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1BeAPP pharma.be, Brussels Nov 23 12
Be (pharmaco)vigilant!Important changes in the
PV-legislation
23-11-2012
Does a safe environment guaranty safety?
M.Sangeleer, MDMedical Affairs Manager, Eli Lilly Benelux
Lecturer at the Free University of Brussels (ULB)
2
The Pharmacovigilance legislation after 2012
BeAPP pharma.be, Brussels Nov 23 12
09/12/10: BeAPP Cultural event:
BeAPP pharma.be, Brussels Nov 23 12 3
Does a safe environment guaranty safety?
Johan Braeckman: « Evolutionism & creationism »
BeAPP pharma.be, Brussels Nov 23 12 4
1.There is always variation
2.There are more organisms that are born that the amount which can survive (struggle for life)
3.The one who survive are the fitests
4.There is natural + sexual selection
5.The process is repetitive from generation to generation (positive feed-back)
6.At the end, adaptations arise
Does a safe environment guaranty safety?
Pharmacovigilance evolution
5
Computerised systemInternationalisation
Proactive approach
EU reg 1235:risk based regulation
Thalidomide
Collection of AR
1962- 1995
•Signal detection•Worldwide databases MAH•Collaboration between states (WHO,…)
20001990- 2000 2012
•Risk Management systems/plans•Embryo of EU worksharing
•Ad hoc surveillance& risk management plans•Involvement of all staleholders•Improvement collaboration
BeAPP pharma.be, Brussels Nov 23 12
Objectives and Key measures of the new PV law
1. 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
2. Reinforcement of patient protection &engagement - increase the communication and transparency Direct reporting to the Agencies (web portals) Information Available on the webportal of Agencies
3. Introduction of impact of drugs on the environment
6BeAPP pharma.be, Brussels Nov 23 12
More actors
ICH CIOMS EC NCAs
EMA HCPs MAHs
7BeAPP pharma.be, Brussels Nov 23 12
Quality? (faster, better, perceived
severity, final outcomes, impact on QOL, motivation?)- Role of Advocacy
groups
Patients: Awareness and engagement – reporting, acting on information
8
Adverse event reportingExpedited 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)
MAH operational pharmacovigilance tasks
BeAPP pharmabe, Brussels Nov 23 12
«OLD» LEGISLATION «NEW» LEGISLATIONPatient 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,…
SERIOUS ADRs to EV- 15 daysNON SERIOUS ADRs to EV: 90 daysNo expectedness
Legislation main changes for the MAH AE expedited reporting
9BeAPP pharma.be, Brussels Nov 23 12
Consequences for MAH
Volumeo Electronic transmission (E2B)-o signal detectiono Different timelines
Identification and « medical validation » of patient reportso Assessing causality?o Perform follow-up with patients? o What about precription medicines? Effect on treating HCP, if more administration is required? Duplicate reports?
10
Which AE?
Resources, Training, adaptations of rules and procedures
BeAPP pharma.be, Brussels Nov 23 12
Which AE?
11
Adverse event reportingExpedited 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)
MAH operational pharmacovigilance tasks
BeAPP pharmabe, Brussels Nov 23 12
«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
Legislation main changes for the MAH
Periodic reporting
12BeAPP pharma.be, Brussels Nov 23 12
MORE EXPLICIT EVALUATIONS OF B/R
13
Ad hoc periodicity according to riskclose link with RMPScientific evaluation > dataTabulations> line listingsCumulative data starting +new information of this periodSummaries 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 point30 days for reports of a longer frequency after the datalock point
On the grounds: more pragmatic approach
BeAPP pharma.be, Brussels Nov 23 12
PSUR-PBRER: worksharing & simplifications
• 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
14
Less work thanks to worksharing?
BeAPP pharma.be, Brussels Nov 23 12
On the format
15
Adverse event reportingExpedited 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)
MAH operational pharmacovigilance tasks
BeAPP pharmabe, Brussels Nov 23 12
«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)
Legislation main changes
Transparency
16BeAPP pharma.be, Brussels Nov 23 12
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.
17BeAPP pharma.be, Brussels Nov 23 12
ISO IDMP standards, a set of internationally harmonised specifications for the unique identification of medicines
Consequences for MAH
18
Resources to hold timelinesQuestions from patients?Volume of events ?
Risk of induced effects?
They state reading the label
might harm the eyes
BeAPP pharma.be, Brussels Nov 23 12
19
Adverse event reportingExpedited 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)
MAH operational pharmacovigilance tasks
BeAPP pharmabe, Brussels Nov 23 12
«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
Legislation main changes for the MAH: Proactive PV
20BeAPP pharma.be, Brussels Nov 23 12
Consequences of RMP provisions
Public summary on the European Web Portal – Readibility for lay reader– Linked with list of products with additional
monitoring
Art 23 regulation
cost + burden for HCP
BeAPP pharma.be, Brussels Nov 23 12 21
Compulsory assessement of impact: studies, surveys,...
MEDIA ATTENTION
Media consequences
Media trained Resources –Crisis and communication management
BeAPP pharma.be, Brussels Nov 23 12 22
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
23
Enough staff needed : reactivity
BeAPP pharma.be, Brussels Nov 23 12
«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
Legislation main changes for the MAH : Organisation
24BeAPP pharma.be, Brussels Nov 23 12
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
25
BeAPP pharma.be, Brussels Nov 23 12
program law published 06/04/12 (entry into force 17/04/12)Circulars 588- 589RD 16 jul 2012 on DSURs payments: (effective 18 oct 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)
26BeAPP pharma.be, Brussels Nov 23 12
BeAPP pharma.be, Brussels Nov 23 12 27
Basic principle remains unchanged
Does a safe environment guaranty safety?
….There is always variation…
It is still no rocket science:…
There is a human factor
Conditions for a safer PV?:
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
28BeAPP pharma.be, Brussels Nov 23 12
Learn to cope with « variation »= Mitigating the « Human Factor »
29BeAPP pharma.be, Brussels Nov 23 12
Does a safe environment guaranty safety?
Maybe we shouldn’t disturb the medical community for
such a minor manifestation?
Probably,… a fitest pharmacovigilance,…..adapted to the variation
Does a safe legal environment guaranty safety? An industry perspective.Impact on SME’s
Bart De Greef, pharma.beKatleen Vandeweyer, Biocodex Benelux
Stability pact
31 10/04/23
Stability pact
32
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?
33
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
34
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 ?
35
Agence fédérale des médicaments et des produits de santé
Before and after 1235: legislation reviewPharma.be/BEAPP
Thierry ROISIN – 23/11/2012
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
38
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
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
39
New legal framework as regards pharmacovigilance of medicinal products for human use
Regulation (EU) No 1235/2010 of the European Parliament and of theCouncil 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 15December 2010 amending, as regards pharmacovigilance, Directive2001/83/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
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
40
GVPs
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
41
GVPs
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
42
GVPs
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
43
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
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
44
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…
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
45
PRAC
New scientific committee within the AgencyPharmacovigilance 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 signalsReview of PSUR assessments Evaluation of protocols and results of PASS Decision on products under additional monitoring…
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
46
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
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
47
PRAC – activities
Activity Involvement
Risk Management SystemsAgreement on RMPs + monitoring their effectiveness
Periodic Safety Update ReportsPSURs
List of harmonised submission frequencies and substances, assessment + recommendation
Eudravigilance + Periodic Safety Update Reports repository
Functional specifications, any substantial changes
Signal DetectionInitial analysis + prioritisationassessment + recommendations
Medicines subject to additional monitoring
Addition to/removal from list, extension of timeframe, symbol
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
48
PRAC – activities
Activity Involvement
Urgent Safety Proceduresfor the EU
Assessment, public hearings, recommendations
Post Authorisation Safety Studies
Consultations on requests (pre and post MA), assessment of protocols (incl. amendments) + recommendations, assessment of results + recommendations
Safety announcements Advice
Literature Adverse Drug Reactions monitoring
Consultation on list of active substances and medical literature subject to monitoring?
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
49
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
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
50
PRAC Decision-making process
PSUR PASS Union procedures (art. 31, 107i)
PRAC recommendation: regulatory action
CMD(h) (no CAP) CHMP (at least 1 CAP)
Position = maint., var., susp., revoc.
Opinion = maint., var., susp., revoc.
If consensus: agreement
NO consensus: position majority
COMMISSION
Decision modifying MA
(CAP)Decision
addressed to MS
MS: adopt measures
MAH: submit variation
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
51
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)
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
52
Union-wide assessment of phvig issuesUrgent Union ProcedureTriggers - 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;
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
53
Strengthened transparency and communicationEuropean 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)
…
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
54
Strengthened transparency and communication
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
55
55
• 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)
Impact for SME
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
56
56
• 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
Impact for SME
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
57
Thank You
Pharma.beafmps/DG Post/Division Vigilance
23/11/2012
58
Agence fédérale des médicaments et des produits de santé - afmps
Place Victor Horta 40/40 1060 Bruxelles
tél. 0032 2 524 80 00fax 0032 2 524 80 01
e-mail [email protected]
www.afmps.be
Contact
Vos médicaments et produits de santé, notre préoccupation
Federal agency for medicines and health products
New pharmacovigilance legislation:
How to smoothen the transition period? EU and Belgian bridging measures
Goethals Sophie, famhp, vigilance department 23 November 2012
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201261
In this presentation …
1. What has been achieved? What to come? How to smoothen the transition period?
EU level Belgium
2. Specific topics where smooth implementation is necessary
Additional monitoring and implementation of ▼ and standardised statements in SmPC and leaflet
Post-authorisation safety studies
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201262
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
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201263
What has been achieved? What to come? How to smoothen the transition period? EU level
1. What has been achieved?
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201264
What has been achieved? What to come? How to smoothen the transition period? EU level
2. What to come? Oct 2013
2014 ?
Jan 2013
Beyond 2013
June 2013
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201265
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 Publication Dec 2012
Module XV - Safety communication Publication Dec 2012
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 Public consultation Q2 2013
Module XVI - Risk minimisation measures Public consultation Dec 2012 / Q1 2013
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201266
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
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201267
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 http://ec.europa.eu/health/files/pharmacovigilance/2012_02_qa_phv.pdf
EMA/ NCA Q&A on practical transitional measures – November updated awaited
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC500127658.pdf
CMDh Q&A http://www.hma.eu/310.html
List of nationally approved substances for which PSURs are required for generic medicinal products during the transitional period
http://www.hma.eu/310.html
Reporting requirements of ICSRs applicable to MAHs during the interim period
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC500127657.pdf
NCAs requirements for PSUR submission during the transitional period
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC500127656.pdf
To come: Q&A on EURD list?
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201268
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 2006 -> 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 [http://www.fagg-afmps.be/nl/geneesmiddelenbewaking/]
a combination of ‘old’ and ‘new’ legislation shall not be accepted. [email protected]
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201269
What has been achieved? What to come? How to smoothen the transition period? Belgium
Patient reporting in Belgium
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201270
What has been achieved? What to come? How to smoothen the transition period? Belgium
Patient reporting in EU
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201271
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 ……
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201272
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 scopeproducts subject to specific conditions will be included under mandatory scope cfr. red text on next slide
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201273
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 toconditions, 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].
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201274
Additional monitoring and implementation of ▼ and standardised statements in SmPC and leaflet
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?
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201275
Additional monitoring and implementation of ▼ and standardised statements in SmPC and leaflet
3. Implementation of ▼ and standardised statements in SmPC and leaflet
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].
a. Selection of black symbol: PRAC recommendation (Oct 2012): inverted black triangle (▼) Commission Decision (before 2 July 2013): Q1 2013 ?
EC public consultation on phasing-in launched 21 Nov 2012- till 10 Jan 2013 [http://ec.europa.eu/health/files/pharmacovigilance/2012_11_09_pb__black.pdf]
b. 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)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201276
Additional monitoring and implementation of ▼ and standardised statements in SmPC and leaflet
4. Wording of standardised statements for additional monitoring
SmPC
Package Leaflet
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201277
Additional monitoring and implementation of ▼ and standardised statements in SmPC and leaflet
5. Wording of standardised statements - encouragement ADR reporting for all medicinal products
SmPC (end of section 4.8)
Package Leaflet (end of section 4.)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201278
Non-interventional post-authorisation safety studies (PASS)
1. 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
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201279
2. … 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. 36-38format of protocol, abstract and final study report
Voluntarily:studies required in RMPany other PASS
Dir. 2001/83 art. 107 m: no promotional character, payments to HCP restricted to compensation of time and expenses incurredprotocol and progress reports: may be requested by MS in which the study is conductedfinal 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]
Non-interventional post-authorisation safety studies (PASS)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201280
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 Legal obligation
Monitor data generated in the study with consideration to benefit-risk of product concerned [Dir. Art. 107m]
Legal obligation Legal obligation
Use of standard formats for protocol and study report [Reg. 520/2012] Template for protocol
[http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/10/WC500133174.pdf]
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 supervisionNational supervision for PASS imposed after authorisation by 1 MS, and conducted only in that MS
(if in RMP)
Registration in EU PAS register Legal obligation GVP recommendation
Quality system Legal obligation GVP recommendation
Non-interventional post-authorisation safety studies (PASS)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201281
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 Legal obligation
Protocol to be submitted upon request to NCA of MS where study is conducted [Dir. Art. 107m + art. 107 n (3)]
Legal obligation cfr. Annex to GVP module VIII
Progress reports to be submitted upon request to NCA of MS where study is conducted [Dir. Art. 107m]
cfr. Annex to GVP module VIII
cfr. Annex to GVP module VIII
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]
Legal obligation Legal obligation
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 ]
Legal obligation Legal obligation
Final manuscript of article to be transmitted to NCAs of MS where product is authorised within 15 days after acceptance [GVP]
recommended recommended
Non-interventional post-authorisation safety studies (PASS)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201282
3. Annex to GVP module VIII: MS' requirements for transmission of information on non-interventional PASS with PRAC oversight
→ Belgium: famhp, vigilance department, [email protected]
Non-interventional post-authorisation safety studies (PASS)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201283
4. Annex to GVP module VIII –Member States' requirements for transmission of information on non-interventional PASS, conducted voluntarily
Non-interventional post-authorisation safety studies (PASS)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201284
5. 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
Non-interventional post-authorisation safety studies (PASS)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201285
6. 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)
Non-interventional post-authorisation safety studies (PASS)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201286
6. EU PAS Registerhttp://www.encepp.eu/encepp_studies/indexRegister.shtml
Non-interventional post-authorisation safety studies (PASS)
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201287
ICSR reporting requirements for MAH during interim period
1. Serious EU ICSRs
[http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC500127657.pdf]
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201288
ICSR reporting requirements for MAH during interim period
2. Serious non-EU ICSRs and non-serious EU ICSRs
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201289
ICSR reporting requirements for MAH during interim period
2. Serious non-EU ICSRs and non-serious EU ICSRs
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201290
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: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/09/news_detail_001616.jsp&mid=WC0b01ac058004d5c1
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.
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201291
PSURs: List of Union reference dates and PSUR frequency
15/05/2012 FAMHP/Vigilance/gss 92
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
1) Risk based PSUR cycle, through comprehensive URD List
2) Condition to MA
3) Routine PSUR cycle
No 1) List URD legally binding 6 months after publication (publication Oct. 2012 -> April 2013)
2) July 2012
3) July 2012
Timelines for submission:
Within 60 days > DLP
Within 70 or 90 days > DLP (GVP)
No 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 93
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
Purely national 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
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201294
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
I nitial Authorisation Phase
Post-authorisation Phase
New MAAs as of September 2012
CHMP Rapporteur A1 A1
CHMP Co-Rapporteur B1 B1
PRAC Rapporteur X2 X2
PRAC Co-Rapporteur A1 A1
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201295
PRAC phasing-in
For “Legacy” centrally authorized medicines (= authorised and on-going), while awaiting formal reappointment from Q1 2013 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).
BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201296
Back up slides
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BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201297
Back up slides
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BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201298
Back up slides
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BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 201299
Back up slides
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BeappFamhp/DG Post/Vigilance Department-Pharmacovigilance
23 November 2012100
Federal agency for medicines and health products - famhp
Place Victor Horta 40/40 1060 Bruxelles
tel. 0032 2 524 80 00fax 0032 2 524 80 01
e-mail [email protected]
www.afmps.be
Contact
Your medicines and health products,our concern
Federal agency for medicines and health products
How to qualify for quality in the near future and be audit ready
Nele Matthijs- 23.11.2012
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date103
-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
How to qualify for quality in the near future and be audit ready
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date104
A journey of quality
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date105
Journey of PhV Legislation
Good Vigilance Practices
Implementing Measure
Regulation & Directive
Incr
easi
ng le
vel o
f de
tail
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date106
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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date107
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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date108
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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date109
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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date110
• 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.
Module I: Pharmacovigilance systems and their quality systems
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date111
•Training
•Facilities and equipment
•Compliance management
•Record management
•Documentation of the quality system
•Monitoring performance & effectiveness of the PV system & its quality system
Module I: Pharmacovigilance systems and their quality systems
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date112
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
Why and how perform quality control
• Are SOPs up-to-date ?
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date113
-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.
Why and how perform quality control
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date114
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 I: Pharmacovigilance systems and their quality systems
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date115
- 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
Module III : Pharmacovigilance inspections
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date116
• 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
Module III : Pharmacovigilance inspections
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date117
• 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 III : Pharmacovigilance inspections
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date118
- 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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date119
• 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)
Module IV : Audits
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date120
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
MOST IMPORTANTLY, PHARMACOVIGILANCE AUDITS ACT AS ONE MECHANISM TO ENSURE THE SAFETY OF PATIENTS IS MAINTAINED
Module IV : Audits
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date121
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
Module IV : Audits
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date122
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
Module IV : Audits
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date123
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
Global Pharmacovigilance System Audits
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date124
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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date125
• 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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date126
• 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
Company Affiliates
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date127
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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date128
Global Pharmacovigilance Inspection Trends
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date129
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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date130
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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date131
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
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date132
A journey of improved quality
How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry
Date133
Federal agency for medicines and health products - famhp
Place Victor Horta 40/40 1060 Bruxelles
tel. 0032 2 524 80 00fax 0032 2 524 80 01
e-mail [email protected]
www.afmps.be
Contact
Your medicines and health products,our concern
Federal agency for medicines and health products
The Belgian consensus on Risk Minimisation ActivitiesNew process
M.L.Bouffioux - 23th November 2012
RMA New processfamhp/DG Post/Division Proper use of medicine
Date136
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.
RMA New processfamhp/DG Post/Division Proper use of medicine
Date137
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.
RMA New processfamhp/DG Post/Division Proper use of medicine
Date138
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)
RMA New processfamhp/DG Post/Division Proper use of medicine
Date139
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
RMA New processfamhp/DG Post/Division Proper use of medicine
Date140
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
RMA New processfamhp/DG Post/Division Proper use of medicine
Date141
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.
RMA New processfamhp/DG Post/Division Proper use of medicine
Date142
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
RMA New processfamhp/DG Post/Division Proper use of medicine
Date143
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 fileTiming suspended:- The holder responds within a maximum of 60 days- If> 60 days: request deniedConclusions:- intention of (modified )RMA approval - Refusal (to reintroduce an application)
RMA New processfamhp/DG Post/Division Proper use of medicine
Date144
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
RMA New processfamhp/DG Post/Division Proper use of medicine
Date145
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
RMA New processfamhp/DG Post/Division Proper use of medicine
Date146
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
RMA New processfamhp/DG Post/Division Proper use of medicine
Date147
References
www.afmps.be -> Usage humain->Médicaments -> Bon Usage -> Additional RMAwww.fagg.be-> 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
RMA New processfamhp/DG Post/Division Proper use of medicine
Date148
Federal agency for medicines and health products - famhp
Place Victor Horta 40/40 1060 Bruxelles
tel. 0032 2 524 80 00fax 0032 2 524 80 01
e-mail [email protected]
www.afmps.be
Contact
Your medicines and health products,our concern
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
152
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.
153
Definitions (2)
• SUSAR– 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
155
Application (2)
– Non-commercial 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 ReportingSponsor 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
157
SUSAR ReportingSponsor 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 ReportingSponsor 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 – Email + CIOMS in attachment = unprotected – Encourage secured company portal system?
159
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 ?
160
SUSAR ReportingSponsor 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 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
165
DSUR reporting (2)
Content • 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
Federal agency for medicines and health products
The Belgian implementation of CT3 (circ. 586 & 593)Kristof Bonnarens – 23/11/2012
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date170
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
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date171
• SUSAR =
SUSPECTED
UNEXPECTED
SERIOUS
ADVERSE
REACTION
CT3 revision and circular letter 586 (2)
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date172
• SUSAR =
SUSPECTED
UNEXPECTED
SERIOUS
ADVERSE
REACTION
Causality between event and IMP
«reasonable causal relationship»
Definitions (1)
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date173
• SUSAR =
SUSPECTED
UNEXPECTED
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)
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date174
• 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 (1)
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date175
• 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
Definitions (2)
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date176
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
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date177
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
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date178
• 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 (1)
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date179
• 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
SUSAR reporting by the sponsor (2)
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date180
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
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date181
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
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date182
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
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date183
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
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date184
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
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date185
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
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date186
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).
The Belgina implementation of CT3famhp/DGPRE/ R&D
Date187
Federal agency for medicines and health products - famhp
Place Victor Horta 40/40 1060 Bruxelles
tel. 0032 2 524 80 00fax 0032 2 524 80 01
e-mail [email protected]
www.afmps.be
Contact
Your medicines and health products,our concern
Federal agency for medicines and health products
How to qualify for quality in IMP safety in the near future
Sarah T’Kindt – 23/11/2012
Subjectfamhp/entity/Division-Unit-Cell
Date190
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
Subjectfamhp/entity/Division-Unit-Cell
Date191
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
Subjectfamhp/entity/Division-Unit-Cell
Date192
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
Subjectfamhp/entity/Division-Unit-Cell
Date193
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
Subjectfamhp/entity/Division-Unit-Cell
Date194
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.
Subjectfamhp/entity/Division-Unit-Cell
Date195
Overview of safety topics during a GCP inspection at the sponsor site (cont.)
• 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
Subjectfamhp/entity/Division-Unit-Cell
Date196
Overview of safety topics during a GCP inspection at the sponsor site (cont.)
• 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 …
Subjectfamhp/entity/Division-Unit-Cell
Date197
Overview of safety topics during a GCP inspection at the sponsor site (cont.)
• 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.
Subjectfamhp/entity/Division-Unit-Cell
Date198
Overview of safety topics during a GCP inspection at the sponsor site (cont.)
• 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
Subjectfamhp/entity/Division-Unit-Cell
Date199
Overview of safety topics during a GCP inspection at the sponsor site (cont.)
• 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
Subjectfamhp/entity/Division-Unit-Cell
Date200
Overview of safety topics during a GCP inspection at the sponsor site (cont.)
• 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
Subjectfamhp/entity/Division-Unit-Cell
Date201
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
Subjectfamhp/entity/Division-Unit-Cell
Date202
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
Subjectfamhp/entity/Division-Unit-Cell
Date203
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
Subjectfamhp/entity/Division-Unit-Cell
Date204
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.
Subjectfamhp/entity/Division-Unit-Cell
Date205
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
Subjectfamhp/entity/Division-Unit-Cell
Date206
Federal agency for medicines and health products - famhp
Place Victor Horta 40/40 1060 Bruxelles
tel. 0032 2 524 80 00fax 0032 2 524 80 01
e-mail [email protected]
www.afmps.be
Contact
Your medicines and health products,our concern
Agence fédérale des médicaments et des produits de santé
PRIORITIES OF THE DGs FOR THE NEAR FUTURE AND TAKE AWAY MESSAGES
Pharma.be/BEAPP
Vanessa BINAME, Director General DG Post – 23/11/2012
Priorities of the DGs for the near future and take away messages
afmps/DG Post
23/11/2012
209
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
Priorities of the DGs for the near future and take away messages
afmps/DG Post
23/11/2012
210
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 2013-2018
• Publication withdrawn MA
Priorities of the DGs for the near future and take away messages
afmps/DG Post
23/11/2012
211
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
Priorities of the DGs for the near future and take away messages
afmps/DG Post
23/11/2012
212
INFORMING THE PUBLIC OPTIMALY
• Publication SPC/PIL
• Website FAHMP
• Campaign concerning proper use medicines for children
• To develop information concerning MD
• Information for patients
Priorities of the DGs for the near future and take away messages
afmps/DG Post
23/11/2012
213
DEVELOPING TRANSVERSALITY
intra and inter DG, i.a. between Vigilance division and DG PRE/DG Inspection
Priorities of the DGs for the near future and take away messages
afmps/DG Post
23/11/2012
214
EALISING AND ESTABLISHING A LEARNING ORGANIZATION CULTURE
• Development cycles
• Knowledge management
• Quality system for pharmacovigilance
• CAF
Priorities of the DGs for the near future and take away messages
afmps/DG Post
23/11/2012
215
• To improve quality of services
• Transparency and communication
IMPORTANT MESSAGE DG POST 2013
Priorities of the DGs for the near future and take away messages
afmps/DG Post
23/11/2012
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Agence fédérale des médicaments et des produits de santé - afmps
Place Victor Horta 40/40 1060 Bruxelles
tél. 0032 2 524 80 00fax 0032 2 524 80 01
e-mail [email protected]
www.afmps.be
Contact
Vos médicaments et produits de santé, notre préoccupation
Federal agency for medicines and health products
DG PRE Priorities Greet Musch – 23/11/2012
The Belgina implementation of CT3famhp/DGPRE/ R&D
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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
The Belgina implementation of CT3famhp/DGPRE/ R&D
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• 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
Expertise
The Belgina implementation of CT3famhp/DGPRE/ R&D
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• 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
Interfaces
The Belgina implementation of CT3famhp/DGPRE/ R&D
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• 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 …
QA of the decision making process
The Belgina implementation of CT3famhp/DGPRE/ R&D
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The Belgina implementation of CT3famhp/DGPRE/ R&D
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• 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 ? )
Stakeholders
The Belgina implementation of CT3famhp/DGPRE/ R&D
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Federal agency for medicines and health products - famhp
Place Victor Horta 40/40 1060 Bruxelles
tel. 0032 2 524 80 00fax 0032 2 524 80 01
e-mail [email protected]
www.afmps.be
Contact
Federal agency for medicines and health products
Priorities of DG Inspection in the near future and take away messages
Josiane Van der ElstDirector General
Organisation chart
Directorate General Inspection 2013: Autocontrol becoming a reality
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The Switch to Make
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
Co-regulation 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
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
Action Plan Autocontrol / Co-regulation
Directorate General 2013: The Veterinary Experience
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
Directorate General 2013: The New Structure
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DG Inspection: current structure
235
236
DG Inspection: new structure to be in line with new vision
236
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
Take Away Messages for 2013
Your medicines and health products,our concern