The TGA Pharmacovigilance Inspection Pilot Program: 2015-2016
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Firsthand overview of the TGA's Pharmacovigilance Inspection programme from the perspective of both the TGA and companies that have participated in the 'Pilot Inspection Programme'.
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The TGA Pharmacovigilance Inspection Pilot Program: 2015-2016
- 1. The TGA Pharmacovigilance Inspection Pilot Program 2015-2016 Mounir Mina Manager, Pharmacist, Complementary Medicine and Medicine Problem Team Signal Investigation Unit Pharmacovigilance and Special Access Branch ARCS Congress 11-12 May 2016
- 2. Overview • Background to the pilot • The sponsors involved • The inspection process • What was Inspected • The Findings • Common Deficiencies • Feedback • Next steps The TGA Pharmacovigilance Inspection Pilot Program 1
- 3. Background to the pilot • March 2015: TGA pilot program announcement, undertaking voluntary pharmacovigilance inspections in Australia. • May 2015: TGA dissemination of pilot information to industry for expressions of interest. • October 2015 - May 2016: 10 volunteer companies took part in the pilot inspection program The TGA Pharmacovigilance Inspection Pilot Program 2
- 4. The sponsors involved • Aim: To inspect a variety of sponsors in order to understand the broad variations in pharmacovigilance systems currently in place in Australia. • Volunteers included: – Large multinational companies – Australian owned and based companies – Smaller biotechnology companies – Generic companies – Complementary /herbal medicine companies The TGA Pharmacovigilance Inspection Pilot Program 3
- 5. The Products Involved • Registered Medicines • Listed Medicines • OTC • Complementary • Vaccines • Innovative medicines • Generic medicines • Topical products • Oral products • Nasal delivery products • IV products • Medicines with RMPs/PSURS • Medicines without RMPs/PSURs The TGA Pharmacovigilance Inspection Pilot Program 4
- 6. The Inspection Process Pre-Inspection • Approximately one month prior to inspection a draft agenda and initial document requests for the inspection were sent to company. • Several documents were requested to be provided prior to inspection to allow for inspector preparation. The TGA Pharmacovigilance Inspection Pilot Program 5
- 7. The Inspection Process Inspection • First day of the inspection: Opening meeting conducted to discuss the inspection process and the background to the inspections and to allow for a company overview of the systems in place. • Throughout the inspection: – Interview sessions were conducted to gain an understanding in of the pharmacovigilance processes undertaken by the company. – Followed by document requests to verify/provide evidence of these company processes. – In between interview sessions inspectors would review documents. • Final day of the inspection: a verbal overview of any deficiencies identified during the inspection was given to the company in the form of a closing meeting. The TGA Pharmacovigilance Inspection Pilot Program 6
- 8. The Inspection Process The TGA Pharmacovigilance Inspection Pilot Program • Opening meeting conducted to discuss the inspection process and the background to the inspections and to allow for a company overview of the systems in place First day of the inspection • Interview sessions were conducted to gain an understanding in of the pharmacovigilance processes undertaken by the company • Followed by document requests to verify/provide evidence of these company processes • In between interview sessions inspectors would review documents Throughout the inspection • a verbal overview of any deficiencies identified during the inspection was given to the company in the form of a closing meeting Final day of the inspection 7
- 9. The Inspection Process Post-Inspection • Four weeks after last document was received by the inspector, a formal inspection report was provided to the company. • The company then had four weeks to respond to the findings – formal Corrective and Preventative Action (CAPA) plan (template provided) – carry out any actions required • The proposed CAPAs were assessed by the inspectors. • Any changes or additions deemed necessary were negotiated. • Once agreed by both parties, the inspection was closed out. The TGA Pharmacovigilance Inspection Pilot Program 8
- 10. What was inspected? 1. ADR collection and processing 2. Processes for ongoing monitoring of safety 3. PSUR production and coordination 4. Maintenance of Reference Safety Information 5. The Australian person responsible for pharmacovigilance The TGA Pharmacovigilance Inspection Pilot Program 9
- 11. Relevant Legislation During the inspection compliance with currently applicable Australian pharmacovigilance regulations and guidelines was assessed: • Therapeutic Goods Regulations 1990 (Regulation 15A) • Therapeutic Goods Act 1989 (Section 28 (5e), 29A and 29AA) • Australian requirements and recommendations for pharmacovigilance responsibilities of sponsors of medicines (Version 1.3, June 2014) • The Conditions‐ standard and specific applying to registered or listed therapeutic goods The TGA Pharmacovigilance Inspection Pilot Program 10
- 12. Grading of deficiencies Critical Deficiency • A deficiency in pharmacovigilance practice or process that has, or may significantly adversely affect the safety or well-being of patients or that poses a potential risk to public health or that represents a serious violation of applicable legislation and guidelines. • Also occurs when it is observed that the sponsor has engaged in fraud, misrepresentation or falsification of data. Major Deficiency • A deficiency in pharmacovigilance practice or process that could potentially adversely affect the safety or well-being of patients or that could pose a potential risk to public health or that represents a significant violation of applicable legislation and guidelines. The TGA Pharmacovigilance Inspection Pilot Program 11
- 13. Grading of deficiencies Other Deficiency • A deficiency in pharmacovigilance practices or processes that cannot be classified as either critical or major, but indicates a departure from good pharmacovigilance practice. Includes deficiencies that would not be expected to adversely affect the safety or well-being of patients • A deficiency may be “other” either because it is judged as minor, or because there is insufficient information to classify it as major or critical. The TGA Pharmacovigilance Inspection Pilot Program 12
- 14. The Findings Number of findings: • Critical findings - 0 • Major findings - 25 • Other findings - 18 0 5 10 15 20 25 30 Findings Critical Major Other The TGA Pharmacovigilance Inspection Pilot Program 13
- 15. The Findings 0 5 10 15 20 AE case collection and processing Maintenance of RSI Significant safety issues communication Submission of PSURs Ongoing monitoring processes Deficiencies in procedural documentation Australian PV person roles and responsibilities Critical Major Other The TGA Pharmacovigilance Inspection Pilot Program 14
- 16. 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 The TGA Pharmacovigilance Inspection Pilot Program 15
- 17. Some common deficiencies identified AE case collection and processing • Lack of due diligence in identification of AEs and special situation reports – Care should always be taken to determine if an enquiry involves an adverse event for collection and reporting purposes. – Often relating to MI enquiry cases • 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 sponsor effectively; include provisions for reconciliation, training. The TGA Pharmacovigilance Inspection Pilot Program 16
- 18. 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 issue • Delays in updating product CMI documents – CMI document needs to be changed within two weeks of the date of the changed PI (Conditions of Registration) The TGA Pharmacovigilance Inspection Pilot Program 17
- 19. 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: issues from review and analysis of AR reports occurring outside Australia action taken by a foreign regulatory agency identification of new risk factors that may impact on the safety or benefit-risk assessment of the product The TGA Pharmacovigilance Inspection Pilot Program 18
- 20. Some common deficiencies identified Submission of PSURs • Schedule of PSUR submissions – The intent of the Conditions of Registration is that PSURs cover periods aligning with the Australian approval date i.e. first PSUR should cover a 6 or 12 month period from the date of approval – It is a requirement that sponsors request the condition to be varied if they are going to deviate from this – In several instances, PSURs submission timelines had been adjusted to align with international birth dates without any formal approval to vary the conditions of registration – The TGA is currently reviewing this requirement The TGA Pharmacovigilance Inspection Pilot Program 19
- 21. TGA Feedback • Pilot was an exercise to offer education and guidance to sponsors – Foundation of TGA’s Regulatory Compliance Framework • Examples of excellent pharmacovigilance processes in place – Organised AR case collection and processing procedures – Comprehensive ongoing monitoring processes – Sufficient training of staff • Commitment by companies to improve pharmacovigilance systems The TGA Pharmacovigilance Inspection Pilot Program 20
- 22. Sponsor Feedback • Participating companies were asked to fill out a questionnaire – Regarding their experience of the inspection – Will help shape any future program in Australia • Responses on a whole have been positive: – helpful in identification of areas in pharmacovigilance system where improvement was needed • time-consuming and challenges with time-zone differences. The TGA Pharmacovigilance Inspection Pilot Program 21
- 23. Next Steps To be determined… • Feasibility of a national pharmacovigilance inspection program • Any decisions and the implementation of an Australian program will involve an industry consultative process. • PV inspections will continue to use a risk-based approach that might include both random and targeted inspections • High level of sponsor compliance to good pharmacovigilance systems required due to increased importance of post-market monitoring The TGA Pharmacovigilance Inspection Pilot Program 22
- 24. Summary • Background to the pilot • Characteristics of sponsors who participated • The Inspection Process • What was inspected • The findings • Common deficiencies • Feedback • Next steps The TGA Pharmacovigilance Inspection Pilot Program 23
- 25. The TGA Pharmacovigilance Inspection Pilot Program 24
Editor's Notes
- March 2015: The TGA announced it would be undertaking a pilot program undertaking voluntary pharmacovigilance Inspections in Australia. May 2015: the TGA disseminated information regarding the pilot to industry bodies in order to gain expressions of interest for pharmaceutical companies wanting to take part in the pilot. October 2015 - May 2016: 10 volunteer companies took part in the pilot inspection program
- Characteristics of the sponsors who participated Volunteers were chosen to encompass both small companies and multinational companies, sponsors of complementary, over the counter and prescription medicines.
- Opening Meeting: introductions, confirm purpose of inspection, discuss expectations, plan & methodology Inspection is a combination of staff interviews and document reviews Open dialogue from the beginning and ongoing verbal feedback throughout the inspection. Studied specific examples to demonstrate the system Verbal feedback of general findings at Closing Meeting
- Opening Meeting: introductions, confirm purpose of inspection, discuss expectations, plan & methodology Inspection is a combination of staff interviews and document reviews Open dialogue from the beginning and ongoing verbal feedback throughout the inspection. Studied specific examples to demonstrate the system Verbal feedback of general findings at Closing Meeting
- The collection and processing of spontaneous ADR reports (including sources of data, the role of medical information/product quality complaints, case receipt, case entry and quality assurance, follow-up, archiving and expedited reporting. As well as contracts with vendors/partners.) The processes used to evaluate the ongoing risk-benefit profile of products (including ongoing monitoring activities: signal detection and evaluation, the management of risk management plans and the reporting of significant safety issues.) PSUR production and coordination (Systems used to produce and submit PSURs to the TGA, including discussion of information included in the reports.) Maintenance of Reference Safety Information (Overview of the management of variation requests (both sponsor and TGA initiated), process for the updating of Company Core Safety Information, PI and CMIs following the identification of new safety information and the implementation of PIs and CMIs following approval.) The roles and responsibilities of the Australian person responsible for pharmacovigilance Background quality systems including standard operating procedures and training were reviewed for each aspect of the pharmacovigilance system analysed.
- Any non-compliances were deemed as deficiencies
- Three types of deficiencies
- Note: Classification of a deficiency is based on the assessed risk level and may vary depending on the nature of products.
- Total number of findings for each type of deficiency identified in the Pilot Program
- Findings broken down further… (starting from bottom up) AE case collection and processing- 19 findings (13 major, 6 other) Maintenance of Reference Safety Information- 9 findings (8 major, 1 other) Communication of significant safety issues- 2 findings (2 major) Submission of PSURs- 5 findings (5 other) Ongoing monitoring processes- 3 findings (2 major, 1 other) Deficiencies in procedural documentation- 3 findings (3 other) The roles and responsibilities of the Australian person responsible for pharmacovigilance- 2 findings (2 other)
- 15 days ADR reporting – mandatory as per PV guidelines (and Regulations) Non-conservative - it is important that seriousness assessments are an independent process to medical evaluation, causality and validity of the case and be based on the adverse event alone. Where outcomes or treatment information is not available, a conservative approach should always be taken.
- Care should always be taken to determine if an enquiry relating to a company product involves an adverse event that has occurred in a patient being treated with the product in question for collection and reporting purposes. Often relating to Medical Information enquiry cases where AEs had not been identified or where reasonable steps to determine if an AE or special situation event, including off-label use had not occurred. Contracts must ensure all safety information (including AEs and special situation reports) is collected and communicated to the sponsor effectively, that reconciliation of cases is described and there is provision for training in pharmacovigilance requirements. The company should have certainty that all safety information is being collected from such sources of data.
- Significant delays in updating the Australian PI with newly identified safety information on a product are not acceptable and may pose a safety risk to the Australian public. TGA expectation is a variation will be submitted within 6 months from identification of any safety related issue in order to ensure that the product information is kept up to date with the current scientific knowledge “There is a continuing obligation to ensure that at all times the CMI complies with the statutory requirements; including consistency with the PI. If the related CMI document needs to be changed as a consequence of the change to the approved PI it must be lodged with the TGA within two weeks of the date of the changed PI.” (Conditions of registration for Australian medicinal products).
- Significant safety issues may include issues identified following review and analysis of reports of ARs that have occurred in a country other than Australia, action taken by a foreign regulatory agency or identification of new risk factors that may impact on the safety or benefit-risk assessment of the product.
- The conditions of registration for Australian medicinal products state that for PSUR submissions reports are to be provided annually, the annual submission may be made up of two PSURS each covering six months. The first report must be submitted to TGA no later than 15 calendar months after the date of the medicines approval letter. The subsequent reports must be submitted no less frequently than annually from the date of the first submitted report until the period covered by such reports is not less than three years from the date of this approval letter. In several instances, PSURs had been submitted to the TGA as required however timeframes have been adjusted to align with international birth dates without any formal approval to vary the conditions of registration. Note: TGA is planning to amend the condition to align PSUR submission with IBDs
- This was a learning exercise for both the TGA and the companies involved. This pilot was an example of education, which forms the foundation for our regulatory work. Unfortunately the report does not include details of the positive points observed during the inspection. We have also seen excellent examples of processes in place… On the whole, we have seen a commitment by companies to improve pharmacovigilance systems.
- Questionnaire responses are still being collected and analysed and will be used to assess the pilot and any future program in Australia. Companies stated that they found the inspection helpful in identification of areas of the pharmacovigilance system where further improvement was needed and generally the process benefited the company in improving pharmacovigilance systems as a whole. It was noted that companies did find the inspection, including lead up and follow on, to be time-consuming and that there were challenges in involving required international colleagues due to time differences.
- Currently the pilot is still being completed, with CAPAs still being finalised and data collected. The TGA will look at the feasibility of making this into a national program – any decision to do so and implementation of an Australian program will take time and will involve an industry consultative process.
- Finally, Thank all those sponsors who volunteered and took part in the pilot. Thank you for your attention.