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Pharmacovigilance responsibilities of medicine sponsors
Australian recommendations and requirements
Your pharmacovigilance system
You should establish and manage a pharmacovigilance system to help you meet your pharmacovigilance responsibilities.
Your pharmacovigilance system should allow you to:
- meet all pharmacovigilance requirements described in these guidelines and applicable legislation
- take any additional pharmacovigilance and risk minimisation actions required by the Risk Management Plan (RMP) (if a RMP is in place)
- investigate and report product quality issues associated with serious adverse reactions and significant safety issues
- critically analyse adverse events and other safety and quality information
- take any action necessary to mitigate an identified safety issue.
Qualified person responsible for pharmacovigilance in Australia
You should have a qualified person responsible for pharmacovigilance undertakings in Australia. Ideally, this person will also be the Australian pharmacovigilance contact person responsible for reporting to the TGA and coordinating pharmacovigilance-related communications between us. The Qualified person responsible for pharmacovigilance in Australia (QPPVA) should ensure that the sponsor has an effective pharmacovigilance system in place and complies with the legal pharmacovigilance requirements.
We recommend the QPPVA:
- lives in Australia
- is permanently and continuously available (or at least within the hours of 9am–5pm AEST Monday to Friday), with a back-up person nominated should the primary QPPVA be absent
- is trained and experienced in pharmacovigilance and relevant legislation in Australia
- is medically qualified, or if not, have ready access to a medically qualified person for any clinical assessments necessary. We prefer that this medically qualified person reside and are medically registered in Australia so they can address adverse reactions, significant safety issues and the benefit–risk balance of medicines in the Australian context.
Please note that the above are recommendations. Ultimately, the QPPVA should be suitably experienced and qualified in order to monitor the safety of your medicines. The characteristics and skills of the individual QPPVA should be dependent on their specific roles and responsibilities and should ensure that you are able to meet your pharmacovigilance requirements.
The QPPVA needs to have adequate understanding of the Australian and global pharmacovigilance processes in order to allow them to have effective oversight of the entire pharmacovigilance system.
Pharmacovigilance operational documents and activities
Develop clear written standard operating procedures (SOPs) for pharmacovigilance to ensure all roles, responsibilities, requirements and timelines are well-defined and understood by all personnel involved.
You should make provisions for regular review for improvements to the system where required.
Where you have identified a need to initiate a safety related update to the reference safety information (that is not a significant safety issue), we expect you to submit safety related updates to reference safety information documents including the Australian product information within a timely manner of identifying the need for change. This ensures safety information available to healthcare professionals and consumers is up-to-date to ensure safe use of your medicines.
Where you have a global parent company, you need to be confident that your SOPs will ensure you become aware of international safety information and regulatory actions in a timely manner. This also applies to activities contracted to third parties. You should review third-party procedures to verify that they are adequate and comply with applicable requirements (see Safety contracts and agreements).
Safety contracts and agreements
As a sponsor you are ultimately responsible for complying with Australian regulatory reporting requirements. You are responsible for the ARTG entries you hold and thus, you MUST ensure you meet your pharmacovigilance responsibilities whether you have contractual arrangements with other sponsors or external organisations. This also applies to overseas companies that belong to your parent company, and to other companies within or outside Australia with which you have commercial or contractual agreements - for example, vendors, partners and contract manufacturers.
Where you outsource pharmacovigilance activities to a third-party (external) person or organisation, you should have a detailed pharmacovigilance contract or agreement in place with them that stipulate the explicit roles and procedures for collecting and reporting safety information to ensure you can comply with your reporting obligations. Further, external companies should be appropriately trained and overseen.
Your pharmacovigilance contract or agreement should specify what safety information is to be collected and how it is to be exchanged, including timelines, reconciliation and reporting responsibilities. Your procedures should prevent you submitting duplicate reports to us.
Staff undertaking pharmacovigilance activities should be appropriately trained in relevant legislation and guidelines, and in the report process and evaluation. Other staff that might receive or process safety reports - for example, clinical development, sales, medical information, legal or quality control staff - should also be trained in collecting and reporting adverse reactions. This ensures that adverse events notified directly to these employees would be reported and communicated through to the pharmacovigilance section for inclusion in the company safety database and for ongoing safety review of a product.
Pharmacovigilance training should be conducted at induction of employment, with an annual refresher at a minimum for all relevant staff as appropriate based on their roles and responsibilities. Training activities undertaken by your staff should be recorded and we may request these documents as evidence of training at any time.
Training recommendations should also apply to external vendors and partners - for example, market research service providers - engaged in pharmacovigilance or who have the potential to identify adverse events. Training on the collection and reporting of adverse events should be clearly stipulated in the contractual agreements and audited regularly.
Monitoring and collecting information
Your pharmacovigilance system should meet any applicable record-keeping and reporting requirements. In terms of monitoring and collecting safety information, your pharmacovigilance system should allow you to:
- identify and collect all information related to the safety of your medicine from all possible sources, including
- spontaneous reports of adverse reactions (including consumer reports to you, or to people who work for you or have a contractual relationship with you)
- internet and social media reports
- reports from non-medical sources
- solicited reports, such as from post-registration studies or post-market initiatives
- reports in international and local literature
- individual adverse drug reaction reports in the TGA's Database of Adverse Event Notifications (DAEN).
- determine if an enquiry involves an adverse reaction - for example, enquiries to your Medical Information section or sales representatives
- encourage consumers and health professionals to submit safety information - for instance by providing adverse reaction reporting forms and contact details on your website
- gather sufficient information to scientifically evaluate reports of adverse reactions and any other safety issues associated with the medicine
- ensure the reports you collect are authentic, legible, accurate, consistent, verifiable and as complete as possible, and follow these up where necessary
- validate suspected adverse reactions and report them to us within the required time frame.
All adverse events that healthcare professionals, patients or consumers notify you of, where the reporter suspects a medicine caused the adverse event, are spontaneous reports. Spontaneous reports of adverse events are considered to be adverse reactions for regulatory purposes. Therefore, you MUST report these adverse reactions to us if they are considered serious, even if you do not agree with the reporter's assessment of the cause. A report is only exempt if the reporter specifically states they believe the events to be unrelated or that a causal relationship can be excluded, and you agree with this assessment.
For spontaneous reports where you do not agree there is a reasonable possibility the suspected medicine caused the adverse event, record both your opinion and that of the reporter in your adverse reaction report and provide the criteria you used to make this judgement.
For regulatory purposes, spontaneous reports are considered to have implied causality. That is, where it is not clear whether a causal association is suspected, the medicine and the adverse event are presumed possibly related and therefore meet the definition of an adverse reaction, unless the reporter explicitly states otherwise.
Reports from consumers are a valuable source of information. You should encourage consumers to report adverse reactions, and to provide mechanisms by which they can do so.
Reports provided by consumers may often lack sufficient clinical detail required for assessing causality or seriousness and therefore you should exercise due diligence in ensuring that the reports are complete and are of high quality by accurately recording, clarifying, analysing and following up on any information received.
You should record all reports of adverse reactions from consumers in the same way you would record adverse reaction reports from any other source, and consider them when you assess overall safety.
You should obtain as much information as necessary to determine the nature and seriousness of the adverse reaction, and seek the reporter's voluntary informed consent to contact the treating doctor for medical confirmation of the adverse reaction and any additional relevant information.
If you cannot obtain consent, use your clinical judgement to assess how serious the reaction was from the available information and guide your subsequent handling of it. If you deem the reaction to be serious, you should make additional attempts as reasonable either to obtain the reporter's voluntary consent to contact the treating doctor, or ask the consumer to provide relevant medical documentation to allow you to assess causality.
When performing consumer follow-up, if the consumer is not comfortable providing you information, you may give them details for direct reporting of adverse reactions to the TGA.
Further follow-up or medical confirmation may not be necessary for an apparently non-serious adverse reaction.
You cannot disclose the identity of the consumer to us without their explicit consent. You should be familiar with your obligations in relation to the collection, use and disclosure of personal information of consumer reports in accordance with the Australian Privacy Principles and the Privacy Act 1988 and any relevant state or territory privacy legislation, and comply with these obligations.
Internet and digital media reports
Internet (including social) and digital media are important sources of reports of suspected adverse reactions.
You should regularly screen internet (such as websites, webpages, blogs, vlogs, social networks, internet forums, chat rooms and health portals) or digital media you own, fund, manage or are responsible for, for potential reports of suspected adverse reactions.
You should screen these media often enough to allow you to report valid adverse reactions within the reporting timeframes based on the date of the post.
You should also consider setting up mechanisms for collecting adverse reaction reports through your company website. You can do this by providing reporting forms or contact details for direct communication. You should encourage reports from all sources, including health professionals and consumers.
You do not need to review internet and digital media not sponsored by your company. However, if you become aware of an adverse experience on an internet or digital site that you do not sponsor, you should review the available information and attempt to follow up the report to determine if it must be reported to us.
Reports of adverse reactions obtained from internet or digital media are considered spontaneous and should be evaluated and followed up to determine whether they meet the requirements for reporting.
You MUST report all valid serious adverse reactions that occur in Australia from company-sponsored internet and digital media to us.
In relation to cases from the internet or digital media, the identifiability of the reporter refers to the existence of a real person.
You should make reasonable attempts to contact the reporter wherever possible to confirm the event and patient details and collect any additional information. For serious adverse reactions, you may post to a public forum/environment and request that the reporter contact you privately to provide more information.
If you do not know what country the primary source is from, use the country where the information was received.
You should keep a record of any adverse reaction reports for ongoing monitoring activities.
Reports from other non-medical sources
You should handle reports of suspected adverse reactions from non-medical sources - for example, the lay press or other media - as spontaneous reports, in accordance with the applicable timeframes. You should make reasonable attempt to follow these reports up to obtain the minimum information you need to make a valid adverse reaction report and determine the seriousness of the adverse reaction.
Solicited adverse event reports can arise from:
- clinical trials
- non-interventional post-registration studies
- other post marketing initiatives such as patient support programs, product familiarisation programs, market research programs and surveys.
For these organised data collection schemes, you should have a system in place to record and document complete and comprehensive case information on solicited adverse events. These adverse events should be systematically assessed to determine whether they are possibly related to the studied (or supplied) medicines.
You should assess causality for all solicited reports - for example, by applying the World Health Organisation Uppsala Monitoring Centre (WHO–UMC) causality assessment system (pdf,78kb) - to decide if it is a serious adverse reaction, and therefore must be reported to us.
Solicited adverse events that the reporting healthcare professional, the investigator, or you as the sponsor judge to have a possible causal relationship to the medicine are considered suspected adverse reactions and therefore subject to reporting requirements.
Adverse reaction reports from non-interventional studies with no systematic adverse reaction collection protocol (i.e. related to medicines other than studied or supplied medicine) are considered spontaneous or unsolicited.
Reports from international and local literature
The international and local scientific and medical literature are a significant source of information for monitoring the safety profile and benefit-risk balance of medicines, particularly in relation to the detection of new safety signals or emerging safety issues.
- undertake regular - no less than weekly - systematic literature review of widely used reference databases such as Medline, Excerpta Medica or Embase, including those that contain the largest number of articles about the medicine (all active ingredients) and its properties. You should use both trade name and active ingredient names of the medicines in your search strategy.
- monitor ongoing safety and efficacy studies, including non‐human teratogenicity and/or carcinogenicity studies for any relevant safety findings
- review and assess both worldwide and relevant local scientific and medical literature articles (including abstracts from meetings and draft manuscripts) to identify, report and record adverse reaction reports and significant safety issues.
Your search strategies should be documented and reproducible. Your procedures for monitoring literature should sufficiently capture up-to-date and comprehensive safety information associated with your medicines. Specific journals reviewed should be relevant to your product range and should capture any relevant articles not included in the systematic literature review.
Where you make a contractual arrangement with a person or organisation to search the literature, you should ensure that you have a detailed agreement that allows you to comply with your reporting obligations.
For adverse reactions associated with your medicine that are reported in scientific and medical literature, you should:
- identify which adverse reactions occurred in Australia
- identify a single patient
- review and assess the information in the publication
If the literature references multiple medicines, you should only consider those the author suggests have at least a possible causal relationship with the suspected adverse reaction.
You should contact the study's author to validate and follow up serious adverse events reported in the literature, specifically by obtaining patient identifiers and other information needed to assess causality.
When reporting Australian cases of serious adverse reaction identified from literature to us, include a copy of either:
- the published article, in English
- an English summary or translation, if the article was not published in English.
Authors are the primary sources for adverse reactions reported from literature. You should follow up and validate any serious adverse events that are reported in the literature by contacting the study's author to obtain further information where possible - specifically any information needed to assess causality and patient identifiers.
Do not submit to us any literature reports of adverse reactions that occur in a cohort of patients but do not identify a patient who experienced an adverse reaction (where reasonable attempts at obtaining this information have not been successful).
Reports from the TGA
Do not routinely report adverse reactions to your medicine that you learn of from us - for example, by interrogating the TGA Database of Adverse Event Notifications (DAEN) - as individual adverse reactions. We encourage you to consult the DAEN regularly to ensure your database is as complete as possible and include these in ongoing signal investigation activities, and reassessment of the benefit-risk profile, including PSUR/PBRERs if required.
However, if the adverse reaction reports could lead to a change in the benefit-risk balance of the medicine, then you MUST notify us of this change as a significant safety issue.
Pharmacovigilance requires that you not only collect information on adverse reactions and significant safety issues, but that you also critically analyse and evaluate these to monitor the on-going benefit-risk profile of your medicine.
Safety issues (or signals) may arise at any stage in the life cycle of a medicine, including the clinical development, manufacturing or in the post-market setting.
You may become aware of safety issues from one or multiple sources which may suggest a new risk or a change in the nature of a known risk associated with your medicine. Safety monitoring activities should include a review of cumulative cases, in order to allow for a comprehensive review of potential safety issues.
You should have a system in place for detecting and investigating such issues in a timely manner.
You should actively investigate signals you think may indicate a true causal association to determine whether they can be verified or refuted. You should also decide whether any regulatory action is warranted based on your assessment of the risk.
If you verify a signal that may change the benefit–risk balance of a medicine, you MUST report it to us as a significant safety issue together with any actions you propose to take, or justification for no further action.
Practical Aspects of Signal Detection in Pharmacovigilance: Report of CIOMS Working Group VIII is a useful resource on this.
Data quality control
The pharmacovigilance data you collect, collate and electronically store MUST be available from a single access point within Australia.
You should be familiar with, and discharge, your obligations in relation to the collection, use and disclosure of personal information in line with the Australian Privacy Principles under the Privacy Act 1988 and relevant state or territory privacy legislation.
Electronic data and paper reports of suspected adverse events should be stored and treated in the same way as other medical records, with appropriate confidentiality for information that identifies the patient, reporter or healthcare professional, and in accordance with privacy laws.
You should apply strict access controls to documents and databases to ensure pharmacovigilance data remains secure and confidential across the complete data path.
Implement procedures to ensure data is secure and remains uncorrupted when transferred within the company or between any third-party organisations.
Data transfer and validation
Have mechanisms in place to ensure that, when you transfer pharmacovigilance data within an organisation or between organisations, all data is fully received. Routine reconciliation of data (for example, adverse reaction cases received from post-registration initiatives) should be undertaken, preferably monthly to ensure the integrity of data transfer and therefore the accuracy of company‐held safety information.
All electronic data should have an audit trail. It should be possible to trace all data entry, modification and deletion, including:
- dates and sources of received data and changes
- dates and destinations of transmitted data.
Conformity of stored data with initial and follow-up reports should be verified by quality control procedures, which permit for the validation against the original data or images thereof. Source data or an image of the source data should be easily accessible.
Source paper documents may be transferred into an electronic copy (and vice versa). You should ensure documents are appropriately validated such that all of the information present in the original format is captured and in a legible manner. We do not require that both electronic and hardcopy versions of the original are retained. Source paper documents can be subsequently destroyed provided a confirmed true and complete electronic copy (with back-up) exists.
Data should be unbiased and unfiltered. Avoid inferences and imputations when recording the information, and include the primary source's verbatim text, or an accurate translation, wherever possible.
Adverse events should be coded by a consistent reproducible method, preferably using the appropriate Lowest Level Terms from the Medical Dictionary for Regulatory Activities (MedDRA).
Staff entering data should be trained in the use of the adverse event terminology, and you should confirm their proficiency. You should verify data is being entered correctly through quality assurance auditing, either systematically or by regular random evaluation.
Records of source documents can be stored either in paper or in electronic form. The storage medium selected should be suitable for the required period of retention i.e. will remain easily accessible and readable over time. Furthermore, consider security and access controls, due to the confidential nature of the data, and ease of retrieval, as you need to provide requested information to us within the specified timeframes.
Commercially confidential information
Adverse reaction reports and other documents submitted to us may contain information that is commercially confidential.
Please refer to Treatment of information provided to the TGA to see how we manage your information.
You should have internal processes to identify and manage duplicate cases at data entry and when generating aggregated reports.
Source data - such as letters, emails, records of telephone calls that include details of an event and images of the source data - should be easily accessible. This allows initial and follow-up reports to be verified against the original data. This verification should be part of your quality-control procedures.