Pharmacovigilance Office of Product Review Dr Jane Cook Office Head Office of Product Review, Monitoring & Compliance Group, TGA 7/10/2011
Overview of talk Overview Post TGA 21 and OPR New Guidelines Key Points How does OPR manage adverse events Safety Signal Detection Investigation Response Questions? 2
Post TGA21 Separation into pre and post market areas - Market Authorisation Group (MAG) and Monitoring and Compliance Group (MCG) MCG includes: Office of Product Review Office of Manufacturing Quality Office of Laboratory Scientific Services Office of Product Review: Devices and medicines adverse event databases Devices and medicines signal detection and investigation RMP evaluation and monitoring Recalls Advertising
Current Reviews Internal: Transparency review Professor Pearce Advertising Review Review of recall procedures External: Horvath Review of Vaccine Safety
Australian Guideline for Pharmacovigilance Responsibilities of Sponsors of Medicines Result of consultation process with industry over several years. Aligns requirements of all sponsors of medicines Differentiates requirements between registered and listed medicines based on risk Comes into effect on 1 October 2011 Until then dual documentation will remain on TGA website and will be removed post 1 October 2011
Key Elements Requirement to submit all serious adverse events within 15 days of becoming aware. While guideline refers to serious expected and unexpected adverse events both must be reported. Need to follow up these reports to provide as much information as possible. A serious adverse event involves hospitalisation, is life threatening, results in death or ongoing impairment/disability. Results in a congenital abnormality or congenital defect, is a medically important event of reaction (usually results in a visit to a healthcare professional). Maintain a record of all adverse events and be able to supply these on request. Notify the TGA within 72 hours of any major safety issue (outlined in guideline).
Specific Issues Periodic Safety Update Reports Requirement for registered medicines as part of conditions of registration Sponsors of listed medicines are required to monitor the safety of their product, can be provided as a case line listing if requested by the TGA. Review of Literature This is encouraged for listed medicines and is not mandatory at this stage. Albeit this could be seen as an element of effective monitoring of the safety of a product. Use of MedDRA terminology Sponsors are requested to provide reports using MedDRA terminology. This facilitates efficient and timely entry into the database. Will allow automatic entry into database once E2B capability in place.
Qualified person responsible for Pharmacovigilance The Qualified Person for Pharmacovigilance should: 1. Have experience in all aspects of pharmacovigilance and if not medically qualified (do not have a medical degree) should report to, or have access to a medically qualified person. 2. Be resident within Australia. The Qualified Person for Pharmacovigilance is responsible for ensuring: 1. The establishment and maintenance of a system which ensures that information about all suspected adverse reactions which are reported to the sponsor are collected and collated and where serious reported to the TGA. 2. The preparation, where the medicinal product is registered, of Periodic Safety Update Reports (PSURs). 3. Monitoring the safety of the sponsor s products once they are on the market and for the duration of the products lifetime. 4.Responding to requests from the TGA for information relating to the effectiveness and safety of the the product 5. The name of the Qualified Person for Pharmacovigilance should be provided to the TGA. 6. The position of Qualified Person for Pharmacovigilance can be held either within the company or contracted out. If the position is contracted out it is important to ensure a clear contract outlining the roles and responsibilities held by that individual is implemented.
Why spontaneous Adverse Event monitoring is undertaken Differences between listed and registered medicines In the case of registered medicines: not all AEs, precautions and contra-indications will be identified in clinical trials undertaken in the pre market phase of a medicine due to relatively small numbers and exclusion criteria The content of the PI/CMI to a large degree largely relies on spontaneous adverse drug reporting to detect safety related events occurring in the post marketing period where the product is used in larger population groups Detects rare AE as population group larger and event therefore more likely to occur In the case of listed medicines Safety profile usually known through established use Can detect clusters that relate to manufacturing quality Long term population effects e.g. potential increased risk of cardiovascular disease (calcium and Vitamin E) 9
Goals of adverse event reporting Complement other sources of information Provide a sample of AEs occurring, not a registry of AEs Most interested in serious AEs hospitalisation or Dr visit/death/disability or sequelae/certain conditions Analysis indicates whether further investigation required
Problems with spontaneous adverse event reporting Occurrence of adverse events research has shown 10% of people presenting to GP have experienced an adverse event in the previous 6 months, of these 7% resulted in hospitalisation (Adverse drug events in general practice patients in Australia - Graeme C Miller et al, Medical Journal of Australia) Significant cause of morbidity Under-reporting international studies have shown maybe as great as 94% (Under-Reporting of Adverse Drug Reactions: A Systematic Review Lorna Hazell1 and Saad A.W. Shakir, Drug Safety 2006)
Volume TGA receives about 12,000 ADR reports a year, in 2010-2011 received around 14,000 Less than a third of these would be considered potentially serious AEs Small percentage contain insufficient information to identify a unique event and are rejected
Who reports 2001-2010 7000 6000 5000 4000 3000 GPs Hospitals Companies Others 2000 1000 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Reporting of Adverse Events Mandatory reporting of serious adverse events to the TGA by sponsors Requirement to monitor safety of a product by a sponsor Not mandatory for health professionals or consumers to report AEs to medicines Some states and territories (6 of 8) have legislation requiring mandatory reporting of Adverse Events Following Immunisation (AEFIs) to S&T Health Departments - these are then reported to the TGA
How reports are received Blue card (health professionals, consumers and sponsors) CIOMS form (international format) from sponsors Letters/emails (health professionals and consumers) Web reporting via TGA website sponsors, consumers & health professionals Telephone via Adverse Medicine Event Line (NPS) consumers
TGA s ADRS Database Scanned reports (Blue cards, faxes, emails) Web reports and further information Lodgement Triage Coding MO Review Posting Acknowledgment Structured Database (Oracle) Interrogation may include case line listings, PRR summaries, crosstab reports, analysis
Assessment of Reports Triage Officer determines if serious, non-serious, CIOMS form and assigns to relevant draw on ebs All done electronically CIOMS contain MedDRA terms (coding terms) entered by clerical staff Reports of non-serious AEs entered by clerical staff e.g. nausea, injection site reaction Reports containing serious AEs are assessed and entered by medical officers
Entry onto database Reports containing AEs are assessed and the reactions coded according to an international coding convention (MedDRA) Most reports contain multiple AEs which are individually entered onto the database for each report OPR has guidelines on coding conventions and the way an AE will be entered e.g. liver injury requires specific information (range of LFT tests are 2xULN) before the coding term can be used
Causality Assessment Based on WHO classification: Certain Probable Possible Unclear Where the AE is assessed as being unclear it is unlikely or not associated with the drug & the report is General Listed, that is the report is accessible but not used in consideration of a safety signal
Follow up information Need sufficient detail to determine causality requires information on concomitant medication, medical history, concurrent illness, time to onset of AE Need to identify confounders and determine temporal association Process for repeat FI requests implemented where a serious unexpected AE or AE of Special interest. Request for information on these is requested on three occasions before no further follow up is undertaken
Signal Detection 3 components Signal identification ideally a mix of proactive and reactive activities to identify harmful effects of medicines, through review of spontaneous ADR reports from healthcare providers, industry and consumers, including the application of data mining tools review of international vigilance activities and reports review of published literature review of post approval studies
PRR Undertaken on a 4 weekly cycle Evaluation by professional staff Thresholds vary between new and older medicines Identifies potential signals further investigated by OPR Assessment and evaluation of a particular AE and medicine can be provided to the Advisory Committee on the Safety of Medicines (ACSOM) for advice
Calculating the PRR REACTION Reaction OF of INTEREST a interest Drug of interest DRUG OF INTEREST All other reactions c d ALL OTHER REACTIONS c d PRR = a/(a+c) b/(b+d) = a(b+d) / b(a+c) Need to have > 3 cases where PRR > 3 a ALL OTHER DRUGS All other drugs b b
Data Mining example AMITRIPTYLINE HYDROCHLORIDE All cases Sole suspected PRR Chest pain 19 14 0.6 Heart rate increased 11 11 1.6 Palpitations 212 29 1.4 Pulmonary embolism Serotonin syndrome 14 13 2.9 123 01 19.7 Tremor 133 119 2.7
Signal Detection 3 components continued Signal assessment elucidation of the nature, magnitude and health significance of safety signals and their impact on the overall benefit-risk of the product Application of appropriate analytical skills in pharmacovigilance, epidemiology, biostatistics, risk assessment and clinical practice Utilisation of international data, expert analysis and advice (ASCOM and/or ad hoc Expert Panels) Liaison with other regulators Informs the regulatory response
Risk-Benefit Assessment The TGA evaluates the risks of individual therapeutic goods and the ingredients used in them, for the population they are intended for; The healthcare provider (the medical practitioner) evaluates risks for the individual patient; and The consumer evaluates risks in terms of their personal values, based on information provided about the product.
Risk-Benefit Assessment Benefit evaluation: Epidemiology and natural history of the target disease(s) Purpose of treatment (cure, prophylaxis, etc.) Summary of efficacy and general toleration data compared with: other medical treatments surgical treatment or other intervention no treatment
Risk-Benefit Assessment Risk Evaluation Background Weight of evidence Analyses Consideration of explanation of problem Predictability, preventability, reversibility Issues related to alternate therapies Review of complete safety profile (other AEs)
Signal Detection 3 components continued Signal response (regulatory response) actions taken to mitigate the risks Alteration of product labelling Communication of important benefit-risk information MSU articles, other publications, interaction with NPS educational activities eg RADAR or Australian Prescriber Product removal suspension, cancellation, recall Decision maker will be in OPR
Pharmacy only medicine for nausea Long established medicine Early 2003 6 reports of hallucination, psychosis, blurred vision in the space of 6 working days On 6 th day (Friday) teleconference with sponsor held, samples obtained for analysis; expert advice was sought - recommended recall 2 further reports following Monday delirium in one passenger necessitating diversion of plane Monday afternoon consumer level recall initiated Presentations consistent with toxicity of active ingredient Assay subsequently showed 10 fold variation in hyoscine levels consequence of manufacturing deficiencies
Questions?