An update on post-market regulatory requirements Elspeth Kay - - PowerPoint PPT Presentation

An update on post-market regulatory requirements

Elspeth Kay Director, Risk Management Plan Evaluation Section Pharmacovigilance and Special Access Branch ARCS Conference 23 August 2018

Overview

• TGA’s regulatory compliance framework
• Pharmacovigilance Inspection Program
• RMP Compliance Monitoring Program

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TGA’s approach to monitoring

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TGA’s approach to compliance

Low compliance risk High compliance risk

TGA’s approach to compliance

Help and support

• Make ongoing

compliance easy Inform and advise

• Help to become and stay

compliant Correct behaviour

• Deter by detection

Enforce

Regulated entity – attitude to compliance

Voluntary compliance

• Effective compliance

systems

• Management is

compliance oriented Accidental non-compliance

• Ineffective and/or developing

compliance systems

• Management compliance
• riented but lacks capability

Opportunistic non-compliance

• Resistance to compliance
• Limited or poor compliance

systems

• Management not compliance
• riented

Intentional non-compliance

• Deliberate non-

compliance

• No compliance systems
• Criminal intent

"Committed to doing the right thing" "Trying to do the right thing but don't always succeed" "Don't want to comply but will if made to" "Decision to be non- compliant"

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Pharmacovigilance Inspection Program

• PV requirements and inspections
• When will I be inspected?
• The inspection process: how to make an inspection a smooth process
• Summary of common findings
• How can we help?

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What are your pharmacovigilance requirements?

www.tga.gov.au/publication/pharmacovigilance-responsibilities-medicine-sponsors

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Pharmacovigilance Inspection Program (PVIP)

• The PVIP began on 1 September 2017, with inspections starting in January 2018.
• The PVIP applies to all sponsors of medicines on the ARTG including:

– Listed or registered – prescription medicines – over the counter medicines – complementary medicines.

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Pharmacovigilance Inspection Program Guidelines

www.tga.gov.au/publication/pharmacovigilance-inspection-program-guidance-medicine-sponsors

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Aims of the PVIP

• safeguard patient safety by ensuring the ongoing positive risk-benefit balance
• f a medicine in the Australian context
• verify sponsor compliance with their pharmacovigilance reporting

requirements (serious ADRs, significant safety issues) and other related legislative requirements

• educate sponsors to assist them to meet their requirements
• promote continuous improvement in pharmacovigilance

‒ PVIP is part of an enhanced vigilance framework for the TGA

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Scheduling of inspections

• Risk-based scheduling

– Routine inspections prioritised based on the risk we have assigned to a sponsor or their pharmacovigilance system.

• How we assess risk:

– Risk assessment survey: open 31 January-31 March 2018: obtained data on inherent product, sponsor, system and inspection-related risk factors. Now using the data obtained from this survey to assist in risk based scheduling of inspections. – Internal intelligence: may include whistleblower information, information from regulatory compliance, previous PV inspection history, overseas agency data – Non-compliance with other TGA requirements: PSUR submission, RMP commitments, GMP findings, PV reporting requirements, updating PIs

• In addition to routine inspections, sponsors may be selected for random or “for cause” inspections

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Current risk areas that are being prioritised for inspection

• Uncertainty about a medicine’s risk profile (including new classes of medicines and provisionally

registered medicines)

• Whether the medicine’s registration requires specific safety conditions
• Products with known or emerging important safety concerns
• Evidence that a sponsor has failed to comply with TGA regulatory requirements such as legislative

pharmacovigilance requirements, good manufacturing process, RMP activities or the submission

• f PSURs
• Compliance history, including previous pharmacovigilance or other inspection findings
• Information on non-compliance with pharmacovigilance requirements from whistleblowers

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The Inspection Process

• Notification, planning and preparation
• Agenda, logistics and initial document requests

Pre-inspection

• Opening meeting
• Interview sessions and document reviews
• Closing meeting

Inspection

• Issuance of inspection report
• CAPA response
• Close-out of the inspection

Post-inspection

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What we inspect

Management

• f AE Reports

Signal Detection Report significant safety issues Reference safety information PSUR and RMP Commitments QMS QPPVA

• versight

Contracts and Agreements Collection of AE Reports

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How to prepare for an inspection (a few pointers)

• Ensure you have nominated an Australian contact person for PV through eBS
• Ensure an appropriate quality management system is in place as a basis for an effective PV

system, including up to date SOPs, training and auditing

• Ensure all potential sources are being monitored for ADRs, including but not limited to marketing

programs, medicines information, product quality complaints, literature, company sponsored internet sites and social media, post market clinical trials etc.

• Ensure you have a robust and secure system to collect, process and analyse safety data
• Ensure all serious Australian ADRs are being reported to the TGA within required timeframes
• Ensure ongoing monitoring for safety signals is occurring on a regular basis and includes ALL

safety data

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How to prepare for an inspection (a few pointers)

• Ensure there are procedures in place to receive notification of significant safety issues from global

counterparts and report to the TGA within required timeframes, where required

• Ensure you have safety agreements in place with required partners and contractors
• Ensure PSURs are complete and submitted on time
• Ensure any RMP commitments are being met
• Ensure the Australian person responsible for PV has appropriate oversight of the system
• Ensure CAPA from any previous PV inspection has been completed
• Ensure all safety data is being held indefinitely for the life of the product and for 10 years after its

removal from the ARTG

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How to ensure the inspection runs smoothly

• Have a designated point of contact for the inspectors and sponsor staff to liaise through (prior to and during

the inspection)

• Make sure you know who to go to in the company for requested information – who does what (i.e. market

research program management, contract management, training of sales representatives etc.)

• Have a database expert available to run requested reports (if applicable)
• Ensure IT systems and any teleconference/video conference facilities are working
• Provide documents in an accessible way to the inspectors i.e. via USB or hardcopy
• Label each document with the specified number given so it can be easily tracked
• If you don’t understand a request - ASK!
• If you cannot provide what we are asking for - TELL US!

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Inspections update

• 10 inspections scheduled for 2018; 5 completed

Critical Major Minor Nil 25

• failure to report significant

safety issues

• deficiencies in case collection,

follow up and seriousness assessment

• late reporting of serious cases
• delay in updating reference

safety information (PI and CMI) 12

• deficiencies in safety data

exchange agreements and company SOPs

• deficiencies in

pharmacovigilance training

• quality management system

procedures

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Some common deficiencies identified

Communication of significant safety issues

• Deficiencies in communicating significant safety issues

– Sponsors must report all significant safety issues to the TGA within 72 hours (Pharmacovigilance Guidelines) – Significant safety issues may include:

• actions taken by comparable international regulatory

agencies for safety reasons

• identification of new safety issue or risk factors that may

impact on the safety or benefit-risk assessment of the product

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Some common deficiencies identified

AE case collection and processing

• Late submission and non-submission of serious Australian cases to

the TGA – All serious adverse reactions occurring in Australia must be reported to the TGA within 15 days of receipt by the sponsor (Pharmacovigilance Guidelines).

• Non-conservative seriousness assessments

– Seriousness assessments should be an independent process to medical evaluation, causality and validity of the case i.e. based on the adverse event alone – Where outcomes or treatment information is not available, a conservative approach should always be taken

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Some common deficiencies identified

ADR case collection and processing (cont’d)

• Identification of ADRs

– Care should always be taken to determine if an enquiry involves an adverse event for collection and reporting purposes. – Literature search processes should be structured to identify both ADRs and general safety information and occur regularly. – Follow up should be performed where information is unclear or lacking, including following up directly with consumers who may hold valuable medicine safety information.

• Deficiencies in the pharmacovigilance contracts and training of vendors

– Omissions, errors and discrepancies in contracts for post-marketing initiatives (e.g. patient support programs and market research), sales, promotion and distribution partners. – Contracts must ensure all safety information is collected and communicated to the medicines sponsor effectively; include provisions for reconciliation of safety data and training of staff.

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Some common deficiencies identified

Maintenance of Reference Safety Information

• Delays in updating Australian Product Information documents

– From when the sponsor became aware of the need to initiate a reference safety change – TGA expectation is a variation will be submitted within 6 months from identification of any safety related change required

• Delays in updating PI and CMI documents

– PI and corresponding updated CMI document must be lodged with the TGA within 2 weeks of the date of registration (for registered products- Conditions of Registration)

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How can we help you?

• What further information or clarification of the guidance would help you meet your PV obligations?
• Would any of the following be useful in helping you understand either the inspection process or PV

responsibilities: – FAQs on PV – Specific training on the inspection process – Specific training on your regulatory responsibilities, the guidelines and our expectations – Specific training on how to produce corrective and preventative action plans – More information on common findings and issues identified – All of the above? – Other ideas? Email: Pharmacovigilance.Inspections@health.gov.au

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RMP Compliance Monitoring Program

• Part of the MMDR reforms for enhanced

medicines vigilance

• Aim: ensure timely implementation of

RMP commitments

• Approach: cooperative compliance,

aligned with the TGA’s regulatory compliance framework

Agree activities for monitoring Identify potential non- compliance Review compliance status Update RMP as required

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RMP Compliance – help & support, inform & advise

• General information in revised RMP Guidance
• RMP evaluation will ensure RMP commitments

are: – clearly documented – feasible and measurable

• If we identify potential non-compliance, we will:

– contact you to clarify compliance status – support you in developing a plan to achieve compliance – continue to monitor to ensure future compliance

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RMP Compliance – correct behaviour and enforce

• If we identify continued non-compliance, we

will: – formally request information on how you will achieve compliance – continue to monitor to ensure future compliance

• Serious non-compliance may be referred to

Regulatory Intelligence and Enforcement: – outcomes of these regulatory actions may be published on the TGA website

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Risk-based prioritisation of activities for monitoring

• High priority activities may include:

– Confirmatory studies for provisionally registered products – Local additional risk minimisation activities

• Including provision of educational materials

for review – Australian-specific additional pharmacovigilance – Local studies to measure effectiveness of additional risk minimisation – Some conditions of registration

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Questions

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