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

3. Anforderungen der RL 2001/20/EG - Art. 16, 17,18 Pflichten des Pr�fers Art. 16 (1) - (3) Berichte �ber alle SAEs an den Sponsor Fristen: unverz�glich, nachfolgend ausf�hrlich schriftlich - (2) AEs, Laboranomalien, die im Pr�fplan f�r die Unbedenklichkeits- entscheidungen als entscheidend bezeichnet werden, sind dem Sponsor innerhalb der im Pr�fplan 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 �ber alle SUSARs an die zust�ndige BOB und die EK, Fristen: 15 d / Todesf�lle 7 d (1) d Unterrichtung der Pr�fer �ber SUSARs (2) Listen aller SSARs, Jahresberichte zur Sicherheit der Pr�fungsteilnehmer

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 f�r die Erstellung, Pr�fung, Vorlage der Berichte zu SAEs/SARs, Modalit�ten der Dekodierung

6. CT-05-EN (fr�her 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 Investigator�s Responsibilities Sponsor�s Responsibilities

8. 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. investigator�s 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. 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. 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 pr�fenden Person Die pr�fende Person informiert den Sponsor innerhalb der im Pr�fplan angegebenen Fristen �ber unerw�nschte Ereignisse oder unerwartete klinisch-diagnostische Befunde, die f�r die Bewertung der Unbedeklichkeit von Bedeutung sind. Dabei sind die ausf�hrlichen Anleitungen f�r die Erstellung, Pr�fung und Vorlage der Berichte �ber unerw�nschte Ereignisse zu beachten

13. Entwurf RVO nach � 42 (3) AMG �� 12 und 13 � 12 Pflichten der pr�fenden Person Die pr�fende Person unterrichtet den Sponsor unverz�glich �ber das Auftreten eines schwerwiegenden unerw�nschten Ereignisses [SAE] und �bermittelt ihm anschlie�end einen ausf�hrlichen schriftlichen Bericht. Die Identifikation der Pr�fungsteilnehmer und �innen in der Unterrichtung und dem schriftlichen Bericht beschr�nkt sich auf die Nennung der entsprechenden Codenummer laut Pr�fplan. Satz 1 gilt nicht f�r solche Ereignisse, �ber die laut Pr�fplan nicht unverz�glich berichtet werden muss.

14. Entwurf RVO nach � 42 (3) AMG �� 12 und 13 � 12 Pflichten der pr�fenden Person (3) Im Fall des Todes eines Pr�fungsteilnehmers oder einer � teilnehmerin informiert der Pr�fer unverz�glich auch die EK, (???) bei multizentrischen Studien alle beteiligten EKs, sowie die zust�ndige BOB

15. Entwurf RVO nach � 42 (3) AMG �� 12 und 13 � 13 Pflichten des Sponsors (1) Der Sponsor dokumentiert ausf�hrlich alle unerw�nschten Ereignisse, die ihm von den Pr�fern mitgeteilt werden. Diese Aufzeichnungen werden der zust�ndigen Bundesoberbeh�rde und, soweit zutreffend, den zust�ndigen Beh�rden anderer Mitgliedstaaten der Europ�ischen Union, in deren Hoheitsgebiet die klinische Pr�fung durchgef�hrt wird, auf Antrag zugeleitet.

16. Entwurf RVO nach � 42 (3) AMG �� 12 und 13 � 13 Pflichten des Sponsors Der Sponsor unterrichtet �ber jeden ihm bekannt gewordenen Verdachtsfall einer unerwarteten schwerwiegenden Nebenwirkung unverz�glich, sp�testens aber innerhalb von 15 Tagen nach Bekanntwerden die Ethik-Kommission, die zust�ndige Bundesoberbeh�rde und, soweit zutreffend, die anderen an der Pr�fung beteiligten Pr�fer sowie die zust�ndigen Beh�rden anderer Mitgliedstaaten der Europ�ischen Union, in deren Hoheitsgebiet die klinische Pr�fung durchgef�hrt wird.

17. Entwurf RVO nach � 42 (3) AMG �� 12 und 13 � 13 Pflichten des Sponsors Der Sponsor �bermittelt bei jedem ihm bekannt gewordenen Verdachtsfall einer unerwarteten schwerwiegenden Nebenwirkung, die zu einem Todesfall gef�hrt hat oder f�hren kann, unverz�glich, sp�testens aber innerhalb von 7 Tagen nach Bekanntwerden, der EK, der zust�ndigen BOB und, soweit zutreffend, den zust�ndigen Beh�rden anderer Mitgliedstaaten der Europ�ischen Union, in deren Hoheitsgebiet die klinische Pr�fung durchgef�hrt wird, alle f�r die Bewertung wichtigen Informationen und informiert innerhalb von h�chstens acht weiteren Tagen �ber alle von ihm oder von der pr�fenden Person in diesem Zusammenhang getroffenen Ma�nahmen.

18. Entwurf RVO nach � 42 (3) AMG �� 12 und 13 � 13 Pflichten des Sponsors Der Sponsor legt der EK, der zust�ndigen BOB und, soweit zutreffend, den zust�ndigen Beh�rden anderer Mitgliedstaaten der Europ�ischen Union, in deren Hoheitsgebiet die klinische Pr�fung durchgef�hrt wird, w�hrend der Dauer der Pr�fung einmal j�hrlich eine Liste aller w�hrend der Pr�fung aufgetretenen Verdachtsf�lle schwerwiegender Nebenwirkungen sowie einen Bericht �ber die Sicherheit der Pr�fungsteilnehmer und Pr�fungsteilnehmerinnen vor.

19. 6. Sponsor�s 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 Sponsor�s 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. Sponsor�s 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 investigator�s causality assessment, both, the opinion of the investigator and the sponsor should be provided with the report.

21. 6. Sponsor�s Responsibilities 6.2.3 Sponsor�s 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. Sponsor�s 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. Sponsor�s 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. Sponsor�s 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 study�s 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. Sponsor�s 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. Sponsor�s 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. Sponsor�s 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. Sponsor�s 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. Sponsor�s 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. Sponsor�s 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. Sponsor�s 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. Sponsor�s 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. Sponsor�s 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. Sponsor�s 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 investigator�s 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.

39. 6. Sponsor�s 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.

40. 6. Sponsor�s 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.

41. 6. Sponsor�s 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.

42. 6. Sponsor�s 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.

43. 6. Sponsor�s 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.