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Pharmacovigilance inspection program: Guidance for medicine sponsors
Version 1.0, September 2017
We take a risk-based approach to the scheduling of pharmacovigilance inspections and prioritise routine inspections based on the risk we have assigned to you or your pharmacovigilance system. Systems with lower risk products or good compliance history are less likely to be inspected regularly. However, random inspections as well as 'for cause' inspections may also occur.
The elements we consider when assigning you risk and consequently determining whether and when we inspect include, but are not limited to:
- product-related factors such as:
- uncertainty about a medicine's risk profile (including new classes of medicines and provisionally registered medicines)
- whether the product has additional pharmacovigilance or risk-minimisation activities
- whether the medicine had specific condition(s) of registration applied due to safety concerns
- if the product has significant Australian sales volume (that is, if a large number of patients are exposed to the medicine)
- product(s) with limited alternatives in the market place
- products with known or emerging important safety concerns
- the type of medicine - complementary, over the counter or prescription medicines.
- sponsor-related factors such as:
- evidence that you have failed to comply with other TGA regulatory requirements such as good manufacturing practice, RMP activities or the submission of PSURs
- data analysis that indicates you may have failed to comply with legislative pharmacovigilance requirements, such as:
- evidence that you have failed to submit adverse drug reaction reports within required timeframes, or
- your adverse drug reaction reports are erroneous, or
- information from prior inspections in Australia or overseas
- whether you supply many products to the Australian market
- changes to, or suspected lack of, resources for pharmacovigilance activities
- experience as an Australian sponsor of medicines included in the ARTG
- organisational changes such as mergers and acquisitions.
- pharmacovigilance system-related factors such as:
- whether you have subcontracted your pharmacovigilance activities, or have employed multiple firms to undertake pharmacovigilance activities
- whether your QPPVA has changed
- changes to your pharmacovigilance safety database(s). These could include changes to the database or to associated databases; the database's validation status and the transfer or migration of data
- changes to your contractual arrangements with pharmacovigilance service providers or to the sites where pharmacovigilance is conducted.
- inspection-related factors such as:
- your compliance history, including previous Australian pharmacovigilance or other inspection findings
- whether you have been subject to a pharmacovigilance inspection previously
- whether re-inspection was recommended by previous inspector(s)
- how long it has been since your last pharmacovigilance inspection
To help us prioritise inspections, we will ask you to complete a biennial report (once every two years) on your pharmacovigilance system via an electronic form made available to all nominated contact persons for pharmacovigilance on the TGA website. The form will ask for information pertaining to the elements we consider when assigning you risk as listed above. Completing the requested fields helps us assign your risk based on predetermined risk scores and prioritise you for inspection. Sufficient time will be given for this survey to be completed. Your risk score obtained from this report will be combined with other risk information known to the TGA in order to prioritise inspections. Your assigned risk score will not be made available to you. If you do not complete the report, we will assign you the highest risk. We may also ask you to complete this form on an ad hoc basis.
Sites to be inspected
We choose the type and number of sites to inspect to ensure we meet the key objectives within the scope of the inspection. In most cases, we limit inspections to Australian affiliate sites; however, we may also inspect overseas sites if appropriate. We will liaise with international regulators in preparation of any international inspections, as appropriate.
Any party or organisation contracted to carry out some or all pharmacovigilance activities in conjunction with, or on behalf of, the sponsor may be inspected to confirm they are capable of supporting the sponsor's compliance with Australian pharmacovigilance obligations. Such inspections will generally be arranged through the sponsor as part of an overall pharmacovigilance inspection.
Types of inspections
Routine pharmacovigilance inspections are scheduled as part of the inspection program. There is no specific trigger for these inspections, although we take a risk-based approach to prioritising them. These inspections are usually system-related inspections, but one or more products may be selected as examples to verify the implementation of the system and provide practical evidence of its functioning and compliance.
'For cause' inspections
'For cause' inspections are undertaken in response to specific triggers where a pharmacovigilance inspection is the appropriate way to examine the issues. 'For cause' inspections generally focus on specific aspects of your pharmacovigilance system or examine identified compliance issues and their impact on a specific product. However, we may also inspect your entire pharmacovigilance system as a result of a trigger. Significant public health concerns or identified noncompliance are expected to be the most common triggers. Some (but not all) of the elements listed under Inspection prioritisation are also triggers.
Pharmacovigilance system-related inspections review the procedures, systems, personnel and facilities in place and determine whether your system meets your regulatory pharmacovigilance obligations. As part of this review, product-specific examples may be used to determine how the pharmacovigilance system operates and whether it complies with requirements.
Product-related pharmacovigilance inspections primarily focus on product-related pharmacovigilance issues, including product-specific activities and documentation, rather than reviewing the system overall. They are likely to be 'for cause' inspections to investigate a specific product issue. Some aspects of the wider system may be examined during a product-related inspection (that is, the system used for that product).
Announced and unannounced inspections
We anticipate the majority of inspections will be announced - that is, we will notify you of them in advance to ensure the relevant personnel will be available for the inspection. However, it may sometimes be appropriate to conduct unannounced inspections or to perform an inspection at short notice (for example, when an announcement could compromise the objectives of the inspection or when prompt inspection is required due to urgent public health concerns).
We may reinspect your pharmacovigilance system as part of our routine inspection program. We prioritise re-inspections by assessing risk factors. If a previous inspection identified a high level of compliance this may increase the time between reinspections. More frequent reinspections may occur:
- where we have identified significant noncompliance
- to verify you have taken action to address inspection findings
- to evaluate your ongoing compliance with your obligations and evaluate changes to your pharmacovigilance system
- when a previous inspection found you had failed to take appropriate corrective and preventative action in response to prior inspections.
These are pharmacovigilance inspections of your premises (or the premises of a firm you have contracted to help fulfil your pharmacovigilance activities) that we perform remotely using communication technology such as the internet or video/tele conferencing. For example, where key sites for pharmacovigilance activities are located outside Australia or a third-party service provider is not available at the inspection site, it may be feasible to interview relevant staff and review documentation via remote access. If the remote inspection reveals issues that require on-site inspection, or the inspection objectives could not be met remotely, we may visit the inspection site.
We have the right to perform a pharmacovigilance inspection at any time (see Legal basis for pharmacovigilance inspections). In exceptional circumstances, we can perform an inspection without notice. However, we would normally give you advance notice of our intention to conduct a pharmacovigilance inspection.
The period of notice served should be sufficient for you to make logistic arrangements, and ensure key personnel are available and have access to relevant data. As a guide, we consider six to eight weeks' notice to be sufficient for a routine inspection.
Notice of the inspection could include, for example, the inspector's name(s), the inspection's objectives and nature, the inspection date and, if known, the address(es) to be inspected. We will also request information about your pharmacovigilance system so we can plan the inspection.
We will notify you of the pharmacovigilance inspection in writing, unless an unannounced inspection is required. We will issue the inspection notification to your Australian pharmacovigilance contact person's nominated email address. We will request confirmation of your availability, ask you to ensure the cooperation of all parties and to confirm in writing that you agree to the inspection of all relevant sites and will make all required documents and databases directly accessible to our inspectors. If the nominated Australian pharmacovigilance contact person is not the QPPVA, the contact person should inform the QPPVA of the notification.
We may also request supporting data demonstrating how your pharmacovigilance system operates, for example your global Pharmacovigilance System Master File (where available), a description of the Australian pharmacovigilance system or further information on specific issues of interest. We will give you clear advice on when and how to submit these.
Preparing for inspection
Once you have been selected for, and notified of, a pharmacovigilance inspection, you need to prepare for it.
We will consider avoiding duplicating inspections conducted as part of another country's pharmacovigilance inspection program when feasible. There may be circumstances where we can perform a more detailed inspection of specific aspects or limit the scope of the inspection. For example, when appropriate, the inspection may focus on reviewing local Australian processes where global processes have recently been subject to a positive international inspection.
We will prepare an inspection plan, which will identify:
- the objectives and scope of the inspection
- our inspection team member(s) and their respective role(s)
- the inspection date and site(s) to be inspected
- the specific documents, electronic tools and systems to be reviewed and which we require access to, insofar as possible
- the expected time and duration of each major inspection activity (premises, processes et cetera)
We will share the inspection plan with you in advance to ensure the relevant personnel, meeting rooms, databases and/or documents are available.
We may also request specific electronic documents prior to the inspection to allow sufficient pre-inspection analysis and inspection planning and will specify a timeframe for their delivery. You may provide such documentation to the TGA by various means in adherence with your data privacy processes; including via secure email, provision of access to secure file hosting service or provision of USB or CD or other means.
Conducting the inspection
The inspection will proceed according to the details set out in the inspection plan. This will be negotiated prior to the inspection and can be amended during the inspection to ensure we achieve the inspection objectives. Any amendment to the plan will be documented. The inspection will take place over several days depending on the complexity of the system.
We may collect relevant information to support the inspection and verify compliance with guidance and the mandated reporting requirements set out in the Pharmacovigilance responsibilities of medicine sponsors - Australian recommendations and requirements by, for example:
- interviewing appropriate staff members regarding pharmacovigilance activities
- reviewing applicable company or contracted organisation policies and procedures regarding pharmacovigilance activities
- examination or demonstration of computers, electronic systems and databases, where required, to obtain data on adverse event cases, product safety and pharmacovigilance activities
- reviewing adverse event case documentation
- reviewing internal and external communication relevant to adverse event cases, product safety and pharmacovigilance activities
- reviewing product-related documentation relevant to adverse event cases, product safety and pharmacovigilance activities
- reviewing staff training records in relation pharmacovigilance activities
If you refuse us access to any relevant record or documentation that our inspectors have a legal right to access, this will be documented in the inspection report so we can decide on further action and consequences.
Our inspection team will have an opening meeting with your representatives before the inspection begins. The lead inspector will chair the meeting.
The purpose of the opening meeting is to:
- introduce the inspection team
- explain the regulatory framework for conducting the inspection
- provide information about the inspection's scope and objectives
- clarify logistics, timeframes and other matters referred to in the inspection plan
- allow you to introduce your representatives attending the inspection
- allow you to present an overview of your pharmacovigilance system
- clarify with you whether there are any anticipated difficulties relating to the conduct of the inspection
Collecting and verifying information
Pharmacovigilance inspections examine your compliance with the relevant Australian legislation and guidelines. The scope of inspections includes, but is not limited to, the following elements as appropriate to the system being reviewed:
- adverse reaction reports
- collection and collation of reports from all sources and sites, including but not limited to cases reported via medical information enquiries, international literature, social media and the internet, market research programs, patient support programs, voluntary patient registries, post-registration studies and partners
- assessment (validation, seriousness, expectedness and causality), coding and processing
- follow-up and outcome recording
- reporting within the specified timeframes to the TGA, where required
- record keeping and archiving.
- periodic safety update reports (PSURs)
- completeness and accuracy of the data included, appropriateness of decisions concerning data that are not included
- addressing safety topics, providing relevant analyses and actions
- formatting according to requirements
- timeliness of submissions.
- ongoing safety evaluation
- use of relevant information sources for signal detection (including global data where relevant)
- appropriately applied analytical methodology
- appropriateness of investigations and follow-up actions such as the implementation of recommendations following data review, including updating reference safety information
- notification to the TGA of significant safety issues that are identified internationally within the specified timeframes
- implementation and ongoing review of the Risk Management Plan and other safety commitments (this may include registries, enhanced surveillance or traceability systems)
- timely identification and provision of complete and accurate data, in particular in response to specific requests for data from us
- implementation of new/updated reference safety information, including internal distribution and external publication
- examination of processes, decision-making, communications and actions relating to a specific trigger and/or product
- pharmacovigilance system
- the integration of pharmacovigilance activities within your quality management system and your adherence to it, including quality control and quality assurance processes
- up-to-date and comprehensive policies and procedures in place regarding your role and responsibilities in relation to your pharmacovigilance system, with appropriate document control
- accuracy, completeness and maintenance of records
- quality and adequacy of training, qualifications and experience of your pharmacovigilance staff
- the fitness for purpose of computerised systems
- your contracts and agreements with all relevant parties reflect their pharmacovigilance responsibilities and activities, and are adhered to
- defined roles and responsibilities for your pharmacovigilance personnel including the QPPVA, including access to the quality system, performance metrics, audit and inspection reports, availability and their ability to take action to improve compliance.
- The QPPVA's involvement and awareness of product-specific issues.
- previous Australian pharmacovigilance inspection findings
- review of the status of the system and/or CAPA plan(s) resulting from previous pharmacovigilance inspections(s)
- review of any significant changes to the pharmacovigilance system since the last pharmacovigilance inspection (such as a change in the pharmacovigilance database, company mergers or acquisitions, significant changes in contracted activities or change of the QPPVA)
- review of process and/or product-specific issues from the assessment of information you provide, or not covered in a prior inspection.
At the end of the inspection, our inspector(s) will conduct a closing meeting with your representatives. The QPPVA should ensure their team attends the meeting. The purpose of the meeting is to:
- summarise the inspection findings to ensure you clearly understand the inspection outcomes
- define the grading deficiencies, if any have been identified
- explain the procedures and timelines for distribution of our inspection report, your response and any follow-up measures
- provide you an opportunity to correct any misconceptions and misunderstandings in the findings.
An inspection may consist of visits to more than one location. If appropriate, a closing meeting may be held at each location inspected.
If the inspection is prematurely terminated due to exceptional circumstances, we will document the reason for the early termination and any deviations from the inspection plan in the inspection report.