Recommendation in RMP evaluation report
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Sponsor’s response
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RMP evaluator’s comment
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Safety considerations may be raised by the clinical evaluator through the consolidated TGA request for information. It is important to ensure that the information provided in response to these include a consideration of the relevance for the RMP, and any specific information needed to address this issue in the RMP. For any safety considerations so raised, the sponsor should provide information that is relevant and necessary to address the issue in the RMP.
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The sponsor reports: “The clinical evaluator recommended additional wording under ‘Dosage’ for inclusion of information relating to fluid and oncotic overload. A statement ‘Infusion rate and volume need to be adapted according to clinical conditions, most notably in the elderly or in the paediatric population.’ has been included in the revised PI documents” and the important potential risk: ‘Hypervolaemia and haemodilution in high risk patients’ has now been included as a safety concern.
[information redacted]If Albunate is supplied in Australia, assurance is provided that safety surveillance will be performed in accordance with CSL Behring's on-going routine pharmacovigilance practices”.
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This is acceptable.
The Delegate has advised that this response is acceptable.
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Notwithstanding the evaluation of the clinical aspects of the safety specification: ‘Potential for off-label use’ of the EU-RMP states that the potential for off-label use is a class-effect for all HA products and it cannot be excluded that HA products are used outside the approved indications. Consequently it is suggested that the sponsor consider including ‘Off-label use’ as an important potential risk. It is noted that routine pharmacovigilance and routine risk minimisation activities are already proposed for this ongoing safety concern and only the ASA need be revised accordingly.
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The sponsor states: “The definition of important identified risk and important potential risk (Good Pharmacovigilance practices (GVP) Annex I) is ‘what constitutes an important risk will depend upon several factors, including the impact on the individual, the seriousness of the risk and the impact on public health’. Currently, there is no available data and/or evidence showing that off-label use of HAS causes serious individual risk or public health concerns. Therefore, ‘off-label use’ has not been listed in the ASA Summary table of Safety Concerns as an important potential risk. Spontaneous and other reports of off-label use will be reviewed in accordance with CSL Behring's ongoing routine pharmacovigilance practices.”
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This is acceptable.
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For completeness it is suggested that the sponsor consider including ‘Use in Pregnancy and lactation’ and ‘Use in paediatric patients’ as missing information. Consideration must be given as to what pharmacovigilance and risk minimisation activities will be proposed for these new ongoing safety concerns and only the ASA need be revised accordingly.
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The sponsor has provided justification for not including ‘Use in Pregnancy and lactation’ and ‘Use in paediatric patients’ as missing information.
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This is acceptable.
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The RMP Questions and Answers (Version 1.3, October 2012) as found on the TGA website state: “The ASA should identify any differences between the EU-RMP and the local implementation of risk management activities, for example: any differences between the risk minimisation activities undertaken as reflected in the content of the EU Summary of Product Characteristics (SmPC) and the proposed Australian PI, and the reasons for the difference.” Consequently the ASA should be revised to include a risk minimisation activities table detailing all planned risk minimisation measures in the Australian context and the EU-RMP context. This table should include a comparison of the actual content and wording of the EU SmPC and the proposed Australian PI and CMI for all of the specified ongoing safety concerns and missing information to identify and provide reasons for any observed differences, particularly where it appears the EU SmPC is more restrictive.
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The sponsor states: “The routine pharmacovigilance and risk minimisation measures undertaken as reflected in the current content of the EU SmPC and the proposed Australian PI are consistent. Human Albumin CSL Behring has no additional risk minimisation measures. A detailed comparison of the actual content and wording of the EU SmPC and the proposed Australian PI (and CMI) has been added as an Annex to the ASA (see section 1.13.1, Australian Specific Annex, Annex 1).”
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This is acceptable.
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A table summarising the pharmacovigilance and risk minimisation activities for all of the specified ongoing safety concerns and missing information proposed for Australia should be included in the revised ASA.
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The sponsor states: “Tables summarising planned pharmacovigilance actions (see section 1.13.1 Australian Specific Annex, 3.2) and risk minimisation activities (see section 1.13.1 Australian Specific Annex, Annex 1) for all safety concerns proposed for Australia have been included in the revised ASA”.
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This is generally acceptable, although Table 3.2: ‘Safety concerns and overview of planned pharmacovigilance actions’ is included in Section 3: ‘Risk Minimisation Plan’ of the ASA. This table should logically be relocated to Section 2: ‘Pharmacovigilance Practice’ of the ASA or included as a separate annex to the ASA. This amendment to the ASA can be dealt with administratively when this document is next updated.
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In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft PI document be revised to include a precautionary statement to the effect that the Albunate product range is not interchangeable with Albumex product range, which may be cross-referenced to the dosage and administration section.
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[information redacted] The distribution and supply of blood products are managed by the NBA. In the case of Albunate being supplied, an appropriate communication plan would be prepared and provided to all stakeholders (including the NBA, the ARCBS and clinicians). Therefore CSL Behring does not propose to include statements about interchangeability in the Albunate PI”.
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This is generally acceptable, although the sponsor should explicitly include such an assurance in a revised ASA, including the provision to the TGA of the details of such a communication plan before Albunate is supplied, preferably before this application is approved.
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In addition the draft EU ‘Guideline16 states: “In section 4.4 a new warning statement is introduced for patients with brain injury and burns taking into consideration the results of the SAFE-TBI study and the most recent Cochrane analysis.” The Delegate is asked to consider whether such a precautionary statement should be included in the Australian PI to enhance safe use of these products.
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The sponsor states: “CSL Behring acknowledges the concerns related to traumatic brain injury (TBI) and burns. The ‘Guideline on core SmPC for human albumin solution’ rev 3.0 is still in draft form while input from stakeholders is reviewed. CSL Behring, as an interested stakeholder, performed a careful analysis of the available data to assess the safety profile of albumin and provided comment on the draft SmPC. CSL Behring’s conclusions were the available data showed no compelling evidence that albumin is harmful in TBI and burned patients and therefore does not propose to change the Albunate PI until the Core SmPC is finalised. Accordingly, the EU SmPC which has recently been updated does not contain such a statement.”
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This is acceptable.
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In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft CMI document be revised to adequately reflect any changes made to the Australian PI as a result of the above recommendations.
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The sponsor states: “The CMI will be updated as appropriate when the changes made to the PI have been finalised.”
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This is acceptable.
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