undesirable medical event for which there is at least a reasonable possibility of a causal relationship between the use of the biological and the event. Such adverse events are considered to be related events and are reportable in accordance with the timeframes and guidance in this document.
Adverse events may be associated with the biological itself or any aspect of the biological, such as the:
- other substances or materials
- delivery systems
There are three types of adverse events:
- serious adverse events
- near serious adverse events
- non-serious adverse events
Assessing relatedness or causality of an adverse event
The potential for adverse events related to a biological depends on several factors including the:
- origin of the biological (autologous or allogeneic)
- ability of cells constituting a biological to proliferate or differentiate
- ability of the biological to initiate an immune response
- life span of the biological in vivo
- site and mode of administration
- type and level of cell manipulation during production
- storage time and conditions
- out-of-specification findings identified during in-process testing of the biological
These factors should be taken into consideration when assessing causality.
All spontaneous reports of biologicals adverse events notified to you by health professionals, patients or consumers are considered to be related adverse events as they convey the suspicions of the person reporting the information (the 'primary source') that there is a causal relationship.
A spontaneous report is an unsolicited communication by a health professional or consumer to a sponsor, manufacturer, regulatory authority or other organisation (e.g. WHO) that describes one or more suspected adverse events in a patient who was given a biological.
For a report to be spontaneous, it should not be derived from a study or any organised data collection system where adverse event reporting is actively sought (solicited).
Stimulated reports are considered to be spontaneous. Stimulated reporting can occur as a result of:
- notification by a 'Dear Health Professional' letter
- publication in the press or on social media
- questioning of health professionals by company representatives
- communication from patient organisations to their members
- class action lawsuits.
Spontaneous reports are reportable in accordance with the guidance in this document, unless:
- the reporter specifically states that they believe the events to be unrelated or that a causal relationship can be excluded
- you agree with this assessment
If you disagree with the primary source about the reasonable possibility of a causal relationship, then both opinions should be recorded in the adverse event report given to the TGA. You should include the criteria on which the assessment was made.
For non-spontaneous (or solicited) reports, for example those from post-ARTG inclusion studies and other post-marketing initiatives (depending on method of data collection), all events judged by the reporting health professional, the investigator, or you as having at least a possible causal relationship with the biological should be considered related adverse events and reported. Non-spontaneous reports of adverse events do not need to be reported if they are not suspected to be causally related to the biological.
There are different methods for determining causality, for example the World Health Organisation Uppsala Monitoring Centre (WHO–UMC) system for standardised case causality assessment.
Serious adverse events
The term serious adverse event for a biological relates to 'an event or occurrence that led to a death or serious deterioration in the state of health of a patient, a user of the biological or another person'.
A serious adverse event for a biological is an adverse event for which one or more of the following is true:
- results in death
- is life-threatening
- requires inpatient hospitalisation
- prolongs existing hospitalisation
- results in persistent or significant disability or incapacity, including permanent impairment of a body function or permanent damage to a body structure
- necessitates medical or surgical intervention to prevent permanent impairment of a body function or permanent damage to a body structure
- is a congenital anomaly or birth defect
- is a medically important event:
- Events that make one of the outcomes above more likely, or that require intervention to prevent one of these outcomes
- For example, events that require intensive treatment in an emergency department or at home but do not result in hospitalisation, such as allergic bronchospasm, a blood disorder or convulsions
Such events occurring in Australia must be reported to the TGA within ten days of the sponsor becoming aware of them (Therapeutic Goods Regulations 1990, Regulation 16AB(b)).
Near serious adverse events
The term near serious adverse event for a biological relates to 'an event or occurrence that, if it occurred again, might lead to the death, or serious deterioration in the state of health, of a patient, a user of the biological or another person'.
A near serious adverse event for a biological is an adverse event which, if it occurs again, might result in one or more of the above outcomes for a serious adverse event. Timely intervention by a health practitioner may have prevented such an outcome from occurring. This category also includes the situation where testing or examination of the biological, or information supplied with the biological or scientific literature has indicated some factor that could lead to one or more of the above outcomes.
Such events occurring in Australia must be reported to the TGA within thirty days of the sponsor becoming aware of them (Therapeutic Goods Regulations 1990, Regulation 16AB(c)).
Non-serious adverse events
All adverse events that do not meet the definition of serious or near serious adverse events are considered to be non-serious adverse events (see Reporting non-serious adverse events).
Serious threat to public health
A serious threat to public health in relation to a biological is considered to exist when any new safety issue is identified which may change the benefit-risk assessment of the product and require action to eliminate or reduce the risk. The term 'public health' in serious threat to public health does not signify the risk to the population (such as a communicable disease), but rather it refers to the risk of adverse events in future individual recipients of biologicals from the same donor.
Safety issues which may change the benefit-risk assessment of a biological include:
- a report of an unexpected or previously unknown serious or near serious adverse event
- a change in the nature, severity or frequency of expected (known) adverse events
- the identification of previously unknown risk factors
- the transmission of an infectious agent, including reactivation of any viral vector
- a signal of a possible teratogenic effect
- A signal indicating a possible teratogenic effect may come from a cluster of cases of similar abnormal outcomes in clinical situations or from nonclinical data
- a signal of possible tumorigenicity
- unexpected lack of efficacy
- issues related to the raw materials used in the biological
- issues related to the delivery system used for the biological
- issues due to misinformation in the product documentation
- issues related to use outside the approved indication or intended use
A serious threat to public health must be reported to the TGA within 48 hours of the sponsor becoming aware of them (Therapeutic Goods Regulations 1990, Regulation 16AB(a)).
Analysis to identify serious threats to public health
We expect you to use your clinical and scientific judgement for discerning which products available in Australia and worldwide are likely to provide relevant safety information for your biological and in determining whether a safety issue is a serious threat to public health. It is anticipated that this may be more difficult for biologicals than for medicines or medical devices.
You may identify serious threats to public health related to a biological as a result of your ongoing review and analysis of all information pertinent to the benefit-risk assessment of the product, for example, from:
- signal detection activities
- review and analysis of adverse event reports
- including adverse events which have occurred in a country other than Australia
- reports about unexpected lack of efficacy
- studies that impact on the evidence for efficacy
- major safety findings from newly completed
- nonclinical studies
- post-ARTG inclusion studies
- clinical trials
- other post-market activities
- the scientific or medical literature
- action taken by an overseas regulatory agency, such as:
- withdrawal or suspension of the availability of the product
- addition of a contraindication, warning or precaution statement to the product documentation or label
- modification of an existing contraindication, warning or precaution for safety reasons
- modification or removal of an indication or intended use for safety reasons