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AGAH Annual Meeting 2004 - Workshop am 29. 02. 04 - Phase I - Studien im neuen regulatorischen Umfeld

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Title: AGAH Annual Meeting 2004 - Workshop am 29. 02. 04 - Phase I - Studien im neuen regulatorischen Umfeld


1
AGAH Annual Meeting 2004 - Workshop am 29. 02.
04 - Phase I - Studien im neuen regulatorischen
Umfeld
Anzeige von Nebenwirkungen aus klinischen
Prüfungen nach dem 01.Mai 2004 Frieder
Hackenberger Fachgebiet Klinische Prüfung/
GCP-Inspektionen hackenbe _at_ bfarm.de
2
Anzeige von Ereignissen / Nebenwirkungen
  • EU-rechtliche Vorgaben
  • Begriffsbestimmungen
  • Meldeverpflichtungen für Prüferund Sponsor,
    12 und 13 der RVO nach 42 (3)
  • Minimum criteria for expedited reportingInformati
    on der EKverblindete Studienhigh morbidity-,
    high mortality-Studien Jahresberichte

3
Anforderungen der RL 2001/20/EG - Art. 16, 17,18
  • Pflichten des Prüfers
  • Art. 16 (1) - (3) Berichte über alle SAEs
  • an den Sponsor
  • Fristen
    unverzüglich,
  • nachfolgend
    ausführlich schriftlich
  • - (2) AEs, Laboranomalien, die im Prüfplan
    für die Unbedenklichkeits- entscheidungen als
    entscheidend bezeichnet werden, sind dem
    Sponsor innerhalb der im Prüfplan angegebenen
    Fristen mitzuteilen.

4
Anforderungen der RL 2001/20/EG - Art. 16, 17,18
  • Pflichten des Sponsors
  • Art. 16 (4) Dokumentation aller
    berichteten AEs
  • Art. 17 (1) a, b Berichte über alle SUSARs an
    die zuständige BOB
    und die EK,
  • Fristen 15 d /
    Todesfälle 7 d
  • (1) d Unterrichtung der
    Prüfer über SUSARs
  • (2) Listen aller
    SSARs,
    Jahresberichte zur Sicherheit
    der Prüfungsteilnehmer

5
Anforderungen der RL 2001/20/EG - Art. 16, 17,18
  • Pflichten der Mitgliedstaaten
  • Art. 17 (1) c, (3) a EU-Datenbank
  • Art. 18 Anleitungen für die
    Erstellung, Prüfung,
    Vorlage der Berichte
    zu SAEs/SARs,
    Modalitäten der Dekodierung

6
Anforderungen der RL 2001/20/EG - Art. 16,
17,18
  • CT-05-EN (früher ENTR/6422/01)
  • Detailed guidance on the collection, verification
    and presentation of adverse reaction reports
    arising from clinical trials on medicinal
    products for human use
  • Discussion in working group
    Dez.2001-June 2002
  • Release for consultation
    12 July 2002
  • Deadline for comments
    02 October 2002
  • Revised draft 5
    13 December 2002
  • Revised draft 7
    21 February 2003Final draft adopted
    21 March 2003
  • Published
    April 2003
  • Revised
    13. February 2004
  • to be published
    April 2004

7
2. Anforderungen der Anleitung CT-05-EN
  • Was wird geregelt?
  • Introduction
  • Legal Basis
  • Scope
  • Definitions
  • Investigators Responsibilities
  • Sponsors Responsibilities

8
Anleitung CT-05-EN
  • Was wird geregelt?
  • 4. Definitions
  • AE Adverse Event Entwurf RVO 3 (8) - UE
  • Any untoward medicinal occurence in a patient or
    clinical trial subject administered a medicinal
    product and wich does not necessarily have a
    causal relationship with this treatment.
  • AR Adverse Reaction
  • All untoward and unintended resposes to an
    investigational medicinal product related to any
    dose administered.
  • UAR Unexpected Adverse Reaction
  • An AR, the nature, or severity of which is not
    consistent with the applicable product
    information (e.g. investigators brochure for an
    unapproved IMP or SPC for an authorised product).

9
Anleitung CT-05-EN
  • 4. Definitions
  • SUSARs - Suspected Unexpected Serious Adverse
    Reactions
  • All adverse events judged by either the
    investigator or the sponsor as having
  • a reasonable suspected causal relation-ship
  • to an investigational or an accompanying
    medicinal product qualify as adverse reactions.

10
Anleitung CT-05-EN
  • 4. Definitions
  • SUSARs Suspected Unexpected Serious Adverse
    Reactions
  • Unexpected adverse reaction an adverse reaction,
    the nature, or severity of which is not
    consistent with the applicable product
    information (e.g. investigator's brochure for an
    unapproved investigational product or summary of
    product characteristics (SPC) for an authorised
    product).
  • Comments
  • When the outcome of the adverse reaction is not
    consistent with the applicable product
    information this adverse reaction should be
    considered as unexpected.
  • Severity The term severe is often used to
    describe the intensity (severity) of a specific
    event. This is not the same as serious, which
    is based on patient/event outcome or action
    criteria.

11
Anleitung CT-05-EN
  • 4. Definitions Entwurf RVO 3 (8)
  • SUSARs - Suspected Unexpected Serious Adverse
    Reactions
  • Any untoward medical occurence or effect that at
    any dose
  • results in death
  • is life-threatening
  • requires inpatient hospitalisation or
    prolongation of existing hospitalisation
  • results in persistent or significant disability
    or incapacity,
  • is a congenital anomaly or birth defect.

12
Entwurf RVO nach 42 (3) AMG 12 und 13
  • 12 Pflichten der prüfenden Person
  • Die prüfende Person informiert den Sponsor
  • innerhalb der im Prüfplan angegebenen Fristen
  • über unerwünschte Ereignisse oder unerwartete
    klinisch-diagnostische Befunde, die für die
    Bewertung der Unbedeklichkeit von Bedeutung sind.
  • Dabei sind die ausführlichen Anleitungen für die
    Erstellung, Prüfung und Vorlage der Berichte über
    unerwünschte Ereignisse zu beachten

13
Entwurf RVO nach 42 (3) AMG 12 und 13
  • 12 Pflichten der prüfenden Person
  • Die prüfende Person unterrichtet den Sponsor
  • unverzüglich über das Auftreten eines
    schwerwiegenden unerwünschten Ereignisses SAE
    und übermittelt ihm anschließend einen
    ausführlichen schriftlichen Bericht.
  • Die Identifikation der Prüfungsteilnehmer und
    innen in der Unterrichtung und dem schriftlichen
    Bericht beschränkt sich auf die Nennung der
    entsprechenden Codenummer laut Prüfplan.
  • Satz 1 gilt nicht für solche Ereignisse, über die
    laut Prüfplan nicht unverzüglich berichtet werden
    muss.

14
Entwurf RVO nach 42 (3) AMG 12 und 13
  • 12 Pflichten der prüfenden Person
  • (3) Im Fall des Todes eines Prüfungsteilnehmers
    oder einer teilnehmerin informiert der
    Prüfer
  • unverzüglich auch die EK, (???) bei
    multizentrischen Studien alle beteiligten EKs,
  • sowie die zuständige BOBund übermittelt
    diesen alle zusätzlich geford-erten Auskünfte.

15
Entwurf RVO nach 42 (3) AMG 12 und 13
  • 13 Pflichten des Sponsors
  • (1) Der Sponsor dokumentiert ausführlich alle
    unerwünschten Ereignisse, die ihm von den Prüfern
    mitgeteilt werden.
  • Diese Aufzeichnungen werden der zuständigen
    Bundesoberbehörde und, soweit zutreffend, den
    zuständigen Behörden anderer Mitgliedstaaten der
    Europäischen Union, in deren Hoheitsgebiet die
    klinische Prüfung durchgeführt wird, auf Antrag
    zugeleitet.

16
Entwurf RVO nach 42 (3) AMG 12 und 13
  • 13 Pflichten des Sponsors
  • Der Sponsor unterrichtet über jeden ihm bekannt
    gewordenen Verdachtsfall einer unerwarteten
    schwerwiegenden Nebenwirkung unverzüglich,
    spätestens aber innerhalb von 15 Tagen nach
    Bekanntwerden
  • die Ethik-Kommission,
  • die zuständige Bundesoberbehörde
  • und, soweit zutreffend, die anderen an der
    Prüfung beteiligten Prüfer
  • sowie die zuständigen Behörden anderer
    Mitgliedstaaten der Europäischen Union, in deren
    Hoheitsgebiet die klinische Prüfung durchgeführt
    wird.

17
Entwurf RVO nach 42 (3) AMG 12 und 13
  • 13 Pflichten des Sponsors
  • Der Sponsor übermittelt bei jedem ihm bekannt
    gewordenen Verdachtsfall einer unerwarteten
    schwerwiegenden Nebenwirkung, die zu einem
    Todesfall geführt hat oder führen kann,
    unverzüglich, spätestens aber innerhalb von 7
    Tagen nach Bekanntwerden,
  • der EK,
  • der zuständigen BOB
  • und, soweit zutreffend, den zuständigen Behörden
    anderer Mitgliedstaaten der Europäischen Union,
    in deren Hoheitsgebiet die klinische Prüfung
    durchgeführt wird,
  • alle für die Bewertung wichtigen
    Informationen
  • und informiert innerhalb von höchstens acht
    weiteren Tagen über alle von ihm oder von der
    prüfenden Person in diesem Zusammenhang
    getroffenen Maßnahmen.

18
Entwurf RVO nach 42 (3) AMG 12 und 13
  • 13 Pflichten des Sponsors
  • Der Sponsor legt
  • der EK,
  • der zuständigen BOB
  • und, soweit zutreffend, den zuständigen Behörden
    anderer Mitgliedstaaten der Europäischen Union,
    in deren Hoheitsgebiet die klinische Prüfung
    durchgeführt wird,
  • während der Dauer der Prüfung einmal
    jährlich
  • eine Liste aller während der Prüfung
    aufgetretenen Verdachtsfälle schwerwiegender
    Nebenwirkungen
  • sowie einen Bericht über die Sicherheit der
    Prüfungsteilnehmer und Prüfungsteilnehmerinnen
    vor.

19
2. Anforderungen der Anleitung CT-05-ENWas
wird geregelt?
  • 6. Sponsors Responsibilities
  • 6.1 General Remarks
  • 6.2 Recording and Evaluation of Adverse Events
    (AEs)
  • 6.2.1 Evaluation of adverse events
  • 6.2.2 Assessment of seriousness
  • 6.2.3 Assessment of causality
  • 6.2.4 Sponsors assessment of expectedness
  • 6.2.5. Data protection of trial subjects
  • 6.3 Reporting od Serious Adverse Reactions
  • 6.3.1 Standards of expedited reporting
  • 6.3.2 Annual safety report
  • 6.3.2.1 Content of the annual safety report
  • 6.3.3.1.1 Line linstings
  • 6.3.2.1.2 Aggegate summary tabulations
  • 6.3.2.1.3 Report on subjects safety
  • 6.3.2.2 Reporting time frame for annual
    safety report
  • 6.3.2.3 Whom to report
  • 6.4 How to inform the investigator?
  • 6.5 Reporting safety issues following completion
    of the CT in EU

20
6. Sponsors Responsibilities
  • 6.2.1 Assessment of seriousness
  • Seriousness shall be determined according to
    definition in Article 2 of the Dir. 2001/20/EC
    taking into account the comments presented in
    Annex I.
  • 6.2.2 Assessment of causality
  • Causality shall be determined according to the
    definition of an adverse reaction as given in
    Article 2 of the Directive 2001/20/EC taking into
    account the comments presented in Annex 1.
  • All adverse events judged by
  • either the investigator or the sponsor
  • as having a reasonable suspected causal
    relationship to an investigational medicinal
    product
  • qualify as adverse reactions.
  • The causality assessment given by the
    investigator should not be overruled by the
    sponsor.
  • If the sponsor disagrees with the investigators
    causality assessment, both, the opinion of the
    investigator and the sponsor should be provided
    with the report.

21
6. Sponsors Responsibilities
  • 6.2.3 Sponsors assessment of expectedness
  • The definition of the term unexpected is given
    in the Directive 2001/20/EC.
  • Reports, have to be considered as unexpected if
    they add significant information on the
    specificity or severity of an expected adverse
    reaction.
  • The expectedness of an adverse event / reaction
    shall be determined by the sponsor according to
    the reference document as defined in the study
    protocol
  • (e.g. investigator's brochure for an unapproved
    investigational medicinal product
  • or summary of product characteristics (SPC) for
    an authorised medicinal product in the EU,
    which is being used according to the terms
    and conditions of the marketing authorisation).
  • When the IMP has a MA in several MS with
    different SPCs, the sponsor must select one of
    them as a reference document for assessing
    expectedness and must mention it in the protocol.

22
6. Sponsors Responsibilities
  • 6.3 Reporting of Serious Adverse Reactions
    (SARs)
  • 6.3.1 Standards for expedited reporting
  • 6.3.1.1 What must be reported
  • 6.3.1.1.1 SUSARs
  • All suspected adverse reactions that are
    both unexpected and serious (SUSARs) and occur
    in a clinical trial are subject to expedited
    reporting.
  • This includes SUSARs associated with
  • the IMP(s) and which occur in the concerned
    trial,
  • the IMP being tested in a clinical trial in the
    community and which occur in a trial
    conducted by the same sponsor in a third country
    (i.e. in non EU countries) ,
  • or which are identified by spontaneous reports
    or a publication (?)
  • or which are transmitted to the sponsor by
    another regulatory authority.

23
  • 6.3.1.1.2 Other observations
  • Other informations also qualify for
    expedited reporting where they might materially
    alter the current benefit-risk assessment of an
    IMP or that would be sufficient to consider
    changes in the IMP administration or in the
    overall conduct of the trial, for instance
  • single case reports of an expected serious
    adverse reactions with an unexpected outcome
    (e.g. a fatal outcome),
  • an increase in the rate of occurrence of an
    expected serious adverse drug reaction, which is
    judged to be clinically important,
  • post-study SUSARs that occur after the patient
    has completed a clinical trial and are reported
    by the investigator to the sponsor.
  • new event relating to the conduct of the trial or
    the development of the IMP where that new event
    is likely to affect the safety of the subjects,
    such as
  • a serious adverse event which could be associated
    with the trial procedures and which could modify
    the conduct of the trial,
  • a significant hazard to the subject population
    such as lack of efficacy of an IMP used for the
    treatment of a life threatening disease,
  • a major safety finding from a newly completed
    animal study (such as carcinogenicity).

24
  • 6.3.1.6 How to report ?
  • 6.3.1.6.1 Minimum criteria for initial expedited
    reporting of SUSARs
  • Information on the final description and
    evaluation of an adverse reaction report may
    not be available within the required time frames
    for reporting.For regulatory purposes, initial
    expedited reports should be submitted within the
    time limits as soon as the minimum following
    criteria are met
  • a suspected investigational medicinal product or
    an accompanied medicinal product
  • an identifiable subject,
  • an adverse event assessed as serious and
    unexpected, and for which there is a reasonable
    suspected causal relationship,
  • an identifiable reporting source,
  • and, when available and applicable
  • an unique clinical trial identification, if
    applicable(Eudract number or in case of non-EU
    trials the sponsor's trial protocol code number)
  • an unique case identification (i.e. case
    identification number in the sponsor's safety
    database for ARs of medicinal products).

25
  • 6.3.1.6.3 Format of the SUSAR reports
  • The CIOMS-I form is a widely accepted
    standard for expedited adverse reactions
    reporting.
  • However, no matter what the form or format
    used, it is important that the basic information
    / data elements described in annex 3, when
    available, be included in any expedited
    report.(some items may not be relevant,
    depending on the circumstances for initial
    expedited reporting see also section 6.3.1.5.1) .
  • Electronic reporting should be the expected
    method for expedited reporting of SUSARs to the
    competent authority. In that case the format and
    content as defined by the ENTR-6101 Detailed
    Guidance on the European database of Suspected
    Unexpected Serious Adverse Reactions
    (Eudravigilance-Clinical Trial Module) should be
    adhered to.
  • 6.3.1.5.4 Form and format of the reports
    about other obser- vations also
    qualifying for expedited reporting
  • Other important observations also
    qualifying for expedited reporting (see section
    6.3.1.1.2 ), should be notified by letter.

26
6. Sponsors Responsibilities
  • 6.3.1.6.5 How to inform the EC of the MS
  • Member States may take measures to permit
    that the Ethics Committee concerned could only
    receive expedited individual SUSAR reports
    occurred to subjects who have been recruited at
    that Member State, provided that
  • a) SUSARs from other Member States or from
    third countries are reported at least
    quarterly, as a line listing accompanied by a
    brief report by the sponsor highlighting the
    main points for concern
  • b) any changes increasing the risk to
    subjects and any new information that may
    affect adversely y the safety of the
    subjects or the conduct of the trial should also
    be provided as soon as possible, but within
    a minimum of fifteen days.

27
6. Sponsors Responsibilities
  • 6.3.1.8 Managing events/adverse reactions in
    blinded trials and high morbidity and
    high mortality diseases
  • As a general rule treatment codes should be
    broken by the sponsor before reporting a SUSAR to
    the competent authority and the Ethics Committee
    of the concerned Member States.
  • Although it is advantageous to retain the
    blind for all patients prior to final study
    analysis, when a serious adverse event may be a
    serious unexpected or otherwise adverse reaction
    which is judged reportable on an expedited basis,
    it is recommended that the blind be broken only
    for that specific patient by the sponsor even if
    the investigator has not broken the blind.
  • It is also recommended that, when possible
    and appropriate, the blind be maintained for
    those persons, such as biometrics personnel,
    responsible for data analysis and interpretation
    of results at the studys conclusion.
  • The unblinding of single cases by
    investigators in the course of a clinical trial
    should only performed if relevant for the safety
    of the trial subject.

28
6. Sponsors Responsibilities
  • 6.3.1.8 Managing events/adverse reactions in
    blinded trials and high
    morbidity and high mortality
    diseases
  • It is recommended that in cases of a blinded
    study, the case is assessed for seriousness,
    expectedness and causal relationship as if it was
    the tested IMP that caused the reaction.
  • If the case is a SUSAR then the case will be
    unblinded.
  • Then two possibilities have to be taken into
    account
  • The administered IMP is the tested IMP The case
    will be reported as a SUSAR to the relevant
    CAies.
  • The administered IMP is an authorised
    comparator The event is re-assessed for
    expectedness according to the SPC as
    included in the protocol.
  • If the event is unexpected the SUSAR will be
    reported
  • otherwise it is a suspected serious ADR and
    not reportable on an expedited basis.

29
6. Sponsors Responsibilities
  • Managing adverse reactions/events in trials with
    high morbidity and high mortality diseases
  • For trials where efficacy end-points could also
    be SUSARs or when a fatal or other "serious"
    outcome is
  • the primary efficacy endpoint in a clinical
    trial,
  • the integrity of the clinical trial may be
    compromised if the blind is broken.
  • Under these and similar circumstances, it may be
    appropriate to reach agreement with competent
    authorities in advance concerning serious events
    that would be treated as disease-related and not
    subject to systematic unblinding and expedited
    reporting.
  • Modalities for reporting these adverse
    reactions must be clearly defined in the
    protocol.

30
6. Sponsors Responsibilities
  • 6.3.1.8 Managing adverse reactions/events in
    trials with high morbidity
    and high mortality diseases
  • For those trials sponsors are highly encouraged
    to appoint an independent Data Monitoring Board
    (DMB) in order to review, on a regular basis
    safety data on the ongoing trial and to recommend
    the sponsor whether to continue, modify or
    terminate the trial.
  • This procedure must be described in the protocol.
  • The DMB opinion and recommendations should be
    notified as soon as possible by the sponsor to
    the competent authority and the Ethics Committee
    in the concerned Member State where they qualify
    for expedited reporting (see section 6.3.1) as
    soon as possible.
  • However cases of SUSARs, in these same studies,
    that are not efficacy endpoints should be
    reported as usual.

31
6. Sponsors Responsibilities
  • 6.3.1.9 Managing SUSARs associated with active
    comparator or placebo
  • 6.3.1.9.1 SUSARs associated with active
    comparator
  • The sponsor must report to the competent
    authority and the Ethics Committee of the
    concerned Member States all SUSARs associated
    with a comparator product in a clinical trial.
  • In addition, it is recommended that the
    sponsor report them to the marketing
    authorisation holder.
  • 6.3.1.9.2 SUSARs associated with placebo
  • Events associated with placebo will usually
    not satisfy the criteria for a serious adverse
    drug reaction and therefore for expedited
    reporting.
  • However, where SUSARs are associated with
    placebo (e.g. reaction due to an excipient), it
    is the sponsor's responsibility to report such
    cases.

32
6. Sponsors Responsibilities
  • 6.3.2 Annual safety reports
  • In addition to the expedited reporting,
    sponsors shall submit,
  • once a year throughout the clinical trial
  • or on request
  • an annual safety report to the competent
    authority and the Ethics Committees of the
    concerned Member States, taking into account all
    available information.

33
6. Sponsors Responsibilities
  • 6.3.2.1 Content of the annual safety report
  • The annual safety report should have
    three parts
  • a line listing of all suspected SARs (including
    all SUSARs) occurred in the concerned trial,
  • aggregate summary tabulation of suspected SARs
    that occurred in the concerned trial,
  • a report on the subjects safety
  • When the sponsor is responsible for
    several clinical trials with the same tested IMP
    in Community, the annual safety report should
    include
  • per trial line listing and aggregate summary
    tabulations,
  • a report on the subjects safety on the tested
    IMP taking into account all the data collected in
    the whole development program.
  • In the case the tested IMP is authorised
    and marketed in any MS, the annual safety report
    could be append as a special part of the in
    Periodic Safety Update Report (PSUR).

34
6. Sponsors Responsibilities
  • 6.3.2.1.2 Aggregate summary tabulations
  • In addition to individual cases line
    listings, summary tabulations of SAR terms for
    signs, symptoms across all patients should
    usually be presented to provide an and / or
    diagnoses overview for the trial.
  • These tabulations ordinarily contain more
    terms than subjects.
  • When the number of cases is very small, a
    narrative description should be more suitable.
  • The aggregate summary tabulation should
    specify the number of reports
  • for each body system
  • for each ADR term
  • for each treatment arm, if applicable (IMP,
    comparator or placebo, blinded treatment).
  • The unexpected ADR terms should be clearly
    identified in the tabulation.
  • As an example, the table in annex 5 can be
    used.

35
6. Sponsors Responsibilities
  • 6.3.2.1.3 Report on the subjects safety
  • The sponsor has to provide with his
    opinion a concise benefit-risk evaluation for
  • the clinical trial
  • or and, if applicable, for all concerned clinical
    trials conducted world wide with the tested
    investigational drug.
  • This report has to should be related to
    the overall safety of the investigational
    medicinal product being tested IMP, that could be
    "investigational product specific" and valid for
    the safety report of all trials that the sponsor
    conduct wold wide.
  • It should be complemented with an
    analysis of the implications for the population
    of the clinical trial, which should be "trial
    specific".
  • It should analyse the safety profile of
    the tested IMP and its impli-cation to subjects'
    exposure, taking into account all available
    safety data.

36
6. Sponsors Responsibilities
  • 6.3.2.1.3 Report on the subjects safety
  • When relevant, the following points should be
    considered
  • relation with dose, duration, time course of the
    treatment
  • reversibility
  • evidence of previously unidentified toxicity in
    the trial subjects
  • increased frequency of toxicity
  • overdose and its treatment
  • interactions or other associated risks factors
  • any specific safety issues related to special
    populations,such as the elderly, the children or
    any other at risk groups.
  • positive and negative experiences during
    pregnancy or lactation
  • abuse
  • risks which might be associated with the
    investigation or diagnostic procedures of the
    clinical trial

37
6. Sponsors Responsibilities
  • 6.3.2.1.3 Report on the subjects safety
  • Supporting results of non-clinical studies or
    other experience with the investigational
    medicinal product that are likely to affect the
    subjects' safety shall also be considered.
  • Where appropriate the measures previously or
    currently proposed to minimise the risks found
    will also be detailed.
  • Finally, a detailed rationale must be given
    on whether or not it is necessary to amend the
    protocol, to change or update the consent form,
    patient information leaflet and the
    investigators brochure.
  • This report will not replace the request for
    protocol amendments, which will follow its own
    specific procedure.

38
  • 6.3.2.2 Reporting time frame for annual safety
    report
  • The reporting time frame for annual reports
    starts with the date of the first authorisation
    of the clinical trial of the sponsor by a
    competent authority in any Member State.
  • This date is designated as the cut off for
    data to be included in the annual safety report.
  • The sponsor should submit annual reports
    within 60 days of the data lock point.
  • However if a sponsor conducts several
    clinical trials with the same tested
    investigational medicinal product in any Member
    State, the reporting period starts with the date
    of the first authorisation for one of these
    trials by the competent authority in any Member
    State and ends after close of the last trial.
  • Furthermore if the sponsor is the marketing
    authorisation holder of the tested IMP and if the
    IMP has a marketing authorisation in any Member
    State and is on the market, the reporting period
    starts with the International Birth Date used for
    the PSUR.
  • The reporting period ends after close of the
    clinical trial/s in last Member State.

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6. Sponsors Responsibilities
  • 6.3.2.2 Reporting time frame for annual safety
    report
  • In the case of short term trials, which are
    regularly finished within a time period for
    maximal 6 months, the safety report should be
    notified within 90 days of the end of trial
    together with the notifying according to
    Directive 2001/20/EC article 10 c).
  • This report should contain at least line
    listings, if appropriate aggregate summary
    tabulations and a statement of the patients
    safety.

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6. Sponsors Responsibilities
  • 6.3.2 Annual safety reports
  • 6.3.2.3 Whom to report ?
  • The sponsor should submit at the same time
    the annual safety report to the concerned
    competent authorities and Ethics Committees
    concerned.

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6. Sponsors Responsibilities
  • 6.4 How to inform the investigators ?
  • The sponsor shall inform all investigators
    concerned on findings that could adversely affect
    the safety of study subjects.
  • If appropriate, the information can be
    aggregated in a line listing of SUSARs in periods
    as warranted by the nature of the clinical
    de-velopment project and the volume of SUSARs
    generated.
  • This line listing should be accompanied by a
    concise summary of the evolving safety profile of
    the investigational medicinal product.
  • In the case of blinded trials the line
    listing should present data on all SUSARs,
  • regardless of the medication administered (e.g.
    active / placebo), thereby when possible and
    appropriate,
  • maintaining the blind be maintained and reducing
    the risk of inadvertently informing the
    investigators with regard to the identity of the
    medication should be avoid.

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6. Sponsors Responsibilities
  • 6.4 How to inform the investigators ?
  • If a significant safety issue is identified,
    either upon receipt of an individual case report
    or upon review of aggregate data, the sponsor
    should issue as soon as possible a communication
    to all investigators.
  • A safety issue that impacts upon the course
    of the clinical study or development project,
    including suspension of the study programme or
    safety-related amendments to study protocols
    should be considered significant.

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6. Sponsors Responsibilities
  • 6.5 Reporting for safety issues following
    completion of the clinical trial in EU
  • After the termination of a CT, any event that
  • could change the risks benefit analysis
  • and may have an impact on the subjects, who
    have participated in it,
  • should be reported as soon as possible to the
    CA/ies concerned together with proposed actions.

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