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Table 3. Additional proposed pharmacovigilance activity Additional activity Assigned safety concern Actions/outcome proposed Estimated planned of final data Phase-3 investigator and assessor blinded 1:1 randomized parallel group multi-centre study. (Category 4) OHSS (important identified risk) Compare efficacy and safety of 2 rhFSH Formulations (AFOLIA pen versus Gonal-f RFF pen) in normal Ovulatory women 35 to 42 years of age undergoing in vitro fertilization (IVF). 21 April 2016 (final Clinical Study Report) Risk minimisation activities The sponsor has concluded that routine risk minimisation activities are sufficient to mitigate the associated with Bemfola. No additional risk minimisation measures are proposed (as described in the EU-RMP). Reconciliation of issues outlined in the RMP report Table 4 summarises the OPR’s first round evaluation of the RMP, the sponsor’s responses to issues raised by the RMP evaluator and the evaluation of the sponsor’s responses. Table 4. Reconciliation of issues outlined in the RMP evaluation report (Round 1) Recommendation in RMP evaluation report Sponsor’s response (or summary of the response) RMP evaluator’s comment 1. Safety considerations may be raised by the nonclinical and clinical evaluators through the consolidated questions and/or the nonclinical and clinical evaluation reports respectively. 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. The evaluator has no further comment regarding this recommendation. 2. It is noted that the approved indications for The company has revised the wording of the indications to This is acceptable from an RMP perspective.
communicated to the TGA when available. incidence of OHSS with Bemfola and the company wishes to address these within this response for the TGA’s review. 7. Given the DLP for this RMP was in 2012 the sponsor is requested to update the TGA with any reports relating to medication error in clinical trials or post-marketing experience. A copy of medication error listing report is provided as requested. This is acceptable from an RMP perspective. 8. Section 4.1 of the ASA states ‘For all eleven important identified risks, routine risk minimization measures are considered sufficient’ however this would appear to refer to identified and potential risks. Also this would appear to be factually inconsistent with no routine risk minimisation activities being proposed for several safety concerns. This should be considered by the sponsor and amended accordingly. The company has reviewed the ASA noting the RMP evaluator’s comments and has revised to address same. Updated copy of ASA is provided. The revised Section 4.1 Routine Risk Minimisation contains the following statement: ‘Based on the safety specifications of Bemfola and the experience with the reference product Gonal-f, it is proposed to manage all safety concerns (identified risks, potential risks and important missing information) by routine pharmacovigilance activities’. The sponsor has erroneously referred in this section to routine pharmacovigilance instead of routine risk minimisation. Also as previously stated, not all safety concerns are managed by routine risk minimisation including
the potential risk ‘immunogenicity’ for which no risk minimisation is proposed in Australia. The aforementioned statement should be amended to reflect the above. In addition section 4.3 of the ASA is titled ‘Additional risk minimisation activities’ however it would appear that a more appropriate title is ‘Evaluation of risk minimisation activities’. The sponsor is advised that the ASA does not follow the current ASA format guidance, as this guidance was not available at the time of submission. However, any ASA updates should be provided in the current ASA format (guidance available at: ) 9. Section 4.1 of the ASA does not contain information on the risk minimisation proposed for the items of missing information and should be amended. If no risk minimisation is proposed for a particular item of missing information then this should be stated. The company has reviewed the ASA noting the RMP evaluator’s comments and has revised to address same. Updated copy of ASA is provided. The sponsor’s amendment is however the evaluator is not convinced that the PI text ‘Treatment with Bemfola should be initiated under the supervision of a physician experienced with the treatment of fertility disorders’ can be considered specific routine risk minimisation for missing information item ‘Use in female patients > 40 years of age’. 10. The ASA makes brief reference to an ‘Instructions for Use’ (IFU) leaflet for the safe use of Bemfola. This was unable to be located in the dossier. The IFU leaflet should be provided for review and assigned in the ASA as risk The patient instructions for use have been included in the proposed Consumer Medicine Information. Copies of revised and clean versions are provided to allow review. The ASA has been updated to include the instructions for The evaluator has no specific objection to the content of the instructions for use leaflet.
Live birth rate 80 (35.7%) 50 (43.9%) 0.15 Follicles at day of hCG 12mm > 15mm > 17mm 11.8 ± 4.73 8.3 ± 3.8 4.9 ± 3.29 11.1 ± 4.23 7.7 ± 3.6 4.5 ± 0.4 0.24 0.14 0.4 E2 day 8 E2 day of hCG 3958.9 ± 3669.4 8982.3 ± 4951.8 3234.0 ± 2428.1 7704.2 ± 5345.8 0.23 0.09