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Karen Whitelock Patient Safety Country Patient Safety Head Austra lia and New Zealand

Reforms and Operations Section Pharmacovigilance and Special Access Branch Therapeutic Goods Administration PO Box 100 Woden ACT 2606

1 May 2017

Dear Sir/Madam

Novart is Pharmaceuticals Australia Pty Ltd ACN 004 244 160 54 Waterloo Road Macquarie Park NSW 2113 PO Box 101 North Ryde NSW 1670 Australia Tel +61 2 9805 3673 Fax +61 2 9888 1627 Email: karen.whitelock@novartis.com

Consultation: Strengthening monitoring of medicines in Australia. Enhanced medicines vigilance. Version 1.0 March 2017.

Please find attached the response from Novartis Pharmaceuticals Pty. Ltd. ['Novartis'] on the TGA's March 2017, consultation paper titled: Strengthening monitoring of medicines in Australia, Enhanced medicines vigilance, version 1.0.

We welcome the opportunity to provide feedback on proposed changes to the existing Australian Medicines Vigilance Framework as proposed in the consultation paper. The proposals are in response to recommendation 27 from the 2015 review of Medicines and Medical Devices Regulations (MMDR) undertaken by an external expert panel.

In this submission, Novartis has commented on the 3 broad areas flagged for enhancement, 1. Adverse Event Reporting, 2. Compliance and 3. Improved Collection and Use of Data, responding to each of TGA's questions as defined below.

1. Adverse Event Reporting a. Implementation of Black Triangle Scheme

TGA proposes to implement a Black Triangle Scheme similar to the one operating in EU member states. Where by a symbol will appear on the approved Pl and CMI, advertising, promotional and educational material for HCPs, relevant texts such as Australian Medicines Handbook and MIMS and dispensing and prescribing software.

Products will be included in the scheme if they are, a new chemical or biological entity, a medicine with provisional registration, including where an extension of indication is provisionally registered.

Other types include, products with a suspected safety risk that TGA assess require prioritised monitoring, extension of indications where there is limited international experience and the safety profile in the Australian environment is not well established, and a new and significant safety concern arises with a registered product which TGA assess requires prioritised monitoring.

i. Do the proposed criteria for inclusion in the Black Triangle Scheme appropriately target new medicines for which adverse events reports should be sought?

Novartis agrees that the defined criteria does fulfil its purpose to target relevant identified medicines. Novartis recommends the TGA indicates their intention with respect to Biosimilar products and the inclusion into the Black Triangle Scheme.

Additional areas for TGA to consider including in updated guidelines would be • Defined process to communicate to sponsors the decision when one of their

medicines is to be include into the Black Triangle scheme o TGA's expectations of sponsor companies once communication has been

received including tim.elines. • Defined process to determine when the product would be removed from the scheme

o Expectations of sponsor once communication is received on removing symbol.

• Details on how and when TGA will perform an analysis of the data and expectations of Sponsor with respect to responding to TGAs data review.

ii. What information, communication and education activities would assist health professional and consumers to understand the Black Triangle Scheme and the importance of reporting adverse events for these medicines?

The experience in the EU has indicated that less than 20% of HCPs and consumers are aware of the EU Black Triangle Scheme and its purpose. Therefore, Novartis recommends a public, broad and continuous awareness program reaching all facets of the Australian Healthcare environment, such as all HCPs (Physicians, Pharmacists, Nurses, and Dentists) and consumers\carers via various industry, medical professional and academic organisations such as National Prescribing Service, Pharmaceutical Society of Australia , Pharmaceutical Guide, Australian Consumer Forum, RACGP and other key stakeholder groups.

Other awareness and educational recommendations include • Media campaign at implementation • Paper leaflets and an electronic knowledge centre for consumers on TGA website, • Web-based training for HCPs and paper leaflets, articles in local medical journals

and medical and lay press • Training at undergraduate courses • Utilising Prescribing and Dispensing applications to highlight Black Triangle products

with pop-up note what this means and expectations of relevant HCPs

To facilitate increased AE reporting, Novartis encourages TGA to implement a simple AE reporting tools such as WebRADAR. This tool has been implemented in a number of EU countries including UK, the Netherlands and Croatia. Globally, Novartis has supported the implementation of this tool and would be willing to support TGA with this initiative.

Novartis would also seek clarification on the proposed transition arrangements to the black triangle scheme, particularly for new classes of medicines. For instance, if a first-in-class product is registered prior to the introduction or implementation of the scheme and another compound in the same class is registered after the scheme is implemented, it could create the misperception of different safety issues.

Novartis would have concerns with the prospect of applying the scheme to PI/CMI package inserts as information in these printed materials can become outdated as new information about the medicine

becomes and available and after the product is released to the market and no longer in control of the sponsor. Novartis believes that a potentially more practical and safer option would be to include the black triangle on the outer carton of newly registered product and to replace pack insert altogether (including Pl pack inserts for injectables) with directions on the outer pack on where to access the latest version of the Pl electronically.

b. Product Information (Pl) reformat Reformatting the Pl to ensure safety information such as indications, Cl , precautions and adverse event information will be made more easily identifiable and accessible to the prescriber

i. Are the proposed changes to the Product Information (Pl) leaflet useful for health professional

Novartis supports the reformatting of the Pl to ensure ease of use for HCPs. Novartis requests TGA to provide further clarity on the proposed format and how the format relates to existing product label formats such as the European, Summary of Product Characteristics (SmPC) and the US Pl. Novartis encourages the TGA to consider the adoption of existing formats such as the EMA SmPC and Medsafe Data Sheet. to facilitate regulatory discussions and implementation of routine risk minimisation in the context of the Pl. Closer alignment of the product information documents between Australia and New Zealand would potentially facilitate complete harmonised of packs, which would lead to significant efficiency and cost savings for companies that supply medicines to both markets. It could also facilitate work-sharing initiatives between TGA and EU and NZ agencies on the proposed new registration pathways.

ii. What support will sponsors need to comply with the new format and what are achievable timelines for implementation of the new format?

Novartis recommends that TGA provide clear and reasonable timelines for the implementation of any changes to the Pl format, a transition period of at least 2 to 3 years would seem reasonable to allow implementation through routine updates to the Pl. Clear guidance is needed to ensure a smooth tran~ition to the new format, particularly for products containing Pl pack inserts (eg. injectables). In addition, guidance will be needed where information is not contained within the existing Pl but is required under the new re-formatted Pl. An Educational program to the relevant HCPs on the Pl changes is also recommended to ensure knowledge across the prescribers, dispensers and administrators of pharmaceutical products.

2. Compliance a. Pharmacovigilance (PV) Inspection Program

Following the 2015\2016 pilot PV Inspection Program, TGA are proposing to formally commence a PV Inspection Program (PVIP) to proactively ensure companies have appropriate PV systems in place and are compliant with legal responsibilities. TGA has defined which factors would be considered when determining which sponsors will be targeted and prioritised. The program will use a risk based approach that includes a component of random inspections. It is noted that sponsors of provisionally registered medicines will be prioritised for the PV Inspection Program.

i. What activities could TGA undertake to assist sponsors in complying with their PV requirements?

Novartis supports TGA's PV Inspection Program and recommends that TGA focus their PVIP on a robust scientific risk based prioritisation approach where, situations that increase the risk of non-compliance is understood and prioritised. Global regulatory agencies with

existing PVIPs, could provide advice to TGA on their PVIP inspection prioritization and risk based decisions making.

Novartis recommends that TGA review the findings from the pilot PVIP, and update their current PV Guidelines, Australian requirements and recommendations of Pharmacovigilance responsibilities for sponsors of medicines to provide clarity of TGA's expectations in the following area.

• 72 Hour Significant Safety Issues o Please define your expectation of when is Day O for Significant Safety Issue o Novartis would strongly recommend that the TGA adopt the EMA definition of

emerging safety issue, which requires a safety signal to be reported once it has been validated by the sponsor.

o Novartis believes that this should be applied to high impact safety issues that lead to changes to the known risk-benefit balance of a medicine and/or impact public health. It should not be applied to other potential safety issues that may require further assessment (e.g. reports of EMA PRAC meetings, FDA tracking a possible safety issue)

o Please define your expectation of sponsor companies with respect to Foreign Label safety updates. In earlier TGA PV guidelines, companies were able to apply a judgement assessment relating to benefit\risk assessment of the foreign label update and application of TGA reportability under the Significant Safety Issue requirement. This approach would align more closely to an adoption of the EU emerging safety issues.

• Please define the expected breath of the PVIP, for example during a PV Inspection, would TGA expect sponsor companies, vendors and licences partners to be available for review.

Once implemented, and as part of the PVIP, Novartis encourages TGA to hold regular stakeholder forum meetings to encourage active and interactive exchange with HCPs, Patients, Industry and other interested parties. Novartis also encourages TGA to make available an annual report of Inspection Findings that details "Hot Topics", this would be a mutually beneficial undertaking to alert sponsor companies to common findings and encourage sponsor companies to remediate any deficiencies.

Novartis also encourages TGA to develop an information pack for sponsor companies to have visibility on PVIP formats with respect to agendas, document requests, reports, CAPA and effectiveness check documentation.

b. RMP Compliance Monitoring TGA are planning on a proactive approach of monitoring RMP commitments to ensure that activities are completed within the agreed time frames and that sponsors have reported when necessary and that they seek agreement with TGA if any changes to the RMP commitments are required.

i. Is the information regarding RMP requirements included in the AusPARs sufficient to inform you of the risk minimisation and pharmacovigilance commitments that have been made by the sponsor?

Novartis agrees that there is sufficient information in the product AusPAR to ensure that details of RMP commitments are publically accessible. However, the information included in the AusPARs varies between different AusPARs, and consistency of included information will help to inform relevant parties about details of RMP commitments. Novartis encourages

TGA to ensure the agreed RMP commitments are clearly documented in the product registration letter for transparency.

ii. What activities could we undertake to assist sponsors in complying with their RMP requirements?

Novartis recommends the following activities to support sponsors complying with their RMP commitments

• Consistency of information included in AusPARs • Implementation of a TGA review process for RMP/ASA updates. Currently there is no

established process to review updates to RMPs/ASAs. This leads to situations where a sponsor has submitted updates to RMPs/ASAs. but has not received a confirmation that the updates are acceptable to the TGA. In such a situation it is unclear whether the previously agreed RMP/ASA are still the agreed documents, or whether the updated RMP/ASA can be implemented by the sponsor.

3. Improved Collection and Use of Data a. Enhancing Data Analytics through linking of health datasets

Novartis supports this initiative and encourages TGA to consider privacy issues with respect to data linking to ensure that the identification of patient's does not inadvertently occur, in the event information is released under FOi legislation. Novartis would urge the TGA to share their findings with stakeholders including sponsor companies. Novartis encourages TGA to provide the details of planned activities in this initiative, to establish feasibility and management of the data sets including possible access to aggregate data for academic research purposes and for sponsors to perform evaluation of risk minimisation activities where appropriate.

b. Adverse Events Management System (ADRS} TGA plans to implement a new ADR IT System to streamline electronic AE reporting. The new system will allow e28 exchange of safety information.

Novartis supports this initiative and will be happy to be involved in pilots or testing activities to facilitate the implementation of e2B exchange of safety information.

c. International Information Sharing As an efficiency, TGA plan to identify opportunities to strengthen their use of overseas reports, in addition to share Australian AE data with WHO and facilitate international regulatory collaboration and contribute to international PV endeavours.

Novartis supports this initiative.

Novartis position: Overall Novartis is supportive of the TGA's undertaking to enhance medicines vigilance by strengthening the monitoring of medicines in Australia.

Concluding Remarks We welcome the TGA's consultation on enhanced medicines vigilance and recommend that TGA consider the recommendations as outlined above.

Novartis thanks the TGA for considering its submission.

' Country Patient Safety Head Novartis Patient Safety