Unit outline BMSC303: Marking rubric for new chemical entity – assignment 2 Below expected standard Standard developing Expected standard Above expected standard Score The report has addressed the...

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Unit outline BMSC303: Marking rubric for new chemical entity – assignment 2 Below expected standard Standard developing Expected standard Above expected standard Score The report has addressed the ‘boxed questions’ that lead to either approval or rejection of the new drug entity. Many errors of key facts or concepts. Key ‘boxed’ questions not addressed or misinterpreted. 0-6 Generally accurate but some errors of fact or misinterpretations of key concepts. Some key ‘boxed’ questions were addressed. 6-12 Depth of content adequate and few misinterpretations of key concepts. All key ‘boxed questions’ were addressed 12.5-18.5 In-depth consideration of response Depth of content appropriate All key ‘boxed questions’ were addressed 19-25 /25 Decision to either approve or reject new drug entity including justification No justification or justification does not support decision 0-3 Decision but limited justification 3.5-6 Decision with some justification 4-10 Decision with comprehensive justification 10.5-14 /14 Written English language Difficult to read and interpret Significant errors in grammar and /or spelling (8 or more) Incorrect use of scientific terminology 0-1.5 Generally clear Some material logically sequenced Some errors in grammar and /or spelling (4-7). Scientific terminology mostly correct 2-3 Clear and understandable. Logically sequenced Few errors in grammar and/or spelling (3 or less) Scientific terminology correct 3.5-5 Clear and understandable Logically sequenced Correct spelling and grammar Correct use of scientific terminology 5.5-7 /7 Referencing No evidence of Vancouver referencing style 0 Some evidence of Vancouver referencing style All sources were credible 1-1.5 Adequate use of Vancouver referencing style All sources were credible 2-3 Good use of Vancouver referencing style All sources were credible 4 /4 TOTAL /50 marks total (converted to 30%) Comments Australian public assessment for ceftaroline fosamil (Zinforo) ASSESSMENT 2 (BMSC303 DRUG DEVELOPMENT) 1 Pharmaceutical company product submission seeking registration as a new chemical entity Disclaimer The material attached is a public version of the chemical entity which has been altered for educational purposes. Altered data therefore does not match information publically available on this product. Content does not represent the TGA or Pharmaceutical company (AstraZeneca) Fictitious Altered Assessment Report Sponsor: AstraZeneca Pty Ltd ASSESSMENT 2 (BMSC303 DRUG DEVELOPMENT) 2 Index PAGE  Product submission 3  Quality findings 7  Non-clinical findings 8 o Pharmacokinetics 10 o Toxicology 12  Non-clinical summary 16  Clinical findings 18 o Pharmacokinetics 19 o Pharmacodynamics 20 o Safety 22  Clinical summary 23  Pharmacovigilance findings 25  Clinical data evaluation 29  Risk-benefit analysis 39 ASSESSMENT 2 (BMSC303 DRUG DEVELOPMENT) 3 Product submission Submission details Type of Submission: Seeking approval as a New Chemical Entity Decision: In Progress Date of Decision: In week 12 (handed to facilitator) Active ingredient: ceftaroline fosamil Product Name: Zinforo Sponsor’s Name and Address: AstraZeneca Pty Ltd 5 Alma Road North Ryde NSW 2113 Dose form: Powder for injection Strength: 600 mg Container: Glass vial Pack size: 10 vials per carton Approved Therapeutic use: Zinforo indicatation sought for the treatment of patients with the following infections proven or strongly suspected to be caused by designated susceptible bacteria:  Complicated skin and soft tissue infections  Community-acquired pneumonia Route of administration: Intravenous (IV) Dosage: Adults: 600 mg every 12 hours by intravenous (IV) infusion over 60 minutes for 5-7 days for community acquired pneumonia (CAP) or 5-14 days for complicated skin and soft tissue infections (cSSTI). Dose reductions are proposed for patients with renal impairment. ARTG Number: Not yet approved Product background This document describes an altered application representing a submission by AstraZeneca Pty Ltd to register a new chemical entity, ceftaroline fosamil (Zinforo), for the treatment of adults with complicated skin and soft tissue infection (cSSTI) or community-acquired pneumonia (CAP). The proposed indications were: Zinforo is indicated for the empirical and directed treatment of patients with the following infections:  Complicated skin and soft tissue infections  Community-acquired pneumonia ASSESSMENT 2 (BMSC303 DRUG DEVELOPMENT) 4  Ceftaroline fosamil is an N-phosphono-type prodrug of ceftaroline (a cephalosporin antibiotic) and is administered by infusion. The proposed treatment regimen is 600 mg every 12 h by 60-min IV infusion, for 5-7 (CAP) or 5-14 days (cSSTI), in patients 18 years and older.  Ceftaroline fosamil is a semi-synthetic pro-drug from the cephalosporin class of β- lactam antibiotics. Ceftaroline fosamil is converted to the active ceftaroline in plasma by a phosphatase enzyme. Ceftaroline is bactericidal in vitro due to inhibition of bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs).  Ceftaroline is stated to be active against bacteria that produce classical Class A β- lactamases such as TEM-1, TEM-2 or SHV-1. However, ceftaroline is not active against Gram-negative bacteria producing extended spectrum β-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), Class B metallo-β- lactamases or Class C (AmpC cephalosporinases). One or more of these mechanisms may co-exist in the same bacterium. Unlike other cephalosporins, ceftaroline is stated to be active against the altered PBPs found in methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP) that result in resistance to these other antibiotics. There is no cross resistance between ceftaroline and any non-β-lactam antibiotics. Regulatory status Table 1 provides a list of major countries in which a similar application had been submitted and/or approved as of November 2012. Table 1. Submission and approval status of Zinforo vials ASSESSMENT 2 (BMSC303 DRUG DEVELOPMENT) 5 List of abbreviations used in this Application AE adverse event Ae amount of unchanged drug excreted into the urine Ae0-t cumulative amount of unchanged drug excreted into the urine from time 0 to time t APTT activated partial thromboplastin time AUC0-t area under the plasma concentration versus time curve from time zero to time t AUC0-∞ area under the plasma concentration versus time curve from time zero to infinity CAP community acquired pneumonia CABP community acquired bacterial pneumonia CE clinically evaluable CI confidence interval CL plasma clearance CLr renal clearance Cmax maximum plasma drug concentration cMITT clinical modified intention to treat CrCl creatinine clearance cSSTI complicated skin and soft tissue infections CT computerised tomography CXR chest X-ray Bias PE% Calculated as the population mean predicted exposure measure minus the individual predicted exposure measure multiplied by 100 and then divided by the individual predicted exposure measure DAE discontinuation due to adverse event DM diabetes mellitus ECG electrocardiogram EOT end of treatment ESBL extended spectrum β-lactamase ESRD end-stage renal disease IM intramuscular IV intravenous IVRS interactive voice response system LC Liquid chromatography LC-MS/MS Liquid chromatography-mass spectrometry/mass spectrometry LFU late follow-up ME microbiologically evaluable MIC minimal inhibitory concentration ASSESSMENT 2 (BMSC303 DRUG DEVELOPMENT) 6 MIC90 minimal inhibitory concentration required to inhibit the growth of 90% of organisms MITT modified intention to treat MITTE modified intention to treat efficacy mMITT microbiological modified intention to treat mMITTE microbiological modified intention to treat efficacy MW Molecular weight MRSA methicillin-resistant Staphylococcus aureus MSSA methicillin susceptible Staphylococcus aureus PBP penicillin binding protein PCS potentially clinically significant PD pharmacodynamic PE predicted exposure PK pharmacokinetic Precision |PE%| Calculated as the absolute value of the PE% PNSP penicillin non-susceptible Streptococcus pneumoniae PRP Penicillinase-resistant penicillin PRSP penicillin resistant