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Submissions received: Guidance on biovigilance responsibilities of sponsors of biologicals

4 October 2017

Between 31 October and 16 December 2016, the TGA sought comments from interested parties on Biovigilance responsibilities of sponsors of biologicals - Australian requirements and recommendations in a consultation that closed on 16 December 2016.

A total of ten submissions were received from the consultation. Of the submissions, there were four from manufacturers/sponsors, one from an industry group, three from organ and tissue banks, and two from other stakeholders. The TGA thanks those individuals and organisations for their feedback. The TGA notes that six respondents were satisfied with the draft biovigilance guidelines and did not have further comments.

All submissions that were not marked as confidential are now available below in PDF format.

More information

Any questions relating to these submissions should be directed to the Signal Investigation Coordinator by email at


How to access a pdf document

TGA response

Submissions received in response to the consultation showed broad stakeholder support for the proposed biovigilance guidelines. However, some modifications were suggested.

Key recurring themes from the submissions included:

  • Clarification of biovigilance-related terminology and definitions
  • Differences in reporting timeframes to medicines
  • Clarification of reporting requirements and processes
  • Providing specific examples to assist understanding

The TGA thanks those who took the time to make a submission and to make comments and suggestions. The feedback received from the consultation process will assist in the development of a useful guidance document for sponsors so that there is a clear understanding of TGA expectations with regard to biovigilance.

A summary of our responses to the consultation feedback by topic is provided below.

The TGA agrees that collaboration across the sector will be important. We have and will continue to work closely with a number of sponsors on their traceability systems. Education of providers and hospitals regarding the importance of maintaining these records may be considered to further collaborate and support sponsors.

Summary of responses to the consultation feedback
Topic Consultation feedback TGA response
Terminology and definitions One respondent noted that both 'reports in the world-wide scientific and medical literature' and 'reports in world-wide literature of adverse reactions that occurred in Australia' are separately listed as sources of information in the guidelines. The respondent seeks clarity. The TGA only requires sponsors to evaluate and report adverse event cases that occurred in Australia from world-wide literature. 'Reports in the world-wide scientific and medical literature' will be removed from the list of sources of information. Sponsors should be aware that literature is not only a source of adverse event reports, but also new significant safety issues.
One respondent commented that the definition of a biological in Australia is different to that of the EU and FDA regulatory agencies and represents a narrower range of products. Australian biologicals most closely resemble advanced therapy medicinal products. The definition of biologicals in Australia, outlined in the Therapeutic Goods Act 1989, is appropriate to the Australian setting. Where possible, the TGA aligns its legislative requirements with other comparable regulators achieving better harmonisation with relevant international standards. At present, there is no international consistency.
A respondent also requested that the guidelines clearly define biologicals in Australia to identify which products are subject to the biovigilance requirements.

The meaning of a biological in Australia is included in:

  • Part 3-2A of the Act - described in guidelines under 'Relevant legislation'
  • On the TGA webpage titled 'Products regulated as biological' - link given in guidelines

The TGA considers the definition of biologicals is sufficiently covered in the guidelines.

Two respondents exhibited confusion with the term public health for 'serious threat to public health' with risk to the general community/population. The TGA appreciates that the use of the term public health in the guidelines differs from the generally accepted definition, which can cause misunderstanding. Public health in 'serious threat to public health' does not signify the risk to the population (e.g. communicable disease), but rather, it refers to the risk of adverse events in future individual recipients from biologicals of the same donor. 'Serious threat to public health' will be redefined or clarified in the guidelines.
One respondent queried whether imported biological products should be labelled 'Australian'. 'Australian products from overseas' will be amended to 'Products from overseas marketed in Australia' for clearer description. The sponsors of biologicals supplied in Australia, regardless of where it is manufactured, are responsible for meeting the regulatory biovigilance requirements for their products.
Reporting timeframes Three respondents noted that reporting timeframes for biologicals align with device vigilance, which are shorter compared to medicines. The reporting requirements for biologicals described in the guidelines reflect the current existing legislation (Section 16AB of the Therapeutic Goods Regulations 1990), and the timeframes are in line with those for medical devices. Sponsors are expected to follow up on all cases to enable proper assessment and submit any new significant information to the TGA as it becomes available.
One respondent suggested that the reporting timeframes for biologicals be made to mirror medicines, consistent with EU requirements. The reporting requirements for biologicals described in the guidelines reflect the current existing legislation (Section 16AB of the Therapeutic Goods Regulations 1990), and the timeframes are in line with those for medical devices. We consider this appropriate as a significant proportion of biologicals behave like devices.
In relation to SAS and Authorised Prescriber, a respondent queried whether the reporting requirements and timeframes for biologicals be kept the same as for medicines and devices. The comments regarding reporting requirements for biologicals in SAS and Authorised Prescriber will be forwarded to the appropriate area of TGA for consideration independently of this current consultation. These will be outlined in the relevant guidelines.
One respondent requested further clarification on the definition of 'sponsor awareness' in association to 'Day zero' for the reporting clock start. 'Sponsor awareness' with respect to 'Day zero' will be clarified. Day 0 is the day that any of the sponsor's Australian personnel (including sales representatives, investigators or contractors) becomes aware of a significant safety issue or receives the minimum information necessary for adverse event reporting. The TGA recognises that sponsors may receive and process safety information at global headquarters overseas, before it is disseminated to the local affiliates in Australia for reporting. The TGA expect sponsors to have internal procedures in place that ensure global headquarters will communicate significant safety issues to their Australian staff without delay.
Reporting processes One respondent queried whether the Adverse Drug Reporting System is set up to include biologicals in order to facilitate reporting compliance.

The concerns regarding adverse event reporting for biologicals has been noted and will be forwarded to the appropriate area of TGA for consideration. Currently the TGA accepts adverse event reports through any of the medicines or devices reporting pathways, and through recall notifications where applicable.

For reporting serious threats to public health, in cases where internal processes may result in a delay in submitting a written report, sponsors should consider contacting the TGA by phone firstly. Sponsors should ensure they obtain an acknowledgement of receipt for all communication to the TGA.

Traceability One respondent expressed concerns regarding the challenges for sponsors to meet traceability requirements. It was recommended that the TGA have a collaborative and supportive role in developing traceability measures.

The TGA recognises that traceability could be challenging for sponsors, but we have seen some good examples of sponsors being able to set up such systems and putting in place mechanisms to encourage hospitals to participate.

At present, traceability is maintained by the sponsor with documentation that is able to match donor reference numbers with batch/lot numbers of the released product, and products are released for specific patients. Batch/lot numbers should be included in the medical records and in some cases on patient cards to facilitate adverse event reporting.

Of note, sponsors of some biologicals have been required to implement donor-to-recipient (and vice versa) traceability systems as part of the RMP. The nature and operations of the traceability system aren't prescribed by our guidance but are determined on a case-by-case basis. Basically, we negotiate with the sponsor on this until we are satisfied that the system they are proposing will adequately trace materials. We monitor this by requiring sponsors to provide us with reports (usually annual) describing the proportion of product for which they have complete traceability information – the sponsor should be monitoring this continuously and proposing improvements to the system if it's not performing as expected. In some cases, sponsors have implemented systems whereby they won't supply a particular hospital with any more product until they have provided information about recipients of previously supplied product.

The EMA's 'Guideline on safety and efficacy follow-up – risk management of advanced therapy medicinal products (pdf,207kb)' goes into quite a bit of useful detail about how traceability systems can be set up. Although this document is not presently adopted by the TGA, we frequently refer to it for advice.

Transmission of infectious agents One respondent noted that the statement 'Any suspected transmission of an infectious agent is considered a serious threat to public health' is incorrect for a transplant of a living integrated biological system, such as a corneal transplant. It was noted that the European Directorate for the Quality of Medicines and Healthcare (EDQM) uses the term 'unexpected' for primary infections possibly transferred from the donor to recipient. The TGA acknowledges that there are some exceptions and sponsors need to use clinical judgement to determine if cases of transmission of infectious agents are considered serious threats to public health. The TGA agrees that it is appropriate to alter the wording in the guidelines to state that 'Unexpected transmission of an infectious agent may constitute a serious threat to public health' and highlight the importance of clinical judgement regarding reporting and follow up.
Unexpected lack of efficacy One respondent raised the issue that in cases of transplantation of a complex and integrated living biological system, predictions on efficacy and thus, unexpected lack of efficacy, is a nebulous undertaking – particularly in an individual instance. The respondent suggested the use of a statement in line with the EDQM; 'unexpectedly delayed or absent engraftment or graft failure'. More clarification is required regarding biologicals and unexpected lack of efficacy. The TGA acknowledges the problems of identifying lack of efficacy with cell and tissue therapies, but the guidelines apply to all biologicals. The TGA agrees that it is worth considering EDQM guidance documents, although definitions should be non-specific. The sponsor should use clinical judgement on a case-by-case basis. The TGA will include examples to assist the sponsor.
Biovigilance contact person One respondent expressed concerns regarding the requirement of a nominated contact person to be a registered medical practitioner who is permanently available.

The TGA notes that nominated contact person is distinct from the person responsible for biovigilance. The contact person does not need to be medically qualified. The person responsible for biovigilance, however, should understand the Australian market that the product is supplied in to, so it is recommended that this person is a locally qualified medical practitioner.

Further, 'permanently and continuously available' 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 can be reached to seek advice in emergency situations.

These will be further clarified in the guidelines.

Literature reviews One respondent queried about what information and products should be reviewed in literature and for adverse event reports. The respondent also commented on the difficulties with weekly literature reviews. Sponsors should exercise clinical judgement at all times to determine what safety information and products may be relevant and should be considered, but for biologicals, adverse event reports mostly refer to the sponsor's product only. Sponsors are requested to undertake regular (weekly) systematic review of literature to identify adverse event reports and serious threats to public health. Biovigilance activities can be contracted to external parties. Sponsors need to ensure that they collect and investigate all pertinent and up-to-date safety information related to their product.
Recalls, quality defects and contaminated or counterfeit biologicals One respondent queried recalls in relation to an implant and what situation would a sponsor report an adverse event resulting from the implantation of a counterfeit product. Counterfeits of the sponsor's products, of which they are aware, should be notified to the TGA regardless whether a recall is warranted or an adverse event has been reported. This aligns with the pharmacovigilance requirements for medicines. It is important to note that recall actions encompass not only recalls, i.e. removal from supply or use from the market, but also includes recall for product correction or hazard alert. This will be further clarified.
Other post-market initiatives One respondent commented that negative outcomes in recipients through solicited information gathering did not fit the criteria for a reportable adverse event. Suspected serious adverse events received from post-marketing initiative reports are subject to the regulatory reporting requirements. For solicited adverse event reports, sponsors are required to assess causality to determine whether they should be submitted to the TGA. Adverse event reporting from other post-marketing initiatives, including market research and market research programs, will be clarified.
Overdose, abuse, off-label use, misuse, administration error or occupational exposure One respondent suggested examples, especially related to tissue banks. The TGA agrees that this section is unlikely to be particularly relevant to the tissue banks. Overdose and abuse are unlikely. Examples of off-label use are more likely to apply to cellular therapies, for example use of allogeneic T-cell preparations for conditions in which clinical trials have not been performed, or administering cells via unapproved procedure (e.g. intravenous instead of intraarticular). The guidelines capture all biologicals in general and there will be some requirements for which the sponsor's requirements are not applicable and sponsors are expected to practice clinical judgement.