Biovigilance responsibilities of sponsors of biologicals
Australian requirements and recommendations
Your biovigilance system
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.
A biovigilance system is used to fulfil the tasks and responsibilities associated with the detection, assessment, understanding and prevention of adverse effects of biologicals. It needs to be designed to monitor the safety of authorised biologicals and detect any change to their benefit-risk balance.
A biovigilance system is not in itself required by Australian legislation, but such a system is required for you to be able to meet legislated requirements for reporting adverse events and serious threats to public health.
A biovigilance system will:
- allow you to take responsibility and liability for your products
- ensure appropriate action is taken when necessary
Where a risk management plan (RMP) is required, the biovigilance system must support your ability to undertake the biovigilance activities described in the plan. An RMP is usually a requirement for new applications for class 3 and 4 biologicals and selected class 2 biologicals (see Risk management plans for medicines and biologicals - Australian requirements and recommendations).
Objectives of a biovigilance system
Your biovigilance system needs to enable you to undertake:
- all routine biovigilance requirements described in these guidelines
- any additional biovigilance activities required through the RMP (if an RMP is required)
- all traceability and other biovigilance requirements imposed on you through
Therapeutic Goods Orders, an RMP or as conditions of registration
- the investigation and reporting of product quality issues
- the critical analysis of adverse events and other safety and quality information
- any activities needed to mitigate an identified safety issue
Biovigilance contact person
You should nominate a biovigilance contact person in Australia for all of the biologicals you sponsor. This person will be our primary contact to direct requests for biovigilance information and is responsible for reporting and coordinating biovigilance communication between you and the TGA.
We ask that you notify us of the biovigilance contact person:
- within 15 calendar days of a product being entered in the ARTG
- within 15 calendar days of any change in details of the nominated contact person
Please note that the biovigilance contact person may be different to the person responsible for biovigilance in Australia, although ideally they are the same person.
Person responsible for biovigilance in Australia
Every sponsor is legally responsible for meeting biovigilance requirements for their products, even if their products are the same as products belonging to other sponsors. You should have a person who takes responsibility for biovigilance of your biologicals in Australia. This person can also be the biovigilance contact person and should ensure that you comply with biovigilance legislation and have an effective biovigilance system in place.
We recommend that this person:
- lives in Australia
- is permanently and continuously available (or at least within the hours of 9am–5pm AEST Monday to Friday), with a back-up person appointed should the primary person responsible for biovigilance be absent. Please note this means the person is contactable when required, e.g. by phone, and not necessarily on-site full-time. Ultimately, sponsors need to be confident that the person responsible for biovigilance can be reached to seek advice in emergency situations
- is trained or experienced in biovigilance and relevant legislation in Australia
- is medically qualified, or if not, have ready access to a medically qualified person for any clinical assessments necessary. We prefer that this medically qualified person resides and is medically registered in Australia so they can address adverse events, serious threats to public health and the benefit–risk balance of biologicals in the Australian context
The person responsible for biovigilance in Australia should be suitably experienced and qualified in order to monitor the safety of your biologicals. The characteristics and skills of the individual should be dependent on their specific roles and responsibilities and enable you to meet your biovigilance requirements.
The person responsible for biovigilance in Australia needs to have adequate understanding of the Australian and global (where applicable) biovigilance processes in order to allow them to have effective oversight of the entire biovigilance system.
Adverse event recording and reporting
For recording and reporting adverse events, your biovigilance system should:
- ensure that collected reports are authentic (verifiable), legible, accurate, consistent and as complete as possible for clinical assessment
- be structured to enable serious adverse event reports to be validated in a timely manner and submitted to the TGA within the legal reporting timeframes
- enable you to provide within a specified timeframe any additional information requested by the TGA to assist with evaluation of the benefits and risks of a biological, including information about the volume of sales or prescriptions of the product concerned
Traceability of biologicals
You are required to be able to trace a biological from donor to product release [Therapeutic Goods Order (TGO) No. 87, subsection 6(1)]. For higher risk biologicals that require an RMP, a product-specific condition of registration is included that requires product traceability from the donor to the recipient.
Procedures are to be documented for tracing products from donor to recipient and from recipient to donor, so that disease transmission between donor and recipient can be investigated. You should be able to match donor reference numbers with batch or lot numbers of the released biological, and biologicals that are released for specific patients. Batch or lot numbers should be included in the medical records and in some cases on patient cards to facilitate adverse event reporting.
It is important that you can locate and identify a biological at any stage including when in:
- distribution to the recipient
The donor, tissue establishments, manufacturing facilities, medical facilities and recipients must all be identifiable.
Traceability also covers the ability to locate and identify all relevant data relating to products, materials and people that have come into contact with the biological.
Related information and guidance
Analysis of safety information
Biovigilance does not just consist of collection, but also of scientific evaluation and critical analysis of adverse event reports and any other safety issues associated with the biological. Safety issues arise from adverse event reports, but also arise from more general situations and may occur at any stage in the development, manufacturing, administration or follow-up of a product. Your system should enable you to detect and investigate safety issues.
You need to have systems in place to detect safety signals. Such signals arise from one or multiple sources (including observation and experiments) and suggest a new potentially causal association or a new aspect of a known association, between the biological and an event or set of related events.
You should actively investigate signals you judge to be of sufficient likelihood of being true associations to determine whether they can be verified or refuted. If a verified signal may change the benefit-risk profile of a biological, you must report it to the TGA as a serious threat to public health.
Monitoring and collecting safety information
A biovigilance system should encompass the monitoring and collection of information from as many sources as possible.
Information relating to the safety of your biological can be identified from a variety of sources including:
- reports made directly to you by health professionals or consumers
- worldwide scientific and medical literature
- reports in internet and digital media
- reports from non-medical sources
- post-ARTG inclusion studies
- other post-market initiatives
You should have mechanisms in place to collect full and comprehensive case information from all sources and to evaluate that information in a timely manner.
Reports made to you
Information on all suspected adverse events reported to you or people who work for or have a contractual relationship with you (such as medical and sales representatives, vendors, marketing organisations, partners and contract manufacturers) is to be collected, collated, analysed, followed up and held so that it may be accessed at a single point within Australia.
The medical and scientific literature is a significant source of information for the monitoring of the safety profile and risk-benefit balance of biologicals and for the detection of new safety signals and emerging safety issues.
- undertake regular (weekly) systematic review of the literature in widely used reference databases that contain the largest reference of scientific and medical publications in relation to the biological and its properties
- review and assess reports of adverse events from the scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, to identify, record and report adverse events and serious threats to public health
- ensure that, where contractual arrangements are made with a person or organisation to perform literature searches, detailed agreements exist that enable you to comply with all reporting obligations
For adverse events reported in the worldwide literature, you should endeavour to identify the cases that occurred in Australia and report these to the TGA if they are serious or near serious. When you cannot determine whether the event occurred in Australia, you should:
- keep records of the adverse events
- produce a report if requested by the TGA
- consider the report for discussion in any future Periodic Safety Update Reports (PSURs), if a PSUR is required
- consider the report in any global analysis of adverse events
Reports in internet and digital media
You should consider using your websites to facilitate the collection of adverse event reports. You can do this by providing reporting forms or contact details for direct communication. You should encourage reports from all sources, including health professionals and consumers.
- You should regularly screen for reports of suspected adverse events the internet (such as websites, webpages, blogs, vlogs, social networks, internet forums, chat rooms and health portals) and digital media under your management or responsibility
- You do not need to review internet and digital media not sponsored by your company
- If you become aware of a report of a suspected adverse event described in any non-company sponsored digital medium, you should assess the report to determine whether it qualifies for reporting, and if so, you should report it within the timeframes below
For digital media that you own, pay for or control, the reporting timeframes are considered to start on the date that the information was posted. This means that screening needs to be sufficiently frequent to report:
- serious threats to public health within 48 hours
- serious adverse event reports within ten calendar days
- near-serious adverse event reports within 30 calendar days
For such reports, it is important that the reporter is identifiable, that is, you can verify the existence of a real person:
- You should make reasonable attempts to contact the reporter wherever possible to confirm the event and patient details and collect any additional information
- For serious adverse events, you may post to a public forum and request that the reporter contact you privately to provide more information
If you do not know what country the primary source is from, use the country where the information was received.
Reports from non-medical sources
You should handle a report of a suspected adverse event from a non-medical source, for example the lay press or other media, as a spontaneous report. You should make reasonable attempt to follow up the case to obtain the minimum information that constitutes a valid adverse event report and to determine the seriousness of the adverse event.
It is important to have an appropriate quality management system in place and to document all of the processes in place for the biovigilance system.
- applicable biovigilance legislation and guidelines
- privacy legislation
- report processing and evaluation
Other personnel who may receive or process safety reports (e.g. clinical development, sales, medical information, marketing, legal, quality control) should be trained in adverse event collection and reporting.
The roles, responsibilities and required tasks of biovigilance need to be understood by and available in writing to all relevant parties.
Clear written standard operating procedures should provide for:
- quality control of the biovigilance system
- change to the biovigilance system
This is also applicable to activities that are contracted out to third parties, whose procedures the sponsor should review to verify that they are adequate and compliant with applicable requirements.
Retention of records
It is required that you retain all biovigilance documents, including records of all reports of adverse events associated with the use or administration of your biological, for as long as the product is approved for inclusion in the ARTG and for at least 10 years after it ceases to be included in the ARTG (see Record-keeping requirements).
Data quality control
You must be familiar with and discharge obligations in relation to the collection, use and disclosure of personal information in accordance with the Australian Privacy Principles under the Privacy Act 1988, and any relevant state or territory privacy legislation.
Electronic data and paper reports of suspected adverse events 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.
You should apply strict controls to documents and to databases to assure security and confidentiality of biovigilance data with access to authorised personnel only. This security extends to the complete data path.
You should implement procedures to ensure security and non-corruption of data during data transfer.
Data needs to be collected, collated and held so that it may be accessed at a single point within Australia.
It is preferable for data entry to use the appropriate Lowest Level Terms from the Medical Dictionary for Regulatory Activities (MedDRA).
Data entry staff should be instructed in the use of the terminologies, and their proficiency should be confirmed.
Quality assurance auditing, either systematically or by regular random evaluation, should verify that data is being entered correctly with the appropriate use of terminologies.
There should to be an audit trail for electronic data. It needs to be possible to trace:
- data entry
- data modification
- dates and sources of received data
- dates and destinations of transmitted data
Handling duplicate cases
There should be a procedure to identify and manage duplicate cases at data entry and during the generation of aggregated reports.
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. This enables initial and follow-up reports to be verified against the original data. You need to include this verification process in quality control procedures.
When biovigilance data is transferred within an organisation, or between organisations with contractual agreements, there should be mechanisms to establish that all notifications are received. This includes, but is not limited to, undertaking a confirmation or reconciliation process.