Standard operating procedure
Title: Handling of standard requests for data analysis
Status: PUBLIC
Document no.: SOP/H/3326
Lead author
Approver
Effective date: 25-SEP-12
Name: Andrej Segec
Name: Peter Arlett
Review date: 25-SEP-15
Signature: ON FILE
Signature: ON FILE
Supersedes:
Date: 21-SEP-12
Date: 21-SEP-12
SOP/H/3326 (05-SEP-11)
TrackWise record no.: 3664
1. Purpose
This document describes the process which is followed by members of the Pharmacovigilance and Risk
Management sector (P-PV) in situations when a standard request for data analysis, i.e. information
about a suspected adverse reaction associated with a medicinal product and/or a substance contained
in EudraVigilance is received from within the European Medicines Agency, the European Commission,
the Committee for Medicinal Products for Human Use (CHMP), the Pharmacovigilance Risk Assessment
Committee (PRAC), the National Competent Authorities (NCAs) or the rapporteurs.
This procedure also applies to requests for access to information or documents, taking into account the
levels of access as outlined in the EudraVigilance Access Policy (NB access for stakeholder group IV is
not governed by this procedure unless the data output as described in Annex 1 and 2 of the EV Access
Policy is sufficient to answer the request).
In the spirit of transparency and openness, all reasonable efforts to provide the requester with the
desired EV data shall be made. The necessity of timely provision of safety data received in
EudraVigilance sets the basis for a standardised approach as described in this document.
2. Scope
This SOP applies to staff of the following sections within the Pharmacovigilance and Risk Management
sector (PV) of the Patient Health Protection unit (P-PV): Signal Detection and Data Analysis (P-PVSDA), Data Collection and Management (P-PV-DCM) and Coordination and Networking (P-PV-CN).
7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom
Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416
E-mail info@ema.europa.eu Website www.ema.europa.eu
An agency of the European Union
© European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.
3. Responsibilities
It is the responsibility of the Head of Sector (HoS) to ensure that this procedure is adhered to within
his/her Sector. The responsibility for the execution of a particular part of this procedure is identified in
the right-hand column of 9. Procedure.
4. Changes since last revision
Major revision.
5. Documents needed for this SOP
•
WIN/H/3266 – Performing data analysis on EudraVigilance data using EVDAS
•
Tracking of standard queries received and output provided as well as the rota for leaders and
validators are based on an Excel spreadsheet tracking table (Tracking of data analysis requests.xls)
saved under the following location in DREAM:
Cabinets/13.
Analysis
•
Projects/EudraVigilance
-
NEW
STRUCTURE/Pharmacovigilance/Data
Templates for response letters (according to requested product type) are saved under the following
location:
X:\Templates\Others\Eudravigilance\For SOP H 3326
•
Templates for transmission slips are saved under the following location:
X:\Templates\Others\Eudravigilance\For SOP H 3326
6. Related documents
•
SOP/H/3289 - Handling of request for data analysis clarifying critical aspects of medicines
benefit/risk profile
•
EudraVigilance Access Policy for medicines for human use (Doc. Ref.: EMA/759287/2009)
www.ema.europa.eu/docs/en_GB/document_library/Other/2011/07/WC500108538.pdf
•
The EMEA Code of Conduct (Doc. Ref.: EMEA/6470/03/2368)
•
Memorandum of Understanding between the National Competent Authorities of the European
Economic Area, the European Medicines Agency and the European Commission on the sharing of
EudraVigilance data, and other safety and pharmacovigilance related confidential documents
and/or information relating to medicinal products for human use (Doc. Ref. EMEA/311898/2006)
•
Common guidelines on practical arrangements for the sharing of scientific data between the
scientific committees and panels of European agencies and the scientific committees of the
commission (version revised by DG SANCO following a consultation of the commission legal
service). Brussels, 10.11.2008
http://ec.europa.eu/health/ph_risk/documents/cons_draftguidelines_confidentiality_081110_final.
pdf
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•
EV-EWG Guideline on the use of statistical signal detection methods in the EV data analysis
system. (Doc. Ref. EMEA/106464/2006)
•
Rules for the implementation of Regulation (EC) No 1049/2001 on access to EMEA documents
(Doc. Ref. EMEA/MB/203359/2006 Rev 1 Adopted)
www.ema.europa.eu/docs/en_GB/document_library/Other/2010/02/WC500070829.pdf
•
SOP/EMA/0041 - Handling of Requests for Access to Documents
•
SOP/EMA/0019 - Handling of Requests for Access to Information
•
European Medicines Agency policy on access to documents (related to medicinal products for
human and veterinary use) (Doc. Ref. EMA/110196/2006)
•
Regulation (EC) No 1049/2001 of the European Parliament and of the Council of 30 May 2001
regarding public access to European Parliament, Council and Commission documents
•
Working arrangement between the European Medicines Agency (EMA) and the European Monitoring
Centre for Drugs and Drug Addiction (EMCDDA) (Doc. Ref. EMA/379344/2010)
•
Records management policy (Doc. Ref. EMA/590678/2007)
www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC50008
9596
•
SOP/H/3293 - Management of the Pharmacovigilance and Risk Management Sector (P-PV)
helpdesk (Doc. Ref. EMA/94209/2009)
•
Procedure to deal with access to personal data, and rectification of inaccurate or incomplete data,
in case of requests from data subjects in accordance with the provisions laid down in Directive
96/46/EC (Doc. Ref. EMA/333505/2012).
7. Definitions
EudraVigilance (EV) - the European data-processing network and management system as
established in accordance with Regulation (EC) No 726/2004 and Directive 2001/83/EC. It allows the
Agency to manage the electronic data exchange of Individual Case Safety Reports (ICSRs) and to
support the EU pharmacovigilance and risk management activities at Community level.
EudraVigilance
Datawarehouse
and
Analysis
System
(EVDAS)
–
the
EudraVigilance
Datawarehouse and Analysis System has been designed to allow users to analyse safety data collected
in EudraVigilance in view of allowing better-informed decisions about the safety profile of medicinal
products. It provides a range of analytical tools: from measuring reporting compliance for regulatory
purposes, to pharmacovigilance analyses (such as signal detection tools).
MedDRA - the Medical Dictionary for Regulatory Activities - is a medical terminology used to classify
adverse event information associated with the use of biopharmaceuticals and other medical products
(e.g. medical devices and vaccines). Coding these data to a standard set of MedDRA terms allows
health authorities and the biopharmaceutical industry to more readily exchange and analyse data
related to the safe use of medical products.
•
SOC – System Organ Class - Highest level of the terminology, and distinguished by anatomical or
physiological system, aetiology, or purpose
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•
HLGT – High Level Group Term - Subordinate to SOC, superordinate descriptor for one or more
HLTs
•
HLT – High Level Term - Subordinate to HLGT, superordinate descriptor for one or more PTs
•
PT – Preferred Term - Represents a single medical concept
•
LLT – Low Level term - Lowest level of the terminology, related to a single PT as a synonym,
lexical variant, or quasi-synonym (Note: All PTs have an identical LLT).
•
SMQs – Standardised MedDRA Queries - are groupings of terms from one or more MedDRA
System Organ Classes (SOCs) that relate to a defined medical condition or area of interest. They
are intended to aid in case identification. The included terms may relate to signs, symptoms,
diagnoses, syndromes, physical findings, laboratory, and other physiologic test data etc., related to
the medical condition or area of interest.
P-PV-DCM Analysts – staff members of P-PV-DCM involved in provision of redacted line listing for
request for access to documents and in answering sensitive and complex queries in collaboration with
P-PV-SDA.
P-PV-Helpdesk - coordination point for requests received by the P-PV Sector through P-PVHelpdesk@ema.europa.eu.
Proportional Reporting Ratio (PRR): For a given medicine, the PRR is the proportion of all reactions
to a drug which are for a particular medical condition of interest, compared to the same proportion for
all drugs in the database, in a 2 x 2 table.
Request for access to documents - any written request for access to any document produced or
received and held by the Agency. These requests shall be handled in accordance with the Rules for the
implementation of Regulation (EC) No 1049/2001 on access to EMA documents. Request for specific
Individual Case Safety Reports (ICSRs) from EudraVigilance are considered as access to documents
and these will be provided as a redacted line listing containing the ICH E2B fields as referred to in
Annex I of the EV Access Policy for medicines for human use.
Request for access to information - external request requiring an answer from the Agency and not
falling within the scope of access to documents. These requests shall be handled in accordance with
the EMA Code of Conduct. Requests for numbers of ICSRs received in EV for a particular medicinal
product/adverse reaction are considered as access to information.
Standard request for data analysis – a request for analysis of data (i.e. a drug-event pair)
contained in EudraVigilance received from a party that can be provided with this information in
accordance with the EudraVigilance Access Policy, Code of Conduct, Memorandum of Understanding
and Common guidelines as listed in section 6 of this SOP or a request falling under the scope of Access
to Information/Documents. A standard request can be related to an active substance, substance
combination or one or more medicinal products and any level of MedDRA, preferably at the level of
preferred term (PT). A standard query will typically contain:
•
Drug(s) and adverse reaction(s) of interest
•
Output criteria (number of cases, number of fatal cases, cases over time, paediatric cases, case
line listing, geographical distribution etc.)
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Any query meeting these criteria will be considered a standard query for data analysis unless its
complexity requires a more in-depth analysis (refer to SOP/H/3289).
Example of a standard request: Please provide data from EV on anaphylactic reaction with
SUBSTANCE. Focus on data for centrally authorised products – PRODUCT1 and PRODUCT2, received
since 30 June 2008 (last review). Desired output: number of cases and line listing.
Standard request coordinator – staff member of P-PV-SDA responsible for coordination of requests
for data analysis, i.e. receipt, allocation of resources, coordination of responses and tracking of data
analyses.
Standard request leader – staff member of P-PV-SDA (exceptionally of P-PV-DCM) responsible for
planning and execution of analysis, coordination of validation, coordination with the standard request
coordinator and/other sections as applicable, drafting and finalising the response letter including signoff, archiving of relevant documents and tracking of analysis outcomes. The responsibilities of the
standard request leader would also include answering any follow-up questions or clarifications
requested by the original applicant or the internal network.
Standard request validator – staff member of P-PV-SDA (exceptionally of P-PV-DCM) responsible for
validating
the
analysis
performed
by
the
standard
request
leader,
i.e.
scrutinising
the
product/substance selection, MedDRA selection and any additional criteria applied to the analysis in
order to verify the results; also involved in review of response letter and back-up of request leader in
their absence.
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8. Process map(s)/ flow chart(s)
START
1. Receive and track
a request for EV data
2. Can request
be readily
answered?
Yes
2.1 Answer request
according to SOP/H/3293
No
3. Forward request to
standard request
coordinator
END
4. Receive a standard
request
5. Can data be
provided?
No
5.1 Inform requester of
denied access
Yes
6. Allocate team members
and timelines
END
7. Receive a standard
request for data analysis
8. Retrieve requested data
from EVDAS
9. Analyse data
10. Validate data
11. Draft reply
Go to step 12
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From step 11
12. Agree reply internally
and with Section Head/
EV Business Leader
13. Send response to
originator
14. Update tracking table
15. Save documents
END
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9. Procedure
Step
Action
Responsibility
1
Receive and track a request for EV data.
P-PV-Helpdesk
All requests for EV data received by the Agency (via EMA
information, Medical Information, Press Office etc.) are forwarded
to P-PV-Helpdesk (P-PV-Helpdesk@ema.europa.eu) which is the
central coordination point in P-PV.
2
Consider whether the request for EV data can be resolved by
P-PV-Helpdesk
addressing the applicant to the publication of the web reports on
the European database of suspected adverse drug reaction reports
(www.adrreports.eu) or any other existing public data.
If request can be answered, go to step 2.1.
Otherwise, continue with step 3.
2.1
Answer and track request by directing the applicant to the relevant
P-PV-Helpdesk
data source in accordance with SOP/H/3293.
END of procedure
3
Forward request for EV data to the standard request coordinator in
P-PV-Helpdesk
P-PV-SDA.
4
Receive a request for data analysis from the P-PV-Helpdesk. If a
Standard request
request is exceptionally received from another source, forward it to
coordinator
P-PV-Helpdesk@ema.europa.eu as soon as possible, however no
later than 1 working day following receipt of the request.
Assess the request to determine that it is a standard request for
data analysis and can be answered according to the provisions of
the EudraVigilance Access Policy. If the request is not specific
enough and requires further clarifications or the data cannot be
provided
(e.g.
clinical
trials
data
for
stakeholders
II),
the
appropriate comunication to the applicant should be sent via P-PVHelpdesk or Press Office for press requests.
The timeliness for answering the request will be re-established
once clarifications are received and when the request contains the
minimum required information to be completed (e.g. drug name).
If requests accummulate, priority will be given to requests with the
greatest implications for public health protection.
In exceptional cases, for example in the event of an application
relating to a very large number of documents or to a very large
number of products/active substances, the applicant will be
informed of the time limit extension.
In such cases, the principle of proportionality will be applied in
order to avoid that performance of core tasks assigned to the
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Step
Action
Responsibility
Section is jeopardised, i.e. to “provide the Member States and the
Institutions of the Community with the best possible scientific
advice on any question relating to the evaluation of the quality,
safety and efficacy of medicinal products for human or veterinary
use which is referred to it”, as laid down in Regulation (EC) No
726/2004.
5
Ascertain whether data analysis can be provided. Exceptions to
Standard request
access to documents listed in Article 4 of Regulation (EC) No
coordinator
1049/2001 should apply.
Requests for information and documents which cannot be provided
in accordance with the EudraVigilance Access Policy (e.g. reports
from clinical trials) will be refused.
For requests for access to personal data, refer to the Procedure to
deal with access to personal data, and rectification of inaccurate or
incomplete data, in case of requests from data subjects in
accordance with the provisions laid down in Directive 96/46/EC to
ascertain that the data can be provided.
If data can be provided, go to step 6.
Otherwise, continue with step 5.1.
5.1
Inform requester of grounds for refusal of access to data. Any
Standard request
refusal must be duly justified.
coordinator
END of procedure
6
Allocate a reference number to the request according to the
Standard request
sequence recorded in the Tracking of data analysis request.xls (as
coordinator
per section 5 of this SOP). The reference numbers are formed by
the acronym “SDA” followed by a 9 digits number containing the
year, month and 3 digits sequential number (e.g. SDA201203001).
Allocate the standard request leader and validator according to the
existing rota which runs alphabetically for leaders and in reverse
order for validators. Omissions from the rota are granted by the
Section Head in justified circumstances/at times of increased
workload.
Consider whether
the
query is sensitive
(i.e. parliamentary
questions, queries involving the Legal sector, queries involving the
European Ombudsman or queries identified as sensitive by the
origin section) or complex data analysis needs to be performed
(e.g. new type of request, data not readily available via EVDAS,
complex data manipulation required etc.). Inform P-PV-DCM
immediately
via
the
email
address
P-PV-DCM-
Analysts@ema.europa.eu if their involvement is required, i.e. to
construct a new query or validate results using SAS. In such cases,
the leader or validator can be appointed from P-PV-DCM.
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Step
Action
Responsibility
Allocate the manager for sign off of the response letter considering
the sensitivity of the data and its implications.
The deadlines for reply are stipulated in the Agency’s Code of
Conduct
for
requests
for
access
to
information
(“within
a
reasonable time limit, without delay, and in any case no later than
two months from the date of receipt”) and in Regulation (EC) No
1049/2001 for requests for access to documents (“15 working
days”).
If
a
request
is
received
for
both
information
and
documents, the deadline for access to information applies.
For requests from the internal network, it is advisable to agree the
deadlines with the requester, in case the information is needed for
a specific event such as a CHMP or PRAC plenary meeting.
Create a folder in Dream (as per section 10 of this SOP) where all
documents will be stored, taking note of the naming convention:
PRODUCT NAME-SDAYYYYMMXXX.
Save the original request together with the communication to the
leader/validator in the folder created in DREAM.
Send the request to both leader and validator taking note of the
following convention for the subject of the email: Access to
information/documents - Drug name (where applicable) / issue in
question (where applicable) – SDA reference number. P-PV-DCM
should be also informed about the requests for access to
documents where a redacted line listing of ICSRs needs to be
provided.
For the cases where the request is related to regulatory actions or
implications in the signal management process are foreseen, the
SDA signal detection validator of the product is also informed.
7
Receive a standard request for data analysis via email from the
standard
8
request
coordinator.
Inform
the
standard
request
Standard request
leader and
coordinator if an extension of deadlines needs to be requested.
validator
Based on the criteria of the standard request agreed with the
Standard request
validator, perform analyses in EVDAS to retrieve the necessary
leader
information.
The following aspects should be considered for analysis:
•
For
requests
falling
Information/Documents
under
from
the
scope
of
Stakeholders
Access
I,
all
to
data
elements for all ICSRs can be provided - unless specified
otherwise, include both post-marketing and clinical trials
modules of EV (EVPM and EVCTM, respectively) and all
report types;
•
for
requests
falling
under
the
scope
of
Access
to
Information/Documents from Stakeholders II, III and IV,
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Step
Action
Responsibility
only spontaneous reports should
be
included,
where
medicinal product characterization is reported as ‘suspect’
or ‘interacting’ - refer to the EudraVigilance Access Policy
(Annex 1) for further details;
select the appropriate level of MedDRA considering also
•
HLTs, HLGTs, SOCs and SMQs due to its granular nature
include
•
Spontaneous
reports
only
for
calculation
of
PRR/dynamic PRR (see further in EV-EWG Guideline on the
use of statistical signal detection methods in the EV data
analysis system);
for
•
medicinal
product
information
regarding
centrally
authorised products, use the ‘scientific composition (high
level)’ or ‘recoded medicinal product (high level)’ option in
EVDAS;
for other medicinal products, use the ‘reported medicinal
•
product-substance(s)’ option in EVDAS. Verify medicinal
product names and active substance names and synonyms
for inclusion from a relevant comprehensive data source
(e.g. Martindale: The Complete Drug Reference).
NB Always obtain a corresponding line listing - to be stored as per
step 15.
9
Once the final listing is obtained, provide a summary of the data as
Standard request
requested (subtotals for fatal/nonfatal; EEA/non-EEA; median age,
leader
etc.).
For requests falling under the scope of Access to Documents from
Stakeholders II, III and IV, forward the obtained line listing
containing ‘EV Local number’ as case identifier to P-PV-DCMAnalysts@ema.europa.eu in order to expand and redact the line
listing. For further information, please refer to the EudraVigilance
Access Policy (Annex I) for details on data elements inclusion.
10
Validate the data, or perform a second person verification either
Standard request
with EVDAS or with SAS, depending on the complexity of the
validator
query.
Scrutinise
the
selection
of
medicinal
product/active
substance name(s) for completeness and false positives, consider
the
appropriateness of MedDRA
selection and
consider
any
additional criteria applied to the analysis in order to verify the
results.
The same results must be obtained in order to validate the analysis
and any discrepancies must be investigated. The results should
also be cross-checked against any publicly available data, i.e. data
already released in compliance with EudraVigilance access policy
(www.adrreports.eu).
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Step
Action
Responsibility
11
Draft a response letter to the requester focusing on the information
Standard request
requested. Provide a brief interpretation of the key data elements.
leader
Prepare a transmission slip with slots for signature of the leader,
validator, DCM Analyst (if applicable), SDA Section Head, DCM
Section Head (if applicable) or EV Business Leader and Head of
Sector/Head of Unit where necessary.
For Access to Information/Documents queries, use letter template
and transmission slip template as provided is section 5 of this SOP.
12
Agree the draft with standard request validator (peer-review) and
Standard request
with SDA Section Head or EV Business Leader, DCM Section Head
leader
and Head of Sector/Head of Unit where necessary. Consult legal
service for queries made by the European Ombusband or in context
of a lawsuit with the potential involvement of the Agency or
otherwise controversial.
13
Send response to requester via the route of initial request (product
Standard request
team leader, P-PV-helpdesk, EMA Info, Press office etc.), with
leader
standard request coordinator, validator and, if applicable, P-PVDCM-Analysts@ema.europa.eu and the product team leader in
copy. For tracking pusposes the P-PV-helpdesk should be always
copied where the answer is provided via other routes (e.g. Press
office).
14
15
Update tracking table for archiving and consistency purposes.
Standard request
Provide a summary of the query including the major findings.
leader
Save the following documents in the folder created by the standard
Standard request
request coordinator in step 6 (located as per section 10 of this
leader
SOP):
•
results of the leader’s analysis and reasoning for medicinal
product/active substance and MedDRA selection (this will
include the results of the EVDAS reports where applicable)
•
corresponding line listing (MS Excel format)
•
results of analysis validation
•
draft response letter
•
signed final response letter (scanned) as new version of the
draft response letter
•
signed transmission slip (scanned)
•
circulation of the final response
•
any other relevant documents.
10. Records
Tracking of standard queries received and output provided as well as the rota for leaders and
validators are based on an Excel spreadsheet tracking table (Tracking of data analysis requests.xls)
saved under the following location in DREAM:
Cabinets/13. Projects/EudraVigilance - NEW STRUCTURE/Pharmacovigilance/Data Analysis
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All documents as described in step 15 are to be stored under the following location in DREAM - these
documents are considered records according to the Agency’s Records management policy:
Cabinets/13. Projects/EudraVigilance - NEW STRUCTURE/Pharmacovigilance/Data
Analysis/DWH Analysis/Product Analysis/YEAR/PRODUCT NAME-SDAYYYYMMXXX
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