Table 1: Summary of ongoing safety concerns Summary of safety concerns Important identified risks Malignancy (including lymphoma and leukaemia) Serious and opportunistic infections (including TB, Legionella, Listeria, parasitic infection) Lupus-like reactions Sarcoidosis and/or granulomas Injection site reactions Allergic reactions Severe cutaneous adverse reactions (including toxic epidermal necrolysis and Stevens-Johnson Syndrome) Systemic vasculitis (including ANCA positive vasculitis) Macrophage activation syndrome Central demyelinating disorders Peripheral demyelinating events (CIDP and GBS) Aplastic anaemia and pancytopenia Interstitial lung disease (including pulmonary fibrosis and pneumonitis) Autoimmune hepatitis events in patients with history of viral hepatitis (including hepatitis B virus reactivation) Important identified risks – specific indications Change in morphology and/or severity of psoriasis Worsening of CHF in adult subjects Important potential risks – all indications Autoimmune renal disease Pemphigus/pemphigoid Amyotrophic lateral sclerosis Myasthenia gravis Encephalitis/leukoencephalomyelitis Progressive multifocal leukoencephalopathy Liver failure Hepatic cirrhosis and fibrosis Severe hypertensive reactions Adverse pregnancy outcomes
Recommendation in RMP evaluation report Sponsor’s response (or summary of the response) RMP evaluator’s comment TGA recommendation 1: Safety considerations may be raised by the nonclinical and clinical evaluators through the consolidated section 31 request and/or the Nonclinical and Clinical Evaluation Reports respectively. The issues identified by the sponsor as relevant to the RMP were: Section 1) Any association between opioid use / Body Mass Index (BMI) and the incidence of TEAEs (Q8) Section 2) Any explanation for the lower incidence of injection site reactions Section 3) Any comment for the incidence of antibodies Section 4) Data from the open extension study and discussion for any safety concerns, including results post-switching. All of the questions have been answered separately in the sponsor’s response to the clinical questions. The following is a brief summary, and the actions required regarding the RMP are discussed. Section 1) No significant difference in the incidence of TEAEs was observed between opioid users / and across categories of BMI values. There are no pre-existing safety concerns proposed in the RMP for SB4 related to this question. As no safety concerns were raised in this section, the Applicant believes that there is no need for further discussion to address these issues in the RMP. Section 2) Injection site reactions (ISRs) are designated as an important identified risk in the RMP for SB4. However, as a decreased risk compared with the originator Enbrel was reported, the sponsor does not consider this finding a safety concern. Besides this, the study is already described in the RMP section SVII.3.1.5 Injection site reactions. Therefore the Applicant concludes there is no need for further discussion. Section 3) Similar to question 2, the sponsor does not consider lower immunogenicity to be a safety concern. Also, immunogenicity is not listed as a safety concern in the RMP for SB4. As described The sponsor’s response is acceptable and no modification to the RMP is required at this point in time. This may change when the final CSR for Study SB4-G31-RA which includes the 100 week data is provided. non-
consideration for applicability in the RMP for SB4. TGA recommendation 2: The following statement in the ASA should be amended as highlighted: ‘For additional risk minimisation, a format similar to the EU-RMP (such as the patient alert card [PAC] and educational programs) will be provided, with separate review and approval by the TGA’. The sponsor has revised the implementation plan of additional risk minimisation in Australia according to the TGA recommendation. The sponsor’s response is acceptable. TGA recommendation 3: The ASA states: ‘In order to inform regarding the safe and proper use of the the sponsor will develop and implement an additional risk minimisation plan in the form of a training and educational program for patients, HCPs, and company staff, specifically for the safe use of the However, as previously noted the ASA also states: ‘Availability of a needle free demonstration device: This device allows patients to practice injections prior to using the actual pre-filled These devices have been made available to clinicians for training purposes in the clinician’s office’. Given the existing presence in the Australian market of the innovator administered presumably via a different auto-injector device, it is agreed that a range of HCPs, not just the prescriber, will require an educational program to be able to inform patients on the safe and proper use of the auto-injector. This would include making the The sponsor has revised the plan to provide the demonstration device to clinicians for patient education purposes. The needle-free demonstration devices will now be made available to all relevant healthcare professionals at their practice sites, not only to clinicians. In addition, the sponsor has replaced the term ‘use’ with ‘administer’ for clarity. The revised statement is (changes underlined): ‘3.2.1 Potential for medication errors – pen Additional risk minimisation activities: Training program will be launched to avoid medication errors that can occur from auto-injectors and help HCPs and patients to administer SB4 properly. Availability of a needle free demonstration device: This device allows patients to practice injections prior to using the actual pre-filled auto-injector. These devices have been made available to all relevant HCPs for The sponsor’s response is acceptable.