Unit outline BMSC303: Marking ruic for new chemical entity – assignment 2 Below expected standard...

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Unit outline  BMSC303: Marking ruic 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 eors of key facts or concepts.    Key ‘boxed’ questions not addressed or misinterpreted.      XXXXXXXXXX0-6 Generally accurate but some eors of fact or misinterpretations of key concepts.  Some key ‘boxed’ questions were addressed.   XXXXXXXXXX-12 Depth of content adequate and few misinterpretations of key concepts.   All key ‘boxed questions’ were  addressed     XXXXXXXXXX In-depth consideration of esponse  Depth of content appropriate  All key ‘boxed questions’ were  addressed  19-25                       /25 Decision to either approve or reject new drug entity including justificationNo justification or justification does not support decision  XXXXXXXXXX Decision but limited justification   XXXXXXXXXX-6 Decision with some justification   4-10 Decision with comprehensive justification   XXXXXXXXXX14                          /14 Written English language Difficult to read and interpret  Significant eors in grammar and or spelling (8 or more)  Incoect use of scientific terminology                      0-1.5 Generally clear  Some material logically sequenced  Some eors in grammar and /or spelling (4-7).  Scientific terminology mostly coect   XXXXXXXXXX Clear and understandable.  Logically sequenced  Few eors in grammar and/or spelling (3 or less)  Scientific terminology coect   XXXXXXXXXX5-5 Clear and understandable  Logically sequenced  Coect spelling and grammar  Coect use of scientific terminology    XXXXXXXXXX5-7         7 ReferencingNo evidence of Vancouver eferencing style                            0                                   Some evidence of Vancouver eferencing style  All sources were credible   XXXXXXXXXX Adequate use of Vancouver eferencing style  All sources were credible      XXXXXXXXXX2-3 Good use of Vancouver eferencing style  All sources were credible            XXXXXXXXXX44 TOTAL          /50 marks total (converted to 30%)Comments Australian public assessment for ceftaroline fosamil (Zinforo)ASSESSMENT 2 (BMSC303 DRUG DEVELOPMENT) 1Pharmaceutical 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 ReportSponsor: AstraZeneca Pty Ltd ASSESSMENT 2 (BMSC303 DRUG DEVELOPMENT) 2Index XXXXXXXXXXPAGE 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   39ASSESSMENT 2 (BMSC303 DRUG DEVELOPMENT) 3Product 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 y a phosphatase enzyme.  Ceftaroline is bactericidal in vitro due to inhibition of acterial 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 caapenemases (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 esistance 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) 5List of aeviations 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) 6MIC90 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

Vidya · Accepted Answer

PHARMACEUTICAL COMPANY PRODUCT SUBMISSION SEEKING REGISTRATION AS A NEW CHEMICAL ENTITY
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Comment on necessity of on-going pharmacovigilance requirements to monitor bacterial resistance to ceftaroline with reference to the following: 
1. Patient cohorts for which approval is sought 
Bacterial resistance monitoring of ceftaroline should be performed for at least the next consecutive three batches of the patient cohorts in order to get appropriate pharmacovigilance data for the drug.
2. Length of monitoring required and extent to use within Australia
For the use of ceftaroline fosamil in Australia, the monitoring should be performed for a minimum of three consecutive batches and the observations should be reported.
3. How coverage and reporting might be managed for remote surveillance sites
All the remote surveillance sites must be brought into a loop and the reporting and coverage should be followed up on a regular basis.
4. Overlap with other surveillance for bacterial resistance within Australia
The batch analysis with complete specifications of bacterial resistance throughout Australia should be tracked and appropriate settings for this tracking system should be developed and maintained in the country. 
Any other considerations you think might need to be added?
The stability studies are also to be performed for the product.
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Is this is acceptable given the relatively short period of patient treatment with ceftaroline fosamil and the drug’s limited activity in genotoxicity assays?
It is acceptable given the relatively short period of patient treatment with ceftaroline fosamil and the drug’s limited activity in genotoxicity assays.
Is additional information needed for reproductive toxicity?
The studies to determine the placental transfer possible and also the excretion of ceftaroline fosamil as well as its metabolites in milk should be performed for understanding the reproductive toxicity.
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Are these impurities of concern with use of the product?
As per the ICH qualification threshold, the impurities associated with this drug product is excess. Hence, it is to be taken into consideration while studying the product for its usage.
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Questions for application 
 Is toxicological qualification of impurities adequate?
Beside the absence of satisfactory toxicological capability of two impurities, there were no significant inadequacies with the dossier of studies.
 Do pharmacology studies and demonstrations of ceftaroline’s bactericidal efficacy in both in vitro and in vivo assays, support its use for the proposed clinical indications?
The blend of essential pharmacology studies and exhibitions of ceftaroline's bactericidal viability in both in vitro and in vivo tests, upholds its utilization for the proposed clinical signs or indications..
 With the exception of antibiotic-associated diarrhoea, no clinically relevant hazards were identified in the secondary pharmacodynamics and safety pharmacology studies as occurring at ceftaroline concentrations approximating expected clinical plasma levels. Are there other concerns? 
Except for anti-microbial related the runs, no clinically significant risks were recognized in the optional pharmacodynamics and security pharmacology concentrates as happening at ceftaroline focuses approximating expected clinical plasma levels. There are no other major concerns.
 Repeat-dose toxicity studies identified the kidney as the major target organ is this finding was of clinical significance?
Kidney was identified as the significant objective organ by the repeat-dose toxicity studies, be that as it may, this finding was of clinical importance.
 Does Ceftaroline/ceftaroline fosamil pose a genotoxic or carcinogenic hazard based on the information provided?
Ceftaroline/ceftaroline fosamil isn't considered to represent a genotoxic or cancer-causing danger.
 Is the proposed pregnancy category appropriate?
The embryofetal development studies showed absence of significant or huge impacts. This supports its proposed position in Pregnancy Category B1.
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Are these recommendations adequate and is anything else need to be considered in terms of the current pharmacovigilance plan?
These proposals are steady with the exhortation given by Advisory Committee on the Safety of Medicines (ACSOM), which ought to be likewise viewed as in the reaction given by the support.
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Significance – does efficacy and safety for MRSA need to be determined?
It is essential to obviously educate prescribers that the accessible clinical information doesn't uphold the utilization of Zinforo in CAP because of MRSA. Accordingly, it is suggested that the Delegate consider adding the accompanying safeguard from the European Summary of Product Characteristics (SmPC) to the safety measures segment of the proposed Australian PI.

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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