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

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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
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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

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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.
  

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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

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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

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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

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2. Anforderungen der Anleitung CT-05-EN

• Was wird geregelt?
• Introduction
• Legal Basis
• Scope
• Definitions
• Investigators Responsibilities
• Sponsors Responsibilities

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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).
  

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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.

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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

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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.

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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.

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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.

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• 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).

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• 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).

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• 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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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).

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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.

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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.

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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

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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.

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• 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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