Biopharmaceutics During the development of pertuzumab a comprehensive strategy consisting of in vitro binding characterisation, antiproliferative activity and nonclinical pharmacokinetic (PK) studies demonstrated biocomparability of different generations of drug substance and drug product. Once biocomparability was demonstrated, no additional clinical biocomparability studies were conducted. Advisory committee considerations This application was noted at the 149th (December 2012) meeting of the Pharmaceutical Subcommittee (PSC) of the Advisory Committee on Prescription Medicines (ACPM). Quality summary and conclusions The administrative, product chemical, pharmaceutical and microbiological data submitted in support of this application have been evaluated in accordance with the Australian legislation, pharmacopoeial standards and relevant technical guidelines adopted by the TGA. The following evaluations were completed: Primary evaluation Endotoxin safety Viral/prion/transmissible spongiform encephalopathies (TSE) safety Container safety Sterility Issues regarding manufacturing and quality were raised with the sponsor during the evaluation phases and have been resolved. The quality evaluators recommend that Perjeta (pertuzumab, rch) concentrate for IV infusion 420 mg be approved with conditions of registration relating to: release testing Certified Product Details (CPDs) III. Nonclinical findings Introduction Overall quality of the nonclinical dossier The submitted nonclinical data were in general accordance with ICH Topic S9 Nonclinical Evaluation for Anticancer Pharmaceuticals (EMEA/CHMP/ICH/646107/2008). A deficiency was that toxicity studies were only conducted in one species. This was justified on the basis of the ability of pertuzumab to bind to the HER2 receptor in the species used (cynomolgus monkeys). Although there was no evidence of major safety issues with pertuzumab this is still a deficiency in the submission. All pivotal repeat-dose toxicity and reproductive toxicity studies were compliant with Good Laboratory Practice (GLP) principles. For information relating to the primary pharmacology the submission relied entirely on published studies. Safety related studies were confined to repeat-dose toxicity studies conducted in one species (cynomolgus monkeys) and involved only small numbers of animals. These pivotal studies reached exposure levels that were in excess of expected trial,
The clinical evaluator also recommended various revisions to the PI; details of these are beyond the scope of the AusPAR. V. Pharmacovigilance findings Risk management plan The sponsor submitted an Australian RMP Version 1.0 dated March 2012 (data lock point 28 November 2011) which was reviewed by the TGA’s Office of Product Review (OPR). A summary of the RMP is shown in Table 7. Table 7. Summary of Risk Management Plan Safety Concern Proposed Pharmacovigilance Activities (Routine and Additional) Proposed Risk Minimisation Activities (Routine and Additional) Important identified risks Exacerbation of neutropenia Routine Routine Infusion-associated reactions Routine Routine Hypersensitivity/ Anaphylaxis Routine Routine Important potential risks Oligohydramnios Routine Routine Interstitial lung disease (ILD) Routine None Important missing information Patients with hepatic impairment Routine Routine Patients with renal impairment Routine Routine Patients with cardiovascular impairment Routine Routine Male patients Routine None Pregnant women Routine Routine