zilongwang/ReadingBank huggingface dataset:
74. Richard Rayn Wimbush Male 75. Nkosinathi Vusi Dlamini Male 76. Qalakahle Anqoba Mkhize Male 77. Lehlohonolo Mphatse Male 78. Letlhogonolo Ditsele Male 79. Lethuxolo Zulu Male – Coach 80. S'busiso Williams Male – Assistant Coach/Manager BASKETBALL 81. Lethosa Dampies Female 82. Jordan Joyce Seale Female 83. Chulumanco Mgobozi Female 84. Thando Tshepiso Mothiba Female 85. Hannah Noela Patricia Palane Female 86. Reneilwe Mosala Female 87. Mimi Grace Nhlapo Female 88. Palesa Nomsisi Dodo Female 89. Kamohelo Mampiti Raphoto Female 90. Rorisang Lesenyego Female 91. Caroline Maine Female 92. Lerato Asavela Ntsimane Female 93. Thesline Davids Female – Coach 94. Nompumelelo Ramatsoga Female – Assistant Coach/ Manager BOXING 95. Siphesihle Siza Funulwazi Ngiba Male 96. Ishmaeel Kadiri Male 97. William J. Smith Male 98. Sakhile Sandiso Hlatshwayo Male 99. John Paul Masamba Male 100. Asakhe Hedeni Male 101. Asemahle Willem Male 102. Sinovuyo Mtintelwa Male 103. Vuyolwetu Dila Female 104. Amorie Gonsalves Female 105. Philile Ndelu Female 106. Nkosinathi Male – Coach 107. Khangelani Jack Male – Coach FOOTBALL MEN
Confidentiality templates – Ausgrid’s transitional proposal – 31 January 2014 Title, page and paragraph number of document containing confidential information. Description of the confidential information. Topic the confidential information relates to (e.g. capex, opex, WACC etc.) Identify the recognised confidentiality category that the information falls within. Provide a brief explanation of why the information falls into the selected category. If information falls within ‘other’ please provide further details on why the information should be treated as confidential. Specify reasons supporting how and why detriment may be caused from disclosing the identified information. Provide any reasons supporting why the identified detriment is not outweighed by the public benefit (especially public benefits such as the effect on the long term interests of consumers). Attachment H ‘Indicative Price List for public Lighting services - Pre-2009 capital charges’– pages 1-4 (4 pages) Public lighting: customer specific pre-2009 capital charges Customer specific prices Other – third party pricing information These prices have been kept confidential during the 2009-14 period. For the transitional year, these prices are to be escalated by CPI and it would therefore be appropriate for these escalated prices to remain confidential for the transitional year. No detriment to Ausgrid in disclosure of these prices. Any potential detriment from the disclosure would arise for the customers through the disclosure of their pricing information. No detriment to Ausgrid, therefore not applicable Appendix B to Attachment K ‘Ausgrid’s pricing methodology for transmission standard control services’, page 17 (1 page) Confidential Appendix B to Ausgrid’s current Transmission Pricing Methodology which sets out the conditions of approval of a discount in transmission charges for a customer which was approved by the ACCC in 2002, expiring in 30 June 2017. Approved discount in transmission charges for an Ausgrid (transmission connected) customer. Other –third party pricing information The approval by the ACCC of the discount was given on 6 June 2002 and the terms of that prudent discount have been kept confidential since that time, including as the Confidential Annexure B to the Pricing Methodology. There is no specific detriment to Ausgrid arising from the disclosure of the information. Any potential detriment from the disclosure would arise for the customers through the disclosure of their pricing information.
Title of extended abstract (use ‘Title’ style) Author One1, Author Two2 and Author Three3 (initials and surnames only) Note: Presenting author’s name should be underlined. 1. Position title, Organisation Name, City State Postcode. Email: 2. Position title, Organisation Name, City State Postcode. Email: 3. Position title, Organisation Name, City State Postcode. Email: …etc (USE 1’ STYLE) Text here… (Use ‘Body Text’ style) Note: please start your extended abstract here (up to 1000 words). Do not include a separate abstract. Figures should be placed within the body of the extended abstract soon after being mentioned. Crop images to best reflect subject matter. Insert image using ‘Image style’ FIG 1 – Caption … Tables should be placed within the body of the extended abstract soon being mentioned. Column 1 (Use ‘Table text header row’ style) Column 2 Column 3 X (Use ‘Table text’ style’) 10 50 Y 20 55 Z 30 62 X 40 50 Y 60 50 Z 20 35 x 15 10 TABLE 1 – Caption … ACKNOWLEDGEMENTS (USE 1’ STYLE) Text here… (Use ‘Body Text’ Note: please acknowledge collaborators here or anyone who has helped with the extended abstract. It may also be appropriate to acknowledge company approval to publish.
12/12/2008 9.3 Major revision. Gaming Operators may install gaming equipment as detailed on the “Certification & Conditional Approval” issued by an Accredited Test Facility. S. Newland 5/06/2009 10.0 Major revision. Adoption of National Standards Revision 10.0 S. Newland 17/07/2009 10.1 Minor revision. Dispensation may be considered regarding HMAC-SHA1 PSD Verification for EGM’s approved prior to 5th Dec 2007. S. Newland 1/03/2013 Minor revision 10.2 Removal of clauses in line with National Standards Reform objectives. Change of Department name to ‘Department of Business’. Term ’Recommendation for Approval’ added. Term ’Licensee’ added. The word ‘link’ removed from NT.3.5.1. & NT.3.5.2. NSD section expanded. TITO clause added. Colour photo of gaming equipment. Sample of gaming machine platform requirement. Submission material may be supplied via FTP. Expansion of Consignment or Movement Advice. S. Newland 28/05/2013 10.3 Banknote Acceptors approved for Community gaming machines. S. Newland 21/4/2015 10.4 Remove section 3.5 of general requirements. Adoption of National Standards 2015. J Sealy
Assuming an enrollment rate of 50 patients per month (20 months to complete enrollment) and study duration of approximately 64 months, a total sample size of approximately 1000 patients was planned. Statistical methods All time-to-event endpoints were analysed using Kaplan-Meier methods to estimate survival distributions and the median time-to-event. For rPFS and OS the treatments were compared using the stratified log rank test. Only one analysis of rPFS was planned, after 378 events. Three interim analyses and one final analysis of the OS endpoint were planned, after 116, 311, 425 and 773 events (corresponding to approximately 15%, 40%, 55% and 100% of the total events). The first interim analysis was scheduled for the same time as the rPFS analysis. The purpose of the interim analyses was to terminate the study if superiority of abiraterone was demonstrated. O’Brien-Fleming stopping boundaries, incorporating an alpha-spending function were used. Subgroup analyses were conducted for both rPFS and OS with the HR within each subgroup estimated using a non-stratified Cox proportional hazard model. Various sensitivity analyses were also planned, including investigator-assessed rPFS. The secondary endpoints were analysed using the Hochberg test procedure, with the overall level of significance controlled at the 2-tailed, 0.05 level. Analyses of other endpoints did not include adjustments for multiplicity for multiple comparisons. Each endpoint was tested at a 2-tailed 0.05 level of significance. Participant flow A total of 1,088 subjects were randomised and 1,082 received treatment. At the 20 December 2011 cut-off date 31% of patients in the abiraterone arm and 16% of subjects in the placebo arm were still receiving treatment. A flow diagram for the study is shown in Figure 1. Reasons for discontinuation are shown in Table 4 and Table 5. Figure 1:Pivotal study 302 - Participant flow and analysis sets. Table 4: Pivotal study 302 – Discontinuations Table 5: Pivotal study 302 – Discontinuations due to unequivocal clinical progression Major protocol violations/deviations Major protocol violations are shown in Table 6. These were balanced between treatment arms. Table 6: Pivotal study 302 – Major protocol violations Baseline data Baseline data indicate that the two groups were well matched at baseline. The groups were also well matched with respect to baseline BPI-SF pain scores and analgesic use.
Pharmacokinetics Studies providing pharmacokinetic data Table 1 (below) shows the studies relating to each pharmacokinetic topic. 1. Submitted pharmacokinetic studies. PK topic Subtopic Study ID PK in healthy adults General PK - Single dose M/34273/ 05 00 M/34273/ 03 04 M/34273/ 01 - Multi-dose LAS-PK-12A M/34273/ 06 Bioequivalence† - Single dose Not applicable - Multi-dose Food effect Not applicable PK in special populations Target population §- Single dose - Multiple dose M/34273/ 21 M/34273/ 09 Hepatic impairment None impairment M/34273/08 None Elderly None PK Males versus females None PK interactions Not evaluated None Population PK analyses Healthy subjects None Target population None None † Bioequivalence of different formulations. § Subjects who would be eligible to receive the drug if approved for the proposed indication. related
Pharmacodynamics Studies providing pharmacodynamic data Table 12 shows the studies relating to each pharmacodynamic topic. 12. Submitted pharmacodynamic studies. PD Topic Subtopic ID Primary pharmacology: Secondary Pharmacology In male COPD patients To characterise PIF generated through Novolizer and the Handihaler dry powder inhalers by COPD patients Effect on QT intervals M/34273/21 Gender other genetic and Age-Related Differences in PD Response Effect of gender None Effect of age None PD Interactions Not evaluated None Population PD and PK-PD analyses Healthy subjects Not applicable Target population None None of the pharmacodynamic studies had deficiencies that excluded their results from consideration. Summary of pharmacodynamics The information in the following summary is derived from conventional pharmacodynamic studies in humans unless otherwise stated. Mechanism of action Aclidinium bromide is a competitive, selective muscarinic receptor antagonist (also known as an anticholinergic) with a longer residence time at the M3 receptors than the M2 receptors. M3 receptors mediate contraction of airway smooth muscle. Inhaled aclidinium bromide acts locally in the lungs to antagonise M3 receptors of airway smooth muscle and induce bronchodilation. Nonclinical in vitro and in vivo studies showed rapid, dose-dependent and long-lasting inhibition by aclidinium bromide of acetylcholine-induced bronchoconstriction. Aclidinium bromide is quickly broken down in plasma and the level of systemic anticholinergic side effects is therefore low. The affinity of aclidinium bromide, LAS34823 and LAS34850 for various receptors and enzymes was studied in radioligand binding assays and enzymatic studies, respectively. Aclidinium bromide showed only moderate affinity (IC50 ≥ 1 μM) on (α)1 (non-selective) receptors, histaminergic (H)1 (central) receptor, Neurokinin (NK)1 receptors and had moderate inhibitory effects on 5-hydroxytryptamine (5-HT) uptake, in
Question 2: What are the mean serum adalimumab trough concentrations at Weeks 0, 2, 4, 8, 32 and 52 in Study M06-827 when the 24 non-GCP compliant subjects are included in the analyses (by randomised treatment group and dose)? Sponsor’s response: In Table 14 of its response, the Sponsor provided a summary of serum adalimumab trough concentrations by dose in all subjects with ulcerative colitis i.e. including the 24 non-GCP compliant subjects. Clinical comment to response: Inclusion of the 24 non-GCP compliant subjects in the analyses did not affect the mean adalimumab trough concentration through the 52-week study period. Question 3: What are the results of the primary efficacy endpoints and first ranked secondary endpoint when the 24 non-GCP compliant subjects are included in the primary analysis (ITT) set in Study M06-827? Sponsor’s response: In Table 15 of its response, the Sponsor has provided the results of the co-primary and ranked secondary efficacy endpoints of Study MO6-827 which included the 24 non-GCP compliant subjects. Clinical comment on response: The results were consistent with the primary and secondary efficacy analyses in Study Question 4: What was the baseline AAA, HACA and anti-TNF status for the non-GCP subjects (by randomised treatment group)? Sponsor’s response: In Table 16 of its response, the Sponsor provided the results of baseline AAA, HACA and status for the 24 non-GCP subjects by randomised treatment group versus the ITT population. One of the anti-TNF naive subjects developed AAA (measured at Week 32). Clinical comment to response: The 24 non-GCP subjects generally had lower rates in all three parameters compared with the ITT population and therefore their exclusion from the primary ITT population is unlikely to adversely affect the overall efficacy results. Note: Questions and evaluation of responses regarding the PI and CMI are not included in this Extract from the Clinical Evaluation Report Final round evaluation of clinical data submitted in response to questions The Sponsor’s responses to the Clinical Questions are generally considered satisfactory. There are no further clinical questions relating to this submission.
Clinical questions The only questions raised by the evaluator concerned the Product Information document and discussion of these are beyond the scope of this AusPAR. Second evaluation of clinical data submitted in response to questions Second round benefit-risk assessment Second round assessment of benefits After consideration of the responses to clinical questions, the benefits of adalimumab in the proposed usage were considered to be unchanged from those identified in the First Round Evaluation. Second round assessment of risks After consideration of the responses to clinical questions, the risks of adalimumab in the proposed usage were considered to be unchanged from those identified in the First Round Evaluation. Second round assessment of benefit-risk balance The benefit-risk balance of adalimumab, given the proposed usage, was considered to be favourable. Second round recommendation regarding authorisation The evaluator recommended that adalimumab should be approved for the additional indication of: Non-Radiographic Axial Spondyloarthritis Humira is indicated for reducing signs and symptoms in patients with non-radiographic axial spondyloarthritis. References Appel H. et al. Serum levels of biomarkers of bone and cartilage destruction and new bone formation in different cohorts of patients with axial spondyloarthritis with and without tumor necrosis factor-alpha blocker treatment. Available online <> Barkham N et al. Clinical and Imaging Efficacy of Infliximab in HLA–B27–Positive Patients With Magnetic Resonance Imaging–Determined Early Sacroiliitis. Arthritis & Rheumatism Vol. 60, No. 4, April 2009, pp 946–954 Braun J et al. Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: a multicentre randomised controlled trial. Ann Rheum Dis 2006;65:1147–1153. Braun J et al. 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 2011;70:896–904 Chen J and Liu C. Methotrexate for ankylosing spondylitis (Protocol).
TB screening brochure TB screening checklist Publications on specific safety topics In regard to routine risk minimisation the draft Product Information and Consumer Medicine Information were considered to be satisfactory. The following table (Table 2) summarises the OPR’s evaluation of the RMP, the sponsor’s responses to issues raised by the OPR and the second round OPR evaluation of the sponsor’s responses. Table 2. Reconciliation of issues outlined in the RMP report. Continued across 2 pages. Recommendation in RMP evaluation report Sponsor’s response OPR evaluator’s comment Safety considerations may be raised by the clinical and evaluators through the TGA’s consolidated requests and/or the nonclinical and clinical Evaluation Reports respectively. It is important to ensure that the information provided in response to these includes consideration of the relevance for the Risk Management Plan and any specific information needed to address this issue in the RMP. For any safety considerations so raised, please provide information that is relevant and necessary to address the issue in the RMP. The safety profile of adalimumab is well established and no safety issues requiring further consideration were raised in the TGA”s consolidated request for information. AbbVie has not yet received a copy of the clinical evaluation report. This was considered acceptable. The sponsor should provide further detail of the education program for Australia including whether it is already in use, draft education materials and a distribution plan. The sponsor has provided further detail and draft versions of the educational materials. The current and planned activities as outlined in the sponsor’s response were acceptable from a RMP standpoint. Such detail should be included in the Australian-specific Annex when it is next updated and provided to the TGA. The RMP states that "affiliates are implementing country-specific evaluations". The sponsor should provide more detail on the Australian specific evaluation of the effectiveness of the education program. Abbvie is currently developing an evaluation tool to assess the effectiveness of the Australian educational program. An online survey will be conducted by an independent third party vendor each year for 2 years after approval of new indications. Participants will be a representative cross section of potential Humira prescribers. This approach was considered acceptable. Once developed, further detail of this assessment should be included in an updated to the risk minimisation section of the Australian-specific Annex and submitted to the TGA.
Patients ≥ 40kg body weight Moderate CD Severe CD Frequency Induction 160 mg 160 mg Initial Dose (Day 0) as four 40mg injections OR as two 40mg injections on Day 0 and two 40mg injections on Day 1 80mg 80mg Second Dose (Day 14) as two 40mg injections Maintenance 20mg 40mg Starting Day 28 & continuing fortnightly Some patients may benefit from increasing the frequency to weekly if a disease flare or an inadequate response is experienced during maintenance dosing. Continued therapy should be carefully considered in a subject not responding by week 12. Good nutrition should be encouraged alongside pharmacological therapy to allow appropriate growth. Ulcerative colitis Dose Frequency Induction 160 mg Initial Dose (Day 0) as four injections OR as two injections on Day 0 and two injections on Day 1 80mg Second Dose (Day 14) as two injections Maintenance 40mg Starting Day 28 & continuing fortnightly During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines. Some patients who experience decrease in their response may benefit from an increase in dosing frequency to 40 mg Humira every week. Humira should not be continued in patients who do not achieve a clinical response in the first 8 weeks of treatment. Efficacy of Humira in the treatment of ulcerative colitis has not been demonstrated in patients who've failed previous anti-TNF therapy (see CLINICAL TRIALS). Psoriasis The recommended dose of Humira for adult patients is an initial dose of 80 mg, followed by 40 mg fortnightly, starting one week after the initial dose. Preparation of Humira Humira is intended for use under the guidance and supervision of a physician. Patients may self-inject Humira if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. Sites for self-injection include thigh or abdomen. Injection sites should be rotated. New injections should never be given into areas where the skin is tender, bruised, red or hard. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Humira should not be mixed in the same syringe or vial with any other medicine. Any unused product or waste material should be disposed of in accordance with local requirements. Humira contains no antimicrobial agent. Discard any residue.
The sponsor should provide a tabular ‘Summary of the Risk Management Plan in Australia’ in a revised ASA, including reference to specific wording pertaining to the routine risk minimisation activities for all the specified ongoing safety concerns in the proposed Australian PI and CMI. The sponsor provided Table 4: ‘Summary of the Risk Minimisation Plan in Australia’ in the revised ASA. There were a number of discrepancies observed between Table 4 of the ASA and the source document: EU-RMP Version 10.1 (dated October 2012) – see above. In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft product information document be revised as follows: For the important identified risks: ‘Melanoma’ and ‘Merkel cell carcinoma (Neuroendocrine carcinoma of the skin)’, a statement such as “Melanoma and Merkel cell carcinoma have also been reported in patients treated with TNF-antagonists including adalimumab” should be included in the PRECAUTIONS section of the PI under the sub-heading: ‘Malignancies’ and crossed referenced to the ADVERSE EFFECTS section of the PI. This would align with the approved UK SPC and enhance safe use of these products The sponsor states that the Precautions section of the Australian PI for Humira has been updated to include text relating to Melanoma and Merkel cell carcinoma under the Malignancies. This is acceptable. In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft consumer medicine information document be revised to adequately reflect any changes made to the Australian PI as a result of the above recommendations. The sponsor states that the Side effect section of the Humira CMIs have been updated to reflect changes to the PI relating to Melanoma and Merkel cell carcinoma. This is acceptable. VI. Overall conclusion and risk/benefit assessment The submission was summarised in the following Delegate’s overview and recommendations:
rationalised, including the deletion of ‘Subjects with renal or liver impairment’. It would appear the only justification offered for such change is ‘Missing information was updated’, which is considered to be inadequate. Consequently the sponsor should provide compelling justification for apparent changes to the missing information items previously accepted for Humira or alternatively reinstate these safety concerns, which need only be reflected in a revised ASA. due to underlying conditions, such as diabetes, renal or liver failure, human immunodeficiency virus infection, and alcohol or illicit drug abuse or medications (such as post cancer chemotherapy and anti-rejection drugs for organ transplant), that may have increased known risks of infection or other unknown risks related to the condition or to the concomitant medications. The sponsor has also provided justification for other changes to missing information items. No justification for the deletion of additional risk minimisation activities for the important identified risk: ‘Reactivation of hepatitis B’ has been provided and it appear safety messages relating to this safety concern are still included in the educational materials attached as appendices to the ASA. The sponsor should correct these omissions by revising Table 4: ‘Summary of the Risk Minimisation Plan in Australia’ and Table 5 of the ASA to reinstate additional risk minimisation activities for the important identified risk: ‘Reactivation of hepatitis B’. The sponsor states: ‘AbbVie like to point out that this information has been captured in version 4.0 of the ASA, which was submitted recently. Please refer to Table 3, Overview of Ongoing and Planned Pharmacovigilance Actions, on page 46 (of 79)’. This is acceptable. However, the omission of the important identified risk: ‘Reactivation of hepatitis B’ as a key safety risk warranting a HCP and patient educational program the sub-heading: ‘Risk Minimisation Program’ (page 56 of the ASA) and the omission of additional risk minimisation activities for the important identified risk: ‘Reactivation of hepatitis B’ from Table 5: ‘Summary of the Risk Management Plan in Australia’ of the ASA should be corrected when this
Copyright © Commonwealth of Australia 2014 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <>.
According to the RMP, this refers to a study completed in 2010. In the response the sponsor should provide information on whether this activity is completed and should therefore be removed from the pharmacovigilance plan. risks ‘fistulae (other than GI)’ and ‘cardiac disorders (exc. CHF and ATE)’. updated version of the ASA with their response. The evaluator maintains the following recommendations regarding the draft product information made in a previous evaluation for bevacizumab: That the specific term ‘physeal dysplasia’should be added to the nonclinical section of the PI to be consistent with the EU Summary of Product Characteristics (SmPC) and communicate this important potential risk. That under ‘Precautions-wound healing’ a statement such as the following found in the SmPC should be added: ‘Serious wound healing complications, including anastomotic complications, have been reported, some of which had a fatal outcome ‘. The following statement has been proposed for inclusion in the Precautions section of the Avastin PI via Safety-Related Request which is currently under review by TGA: ‘In a 26 week in cynomolgus monkeys, physeal dysplasia was observed in young animals with open growth plates, at bevacizumab average serum concentrations below the expected human therapeutic average serum concentrations.’ The following statement has been proposed for inclusion in the Precautions section of the Avastin PI via Safety-Related Request PM-2014-01869-1-4 which is currently under review by TGA: ‘Serious wound healing complications, including anastomotic complications, have been reported, some of which had a fatal outcome. ‘ This is acceptable. Summary of recommendations It is considered that the sponsor’s response to the TGA’s request for further information has adequately addressed all of the issues identified in the RMP evaluation report. ACPM trial
Table 16: Incidence of VELCADE Adverse Drug Reactions reported in ≥ 10% of patients in the Phase 3 Relapsed Multiple Myeloma Study comparing VELCADE IV and SC IV SC (N=74) (N=147) MedDRA System Class Total ---- n (%) ---- Total ---- n (%) Preferred Term n (%) 3 ≥ 4 n (%) 3 ≥ 4 Blood and lymphatic system disorders Anaemia 26 (35) 6 (8) 0 53 (36) 14 (3) Leukopenia 16 (22) 4 (5) 1 (1) 29 (20) 9 (6) 0 Neutropenia 20 (27) 10 (4) 42 (29) 22 (3) Thrombocytopenia 27 (36) 8 (8) 52 (35) 12 (8) 7 (5) Gastrointestinal disorders Abdominal pain 8 (11) 0 0 5 (3) 1 (1) 0 Abdominal pain upper 8 (11) 0 0 3 (2) 0 0 Constipation 11 (15) 1 (1) 0 21 (14) 1 (1) 0 Diarrhoea 27 (36) 3 (4) 1 (1) 35 (24) 2 (1) 1 (1) Nausea Vomiting 14 (19) 12 (16) 0 0 0 1 (1) 27 (18) 17 (12) 0 3 (2) 0 0 General disorders and administration site conditions Asthenia 14 (19) 4 (5) 0 23 (16) 3 (2) 0 Fatigue 15 (20) 3 (4) 0 17 (12) 3 (2) 0 Pyrexia 12 (16) 0 0 28 (19) 0 0 Infections and infestations Herpes zoster 7 (9) 1 (1) 0 16 (11) 2 (1) 0 Metabolism and nutrition disorders -------------- -------
Abdominal pain 8 (11) 0 0 3 (2) 0 0 Constipation 11 (15) 1 (1) 0 21 (14) 1 (1) 0 Diarrhoea 27 (36) 3 (4) 1 (1) 35 (24) 2 (1) 1 (1) Nausea Vomiting 14 (19) 12 (16) 0 0 0 1 (1) 27 (18) 17 (12) 0 3 (2) 0 0 General disorders and administration site conditions Asthenia 14 (19) 4 (5) 0 23 (16) 3 (2) 0 Fatigue 15 (20) 3 (4) 0 17 (12) 3 (2) 0 Pyrexia 12 (16) 0 0 28 (19) 0 0 Infections and infestations Herpes zoster 7 (9) 1 (1) 0 16 (11) 2 (1) 0 Metabolism and nutrition disorders Decreased appetite 7 (9) 0 0 14 (10) 0 0 Musculoskeletal and connective tissue disorders Pain in extremity 8 (11) 2 (3) 0 8 (5) 1 (1) 0 Nervous system disorders Headache 8 (11) 0 0 5 (3) 0 0 Neuralgia Peripheral sensory neuropathy 17 (23) 36 (49) 7 (9) 10 (14) 0 1 (1) 35 (24) 51 (35) 5 (3) 5 (3) 0 0 Psychiatric disorders Insomnia 8 (11) 0 0 18 (12) 0 0 Respiratory, thoracic and mediastinal disorders Dyspnoea 9 (12) 2 (3) 0 11 (7) 2 (1) 0 Note: Percentages in 'Total' column for each group calculated with the number of subjects in each group as denominator.
adult patients with previously untreated mantle cell lymphoma (MCL). Routes of administration: Intravenously (IV) or subcutaneously (SC) Dosage: The recommended dosage for bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) for the treatment of patients with previously untreated Mantle Cell Lymphoma is 1.3 mg/m2 body surface area twice weekly for 2 weeks on days 1, 4, 8, and 11 followed by a 10 day rest period on days 12-21. This 3 week cycle is considered a treatment cycle. ARTG number: 238257 Product background This AusPAR describes the application by Janssen-Cilag Pty Ltd to extend the indication for Velcade (trade name; active ingredient, bortezomib). Bortezomib is currently registered for the treatment of multiple myeloma. The proposed indication is for combination treatment with bortezomib and rituximab, cyclophosphamide, doxorubicin and prednisone in adults with previously untreated mantle cell lymphoma (MCL). The proposed dosing regimen for MCL is 1.3 mg/m2 IV bortezomib twice weekly for two weeks (on days 1, 4, 8 and 11, ≥72 h between doses), followed by a 10 day rest period (days 12-21). This 3 week cycle is repeated for 6 cycles, with an optional additional 2 cycles. This dosing regimen is the same as that approved for multiple myeloma indications. Details of the dosing regimen for the combination are provided in the Product Information (PI). Regulatory status The international regulatory status for frontline MCL at the time of this submission is listed in Table 1. Table 1: International regulatory status. Country Date submitted or intend to submit Approval date Approved indication EU* 12 Jun 2014 30 Jan 2015 Velcade in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation
For the most recent Product Information (PI), please to the TGA website <>. Copyright © Commonwealth of Australia 2018 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <> .
Clinical safety Studies providing evaluable safety data Pivotal studies that assessed safety as the sole primary outcome AC-052-367 (FUTURE-2) Study AC-052-374 (FUTURE-3) Extension Study AC-052-392 (FUTURE-4) Extension. Pivotal and/or main efficacy studies Study AC-052-391 (FUTURE-4). Other studies AC-052-116 Study AC-052-365 (FUTURE-1) AC-052-373 (FUTURE-3). Studies that assessed safety as the sole primary outcome Study AC-052-367 (FUTURE-2) Study design, objectives, locations and dates Study AC-053-367 (FUTURE-2) was a multicentre, multinational, open label, non comparative, Phase III extension study of a 12 week open label, single arm study (FUTURE-1). The primary objective was to assess the long term safety and tolerability of the paediatric formulation of bosentan in children with idiopathic or familial PAH. Secondary objectives included an exploratory evaluation of functional capacity, QoL, physicians’ and parents’ GCIS, time to PAH worsening, time to initiation of new therapy for PAH and time to new onset or worsening of right heart failure. Another objective was to assess long term vital status. Figure 22: Study AC-053-367 (FUTURE-2) design Inclusion and exclusion criteria The inclusion and exclusion criteria for the FUTURE-1 Study were provided. Study treatments All patients received a paediatric oral formulation of bosentan. The drug was to be administered orally, irrespective of meals, and dispersed in a teaspoon of water before being administered (not mixed with food). It was to be taken in the morning and approximately 12 hours later in the evening. The treatment dose of bosentan in FUTURE-2 was to be 4 mg/kg BD until the end of the study. If this dose was not well tolerated, it could be down-titrated to 2 mg/kg BD. Patients weighing 30 kg or over were to receive a maximum dose of 120 mg BD and a maximum of 64 mg BD if down titration was necessary. Safety variables and outcomes The tolerability and safety endpoints were:
Table 7: Paediatric studies included in the submission PK topic Age group Study ID Synopsis Intrinsic factor PK study reports Children FUTURE-1 An open label, multicentre study to assess the PK, tolerability, and safety of a paediatric formulation of bosentan in children with idiopathic or familial PAH. Population PK analyses FUTURE-3 PopPK of bosentan in children with PAH Uncontrolled clinical studies Children FUTURE-2 An open label, long term, safety, and tolerability extension study using the paediatric formulation of bosentan in the treatment of children with idiopathic or familial PAH who completed FUTURE-1. FUTURE-3 An open label, randomised, multicentre, multiple dose to evaluate the PK, tolerability, safety and efficacy of the paediatric formulation of bosentan BD versus TDS in children from 3 months to less than 12 years of age with PAH. FUTURE-3 extension A prospective multicentre, open extension of Future 3 to assess the safety, tolerability and efficacy of the paediatric formulation of bosentan BD versus TDS in children with PAH. Reports of analyses of data from more than one study FUTURE-2 FUTURE-3 FUTURE-4 This document is a compilation of appendices referred to in the Summary of Clinical Efficacy. FUTURE-1 FUTURE-2 FUTURE-3 This document provides an analysis of the pooled long term safety data from the FUTURE Study series 1 to 4 Extension.
Cervical dystonia 6: Cervical Dystonia, Adverse Reactions Body System Preferred Term Gastrointestinal disorders: Very common: dysphagia Uncommon: dry mouth, nausea General disorders: Common: injection site pain Uncommon: asthenia Musculoskeletal and connective tissue disorders Common: neck pain, muscular weakness, musculoskeletal pain, musculoskeletal stiffness Uncommon: muscle spasm Nervous system disorder: Common: headache Uncommon: presyncope, dizziness, speech disorder Respiratory thoracic and mediastinal disorders: Uncommon: dysphonia, dyspnoea Unknown: upper respiratory tract infection Skin and subcutaneous tissue disorders: Uncommon: hyperhidrosis, rash Note: on placebo-controlled, active-controlled and uncontrolled Blepharospasm Table 7: Blepharospasm, Adverse Reactions Body System Preferred Term Nervous system disorders: Uncommon: headache Unknown: facial paresis Eye disorders: Common: eyelid ptosis, dry eyes, blurred vision Uncommon: visual impairment; diplopia, lacrimation increased Gastrointestinal disorders: Common: dry Uncommon: dysphagia General disorders: Common: injection site pain Uncommon: fatigue Musculoskeletal and connective tissue disorders: Uncommon: muscular weakness Note: on placebo-controlled, active-controlled and uncontrolled studies Post-stroke spasticity of the upper limb Table 8: Post-stroke spasticity of the upper limb, Adverse Reactions Body System Preferred Term Gastrointestinal disorders: Uncommon: dysphagia General disorders: Uncommon: asthenia; feeling hot Musculoskeletal and connective tissue disorders: Common: muscular weakness Uncommon: pain in extremity trial
Table 7: Reconciliation of issues outlined in the RMP report Recommendation in RMP evaluation report Sponsor’s response PMSB evaluator comment Safety considerations may be raised by the nonclinical and clinical evaluators through the consolidated request for further information 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 Risk Management Plan, 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. There was no nonclinical evaluation relevant for this application. In the round Clinical Evaluation Report issued 1 May 2014, there are no new safety considerations raised by the clinical evaluator that would require further consideration in the Risk Management Plan. The response has been It is recommended that the in the EU-RMP providing details and milestones regarding the ongoing/planned studies be updated. Furthermore, the sponsor should submit the final PASS protocol, and the final outcome of the outcome Study BAY for review. Revision has been made to the ASA to the EU-RMP to provide an update of the milestones of the ongoing/planned studies. A commitment is provided that the final PASS protocol, and the final outcome of the outcome Study BAY 86-5321/16598 will be submitted to the TGA for review when they become available. This is considered acceptable. It is recommended that the sponsor implements educational materials for patients to accurately inform patients the frequency of side effects associated with the use of Eylea. The sponsor has considered the issues raised in the RMP evaluation report and hereby accepts the RMP recommendation to implement patient educational materials as an additional risk minimisation activity to inform patients about the frequency of side effects associated with the use of Eylea. The ASA has been updated accordingly and a draft content of the patient educational material for implementation in Australia is provided in the Appendix of the updated ASA. This is considered acceptable. However, it is recommended that the final version of the educational materials be submitted to the TGA for review. It is recommended that the sponsor undertakes further risk minimisation activities to prevent The sponsor has considered the issues raised in the RMP evaluation report and hereby Pending the Delegate’s approval this
Opportunistic infection Infusion-related reaction Hyperglycaemia Stevens-Johnson syndrome/Toxic epidermal necrolysis Tumour syndrome Anti-therapeutic antibodies Important potential risks Pancreatitis acute Hepatotoxicity Pulmonary toxicity Reproductive toxicity Thymus depletion (paediatric) Infection with drugs modifying CYP3A4 activity Missing information Safety in paediatrics Safety in the elderly Safety in patients with hepatic, cardiac or renal impairment Long term safety Comment: The Summary of Safety Concerns is unchanged in PSUR 6 as ‘GI complications’ was recognised as a new important potential risk during the reporting period. Safety issues with the potential for major regulatory impact Comment: Information regarding the safety issues described below is collated from the PSURs. In general, the signal evaluation is presented in the PSUR as an overview of the condition followed by a description of the findings in the ‘Pivotal Phase II Studies’. For new signals, a more comprehensive cumulative review may also have been performed. PSUR 5 provides a summary table of numbers up to data lock point for that update, as sourced from the clinical trials programme and from post-marketing sources. The safety findings of the Phase III study, SGN35-005 (described in the efficacy and safety sections above) have not been included in the updates in the PSUR 5, although a study synopsis is provided elsewhere in the PSUR. Two new safety concerns were addressed in PSUR 6: gastrointestinal complications and posterior reversible encephalopathy syndrome (PRES). These have been included below. Notes are made where information related to the risk have been included in the European SmPC to be consistent with the terminology used in the PSURs. This information in general is also included in the Australian version of the SmPC (the Product Information). Neurological toxicity Peripheral neuropathy Peripheral neuropathy is a relatively common dose-limiting toxicity of brentuximab vedotin and is discussed at length in several of the PSURs, most recently in PSUR 5. Peripheral neuropathy, including peripheral sensory neuropathy and peripheral motor neuropathy, emerged as a clinically important neuromuscular AE early in the clinical program of brentuximab vedotin. It ranged from mild distal paraesthesia, affecting fingers and
Table 5. Reconciliation of issues outlined in the RMP report Recommendation in RMP report Sponsor’s response RMP evaluator’s comment 1. Safety considerations may be raised by the clinical evaluators through TGA requests and/or the Clinical Evaluation Report. It is important to ensure that the information provided in response to these includes 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, please provide information that is relevant and necessary to address the issue in the RMP. The sponsor acknowledges that further change to the RMP may be requested and commits to responding to these as they occur. This is considered acceptable in the context of this application for RMP purposes. 2-3. Administrative questions and recommendations. An updated ASA was included as requested This is considered acceptable in the context of this application for RMP purposes. 4. The sponsor should provide an update on Studies NCT01780662, C25003, SGN35-011, SGN35-014, and X25001 with regard to interactions with other anticancer agents. An update on the requested studies was provided. The sponsor’s response has been noted. 5. The sponsor should provide a summary of the post-market experience with overdose. Background: Overdose is the administration of a quantity of a medicinal product given per administration or day that is above the maximal recommended dose according to the authorised PI. Overdose can be accidental, prescribed or intentional, with clear labelling guidelines a key in minimising medication errors. Depending on the therapeutic index of the drug and the dose given to the patient, an adverse drug reaction may or may not be the outcome of an overdose. A post-market analysis of the Global Safety Database (GSDB) for brentuximab vedotin was performed to provide a summary of the post-marketing experience with overdose and to determine if there is an association of overdose and adverse events. Methodology: The Marketing Authorisation Holder (MAH) performed a cumulative review of the GSDB with a data lock of 15 January 2016 for all cases from post-marketing sources (literature, spontaneous, post-marketing surveys and regulatory authorities’ reports) that met an Overdose specialized search query criteria, which encompasses the following 4 preferred terms: High The sponsor’s response has been noted.
Pharmacodynamics Studies providing pharmacodynamic data Table 4 shows the studies relating to each pharmacodynamic topic and the location of each study summary. Table 4: Submitted pharmacodynamic studies. PD Topic Subtopic Study ID * Primary Pharmacology Effect on Seizures N01114 § N01193 § N01252 § N01253 § N01254 § N01358 § N01125 § N01199 § N01379 § * * * * * * * * * Effect on evoked pain Subjective drug effects Photosensitive epileptiform discharges N01079 N01295 N01069 § * * * Secondary Pharmacology Effect on Saccadic eye movements N01066 EP0041 * Smooth pursuit eye movements Adaptive tracking Effect on Number Pairs task Effect on Choice Reaction Time Effect on Tapping Test Effect on ARCI 49 Effect on Bond and Lader’s VAS EP0041 EP0041 N01066 N01066 N01079 N01066 N01066 N01069 N01118 N01079 N01295 N01066 N01067 N01118 * * * * * * * * *
Table : Sponsor’s bridging strategy Symbicort Rapihaler Evidence supporting therapeutic equivalence with Symbicort Turbuhaler Clinical studies / in data TGA approval status 50/3 Clinical (D5897C00003) demonstrating in vivo therapeutic equivalence with Symbicort Turbuhaler 100/6 Clinical evaluator recommended approval on demonstration of therapeutic equivalence [and subsequently registered] 100/3 Combination of proven in vivo therapeutic equivalence in clinical studies for formulation strengths that bracket Symbicort Rapihaler 100/3 ( 50/3, 100/6, and 200/6) and in vitro data showing linear dose relationships for both active ingredients from all formulation strengths Approval sought via therapeutic equivalence demonstrated for 50/3, 100/6, and 200/6 and in vitro data across all 4 Rapihaler strengths 100/6 Clinical demonstrating in vivo therapeutic equivalence with Symbicort Turbuhaler 100/6 Approved by TGA; based on demonstration of therapeutic equivalence 200/6 Clinical study demonstrating in vivo therapeutic equivalence with Symbicort Turbuhaler 200/6 Approved by TGA; based on demonstration of therapeutic equivalence In terms of the formulation, the only difference between the new Symbicort Rapihaler 50/3 and 100/3 strengths and the approved higher strength Rapihaler products is the concentration of the drug substances. The composition of excipients is identical for all the strengths. All the Rapihaler products use the same valve metering chamber volume. The Symbicort Rapihaler 100/3 formulation strength has been developed to deliver, ex actuator, twice the dose of budesonide and an equivalent dose of formoterol as is delivered by the Symbicort Rapihaler 50/3 (that is, the same relationship as for Symbicort
Table 1. Overseas regulatory status. Procedure Country Date of submission Date of Approval Proposed indication USA (under the name Uceris) 14 Dec 2011 14 Jan 2013 Induction of remission in patients with active, mild to moderate ulcerative colitis (UC). Netherlands (RMS) 30 May 2011 28 Feb 2013 Induction of remission in adult patients with active, mild to moderate UC, where 5-ASA salicylic acid) treatment is not sufficient. European (EU) via Mutual Recognition Procedure (MRP) Austria Apr 2014 17 Dec 2014 Belgium 26 Nov 2014 Bulgaria Ongoing Croatia 09 Dec 2014 Cyprus Ongoing Czech Republic 14 Jan 2015 Estonia 31 Mar 2015 Finland 12 Dec 2014 Germany 13 January 2015 Greece Ongoing Hungary 19 November 2014 Iceland 22 January 2015 Ireland 05 December 2014 Italy Ongoing Latvia 27 January 2015 Lithuania 23 December 2014 Luxembourg 01 April 2015 Ongoing Norway 27 November 2014 Poland 23 January 2015 Portugal 01 December 2014 Romania 19 February 2015 Slovakia 19 February 2014 Slovenia 18 March 2015 Spain Ongoing Sweden 04 January 2015 United Kingdom 19 November 2014 EU via DCP (submitted in 15 countries)* Rejected August 2012 Induction of remission in patients with active, mild, to moderate UC. Canada April 2015 Ongoing Induction of remission in adult patients with active, mild, to moderate UC. Brazil 05 November 2014 Ongoing Israel 08 April 2014 Ongoing Jordan 23 July 2014 Ongoing Kuwait 07 December 2014 Ongoing trial