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Presentation: Biovigilance

TGA presentations: Biotherapeutics Association of Australasia 2016 AGM, TGA Workshop & Education Session

1 November 2016


These presentation papers are provided on the TGA's website solely for the purpose of indicating or suggesting what TGA representatives spoke about to the various conferences and seminars to which it relates. The papers are not legislative in nature and should not be taken to be statements of any law or policy in any way.

The Australian Government Department of Health (of which the TGA is a part) advises that (a) the presentation papers should not be relied upon in any way as representing a comprehensive description of regulatory requirements, and (b) cannot guarantee, and assumes no legal liability or responsibility for, the accuracy, currency or completeness of the information contained in the presentation paper.


  • Presented by: Bronwen Harvey, Signal Investigation Unit, Pharmacovigilance and Special Access Branch, Therapeutic Goods Administration
  • Presented at: Biotherapeutics Association of Australasia 2016 AGM, TGA Workshop & Education Session, Canberra
  • Presentation date: 13 October 2016
  • Presentation summary: An overview of the biovigilance, including roles and responsibilities of sponsors.



Dr Bronwen Harvey
Director, Signal Investigation Unit
Pharmacovigilance and Special Access Branch, TGA

Biotherapeutics Association of Australasia 2016 AGM, TGA Workshop & Education Session

Slide 1 - Outline

  • What are biologicals?
  • Regulatory framework for biologicals
  • What is biovigilance?
  • Responsibilities of sponsors of biologicals
    • reporting adverse events
    • recalls
  • Sponsors' biovigilance systems
  • TGA process
    • development of draft guidance, consultation, finalisation of guidance
    • regulatory aspects
  • Questions and discussion

Slide 2 - What are biologicals?

Short definition = human tissue and cell-derived products

Definition of a biological in the TG Act (Part 3-2A–Biologicals)

32A Meaning of biological

  • (1) Subject to subsection (3), a biological is a thing that:
    • (a) either:
      • (i) comprises, contains or is derived from human cells or human tissues; or
      • (ii) is specified under subsection (2); and
    • (b) is represented in any way to be, or is, whether because of the way in which it is presented or for any other reason, likely to be taken to be:
      • (i) for use in the treatment or prevention of a disease, ailment, defect or injury affecting persons; or
      • (ii) for use in making a medical diagnosis of the condition of a person; or
      • (iii) for use in influencing, inhibiting or modifying a physiological process in persons; or
      • (iv) for use in testing the susceptibility of persons to a disease or ailment; or
      • (v) for use in the replacement or modification of parts of the anatomy in persons.

[In addition, the Secretary can specify things to be or not to be biologicals by instrument]

Slide 3 - Regulatory framework for biologicals

  • Provides the legislative basis for the regulation of human tissue and cell-derived products that are supplied in, or exported from, Australia.
  • Legislation commenced May 2011 - transition period (3 years+)
  • Information on TGA website at Regulatory framework for biologicals
  • Australian Regulatory Guidelines for Biologicals
  • Not biological medicines
  • Similar, but not identical, to the EMA's Advanced Therapy Medicinal Products (ATMPs) which are medicines for human use that are based on genes or cells

Slide 4 - What is biovigilance?

  • The science and activities relating to the detection, assessment, understanding and prevention of adverse events or any other problems related to biologicals
  • Therapeutic product vigilance in Australia
    • Pharmacovigilance
    • Medical devices vigilance
    • Biovigilance
  • Includes quality issues
  • Other terms - post-market monitoring / surveillance
  • Systematic collection and analysis of information to improve patient safety

Slide 5 - Responsibilities of sponsors of biologicals

  • Therapeutic Goods Act 1989 and Therapeutic Goods Regulations 1990
  • Sponsors of biological products on the Australian Register of Therapeutic Goods (ARTG) must report to the TGA
    • Serious threat to public health = 48 hours
    • Serious adverse event = 10 calendar days
    • Near serious adverse event = 30 calendar days
  • This terminology used as biologicals legislation was based on devices legislation
  • All classes of biologicals
  • Uniform Recall Procedure for Therapeutic Goods
    • Recalls, quality defects, contaminated biologicals = as soon as possible

Slide 6 - Biovigilance guidance

  • Draft guidance has been developed based on the TGA pharmacovigilance and medical device vigilance guidance
  • Also based on relevant pharmacovigilance guidance, standards and terminology
    • European Medicine Agency (EMA) Good Pharmacovigilance Practice (GVP)
    • International Conference on Harmonisation of Technical Requirements Technical Requirements for Pharmaceuticals for Human Use (ICH)

Slide 7 - Adverse events (1)

  • Any undesirable medical event that occurs in temporal relationship with (during or after) the use of a biological product
    • symptom, sign (eg abnormal laboratory finding), disease or injury
    • at least a reasonable possibility of a causal relationship between the use of the biological and the event
  • Serious adverse event
    • 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
  • Near serious adverse event
    • 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

Slide 8 - Adverse events (2)

  • AEs may relate to the biological itself or any aspect of the biological
    • Solutions
    • Excipients
    • other substances or materials
    • Packaging
    • delivery systems

Slide 9 - Adverse events (3)

  • Potential for AEs depends on
    • 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

Slide 10 - Serious adverse events (SAEs)

  • 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

Slide 11 - How to report adverse events

  • Minimum data for a valid report
    • an identifiable patient (but do not send name to the TGA
    • one or more suspected biological or delivery system or other aspect of a biological
    • one or more suspected adverse events (events with a reasonable possibility of causal relationship)
    • one or more identifiable reporters
  • Only adverse events that have occurred in Australia
  • Provide as much information as possible to facilitate assessment of the AE
  • Range of reporting formats available, including direct data entry online
    • More information on TGA website at Reporting problems
    • Will develop specific formats for biologicals - currently use either medicines or medical devices reporting processes

Slide 12 - Examples

  • Some reports of tissue related adverse events received over the past 3 years
    • Pulmonary heart valve - leaflet tear and bleeding
    • Heart valve - sterility concerns - recipient had an infection
    • Bone (femoral head) - several reports relating to new information about the donor such as malignancy

Slide 13 - Serious threat to public health

  • Any identified safety issue which may change the benefit-risk assessment of the product and require action to eliminate or reduce that risk, such as
    • 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 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

Slide 14 - How to report a serious threat to public health

  • In writing and sent by email to the
    • Subject line = 'Urgent - serious threat to public health - [descriptor: name or number of biological, name of sponsor, or some other descriptor]'
    • describe the evidence for the threat
    • indicate the action that the sponsor is proposing to take to eliminate or reduce the risk
      • the action may relate to conditions of inclusion in the ARTG including amendments to the label or the product information or any other change
    • clearly identify the person in Australia who is taking responsibility on behalf of the sponsor for the accuracy and veracity of the information in the report
    • include contact details of the person reporting on behalf of the sponsor, preferably the nominated biovigilance contact person

Slide 15 - Recalls and quality issues

  • Notify suspected or confirmed quality defects and contaminated or counterfeit biological products to the TGA with the least possible delay
    • Uniform Recall Procedure for Therapeutic Goods (URPTG)
      • New version will include biologicals
  • May be necessary to implement urgent measures to protect public health
    • for tissues usually "Hazard Alerts" but may involve a recall
  • Use the Human blood and tissues recall report form or phone TGA Recalls on 1800 020 512

Slide 16 - System for Australian Recall Actions (SARA) - Biologicals

Recall action commencement date Product name / description Reason for recall action Recall action
17/06/2014 Pulmonary Valve Allograft Staph epidermis isolated from nutrient broth Hazard Alert
24/04/2014 Corneo-scleral Disc (Normothermic) Potentially untraceable microbiology results Hazard Alert
31/05/2013 Bone Fragments - Milled irradiated femoral head At 2nd donation, donor found to have mantle cell lymphoma Hazard Alert
17/04/2013 Pulmonary Valve Transplant Positive microbiological culture from implant tissue culture Hazard Alert
19/03/2013 RegenerOss Allograft Block Max/Mand Blocks Assays used to test donors for HBsAG and Hep C not licensed for donor testing Hazard Alert
1/03/2013 Bone Fragments - Milled irradiated femoral head Donor melanoma removed 10 months after donation Hazard Alert
15/02/2013 Bone Unprocessed - Whole femoral head non-irradiated allograft Donor diagnosed with oesophageal cancer Hazard Alert
22/01/2013 Corneal Grafts Multiple myeloma found later in bones from same donor Hazard Alert
8/01/2013 QHVB Pulmonary Allograft Conduit (Human cardiovascular tissue) Retained samples showed positive microbial growth Hazard Alert

Slide 17 - Biovigilance system

  • Not a legislated requirement
  • but
  • Needed to enable sponsors to meet their biovigilance responsibilities including
    • routine biovigilance
    • additional biovigilance specified in the Risk Management Plan (RMP)
      • where an RMP is required
    • all traceability and any other requirements specified as conditions of registration
    • the critical analysis of adverse events and other safety and quality information
    • any activities needed to mitigate an identified safety issue

Slide 18 - Traceability

  • Sponsor needs to be able to locate and identify a biological during any step in the process from donor to recipient (including disposal)
  • 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
  • Required
    • Therapeutic Goods Order No. 87 6(1)
    • Class 3 and 4 biologicals (where an RMP is required) - a product specific condition of registration requires traceability to the recipient

Slide 19 - Where to from here?

  • Biovigilance guidance - drafting now completed
  • The draft guidance was endorsed by the TGA Regulatory Practice Committee (RPC) for consultation
  • Consultation will commence shortly and be in parallel with RMP guidance which has been revised to include specific biologicals advice
  • Will be a public consultation - information on TGA website + invitation
  • Consideration of responses → finalisation and publication of final guidance
  • Regulatory aspects to be determined
    • The equivalent pharmacovigilance guidance is included in the Therapeutic Goods Regulations 1990
    • Conditions of registration

Slide 20 - Questions?

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