Be (pharmaco)vigilant! Important changes in the

Be (pharmaco)vigilant! Important changes in the
PV-legislation BeAPP pharma.be, Brussels Nov 23 12

Does a safe environment guaranty safety?
The Pharmacovigilance legislation after 2012 Does a safe environment guaranty safety? M.Sangeleer, MD Medical Affairs Manager, Eli Lilly Benelux Lecturer at the Free University of Brussels (ULB) BeAPP pharma.be, Brussels Nov 23 12

09/12/10: BeAPP Cultural event: Johan Braeckman: « Evolutionism & creationism » BeAPP pharma.be, Brussels Nov 23 12

There is always variation There are more organisms that are born that the amount which can survive (struggle for life) The one who survive are the fitests There is natural + sexual selection The process is repetitive from generation to generation (positive feed-back) At the end, adaptations arise BeAPP pharma.be, Brussels Nov 23 12

Pharmacovigilance evolution
Thalidomide Computerised system Internationalisation Proactive approach EU reg 1235:risk based regulation Ad hoc surveillance& risk management plans Involvement of all staleholders Improvement collaboration Risk Management systems/plans Embryo of EU worksharing Signal detection Worldwide databases MAH Collaboration between states (WHO,…) Collection of AR 2000 2012 BeAPP pharma.be, Brussels Nov 23 12

Objectives and Key measures of the new PV law
Reinforcement and modernisation of current system (more rapid decisions): Additional Monitoring - ↗signal detection Pro-active Risk Management Plan for all products = CONDITION for registration Harmonisation of decisions and work sharing: reduction of redundancy Harmonisation of post –marketing, non- interventional studies for safety and efficacy (PAES/PASS) Reinforce the link between safety evaluations and regulatory actions Reinforcement of patient protection &engagement - increase the communication and transparency Direct reporting to the Agencies (web portals) Information Available on the webportal of Agencies Introduction of impact of drugs on the environment BeAPP pharma.be, Brussels Nov 23 12

BeAPP pharma.be, Brussels Nov 23 12
More actors ICH CIOMS EC NCAs EMA HCPs MAHs Quality? (faster, better, perceived severity, final outcomes, impact on QOL, motivation?)- Role of Advocacy groups Patients: Awareness and engagement – reporting, acting on information BeAPP pharma.be, Brussels Nov 23 12

MAH operational pharmacovigilance tasks
Adverse event reporting Expedited reporting of ICSR Periodic reporting Labels updates (4.8) Proactive surveillance Risk management plan Risk assessment Risk minimisation plan Risk minimisation activities Studies: PASS- PAES Labels updates (4.4) BeAPP pharmabe, Brussels Nov 23 12

Legislation main changes for the MAH
AE expedited reporting «OLD» LEGISLATION «NEW» LEGISLATION Patient reporting: no legal basis Electronic reporting:no legal basis Definition of ADR: « under normal conditions » SERIOUS ADRs to EV- 15 days Patient reporting: legal basis Electronic reporting legal basis Definition of ADR: also in case of off label use, misuse,… NON SERIOUS ADRs to EV: 90 days No expectedness 9 BeAPP pharma.be, Brussels Nov 23 12

Consequences for MAH Which AE? Which AE? Volume Electronic transmission (E2B)- signal detection Different timelines Identification and « medical validation » of patient reports Assessing causality? Perform follow-up with patients? What about precription medicines? Effect on treating HCP, if more administration is required? Duplicate reports? Resources, Training, adaptations of rules and procedures BeAPP pharma.be, Brussels Nov 23 12

Legislation main changes for the MAH
Periodic reporting «OLD» LEGISLATION «NEW» LEGISLATION PSUR PSURs for all MAs PSUR Worksharing on voluntary basis NO central filing Periodic Benefit Risk Evaluation Report submission +cycle in function of risks Worksharing: legal basis Central repository BeAPP pharma.be, Brussels Nov 23 12 12

MORE EXPLICIT EVALUATIONS OF B/R
On the grounds: more pragmatic approach Ad hoc periodicity according to risk close link with RMP Scientific evaluation > data Tabulations> line listings Cumulative data starting +new information of this period Summaries of studies incl in unauthorised indications Extensive chapters on signal detection; benefit/risk evaluation Therefore , MAH is granted 10 extra days for 6 or 12 monthly reports after the datalock point 30 days for reports of a longer frequency after the datalock point BeAPP pharma.be, Brussels Nov 23 12

PSUR-PBRER: worksharing & simplifications
On the format Unique List of Union Reference Dates & frequencies: EURD list Single assessment (variation, suspension, revocation all over EU) Repository for submission of PSURs (Common European Submission Platform) No PSUR anymore for generics and « well established use » medications Less work thanks to worksharing? BeAPP pharma.be, Brussels Nov 23 12

Legislation main changes
Transparency «OLD» LEGISLATION «NEW» LEGISLATION Eudrapharm not used- few transparency Transparency: SPC,PIL to be published EudraPharm (EVPMD) to be populated and up to date SPC,PIL and summary of SPC (lay public) +PAR (summary for the public, condition of MA) BeAPP pharma.be, Brussels Nov 23 12 16

Scope and timelines Timelines broken down into steps: July 2, 2012 : MAH submit information on ALL medicinal products in EVPDM 2 July 2012 : variations/suspensions/revocations within 15 calendar days >1 Jan 2015 : MAH can submit using the new standard (IDMP ) >31 Dec 2015: All product information must be resubmitted according to ID MP. ISO IDMP standards, a set of internationally harmonised specifications for the unique identification of medicines BeAPP pharma.be, Brussels Nov 23 12

Consequences for MAH They state reading the label might harm the eyes Resources to hold timelines Questions from patients? Volume of events ? Risk of induced effects? BeAPP pharma.be, Brussels Nov 23 12

Legislation main changes for the MAH:
Proactive PV «OLD» LEGISLATION «NEW» LEGISLATION RMP if required RMP not evaluated PASS/PAES: no legal basis Additional monitoring: no legal basis RMP for all applications (proportionate to risks) Legal basis for evaluation of the RMP-RMAactivities PASS/PAES legal basis Additional monitoring: legal basis 20 BeAPP pharma.be, Brussels Nov 23 12

Consequences of RMP provisions
Compulsory assessement of impact: studies, surveys,... cost + burden for HCP Public summary on the European Web Portal Readibility for lay reader Linked with list of products with additional monitoring MEDIA ATTENTION BeAPP pharma.be, Brussels Nov 23 12 21 21

Media consequences Media trained Resources –Crisis and communication management BeAPP pharma.be, Brussels Nov 23 12

RMP in Belgium: Introduction of timelines…..
PAES-PASS: Written approval/denial given by belgian authorities/PRAC after 60 days MAH has 30 days to express its wish to react to PASS/PAES requirement Need to report on the progress reports ( timing to be agreed) Risk minimisation activities local approval process: 2 months if no Medicines Commission 4 months if Medicines Commission and external expert Clock stops and timelines for MAH too Enough staff needed : reactivity BeAPP pharma.be, Brussels Nov 23 12

Legislation main changes for the MAH :
Organisation «OLD» LEGISLATION «NEW» LEGISLATION Detailled Description Pharmacovigilance System Renewal submission 6 month before expiration of validity Signal detection: no legal basis POST MA inspections Free of charges Pharmacovigilance system master file Renewal submission 9 month before expiration of validity Signal detection: legal basis (at least once monthly) PRE and POST MA inspections and more focus on sharing information between CA Fees to be payed at EU and natonial level BeAPP pharma.be, Brussels Nov 23 12 24

Contributions in Belgium??
Funding for PV resources/staffing at the AFMPS/FAGG: 58€/registration-All products 0,0118€/sold pack / National-MRP products 650€/DSUR for IMPs program law published 06/04/12 (entry into force 17/04/12) Circulars RD 16 jul 2012 on DSURs payments: (effective 18 oct 12) BeAPP pharma.be, Brussels Nov 23 12

Conclusions: Does a safe environnement guaranty safety?
Maximising benefit, minimising risk of medicines, so focus on benefit/risk More pragmatic , risk-based approach Focus on transparency Volume of events – balanced by more efficient signal detection- duplicates? Effect of increased patients/media interactions ? New formats & cycles Processes & workload: will increase at first Simplification/harmonisation: reduce duplicate work at long term Timelines: more dynamic system reactivity will be needed (on demand PASS, PBRER, RMAs) Fees?: will they put staffing at risk? (SME) BeAPP pharma.be, Brussels Nov 23 12

Basic principle remains unchanged It is still no rocket science:… There is a human factor ….There is always variation… BeAPP pharma.be, Brussels Nov 23 12

Conditions for a safer PV?:
Learn to cope with « variation »= Mitigating the « Human Factor » Awareness & education of all stakeholders including patients, patients associations and HCP- (manage duplicates) Resources to hold timelines at both MAH/NCA/…PRAC? Sufficient skilled users of signal detection tools Multidisciplinary teams (RMPs) Learn to cope with media BeAPP pharma.be, Brussels Nov 23 12

Probably,… a fitest pharmacovigilance,…..adapted to the variation Maybe we shouldn’t disturb the medical community for such a minor manifestation? BeAPP pharma.be, Brussels Nov 23 12

Bart De Greef, pharma.be Katleen Vandeweyer, Biocodex Benelux
Does a safe legal environment guaranty safety? An industry perspective. Impact on SME’s Bart De Greef, pharma.be Katleen Vandeweyer, Biocodex Benelux

Stability pact 1/04/2017

Stability pact

Major challenges for SMEs
SMEs oriented towards Rx, OTC medicines, MD, food, cosmetics…. Less complaints We take our responsibility! Requirements on Update EUDRAPharm: (European medicines database) Submitting product data =>mandatory from 2 July 2012 EXtended EudraVigilance Medicinal Product Dictionary (XEVMPD) specific tool for SME foreseen in EVWEB PSMF (audits/inspections, patients support programs, subcontracts,…) RMP-RMA-PASS/PAES Patients/public management=>who will manage media reactions?

IMPACT FOR SMEs Guidance from NCAs - has there been enough and oriented for SMEs? Complying with the Electronic transmission As an SME, I cannot afford to spend tens of thousands of Euro on a PV database and a gateway: EVWeb: one off-training course, free tool Contract it out: Stakeholder roles and responsibilities =>importance of well defined contract (detailed description of delegated tasks, data exchange, agreed timelines, definitions,…) MAH retains full responsibility MAH need to ensure an effective quality system =>Evaluate risk/benefit Impact on competitiveness and business profit

Costs for a SME? Workload…will it be reduced or augmented?
Software tools and technology costs? MEdDRA terms is free to use in EVWEB for Small & micro-sized but not for medium sized Human Resources and training needs – what impact will these have on SME business? Insourcing vs. outsourcing? Fees: EU vs Belgium as NCA Special fee for inspections ?

Thank you for your attention

Before and after 1235: legislation review
Pharma.be/BEAPP Thierry ROISIN – 23/11/2012

Plan New legal framework as regards pharmacovigilance of medicinal products for human use GVPs Legislation : main changes PRAC Union-wide assessment of phvig issues Strengthened transparency and communication Impact for SME

New legal framework as regards pharmacovigilance of medicinal products for human use
Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15 December 2010 amending, as regards Pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products (specific provisions on centrally authorised products and EMA tasks) Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use (nationally authorised products and common provisions) Adopted by both Council and EU parliament and publication on 31 Dec 2010 Most of the provisions came into force in July 2012

Legislation : main changes
«OLD» LEGISLATION «NEW» LEGISLATION DDPS RMP if required Definition of ADR: under normal conditions SERIOUS ADRs to EV Patient reporting: no legal basis PSURs for all MAs PSUR WS on voluntary basis Pharmacovigilance system master file RMP for all applications (proportionate to risks) Definition of ADR: also in case of off label use, misuse,… SERIOUS and NON SERIOUS ADRs to EV Patient reporting: legal basis PSURs submission in function of risks PSUR WS: legal basis

Legislation : main changes
«OLD» LEGISLATION «NEW» LEGISLATION Renewal submission 6 month before expiration of validity Signal detection: no legal basis PASS: no legal basis PAES: no legal basis Additional monitoring: no legal basis PhVWP Renewal submission 9 month before expiration of validity Signal detection: legal basis PASS: legal basis PAES: legal basis Additional monitoring: legal basis PRAC New urgent union procedure More transparency …

New scientific committee within the Agency
PRAC New scientific committee within the Agency Pharmacovigilance Risk Assessment Committee - Reg art. 56(1)(aa) Mandate – Reg. art. 61a §6 “ All the aspects of the risk management of medicines … having due regard to the therapeutic effect of the medicinal product …”: Recommendations to CHMP and CMD(h) on Phvig issues Role in agreement and monitoring of RMPs Prioritisation and review of emerging safety signals Review of PSUR assessments Evaluation of protocols and results of PASS Decision on products under additional monitoring …

Appointed by each Member State:
PRAC - composition Appointed by each Member State: Appointed by the European Commission following a public call for expressions of interest: 1 member + alternate 27 + EEA countries non voting members 1 patient organisations rep + alternate 1 healthcare professionals rep + alternate 6 members to ensure relevant expertise available

PRAC – activities

Interaction with CHMP and CMD(h)
PRAC Interaction with CHMP and CMD(h) PRAC provides recommendations to CHMP and CMD(h) – Reg. art. 56(1)(aa) CHMP / CMD(h) shall rely on the scientific assessment and recommendations of PRAC for the fulfilment of its phvig tasks, including the approval of risk management systems and monitoring their effectiveness – Reg. art. 5(2) / Dir. art. 27 Explanation on the scientific grounds for differences if opinion / agreement is not in accordance with PRAC recommendation

Decision-making process
PRAC Decision-making process PSUR PASS Union procedures (art. 31, 107i) PRAC recommendation: regulatory action CHMP (at least 1 CAP) CMD(h) (no CAP) Opinion = maint., var., susp., revoc. Position = maint., var., susp., revoc. If consensus: agreement NO consensus: position majority COMMISSION MS: adopt measures Decision modifying MA (CAP) Decision addressed to MS MAH: submit variation

Union-wide assessment of phvig issues
Two procedures for Union-wide post- authorisation assessment of PhVig issues Dir. art. 107i-l = urgent union procedure (revision current art. 107) Dir. art. 31 in other cases Dir. art. 36 deleted PRAC should always give its recommendation when the reason for taking action is based on PhVig data (regardless of whether centralised or non centralised procedures, urgent or normal procedure) – Dir. Cons (25a) Procedures laid down in Directive 2001/83/EC to be followed, also for centrally authorised products – Reg. cons. (9a)

Union-wide assessment of phvig issues
Urgent Union Procedure Triggers - Dir. art. 107i Urgent action necessary, as a result of the evaluation of phvig data. MS / Commission: considers suspending or revoking a MA; considers prohibiting the supply of a medicinal product; considers refusing the renewal of a MA; is informed by the MAH that, on the basis of safety concerns, he has interrupted the placing on the market of a medicinal product or withdrawn a MA, or that he intends to do so; considers that new contraindications, a reduction in the recommended dose, or a restriction to the indications is necessary;

Strengthened transparency and communication
European and national (safety) web portals National medicines web-portal – Dir. art. 106: summaries of RMP (national MA) list of medicinal products referred to in Article 23 of Reg. information on the different ways for reporting suspected ADRs, including the web-based structured forms (Reg. art. 25) .. European medicines web-portal – Reg. art. 26: agendas and minutes from each meeting of the CHMP and PRAC and the CMD(h) as regards phvig activities summary of the RMP (CEP authorised products) Assessment conclusions, recommendations, opinions, agreements and decisions (for PSURs, urgent union procedure, PASS) taken by CHMP, PRAC, Commission, NCA and CMD(h) …

Strengthened transparency and communication

Impact for SME all the provisions of the phv legal framework (obligations for MAHs) are also applicable for SME Consequently, each MA must have a pharmacovigilance system possibility to subcontract certain activities to another organisation or person (cfr I.C.1.5. module I GVP) 55

Impact for SME completeness and accuracy of the PSMF
In case of subcontract, the MA retains full responsibility for the completeness and accuracy of the PSMF The ultimate responsibility for the fulfilment of all phv tasks and responsibilities and the quality and integrity of the phv system always remains with the MAH The MAH shall ensure that an effective quality system is applied in relation to the subcontracted tasks 56

Thank You

e-mail welcome@fagg-afmps.be
Contact Agence fédérale des médicaments et des produits de santé - afmps Place Victor Horta 40/40 1060 Bruxelles tél fax

New pharmacovigilance legislation:
How to smoothen the transition period? EU and Belgian bridging measures Goethals Sophie, famhp, vigilance department 23 November 2012

In this presentation … What has been achieved? What to come? How to smoothen the transition period? EU level Belgium Specific topics where smooth implementation is necessary Additional monitoring and implementation of ▼ and standardised statements in SmPC and leaflet Post-authorisation safety studies

Background 2010 Legislation: key achievements / challenges Clear tasks and responsibilities for all parties Improved EU decision-making procedures Proactive and proportionate risk management Higher quality of safety data Stronger link between safety assessments and regulatory action Strengthened transparency, communication and patient involvement

What has been achieved. What to come
What has been achieved? What to come? How to smoothen the transition period? EU level Dir. 2001/83 amended by Dir. 2010/84 Reg. N° 726/2004 amended by Reg. 1235/2010 EC implementing regulation (EU) No 520/2012 Good pharmacoVigilance Practice: 1. PhV + QS, 2. PSMF, 5. RMS, 6. ICSR, 7. PSUR, 8. PASS, 9. Signals Q&A documents, EURD list, list for signal management worksharing, templates, guidance documents on renewals Implement in business processes: new procedure for requesting and assessing RMP, new procedures related to PSURs / PASS for CAPs, signal detection, new referral procedure, … ICT: art. 57 electronic submission of product information 1. What has been achieved?

What has been achieved? What to come? How to smoothen the transition period? EU level Dir. 2001/83 amended by Dir. 2012/26 Reg. N° 726/2004 amended by Reg. N° 1027/2012 1. Fees Regulation 2. Delegated act on efficacy studies (“may” provision) 3. EC Reports on readability of product information 1. GVP: 2nd wave modules 2. Scientific guidance for PAES Update Q&A documents, EURD list, list for signal management worksharing, templates, Phvig training, Implement in business processes: EMA literature monitoring, PSUR single assessment, programme for monitoring of effectiveness RMM ICT: validation of received art. 57 information, PSUR repository, EudraVigilance enhancement, .. 2. What to come? Oct 2013 June 2013 2014 ? Jan 2013 Beyond 2013

What has been achieved? What to come? How to smoothen the transition period? EU level 2. What to come? GVP second wave modules Module III – Inspections Publication Dec 2012 Module IV – Pharmacovigilance Audits Module XV - Safety communication Module X - Additional monitoring Publication Q1/Q2 2013 Module XI - Public participation Public consultation Q2 2013 Module XII - Continuous pharmacovigilance Public consultation Q1 2013 Module XIII - Incident management Under discussion Module XIV - International collaboration Module XVI - Risk minimisation measures Public consultation Dec 2012 / Q1 2013

What has been achieved? What to come? How to smoothen the transition period? EU level 2. What to come? The 2012 legislation: Pharmacovigilance II Background: ‘Stress test’ of the 2010 legislation detected certain areas where legislation could be further strengthened 25 October 2012 new amending legislation adopted: Directive 2012/26/EU of 25 October 2012 amending Directive 2001/83/EC as regards pharmacovigilance; Applicable from 28 October 2013 Regulation No 1027/2012 of 25 October 2012 amending Regulation No 726/2004 as regards pharmacovigilance; Applicable from 4 Dec 2012 / 5 Jun 2013 Filling gaps: Clarification of scope of ‘referral’ procedures and events that will lead to the initiation of the procedures (especially Urgent Union procedure) Modified Union interest procedure will allow Member States to take provisional measures Voluntary withdrawal – MAH to state reasons Increased transparency: List of products subject to additional monitoring

NCAs requirements for PSUR submission during the transitional period
What has been achieved? What to come? How to smoothen the transition period? EU level 3. How to smoothen the transition period? EC’s Q&A on transitional arrangements EMA/ NCA Q&A on practical transitional measures – November updated awaited CMDh Q&A List of nationally approved substances for which PSURs are required for generic medicinal products during the transitional period Reporting requirements of ICSRs applicable to MAHs during the interim period NCAs requirements for PSUR submission during the transitional period To come: Q&A on EURD list?

What has been achieved? What to come? How to smoothen the transition period? Belgium 1. Achievements: programmawet van 29 maart 2012: herziening retributies wet dd. 3 augustus 2012 tot wijziging van de wet van 25 maart 1964 op de geneesmiddelen, gepubliceerd op 11 september 2012 in Belgisch Staatsblad Safety board, patient reporting, .. 2. Expected soon: ontwerp KB tot wijziging KB 14 dec > advies Raad van State circulaire -> consultatie met industrie 20 nov 2012 3. Transition period: MAHs can apply European new legislation, guidelines, transitional measures, although new directive has not been fully transposed into national law [ a combination of ‘old’ and ‘new’ legislation shall not be accepted.

What has been achieved? What to come? How to smoothen the transition period? Belgium Patient reporting in Belgium

What has been achieved? What to come? How to smoothen the transition period? Belgium Patient reporting in EU

Additional monitoring and implementation of ▼ and standardised statements in SmPC and leaflet
1. Background [Reg 726/2004 whereas clause 17] … some medicinal products are authorised subject to additional monitoring. This includes all medicinal products with a new active substance and biological medicinal products, including biosimilars, which are priorities for pharmacovigilance. Competent authorities may also require additional monitoring for specific medicinal products that are subject to the obligation to conduct a post-authorisation safety study or to conditions or restrictions with regard to the safe and effective use of the medicinal product. Medicinal products subject to additional monitoring should be identified as such by a black symbol and an appropriate standardised explanatory sentence in the summary of product characteristics and in the package leaflet. A publicly available list of medicinal products subject to additional monitoring should be kept up to date by the European Medicines Agency ……

New regulation 1027/2012 amending Reg. 726/2004:
Additional monitoring and implementation of ▼ and standardised statements in SmPC and leaflet 1. Background Mandatory scope [Article 23 (1) of the Regulation] Two categories of medicinal products shall be automatically included in the list : a) “Medicinal products authorised in the Union that contain a new active substance which, on 1 January 2011, was not contained in any medicinal product authorised in the Union”; b) “Any biological medicinal product not covered by point (a) that was authorised after 1 January 2011”. New regulation 1027/2012 amending Reg. 726/2004: extends mandatory scope products subject to specific conditions will be included under mandatory scope cfr. red text on next slide

Optional scope [Article 23 (2) of the Regulation]
Additional monitoring and implementation of ▼ and standardised statements in SmPC and leaflet 1. Background Optional scope [Article 23 (2) of the Regulation] There is also the possibility to include in the list medicinal products subject to conditions, not falling under the mandatory scope. This can be done at the request of the EC or the NCA, as appropriate, following consultation with the PRAC. conditions or restrictions with regard to the safe and effective use [Reg Art 9(4)(c), Dir Art 21a(d)]; to take certain measures for ensuring the safe use of the medicinal product to be included in the risk management system [Reg Art 9(4)(ca), Dir Art 21a(a)]; to conduct post-authorisation safety studies (PASS) / post-authorisation efficacy study (PAES) [Reg Art 9(4)(cb) (cc) and Art 10(a), Dir Art 21a(b)(f) and Art 22a]; stricter reporting of ADRs [Reg Art 9(4)(cb), Dir Art 21a(c)]; conditional approval, i.e. authorisation is granted subject to certain specific obligations (e.g. the performance of further studies), to be reviewed annually by EMA [Reg Art 14(7)]; marketing authorisation under exceptional circumstances [REG Art 14(8), DIR Art 22]; the existence of an adequate pharmacovigilance system [DIR Art 21a(e)]. when a competent authority imposes an obligation on a marketing authorisation holder to operate a risk management system for a medicinal product approved before 2 July 2012 [REG Art 21(2)] or 21 July 2012 [DIR Art 104a].

2. Creating and maintaining the list of product under additional monitoring EMA and NCAs will be responsible for (automatic) inclusion of substances on the list products will normally remain on the list for 5 years for mandatory scope products removal will be tied to the renewal procedure for optional scope products removal will be tied to fulfillment of conditions List to be published on EMA + NCA web portals: Q1 2013? → publication of list to be aligned with EC’s selection of black symbol (2 July 2013) ? Will MAHs know in advance of publication of their products? ? Will national schemes co-exist?

The SmPC and the package leaflet shall include the statement “This medicinal product is subject to additional monitoring”. That statement shall be preceded by a black symbol which shall be selected by the Commission following a recommendation of the PRAC by 2 July 2013*[Reg. 2012/xx to be published], and shall be followed by an appropriate standardised explanatory sentence [Art. 11 and 59 of Directive 2001/83/EC and Art. 23(5) of Regulation (EC) No 726/2004]. Selection of black symbol:  PRAC recommendation (Oct 2012): inverted black triangle (▼) Commission Decision (before 2 July 2013): Q ? EC public consultation on phasing-in launched 21 Nov till 10 Jan 2013 [ Standardised statements for SmPC and leaflet: CHMP endorsement of the QRD template / translation / .. Implementation plan Publication by March / April 2013 (once black symbol is selected by EC)

Wording of standardised statements for additional monitoring SmPC Package Leaflet

Wording of standardised statements - encouragement ADR reporting for all medicinal products SmPC (end of section 4.8) Package Leaflet (end of section 4.)

Non-interventional post-authorisation safety studies (PASS)
Scope of dir. 2001/83, chapter 4 “supervision of PASS”  a post-authorisation study should be classified as a PASS, when the study includes one of the following objectives [GVP, VIII.B.3]: to quantify potential or identified risks to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (eg pregnant women, specific age groups, patients with renal or hepatic impairment) to provide evidence about the absence of a risk to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (eg indications, dosage, co-medication, medication errors) to measure the effectiveness of a risk minimisation activity.  PASS initiated, managed or financed by a MAH non-interventional  If a PASS is a clinical trial: dir. 2001/20/EC and Vol. 10 of Eudralex shall be followed

… voluntarily or pursuant to obligations non-interventional PASS; initiated, managed or financed by MAH applicable legislation Pursuant to an obligation imposed by a competent authority: condition to the MA [Dir. art. 21a and art. 22a / Reg. art. 10 and art. 10a] exceptional circumstances MA [Dir. Art. 22 / Reg. art. 14, §8] Dir. 2001/83 art. 107 m: cfr. infra Dir. 2001/83 art. 107 n-q: regulatory supervision by competent authority (protocol and final study report) Implementing Reg. 520/2012 , art format of protocol, abstract and final study report Voluntarily: studies required in RMP any other PASS  no promotional character, payments to HCP restricted to compensation of time and expenses incurred protocol and progress reports: may be requested by MS in which the study is conducted final report to MS where study conducted,  monitor data and impact on BR GVP: legal requirements applicable to studies conducted pursuant to obligation are recommended, where appropriate, to studies conducted voluntarily [GPV, VIII.B.1]

Management of study (PASS with MAH involvement ) Imposed as an obligation Conducted voluntarily no promotional character payment to HCP restricted … [Dir. Art. 107m] Legal obligation Monitor data generated in the study with consideration to benefit-risk of product concerned [Dir. Art. 107m] Use of standard formats for protocol and study report [Reg. 520/2012] Template for protocol [ Legal obligation (10 Jan 2013) GVP recommendation Prior protocol approval [Dir. Art. 107n-q] regulatory supervision and assessment of study results [Dir. Art. 107n-q] Legal obligation: PRAC supervision National supervision for PASS imposed after authorisation by 1 MS, and conducted only in that MS (if in RMP) Registration in EU PAS register Quality system

Reporting of study information (PASS with MAH involvement ) Imposed as an obligation Conducted voluntarily Any new information which might influence the evaluation of B/R balance to be reported to NCAs of MS where the product is authorised [Dir. Art. 107m] Legal obligation Protocol to be submitted upon request to NCA of MS where study is conducted [Dir. Art. 107m + art. 107 n (3)] cfr. Annex to GVP module VIII Progress reports to be submitted upon request to NCA of MS where study is conducted [Dir. Art. 107m] Final report to be sent to the NCA of the MS where the study is conducted, within 12 months of the end of data collection [Dir. Art. 107m] Reporting of suspected ADRs in studies with primary data collection with 15 days (serious ADRs) or 90 days (non-serious ADRs) [See interim and final arrangements in GVP Module VI, C.4 ] Final manuscript of article to be transmitted to NCAs of MS where product is authorised within 15 days after acceptance [GVP] recommended

Annex to GVP module VIII: MS' requirements for transmission of information on non-interventional PASS with PRAC oversight → Belgium: famhp, vigilance department, May and recommended -> inzoomen op wat lidstaten willen, vnl voor protocol en progress / final reports

Annex to GVP module VIII –Member States' requirements for transmission of information on non-interventional PASS, conducted voluntarily May and recommended -> inzoomen op wat lidstaten willen, vnl voor protocol en progress / final reports

famhp requirements for transmission of information on non-interventional PASS with famhp oversight Protocol (CD-rom), progress reports and final study report incl. abstract to be submitted to famhp, R&D May and recommended -> inzoomen op wat lidstaten willen, vnl voor protocol en progress / final reports

EU PAS Register EU electronic register of post-authorisation studies [GVP, VIII.B.4] repository of all non-interventional PAS conducted in the EU, irrespective of the source of funding and status of investigators (MAH, academia, regulatory or public health authorities, …) will be developed as upgrade of ENCePP study registry transitional period: ENCePP study registry to be used supports EMA to fulfil its obligation to make public protocols and results of PASS imposed as an obligation [Reg. art. 26 (h)] For imposed studies: will not replace regulatory submission For studies conducted voluntarily: accepted by MS (and Belgium) as means for submitting study information (Annex 1 of GVP Module VIII) Reg. Art. 26 (h) protocols and public abstracts of results of the post-authorisation safety studies referred to in Articles 107n and 107p of Directive 2001/83/EC

EU PAS Register Reg. Art. 26 (h) protocols and public abstracts of results of the post-authorisation safety studies referred to in Articles 107n and 107p of Directive 2001/83/EC

ICSR reporting requirements for MAH during interim period
Serious EU ICSRs [

ICSR reporting requirements for MAH during interim period
Serious non-EU ICSRs and non-serious EU ICSRs

PSURs: List of Union reference dates and PSUR frequency
Comprehensive list of active substances and combinations of active substances, authorised in more than one member state, for which PSURs shall be submitted as determined Harmonisation of DLPs and frequency of submission of PSUR for products subject to different marketing authorisations –> enable single assessment based on substances EURD list used to control PSUR submission for generics; grounds for requesting PSURs for generics: concerns based on phvig data / lack of data Agreed by the CHMP/CMDh after consultation of the PRAC [DIR Article 107c (paragraphs 4 and 7), and REG Article 26(g)] Publication on EMA website on 1 October 2012: Legally binding as of April 2013 [DIR Article 107c (7)]. Until then, follow currently agreed PSUR submission frequency and DLP. The list overrules the “routine” submission schedule and any condition laid down in the MA of the products concerned.

PSURs: List of Union reference dates and PSUR frequency

PSURs: overview Old legislation New legislation
Transitional provisions? Situation since July 2012 PSUR requirement: for all MAs Derogation: no routine PSUR for generics, WEU, THMP, homeopathic registration No derogation for routine PSURs applicable PSUR frequency: routine PSUR cycle for most MAs Risk based PSUR cycle, through comprehensive URD List Condition to MA Routine PSUR cycle List URD legally binding 6 months after publication (publication Oct > April 2013) July 2012 Timelines for submission: Within 60 days > DLP Within 70 or 90 days > DLP (GVP) Irrespective of old / new PSUR format: 70 or 90 days > DLP PSUR submission: to MS / EMA (centralised) [Annex 6.2 of Vol. 9 A] E-submission to EMA PSUR repository From 12 months after repository is operational PSUR submission to MS / EMA (centralised) 15/05/2012 FAMHP/Vigilance/gss

PSUR: overview Old legislation New legislation
Transitional provisions? Situation since July 2012 Assessment: centralised procedure informal PSUR work sharing MRP Purely national procedures Clear legal basis for: Assessment of single centrally authorised medicinal product Single EU assessment Purely national procedure No Assessment of centralised products following new procedure (PRAC) Informal PSUR work sharing Mutual Recognition Procedures Content: Focus on presentation of safety data Structured risk evaluation Benefit evaluation Integrated benefit risk evaluation module Transitional period of 6 months in Implementing Measures - draft Between July 2012 and January 2013 old and new formats will co-exist 15/05/2012 FAMHP/Vigilance/gss

PRAC phasing-in For complete new MAAs for CAPs starting as of December 2012: 1 Status-quo with current situation 2 X = open to all PRAC delegates, the selection criteria being the best possible scientific expertise and, where possible, from a different MS compared to the CHMP Rapporteur (A) and CHMP Co-Rapporteur (B) For new MAAs for CAPs under CHMP review or procedures starting in Aug / Sept / Oct / Nov 2012: PRAC Rapp/Co-Rapp stays aligned with CHMP Rapp/Co-Rapp Member States For generics, the PRAC Rap is from the same delegation as the CHMP Rap of the reference medicinal product PRAC: all issues pass through PRAC Limitations in pre-clinical toxicology and phase 1-3 clinical trials •Lack of experience on adverse effects •Exposure in small numbers of people •Short duration •Unlikely to detect ADRs: •Less frequent than 1/1500 •With long latency •Lack of experience in special patient groups •Elderly, children, pregnancy, multiple disease, polypharmacy

PRAC phasing-in For “Legacy” centrally authorized medicines (= authorised and on-going), while awaiting formal reappointment from Q onwards and if PRAC needs to be consulted: PRAC Rapp/Co-Rapp stays aligned with CHMP Rapp/Co-Rapp Member States Referrals (only non-CAPs involved): Co-Rapporteur: Member State triggering the referral. Rapporteur: open to all other Member States, and criterion of best possible and available expertise to be taken into account. Referrals (mixture of CAPs and non-CAPs): Rapporteur: PRAC Rapporteur for the CAP(s). Co-Rapporteur: Member State triggering the referral (whereby also the involvement of the PRAC Co-Rapporteur for the CAP(s) needs to be considered). PRAC: all issues pass through PRAC Limitations in pre-clinical toxicology and phase 1-3 clinical trials •Lack of experience on adverse effects •Exposure in small numbers of people •Short duration •Unlikely to detect ADRs: •Less frequent than 1/1500 •With long latency •Lack of experience in special patient groups •Elderly, children, pregnancy, multiple disease, polypharmacy

Back up slides

Contact Federal agency for medicines and health products - famhp Place Victor Horta 40/40 1060 Bruxelles tel fax

How to qualify for quality in the near future and be audit ready
Nele Matthijs

How to qualify for quality in the near future and be audit ready
What do we expect from industry in relation to safety reporting of drugs. How to be prepared for an inspection ? How to ensure the effectiveness and correctness of our pharmacovigilance system

A journey of quality

Journey of PhV Legislation
Regulation & Directive Increasing level of detail Implementing Measure Good Vigilance Practices

GVP : Good Pharmacovigilance Practice
Apply to marketing-authorisation holders, the Agency and medicines regulatory authorities in EU Member States Cover both centrally authorised and nationally authorised medicines Comprise 16 modules, each of which covers one major process in pharmacovigilance

Just a flavour of the changes
Pharmacovigilance System Master File (PSMF) Expedited reporting (new requirements!) PSUR and the new format (to submit or not to submit?) Risk Management Plans required for all products- effectiveness of risk minimization activities needs to be assessed Inspections and the role of the Supervisory Authority Inspections of contractors

Quality – Quality systems  GVP Module I Inspections  GVP Module III
How to qualify for quality in the near future and be audit ready Quality – Quality systems  GVP Module I Inspections  GVP Module III Audits  GVP Module IV Written for a broad public : basic principles  specific details take out what you need / implement where needed Risk-based approach

Module I: Pharmacovigilance systems and their quality systems
-Legal requirement for quality systems introduced by Directive 2010/84/EU and Regulation (EU) No 1235/2010 The minimum requirements of these quality systems are set out in the Commission Implementing Regulation (EU) No 520/2012 on the Performance of Pharmacovigilance Activities Consistent with the general principles of the ISO 9000 Standards on good quality management practices, Guidance for the establishment and maintenance of quality assured pharmacovigilance systems for MAHs, CAs of MSs and the EMA

Quality cycle: planning, QC, QA, improvements Responsibilities of the MAH regarding EU-QPPV - EU-QPPV qualification – ensure he has acquired adequate theoretical and practical knowledge for the performance of PhV activities - EU-QPPV role and responsibilities : oversight over the functioning of the system in all relevant aspects, including its quality system - Each PhV system can have only one QPPV. 1 QPPV can work for more than 1 MAH for shared of separate PhV systems or act as QPPV for more than 1 PhV system of the same MAH, provided that the QPPV is able to fulfil all obligations.

Training Facilities and equipment Compliance management Record management Documentation of the quality system Monitoring performance & effectiveness of the PV system & its quality system

Why and how perform quality control
To ensure that all PhV processes are controlled : Case translation : in which time period, correct translate? Does MAH check when sending a case to global, there is always an acknowledgment of receipt sent to local? Does the MAH verify the timelines of compliance for transmission of ICSRs, PSURs,..? Check internal timelines for reporting SPC updates RMP compliance and effectiveness : - monitoring compliance and effectiveness of RMP and RMA - is the compliance monitoring performed at regular basis Are SOPs up-to-date ?

Why and how perform quality control
In many cases, error is made to implement QC only at the end of the implementation of a whole of processes  RISK that an error is made at basic level (f.e. : translation (local level), Meddra coding (global level)) A MAH may have a perfect functioning system on signal detection and PSUR evaluation, but when an error occurs at first level or case processing  big impact on the whole process Start QC at each stage as soon possible and for each individual sub process.

There is broad support for quality systems for pharmacovigilance, but also some concern over the burden to implement them, in particular for smaller marketing authorisation holders or for medicinal products with low risks to patients and public health.  every risk, low or high, is a risk  quality is needed  implement step by step  risk-based planning

Module III : Pharmacovigilance inspections
Module provides transparency to the inspection process and gives MAH and NCA guidance on the expectations during inspections Public consultation finished - Final Module III publication in December 2012

• New concepts in addition to the elements included in vol. 9A: Supervisory Authority PSMF location • Pre-authorization inspections • Information sharing on inspections planned and conducted • Communication of non-compliance

• Contact person for pharmacovigilance issues at national level : National nominated persons should report to the QPPV. Reporting in this context relates to pharmacovigilance tasks and responsibilities and not necessarily to line management - Availability 24/24 and 7/7 - Employed in Belgium Dispose the appropriate qualifications for the performance his responsibilities as also have the linguistic properties to talk with his interlocutors in the national language of his choice Circular 520/544/545 related to PhV local QPPV  1 new circular related to the local contact person

Module IV : Audits - Publication December 2012
Provides clear guidance on planning and conducting audits which will help promote standards and harmonisation throughout the European network. - Welcome the development of the risk-based approach requested in the Implementing Measures

Module IV : Audits INDEPENDENCE ( legal requirement, see auditing standards) TRAINING AND QUALIFICATIONS ( In line with Module I- I.B.7 ) EVALUATION OF AUDIT WORK (quality assessment of the auditors work is a professional requirement)

Why Perform Pharmacovigilance System Audits?
Module IV : Audits Why Perform Pharmacovigilance System Audits? To ensure compliance with company procedures and local / global regulatory requirements To ensure company regulatory obligations / commitments are met Increasing Regulatory Inspections –Internal detection of risk is essential To identify process / quality deficiencies and improvements MOST IMPORTANTLY, PHARMACOVIGILANCE AUDITS ACT AS ONE MECHANISM TO ENSURE THE SAFETY OF PATIENTS IS MAINTAINED

Types of Pharmacovigilance System Audits
Module IV : Audits Types of Pharmacovigilance System Audits Global Pharmacovigilance (QPPV – Global Systems and processes) Company Affiliates (i.e., Country Office, Local Operating Company, Marketing Company) Marketing (Licensing) Partners

Global Pharmacovigilance System Audits
Module IV : Audits Global Pharmacovigilance System Audits QPPV : qualification, availability, 24u/7, back-up procedures, training Focus on central Pharmacovigilance processes –Safety Case Processing –Expedited Reporting –Signal Detection / Safety Surveillance –Aggregate Reports (e.g., PSUR, etc.) –Literature Search –Office of the QPPV responsibilities

Global Pharmacovigilance System Audits
Assess compliance with company procedures and global Pharmacovigilance regulations Sample of products across therapeutic areas and a defined timeframe (vehicle to assess the system / process) Systems approach focused on processes

Company Affiliates Primary focus on local contact person (qualifications// job description, availability – back up procedure, training,.. local Pharmacovigilance responsibilities Assess compliance with local and global company procedures and regulatory requirements (as applicable) Evaluate the flow of safety information (from all applicable sources) from initial receipt to reporting to external parties : AE collection Involves many functional groups that impact the Pharmacovigilance system -Pharmacovigilance Sales -Regulatory Affairs Product Quality -Medical/Clinical Information Technology -Marketing Medical Information Not just an audit of local affiliate but also of global processes to support local affiliates

Company Affiliates Reconciliation with Product Quality Complaint handling and medical questions Local quality systems (including compliance monitoring) Regulatory functions (e.g., Aggregate reports submission, Labeling, Regulatory Authority query management, etc.) Contracts and Agreements (Marketing Partners, CROs, consultancy, etc.) : e.g. to verify if resources are sufficient for the required activities as described in the contract (internal/external audit) Promotional Material

Company Affiliates Standard Operating Procedures (SOPs) Training
Verification of respect of RMAs and their tracking Management of PSP (contracts, collect and management of AEs/ARs,…) Document Retention / Archive Electronic systems used to support the Pharmacovigilance system Business Continuity / Disaster Recovery

Marketing (Licensing) Partner Audits
Includes in-licensed and out-licensed product agreements Focus on compliance with Marketing Partner agreement –Ensure Pharmacovigilance roles and responsibilities are defined and performed –Ensure appropriate exchange of safety information Assess compliance with local and global company procedures and regulatory requirements (as applicable) May be performed independently by company, as a joint audit between companies, or by an agreed upon consultant

Global Pharmacovigilance Inspection Trends
Past Present Site based Product safety data specific Independence between Regulatory Authorities globally Limited frequency Mostly FDA Inspections Systems based with safety and /or compliance data as a potential trigger Focused on Pharmacovigilance system –across sites / operations / products Scope includes linkages and relationships across the company to perform Pharmacovigilance responsibilities Increased collaboration across regulatory authorities globally

Examples of deficiencies related to the quality system
Lack of quality control in key processes (local as global processes) - lack in FU of cases : has it been performed, how, when,.. - no control on translation, reporting from sales reps - literature reporting : has it been performed, when, how Missing or incomplete SOPs in key processes - back-up procedure, - quality control, - business continuity) No or incomplete job descriptions - reflection of Management - defines necessary skills and training

Examples of deficiencies related to the quality system
Deficiency on the performance of audits (local affiliates/ global activities) - risk-based approach - audits of contract companies - skills auditors Lack in interaction between departments - reconciliation of PhV data (medical and quality department) - regulatory affairs : update SPCs, variations, PSURs, implementation of referrals (MRP/DCP/NAT) - interaction global / local : awareness of safety issues / RMP / … Lack in responsibilities of the QPPV - incomplete overview - insufficient back-up system

5 Steps You Can Take to Help Ensure Quality in the near future
1 Define the impact of the new legislation on the processes and process documents / database / … 2 Update processes / documents (SOPs, guidance, working instructions, …) / tools as appropriate  risk-based planning 3 Get the concerned people trained in time 4 Perform quality control on the : - training - the performance on PhV activities - the correctness/efficacy of the PhV activity -5 Performance of audits on global and local activities

A journey of improved quality

The Belgian consensus on Risk Minimisation Activities
New process M.L.Bouffioux - 23th November 2012

Reminder Legal basis: Article 6 § 1stocties of the law of 25th March 1964 on medicines, as amended by the law of 3rd August 2012 (MB 11th September 2012) Some marketing authorisations are granted on condition that the MA holder develops additional risk minimization activities (RMA). Justified if essential for the safe and effective use of the medicinal product The need for such possible measures belongs to the risk management plan (RMP) now mandatory in marketing authorization applications. These RMA activities often require that the marketing of the medicinal product is accompanied by materials, educational or informative programmes or services for healthcare professionals and / or patients.

Prior Approval Educational and informational materials, programmes or services shall be subject to the prior approval of the Minister or his delegate (CEO of the FAMHP) - National MAs, DCP, MRP - Centralized marketing authorization - Modification of the RMA without modification of the terms of the marketing authorizations - Variation of the MA-> with new RMA conditions -> with modification of the RMA conditions Implementation should be no later than at the time of the marketing of the medicinal product or, if conditions change, within the time allowed if specified in the MA.

Approval procedure Working group with industry -> consensus on a proposal for an approval procedure which should be implemented in a modification of the Royal Decree of 14th December 2006 (future Article 65 quater)

Introduction of the approval application
Contents of the file: - Standard application form (already available on the FAMHP website) - 2 copies - Copy of the MA and any annexes (conditions – key elements of RMA) - SPC, leaflet (latest approved version) - Copy and / or complete description of the material, programme or service - Copy of the part of the RMP justifying the implementation of the RMA - Terms of implementation – circulation plan - Possibly, in the case of modification, termination terms or removal procedures of the old material

Application validation
Within 15 days the FAMHP checks if the file is complete If OK -> acknowledgment If not OK -> the MA holder is informed by the FAMHP -> 15 days to complete the file If file not complete after 15 days -> application unacceptable -> MA holder informed

Application assessment
Within 45 days from the date of validation of the file the FAMHP sends the applicant the results of its assessment. The FAMHP can consult the Commission for medicines for human use (cfr current circular 532 bis to be adapted) . The delay is then extended to 90 days. In exceptional circumstances (e.g. to consult an external expert) the delay period may be extended by 15 additional days The MAH is informed.

Assessed items Compliance with the SPC, leaflet, approved items within the MA fulfilled conditions – key elements Necessary, sufficient, appropriate materials, programmes or services to promote the safe and effective use of medicine: - evaluation of the appropriate design and form, of the content, of rules of implementation (adapted to the health care system in place in Belgium) Lack of promotional aspects. Information should be clearly focused on the risk minimisation goals

Conclusions of the assessment
1. Positive conclusions -> intention of RMA approval 2. Unfavourable provisional advice Reasons: - Objections to envisaged materials, programmes or services - Request to modify the form and / or content and / or procedures for implementation - Request to complete the file Timing suspended: - The holder responds within a maximum of 60 days - If> 60 days: request denied Conclusions: - intention of (modified )RMA approval - Refusal (to reintroduce an application)

Introduction of the final material
Within 60 days of the letter of intended approval the applicant shall submit a copy of: - The final presentation of the approved version - Translations with a declaration of conformity of these translations

Approval decision Within 5 days of receipt of the final material and translations the FAMHP - Verifies that the documents are complete - Sends the letter with the decision of approval

Implementation at the time of the marketing
- maximum 90 days after approval - if imposed after MA - if modified unless the Minister determines a different timing The MA holder is responsible for the implementation of the RMA and its consistency with the approved dossier

References Circular 532 bis will be adapted to the new procedure
-> Usage humain->Médicaments -> Bon Usage -> Additional RMA Menselijk gebruik -> Geneesmiddelen -> Goed gebruik -> Additional RMA Circular 532 bis will be adapted to the new procedure Standard Form of application EMA Guideline on good pharmacovigilance practices – Module V – Risk management systems (V.B11.2 ) – further extensive guidance on additional risk minimisation measures will be provided in Module XVI 10 focus points published on the FAMHP website Guidelines for the content and form published on the FAMHP website Need for on-going dialogue during the procedure between the file manager and the applicant, in particular to avoid having to appear several times before the medicines commission Keep in mind the goal of public health

Does CT-3 provide more operational transparency
Does CT-3 provide more operational transparency ? An industry perspective J. Van Rampelbergh Head of Clinical Study Unit sanofi-aventis Belgium Info session: Be (pharmaco) Vigilant - 23/11/2012

What’ s CT-3?

Circular letter 586 - National Application of the Revised CT-3 guidance
To implement revised CT-3 in national practice Replaces Circular Letter 460 and provides short term improvement and updated information on management of adverse event/reaction reports arising from Clinical Trials Aim Brightening Clearing Clarifying

Definitions (1) IMP NIMP In the scope but…..
“an untoward or unintended response to a non-IMP which does not result from a possible interaction with an IMP is, by definition, NOT A SUSAR” Circ Letter 586: only a definition of NIMP.

Definitions (2) SUSAR Reference Safety Information (RSI)
Suspected unexpected serious adverse reaction Reference Safety Information (RSI) If SmPC available: most appropriate (with reference to subject safety) version should be selected Otherwise most recent version of RSI (mostly in the Investigator’s Brochure) Will serve to determine and report SUSARs An update/change of the RSI will influence the number of adverse reactions that are reported as SUSAR 154

Application (1) Interventional clinical trials with Investigational Medical Products or with nonIMP Post marketing Pharmacovigilance rules are not applicable, even if marketed drugs are used in the clinical trial Non-interventional trials – Compassionate Use and Medical Need Programs follow post-marketing PV rules But CUP are conducted with medicinal products without marketing authorization

Application (2) Non-commercial trials Investigator Sponsored Trials
Instructions for electronic or paper submission ? Deadline for mandatory reporting through EudraVigilance ? Investigator Sponsored Trials Avoid double reporting by sponsor and investigator? Recommended: Technical agreement in order to delegate to pharma company or an external consultant to perform safety reporting for the investigator without being considered as the sponsor. Quid: non-EudraCT studies ? 156

SUSAR Reporting Sponsor to CA (1)
All unblinded SUSARs occurring in clinical trials Authorized in the EU or by the FAMPH Performed exclusively in a third country or another Member State when the active substance was authorized in the EU Timelines unchanged – 7 days vs 15 days Reporting obligation ends with treatment completion all subjects enrolled in that MS

SUSAR Reporting Sponsor to CA (2)
Format Indirect reporting through EMA EudraVigilance DB (ICHE2B format) Belgian Affiliate or Corporate PV Local studies: Agreement with delegation of power (audits) Double reporting to avoid Direct reporting: Non-Commercial trials Individual case safety reports (ICSR) by paper with waiver Direct reporting possible in Belgium until when ?

SUSAR Reporting Sponsor to LEC
Sponsor of a clinical trial conducted in Belgium should send Belgian SUSAR report to LEC No 6-monthly line listings to LEC needed Format Not specified Electronic if accepted by LEC + CIOMS in attachment = unprotected Encourage secured company portal system?

SUSAR Reporting Sponsor to investigators (1)
Sponsor should also inform all other investigators by means of periodical line listing of SUSARs together with an updated safety profile of the IMP No timelines To be specified by sponsor depending on type of trial ? Drivers to define periodicity ? All SUSARs vs only Belgian cases to LEC? Confusing for investigators and EC Standardize by sponsor in procedure or in protocol (audit) Do investigators need to receive individual cases ?

SUSAR Reporting Sponsor to investigators (2)
Scientific, medical value and transparency of line-listing of all SUSARs to investigators and no longer to (L)EC ? SUSARs with no (direct) consequence on Risk/Benefit – no timelines? SUSAR with change of Risk/Benefit – reporting by Urgent Safety Notification to all parties? 161

Unblinding - GENERAL (1)
CA Belgian unblinded cases through EudraVigilance LEC Belgian unblinded cases – format not specified Why unblinded to LEC ? Guarantee investigators will receive unblinded information ? 162

Unblinding - GENERAL (2)
Investigators Should only receive blinded information unless unblinding necessary for safety reasons Blinded individual SUSARs or line-listing Format not specified Periodicity: not specified or standardized Use of abbreviated DSUR?

Unblinding (2) After unblinding by the sponsor
Case is unexpected = SUSAR Report according to specified rules Case is expected or placebo related = No SUSAR Comparators Sponsor to report SUSAR through EudraVigilance Information towards MAH? How to define a SUSAR with a comparator? RSI? SmPC? 164

DSUR reporting (1) Format Reference Safety Information
Reference ICH E2F, DSUR (previous ASR) To be prepared after first authorization of a clinical trial in Europe Reference Safety Information RSI applicable at the start of reporting periods and to be attached in appendix RSI serves as reference during reporting period RSI changes/updates Substantial amendment to LEC and CA Alignment of DSUR, Investigator’s Brochure and/or RSI update = alignment reporting period and reference doc

DSUR reporting (2) Content Start of DSUR submission to CA
Listing all SUSARs (yearly basis) and Safety Summary To LEC and CA. Quid non LEC ? Start of DSUR submission to CA After first authorization by CA of a clinical trial with this IMP Most recent DSUR to submit with initial CTA dossier, if study start in Belgium is later than first authorization Line listing unblinded SUSARs to fill possible gap? End of reporting Until LVLP in Belgium = End of exposure Or until End of Trial criteria as specified in the protocol

DSUR reporting (3) No DSUR required for trials < 1 year
The Clinical Trial Report (CSR), as a part of the End of Trial notification, will serve as DSUR in this case CSR is not a part of the EOT notification CSR issued max. 1 year later after worldwide EOT No local EOT, only worldwide EOT Recommended to submit DSUR if more short studies < 1 year with same IMP Recommendation or obligation ? 167

Operational Transparency ?
Conclusion Questions ? Ideas ? 168

The Belgian implementation of CT3 (circ. 586 & 593)
Kristof Bonnarens – 23/11/2012

Revision of CT-3 guidance
Revised detailed guidance on the collection, verfication and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’) was published in the ‘Official Journal’ on 11/06/2011 Replaces ‘old’ guidance documents CT3 and CT4 (Detailed guidance on the European database of SUSARs – Eudravigilance /Clinical Trial Module) Aimed to provide short term improvements and clarifications for safety reporting, awaiting the revision of the current Clinical Trial Directive 2001/20/EC

CT3 revision and circular letter 586 (2)
SUSAR = SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION

Definitions (1) SUSAR = SUSPECTED UNEXPECTED SERIOUS ADVERSE
REACTION Causality between event and IMP «reasonable causal relationship»

Definitions (1) SUSAR = SUSPECTED UNEXPECTED • it results in death
SERIOUS ADVERSE REACTION • it results in death • it is life-threatening • it requires hospitalisation or prolongation of existing hospitalisation • it results in persistent or significant disability or incapacity • it is a congenital anomaly or birth defect An important medical event is also ‘serious’ if it jeopardises the clinical trial participant or requires an intervention to prevent a serious outcome

Definitions (1) SUSAR = SUSPECTED UNEXPECTED SERIOUS
ADVERSE REACTION Adverse reactions should be considered as unexpected if the nature OR severity of the reaction(s) is not consistent with the reference information for the IMP.

Definitions (2) RSI: Reference Safety Information
The expectedness of an adverse reaction is determined in the reference safety information (‘RSI’). This should be done from the perspective of events previously observed, not on the basis of what might be anticipated from the pharmacological properties of a medicinal product The RSI is contained in the Summary of product characteristics (‘SmPC’) or the Investigators Brochure Absence of the RSI is the most frequent validation question in 2012

Scope Scope CT-3 : Interventional clinical trials falling under Directive 2001/20/EC Responsibilities regarding safety reporting determined only by Directive 2001/20/EC: Whether IMP has a marketing authorisation or not Provisions on pharmacovigilance as set out in Directive 2001/83/EC and Regulation (EC) No 726/2004 are not applicable, even for NIMPs

SAE reporting by the investigator
Investigator should report all serious adverse events immediately to the sponsor except those specified in the reference safety information Timelines: Immediate reporting <24h Non immediate: ‘appropriate’ time Other critical safety issues: as specified in protocol Causality and seriousness are assessed by the investigator Expectedness assessment by sponsor

SUSAR reporting by the sponsor (1)
Sponsor should report all SUSARs Occuring in a clinical trial authorised in the EU Occuring in trials performed exclusively in a third country or another Member State when the active substance was authorised in the EU Timelines: Fatal or life-threatening: initial report within 7 days + follow-report within additional 8 days Other SUSARs: initial report within 15 days Format Indirect reporting: through EV-CTM Direct reporting: individual case safety report (ICSR – ICH E2B)

SUSAR reporting by the sponsor (2)
Sponsor should equally send the SUSAR report to the EC that issued the single opinion in the memberstate where it occurred No line listings to Ethics Committees needed Sponsor should inform all other investigators by means of a periodical line listing together with an updated safety profile of the IMP

Annual Safety Report (1)
Should be prepared after the first authorisation of a clinical trial worldwide Development International Birth Date – DIBD: First authorisation of a clinical trial worldwide with this IMP DIBD = International Birth Date for authorised drugs: date of the first marketing authorisation in any country worldwide Data lock point – DLP: last day before the anniversary of the DIBD Covered reporting period: 1 year or shorter for aligning purposes

Annual Safety Report (2)
Content and format of the annual safety report should be in line with ICH guideline E2F: Note for guidance on development safety update reports (DSUR) Common standard for periodic reporting on drugs under development among the ICH regions (EU, USA, Canada and Japan) A DSUR should present a comprehensive annual review and evaluation of pertinent safety information related to an IMP, whether it is marketed or not

Implementation of CT-3 revision in Belgium
Circular letter 586: Submission of SUSAR reports and annual safety reports Circular letter 593: Submission fee for annual safety reports

Circular 586: SUSAR reporting in Belgium
SUSARs to be reported to FAMHP: Occuring in a clinical trial authorised by the FAMHP Occuring in trials performed exclusively in a third country or another Member State when the active substance was authorised by the FAMHP Only unblinded SUSARs Indirect reporting through EVCTM Reporting obligation ends with the last visit of the last patient (LPLV) in Belgium

Circular 586: SUSAR reporting in Belgium
SUSARs to be reported to Ethics committee All SUSARs occurring in Belgium for the clinical trials authorised by the Ethics Committee Should not be submitted: 6 monthly SUSAR line listings

Circular 586: submission of ASR
Start of ASR submission to FAMHP after first authorisation of a clinical trial by FAMHP with this IMP An ASR should be submitted until the last visit of the last patient in Belgium or until the End of Trial criteria in the protocol are met for the last ongoing trial with this IMP in Belgium No ASR submission required for trials shorter than 1 year In unprotected pdf format (allowing search and copy/paste functionality) on CDrom with cover letter

Circular XXX : guidance on ASR submission
Royal Decree on ASR submission fee published on 08/10/2012 – entry into force on the 18th of October Practical instructions in the circular letter that will be drafted asap Revision and evaluation of the process after 6 months with stakeholders. Goal = better follow-up of the safety in clinical trials by a risk-appropriate evaluation of the annual safety report (in the DSUR format).

How to qualify for quality in IMP safety in the near future
Sarah T’Kindt – 23/11/2012

Presentation topics Overview of a GCP inspection
Why is it important to focus on reports from clinical trials? Overview of safety topics during a GCP inspection at the sponsor site Safety findings from previous GCP inspections Legislation

Overview of a GCP inspection
Topics to be discussed during a systemic GCP inspection at the sponsor site: The organization & personnel : qualification and training Outsourcing & contract management Project / trial management The IMP Data management Sample management Safety reporting & evaluation Statistics & study reporting Quality management

Why is it important to focus on reports from clinical trials?
For some products, a high proportion of adverse event reports and other safety information comes from clinical trials Reports and other safety information from clinical trials are (usually) high quality data Relevant additional information can be easily obtained (medical history, other AE’s, lab values, etc.) Information can be retrieved in more controlled settings

Overview of safety topics during a GCP inspection at the sponsor site
Preceding a sponsor site inspection there is usually an investigator site inspection of a specific trial from the sponsor to be inspected: The training on site of the study persons concerning the safety reporting process Reconciliation of data between the source, the CRF and the (serious) adverse events that are reported Delegated safety aspects mentioned on the delegation duty log The quality of the monitoring on site The up to date safety information on site

Overview of safety topics during a GCP inspection at the sponsor site (cont.)
Follow up information Information on concomitant medication Evaluation of the SAE form Update of safety information leads to an update of the informed consent form (ICF) The update of the ICF is signed in time by the subjects Confirmation of receipt from the sponsor for the reported information  Findings from the investigator site inspection will be further discussed during the sponsor site inspection.

The set-up of the trial: A clear description of the safety reporting process in the protocol A non confusion definition of the severity grade A defined time period for reporting Expedited reporting according to the requirements The reference safety information (RSI): To indicate the expectedness Usually in the Investigator Brochure (IB) Reference information allocated and updated as per regulation requirements

The DSMB (Data Safety Monitoring Board) The discision making process for the need of a DSMB Documentation of the discisions of the DSMB The written reports of the DSMB Safety procedures: Clear overview of the timelines and the responsibilities for the safety reporting from collection to reporting Flow of distribution of safety information to the concerned investigators: IB – DIL Emergencies The writing of the DSUR The writing of the CSR …

Minutes of the safety management team meetings Communication between the safety (PhVig) department and the Clinical trial unit and involvement of the PhVig department in critical trial processes/document review: Confirmation of the expedited reporting Protocol Case Report Form Clinical Study Report  The trial statistician should be a member of the team responsible for the clinical study report, and should approve the clinical report.

Compliance of the information in the safety database and the safety information in the DSUR and the CSR Reconciliation of the information in the CT database and the safety database The database(s) used for the storage of safety information A risk level QC of the safety database A documented validation of the database(s) Database ready for demonstration and search of specific topics during inspection

The blinding and unblinding process Clear unblinding rules for SUSAR’s An independant safety monitor ISM for blinded trials for which the IMP’s are manipulated in the hospital pharmacy Adequate safety training of the monitors Training and revision training of the safety procedures Training on the discision management of issues and protocol deviations Training of new important information during the trial

The use of a common adverse event dictionary The role of the local affiliates in the safety process and the communication with global. Is there a local database? Are the procedures in line with the global ones? Qualified employees for the review of the events and the medical writing

Safety findings from previous GCP inspections
No confirmation of receipt from the sponsor of the reported SAE from the investigator site No prove of attendance of the concerned study staff on the site initiation visit and/or the investigator meeting Not all adverse events are recorded, only those that the investigator classifies as clinical significant, although the protocol describes that all adverse events must be recorded

Safety findings from previous GCP inspections (cont.)
SAE’s that are reported long after the first aknowledge by the PI and no note to file from the monitor. The procedures are not complete of the way of working doesn’t fit with the procedures Day ‘zero’ not clear from the SOP No identification of the responsible persons during the safety flow Only the safety reporting on paper is explained, while the reporting is now done via E2B No quality control of the information mentioned in the DSUR and CSR

Safety findings from previous GCP inspections (cont.)
The subject identification at the sponsor site contains the name of the subject AE’s that are crossed out on the AE list without any further explanation or indication of the person responsible for this cross out No audit of the CRO who’s responsible for the safety reporting Very poor documented monitoring reports The use of a non-validated local safety database

Legislation Safety reporting falls either under Directive 2001/20/Ec or under the provisions on PhVig as set out in Directive 2001/83/EC and Regulation (EC) No 726/2004.  AE’s may not be reported under both regimes! Law of 07 May 2004: Art. 27 en 28 & the implementing orders Directive 2001/20/EC Directive 2005/28/EC: The IB shall be validated and updated by the sponsor at least once a year Detailed Guidance CT-3: Note: the PhVig rules laid down in Directive 2001/83/EC and Regulation (EC) No 726/2004 do not apply to IMP’s and non-IMP’s.

Legislation ICH E6: Note for Guidance for Good Clinical Practice CPMP/ICH/135/95 ICH E3: Note for Guidance on Structure and Content of Clinical Study Report CPMP/ICH/137/95 ICH E2A: Note for Guidance on Clinical Safety Data Management CPMP/ICH/377/95: Definitions and standards for expedited reporting ICH E2F: Note for Guidance on Development safety Update Reports

PRIORITIES OF THE DGs FOR THE NEAR FUTURE AND TAKE AWAY MESSAGES
Pharma.be/BEAPP Vanessa BINAME, Director General DG Post – 23/11/2012

RECOGNITION AT NATIONAL, EUROPEAN AND INTERNATIONAL LEVEL
Active participation in: QRD WG, Variations WG and European Council meetings Recast medical devices and European WG (MDEG, CIE, …) National coordination medical devices (MD) Development network safety experts

DEVELOPING PARTNERSHIPS WITH THE HEALTHCARE SECTOR
To improve communication with stakeholders (i.a. industry via WG) Human phv/MD : to develop network with HCPs Veterinary phv: to improve feed-back SAM and active participation to the eHealth roadmap Publication withdrawn MA

PERFORMING CORE TASKS IN A PROFESSIONAL MANNER
Monitor of the timelines and deadlines for DG POST processes SOPs (TQM) and corrective actions based on BEMA III MD: plan Capacity planning RMA

INFORMING THE PUBLIC OPTIMALY
Publication SPC/PIL Website FAHMP Campaign concerning proper use medicines for children To develop information concerning MD Information for patients

DEVELOPING TRANSVERSALITY
intra and inter DG, i.a. between Vigilance division and DG PRE/DG Inspection

EALISING AND ESTABLISHING A LEARNING ORGANIZATION CULTURE
Development cycles Knowledge management Quality system for pharmacovigilance CAF

IMPORTANT MESSAGE DG POST 2013
To improve quality of services Transparency and communication

Contact Agence fédérale des médicaments et des produits de santé - afmps Place Victor Horta 40/40 1060 Bruxelles tél fax

DG PRE Priorities Greet Musch – 23/11/2012

EU Strategy Clinical Trial Regulation
Equal and Early Access ( availability of drugs ) Public Health Needs early authorisation in restricted population elderly people cooperation with HTA – bodies in early stage of drug/device development Anti-Microbial Resistance ( Human and Veterinary) Better Regulation ( Veterinary ) Selection/Reconfirmation of “ Centres of Excellence “ Funding IT

Expertise Regulatory expertise Scientific expertise
Strengthen the basic layers - Focus on Clinical expertise - B/R methodology ( Clinical trials , Unmet need , Marketing authorisations , Self Care , Medical Devices : Clinical Investigations and Evaluations - Coördination and integration of EU Scientific Committees (COMP-SAWP-CAT-CHMP- PDCO and PRAC )within the FAMHP … Introducing the concept of “ TAC’s “ Therapeutic Area Coördinators UNEXPECTED SERIOUS ADVERSE REACTION

Interfaces With National Institutions ( RIZIV , KCE, HGR , FOD VVVL ( WIV-CODA ), FAVV …) Within the FAMHP With DG Post - B/R : Clinical assessors and Vigilance assessors - VHB Pre and VHB Post - CI and CE of medical devices ; combined products… With DG Inspection - Triggers for Inspection - Outcome of Findings : impact ? - Ad Hoc dossiers : Veterinary division , Traditional Use , ATMP’s HE, Active Pharmaceutical Ingredients … UNEXPECTED SERIOUS ADVERSE REACTION

QA of the decision making process
Per process and intra process Review of role and responsabilities of the Commission for medicinal products for human and veterinary use Although dreaming of ancient times …

Stakeholders Optimisation of platforms - ad hoc for existing platforms
- sufficient ? compilation ? Opportunities for improvement ? Your Priorities ? Future views (i.e. Role of Be as RMS for human and veterinary medicinal products ? )

Priorities of DG Inspection in the near future
and take away messages Josiane Van der Elst Director General

Organisation chart

The Switch to Make 229 229 229 AS IS: Gothic TO BE: Art Nouveau
Authority – only driven Authority – driven “supra”control in combination direct linear control with sector – driven “delegated” autocontrol of which selfevaluation can be part co-regulation Vertical link Curvilinear, Linkage with environment Cartesian, dissection of system into parts Holistic, treating systems as a whole Limited interface with operators, one –one interaction Strong Interface with operators Mainly rules Rules and guides Ressources “boxed”, strictly dedicated to one task More rational use of capacity Low trust High trust Authority keeps right of final decision and power of sanction 229 229 229

Co-regulation Co-regulation Autocontrol Self evaluation The Interface
Showing the relationship to a central idea Emphasizes both information in the center circle and how information in the outer ring of circles contributes to the central idea Co-regulation Autocontrol Self evaluation Supracontrol The Interface

Action Plan Autocontrol / Co-regulation
Develop further the concept AND Develop one concrete model to start with: Medical Devices is an opportunity to develop a model and put it to the test AND Work in parallel in different other domains of inspection where concrete actions are foreseeable and feasible already Publicity Certification of persons: f.i. QPPV, oxygenotherapy AND Design Coordinator (s) at DG Inspection

Veterinary issues coming up
Fight against antimicrobial resistance is high on the agenda in view of an holistic approach « The Depot » Lacunes in legislation Good Veterinary Practices to be introduced Better Transversal Coordination needed within FAMHP Autocontrol/co-regulation: first steps to be considered Invite stakeholders at our FAMHP house

DG Inspection: current structure
Director General Division Industry Planning of inspections Execution of inspections Issuing of authorisations Division Dispensing Special Investigation Unit Control policy 235 235

DG Inspection: new structure to be in line with new vision
Director General Division Industry Operational Planning of inspections Execution of inspections Division Dispensing Special Investigation Unit Division Autorisations Issuing of autorisations Staff Inspection management including Control Policy Strategic modelling of inspections Including co/regulation 236 236

Take Away Messages for 2013 Autocontrol / co-regulation as a new style of inspection is going to the test Veterinary inspection will take up its rightfull place and leave the position of « underdog » for the benefit of public health A new style structure, a new structure The new structure of DG Inspection sticks with the new vision on inspection

28 days to go till 238

Be (pharmaco)vigilant! Important changes in the

Similar presentations

Presentation on theme: "Be (pharmaco)vigilant! Important changes in the"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Be (pharmaco)vigilant! Important changes in the

Similar presentations

Presentation on theme: "Be (pharmaco)vigilant! Important changes in the"— Presentation transcript:

Similar presentations

About project

Feedback