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Ronapreve
Sponsor
ARTGs
N/A
Device/Product name
Ronapreve
Active Ingredient
Casirivimab/imdevimab
Date of decision
Published
Submission type
New biological entity
ATC codes
Not yet assigned
Decision
Approved for provisional registration
What was the decision based on
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology), clinical (pharmacology, safety and efficacy) and risk management plan information submitted by the sponsor. The benefit-risk profile of Ronapreve was considered favourable for the therapeutic use approved.
What steps were involved in the decision process
Registration timeline
The following table summarises the key steps and dates for this application.
Data was provided as a rolling submission. Under normal circumstances, TGA's assessment (for both provisional and general registration) begins once all information to support registration is available. As part of the Department of Health's response to the pandemic, the TGA has agreed to accept rolling data for COVID-19 treatments, to enable early evaluation of data as it comes to hand.
| Description | Date |
|---|---|
| Positive Designation (Provisional) | 20 August 2021 |
| Submission dossier accepted and first round evaluation commenced | 31 August 2021 |
| Evaluation completed | 13 October 2021 |
| Delegate's Overall benefit-risk assessment and request for Advisory Committee advice | 2 October 2021 |
| Sponsor's pre-Advisory Committee response | 6 October 2021 |
| Advisory Committee meeting | 8 October 2021 |
| Registration decision (Outcome) | 15 October 2021 |
| Completion of administrative activities and registration on ARTG | 18 October 2021 |
| Number of working days from submission dossier acceptance to registration decision* | 33 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Original publication date
Black triangle scheme
Yes.As a provisionally registered product, this medicine will remain in the Black Triangle Scheme for the duration of its provisional registration.
Dose forms
Solution for infusion and injection
Strength
120 mg/mL casirivimab and 120 mg/mL imdevimab
Other ingredients
Histidine, histidine monohydrochloride monohydrate, polysorbate 80, sucrose, water for injections
Containers
Single use and multidose vials
Pack sizes
2 (6 mL single use vials) and 2 (20 mL multidose vials)
Routes of administration
Intravenous infusion and subcutaneous injection
Dosage
Adults
The dosage in adult patients and adolescent patients 12 years of age and older weighing at least 40 kg is 600 mg of casirivimab and 600 mg of imdevimab administered either together as a single intravenous (IV) infusion via pump or gravity or by subcutaneous injection. Intravenous infusion is strongly recommended. Subcutaneous injection is an alternative route of administration when intravenous infusion is not feasible and would lead to delay in treatment.
Casirivimab with imdevimab should be given together as soon as possible after a positive viral test for SARS-CoV-2 and not later than 7 days after the onset of first symptoms.
Paediatric population
The safety and efficacy of casirivimab and imdevimab in children < 12 years of age has not yet been established. No data are available. No dosage adjustment is recommended in paediatric individuals ≥ 12 years of age and older and weighing ≥ 40 kg (see Section 5.2 of the Product Information).
For further information refer to the Product Information.
Pregnancy category
B2Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
What was approved
Ronapreve (casirivimab/imdevimab) was approved for the following therapeutic use:
Ronapreve has provisional approval for the indications below:
Treatment:
Ronapreve is indicated for the treatment of COVID-19 in adults and adolescents (aged 12 years and older and weighing at least 40 kg) who do not require supplemental oxygen for COVID-19 and who are at increased risk of progressing to severe COVID-19.
Post-exposure prophylaxis:
Ronapreve is indicated for the prevention of COVID-19 in adults and adolescents (aged 12 years and older and weighing at least 40 kg) who have been exposed to SARS-CoV-2 and who either:
- have a medical condition making them unlikely to respond to or be protected by vaccination, or
- are not vaccinated against COVID-19. (refer to Section 4.2 Dose and method of administration and 5.1, Clinical Trials)
Ronapreve is not intended to be used as a substitute for vaccination against COVID-19.
The decision has been made on the basis of short term efficacy and safety data. Continued approval of this indication depends on the evidence of longer term efficacy and safety from ongoing clinical trials and post-market assessment.
What is this medicine and how does it work
Casirivimab immunoglobulin G, subclass 1, kappa light chain (IgG1κ) and imdevimab immunoglobulin G, subclass 1, lambda light chain (IgG1λ) are two recombinant human monoclonal antibodies which are unmodified in the fragment crystallisable (Fc) regions. Casirivimab and imdevimab bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus (SARS-CoV-2) with dissociation constants KD = 45.8 picomolar (pM) and 46.7 pM, respectively. Casirivimab, imdevimab and casirivimab and imdevimab together blocked RBD binding to the human angiotensin converting enzyme 2 (ACE2) receptor with half maximal inhibitory concentration (IC50) values of 56.4 pM, 165 pM and 81.8 pM, respectively.
What post-market commitments will the sponsor undertake
- Ronapreve (casirivimab and imdevimab) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicine Information (CMI) for Ronapreve must include the black triangle symbol and mandatory accompanying text for the period of provisional registration.
The Ronapreve European Union (EU)-Risk Management Plan (RMP) (version 0.1, dated 13 July 2021; data lock point 30 April 2021), with Australian Specific Annex (version 1.1, dated September 2021), included with submission PM-2021-03952-1-2, and any subsequent revisions, as agreed with the TGA will be implemented in Australia.
An obligatory component of risk management plans is routine pharmacovigilance.
Routine pharmacovigilance includes the submission of periodic safety update reports (PSURs).
Unless agreed separately between the supplier who is the recipient of the approval and the TGA, the first report must be submitted to TGA no later than 15 calendar months after the date of the approval letter. The subsequent reports must be submitted no less frequently than annually from the date of the first submitted report until the period covered by such reports is not less than three years from the date of the approval letter, or the entire period of provisional registration, whichever is longer.
The reports are to at least meet the requirements for PSURs as described in the European Medicines Agency's Guideline on Good Pharmacovigilance Practices (GVP) Module VII-periodic safety update report (Rev 1), Part VII.B Structures and processes.
Note that submission of a PSUR does not constitute an application to vary the registration. Each report must have been prepared within ninety calendar days of the data lock point for that report.
Additional to the submission of PSURs, expedited monthly summary safety reports (including safety data for patients in Australia and reporting of Australia specific safety concerns) are to be provided for the first 6 months post registration, and thereafter at intervals specified by the TGA.
- Clinical
- The final study reports for the following studies must be submitted to the TGA when they become available:
- R10933-10987-COV-2067
- R10933-10987-COV-2069
- R10933-10987-HV-2093
- R10933-10987-COV-20145
- Updates regarding the clinical activity, efficacy, and effectiveness of casirivimab and imdevimab against the current and future Variants of Concern and Variants of Interest identified by the World Health Organization (WHO) must be provided to the TGA when they become available.
- Updates on timelines of the comparable overseas regulators for conditional and full marketing authorization applications must be provided to the TGA when they become available.
- The final study reports for the following studies must be submitted to the TGA when they become available:
- Submit to the TGA the post-market safety and effectiveness data for the use of repeat doses of Ronapreve in immunocompromised population when seeking full registration of Ronapreve.
Nonclinical
Post approval commitments:
The sponsor is to provide study reports of in vitro selection/escape studies when they become available.
Quality
Laboratory testing and compliance with Certified Product Details (CPD)
- All batches of Ronapreve supplied in Australia must comply with the product details and specifications approved during evaluation and detailed in the Certified Product Details (CPD).
When requested by the TGA, the sponsor must provide product samples, specified reference materials and documentary evidence to enable the TGA to conduct laboratory testing on the Product.
Note: Outcomes of laboratory testing are published biannually in the TGA Database of Laboratory Testing Results and periodically in testing reports on the TGA website.
- The Certified Product Details (CPD), as described in Guidance 7: Certified Product Details of the Australian Regulatory Guidelines for Prescription Medicines (ARGPM), in PDF format, for the medicines must be provided to the TGA upon registration. In addition, an updated CPD must be provided to the TGA when changes to finished product specifications and test methods are approved in a Category 3 application or notified through a self-assessable change.
Post approval commitments:
The sponsor has submitted the list of manufacturing sites along with the responsibilities in the production of Ronapreve and specified functions.
Commitment is required from the sponsor that they maintain the validity of all manufacturer Good Manufacturing Clearance (GMP) Clearances for the duration of product supply to Australia. Additionally, that adherence to the conditions of GMP Clearance approval is upheld.
Medicine Labels
Unless otherwise agreed to by the Secretary following an application under section 9D of the Act, the product must only be supplied with the following labels:
the international label as follows:
- Single Use carton label
- Single Use vial label
- Multi-use vial label
- Multi-use carton label
The sponsor will develop Australian-specific labels for the product, that conform with all relevant Australian labelling requirements, and will take all reasonable steps to implement such labelling before the end of the provisional registration period referred to in subsection 29(3) of the Act (being the period of 2 years starting on the day specified in the ARTG certificate of registration) (noting that, consistent with paragraph 28(5)(aaa) of the Act, changes to such matters as labels that have been agreed to as part of an evaluation under section 25 of the Act may only occur following submission under section 9D of a 'variation' application and approval by the TGA).