DIA Conference Talk USA, The EU Directive - Germany

Managing, Inspecting, and Conducting Clinical Trials after the EU Directive

Dr. Diana A. Taylor, MSc

Establishing Competitive Advantage in Today’s

Pharmaceutical and Biothech Industries:

The Integration of Project Management, Financing, and Outsourcing Porcesses

The Drug Information Association

Philadelphia, USA, February 22nd 2005

[email protected] DIA Philadelphia 02/2005 DAT

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Contents

The German Drug Law and Regulations: How was the EU Directive Implemented into National Law

Project Management: Implementing German Drug Law and Requirements into Company Processes

A Case Study: Practical Experience with the German Authorities


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The German Drug Law

Arzneimittelgesetz, AMG 6th August 2004

GCP-Rechtsverordnung

14th August 2004

3. Bekanntmachung

30 August 2004

www.bfarm.de

Bundesinstitut für Arzneimittel


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The German Drug Law, AMG

The Investigator & the Sponsor - R & R The Role of the Ethics Committees The Duties of the Competent Authority The Inspections in Germany


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The Investigator & the Sponsor

§ 40 (1) German Drug Law

The Investigator and the Sponsor have to comply with the requirements for Good Clinical Practice when conducting clinical trials according to Article 1 Paragraph 3 of the Directive 2001/20/EC of the European Parliament and the Council of 4th April 2001...


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The Investigator defined

§ 4 (25) Prüfer ist in der Regel ein für die Durchführung der klinischen Prüfung bei Menschen in einer Prüfstelle verantwortlicher Arzt

oder in begründeten Ausnahmefällen eine andere Person, deren Beruf auf Grund seiner wissenschaftlichen Anforderungen und der seine Ausübung voraussetzenden Erfahrungen in der Patientenbetreuung für die Durchführung von Forschungen am Menschen qualifiziert.


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The Investigator defined

§ 4 (25) Investigator is usually a medical doctor responsible for the conduct of a clinical investigation in humans in an investigational site,

or in case of a justified exception, another person, whose profession qualifies him/her for the conduct of research in humans on the basis of its scientific requirements and who has experience in patient care through the execution of the profession.


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The Investigator as Manager

§40 (1.5) a clinical investigation may only be responsibly

conducted ... by an adequately qualified investigator

and the director of the clinical investigation is an investigator, a principal investigator or a co-ordinating investigator with proven experience of at least 2 years in clinical investigations with drugs.

Not a medical doctor


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Investigator or Doctor?

§40 (1.9)

a clinical investigation may only be conducted

für die medizinische Versorgung der betroffenen Person ein Arzt ... verantwortlich ist

if for the medical care of the concerned person ... a medical doctor is responsible


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Investigator - Sponsor transfer of duties

Anzeigepflicht des Prüfers nach § 67 des AMG bei der zuständigen Behörde

Abschnitt 4. 12 (3)

Der Prüfer kann dem Sponsor die Durchführung der Anzeigen bei der zuständigen Behörde übertragen und hat dies zu dokumentieren.

The investigator may transfer his duties towards the CA to the sponser and must document this.


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Drug Safety in Clinical trials

§13 Duties of the Sponsor

To document in detail all AE reported by the investigators

To submitt, on request, to the National CA and to the CA of other MS, and to all investigators:

SUSARs within 15 days Death within 7 days + 8 days Issues requiring new benefit/risk assessment within 15 days


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Clear ways - uncertain means

§40 (1.7) Each investigator must be informed by

a scientist responsible for the pharmacological-toxicological tests about their results and foreseeable risks regarding the clinical investigation personally or in writing

consultation or Investigator’s Brochure


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National nuances - international compliance?

one site - many investigators - principle investigator

many sites - Sponsor appoints Leiter der klinischen Prüfung - co-ordinating investigator

according to ICH E6, not to EU Directive investigator principle investigator co-ordinating investigator


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Sponsors, Representatives & Logistics

§ 40 (1.1)

a clinical investigation may only be conducted if

... ein Sponsor oder ein Vertreter des Sponsors vorhanden ist, der seinen Sitz in einem Mitgliedstaat der EU ... hat.

... a sponsor or a representative of the sponsor is available with a residence in one of the MS of the EU


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The changed role of the Ethics Committee

From adviser to authority under the law

Legal responsibility + Legal accountability in place? -


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Functions of the Ethics Committee

Single Opinion - Single Ethics Committee in each Member State

Local Ethics Committees – National regulations

Beginning of the Clinical Trial Amendment of the Protocol End of Clinical Trial


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National nuances with the Ethics Committees in D

§40 (1.2) The Central Ethics Committee - responsibility of

each Federal State

no explicit positive vote from the Ethics Committee - no clinical study, even if the CA gives permission

vote from Ethic Committee is to be monitored by the sponsor

(max 60 days)

The local Ethics Committees responsible for the local clinical study site and its staff supplies the central Ethics Committee with an opinion within

30 days (no monitoring by the sponsor)


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Documents for the Ethics Committee

Member State specific

Protocol related

Investigational medicinal product related

Facilities & staff related

Finance related

Subject related ... The Patient


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Patient Information:

real time with the doctor

§40 (2) Die betroffene Person ist durch einen Prüfer, der Arzt ist, ...

aufzuklären; ihr ist eine allgemein verständliche Aufklärungsunterlage auszuhändigen.

Persönliches Gespräch - “Gelegenheit zu einem Beratungsgespräch mit einem Prüfer ...”

The concerned person must be enlightened by an investigator who is a medical doctor; she/he must be given a generally understandable enlightening materials

Personal conversation - “occasion for a personal consultation with an investigator ...”


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On the presumed will of the minor

§40 (4)

Consent of minors

the explicit wish of the minor is to be considered


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Group benefit

§41 (2.1)

the clinical study must be for the benefit of a minor, suffering a disease

or

§41 (2.2 a)

the clinical study must be of direct benefit for the group of patients, who suffer the same disease


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Protecting the child patient: New demands - New institutions

§42 (1) The Ethics Committee must provide an external expert opinion when giving an opinion on a clinical trial with

children

The BfArM will install a commission for medicines for children and adolescents


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Procedures & Timelines

with the Ethics Committee

§42 - procedures at the Ethics Committee - positive opinion is compulsory - single opinion from a single MS

Application by the Sponsor with the Ethics Committee of

the Investigator

the Principal Investigator

the Co-ordinating Investigator


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Procedures & Timelines with the Ethics Committee

Application – within 10 days confirmation of receipt 14 days deadline for formal deficiencies

* subsequently explicit opinion within 60 days * 1x request for additional informationen – clock stop

Single centre studies (10 + 14 days) * subsequently explicit opinion within 30 days

Single centre Phase I studies from a drug development project known to the EC – within 14 daysIMP for gene therapy, somatic cells, and IMP containing genetically modified organisms (10 + 14 days) subsequently 60 + 30 + 90 daysXenogenic cell therapy - œ Sponsor must monitor deadlines – remind, demand & warn


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Procedures & Timelines with the Ethics Committee

Substantial amendment - 20 days explicit somatic cells, IMP containing genetically

modified organisms, and IMP for gene therapy - 35 days

xenogenic cells - œ Additional investigational site - 30 days

from the central EC, implicit


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Procedures & Timelines

with the Competent Authorities Application - within 10 days confirmation of receipt 14 days deadline for formal deficiencies

* subsequently within 30 days opinion implicit * 1x objection - Sponsor has 90 days to respond * subsequently 15 days explicit

Single centre Phase I studies from a drug development project known to the CA – within 14 daysIMP for gene therapy, somatic cells, and IMP containing genetically modified organisms (10 + 14 days) subsequently 60 + 30 + 90 days explicitxenogenic cells - œ explicitAmendments - 20 days implicit somatic cells, IMP for gene therapy, and IMP containing genetically

modified organisms - 35 days xenogenic cells - œ


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National nuances with the Competent Authority in Germany

Is the BfArM satisfied ?

Implicit authorisation

Sequential application or in parallel with the Ethics Committee

Flexible interpretation of time-lines, e.g. Phase I studies from a drug development project

known to the CA - within 14 days


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Duties of the Competent Authority - the Inspections

adequate number of inspectors

sufficient resources for inspections also on request by EMEA

inspectors are adequately qualified and trained

declaration of interest about any financial ties to inspected parties

suitable means of identification of inspectors


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Inspections after AMG

§64 AMG – supervision

§25 AMG – during application for marketing

authorisation

§15 GCP-V Inspections are conducted on behalf of the EU and

are recognised by the other Member States Inspections are registered in the EudraCT

database


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Contents


Project Management: Implementing German Drug Law and Regulations into Company Processes



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Project Management ... Company Processes

SOP Handbook

specific roles and responsibilities

skills, competencies & CVs

relevant qualifications

appraisal system

continuous education & training


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Implementing German Drug Law into company processes

Arzneimittelgesetz, AMG 6th August 2004

GCP-Rechtsverordnung

14th August 2004

3. Bekanntmachung

30 August 2004

www.bfarm.de

Bundesinstitut für Arzneimittel


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The EudraCT number

Appoint and train a single or a number of Users for the EudraCT databaseAppoint a team responsible for a clinical trialRelease a synopsis for a clinical trial specifying all the information needed for the EudraCT number and also all the MS involved – at least 6 months before the planned application with the competent EC & CACo-ordination between the MS invoved – with which CA will the sponsor apply for the EudraCT numberObtain the application forms from the EudraCT database


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The Application forms

Ensure the application form for the EC and the CA are identical§7 of the GCP-V describes in detail which documents are to be attached to each applicationSubmitt the application both in electronic and in paper format (4 copies); each local EC receives one copy as well (ensure documentation of receipt)Ensure that the documents in each set are identical and completeMonitor the updates of documents with the EC and CA in each MS and between MS


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Approval Amendment End

After approval, ensure complete communication to all involved parties – sponsor, CA, EC & CA in MS involvedSubstantial amendments – definitions – application form – communicationOther amendments – definitions – documentation for inspection – communicationEnd of clinical trial form (90 days) – definition: last visit last patient or data base lock / Termination or Suspension (15 days) – inform CA, EC and CA of MS involvedIf an EudraCT number was received but no clinical trial was initiated: after EU directive – end of trial form, after GCP-V in Germany – no mention – not clarified yetSubmitt a summary of the clinical tgrial report within 1 year after end of trial – internal process management – medical writing


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Inspections in Germany

An inspection may take place before the start of a clinical trial – during the application procedure, during the conduct of a trial and after the end of a trial Ensure that all documents at all sites involved are

complete and available (ICH E6 on GCP) Ensure that requirements concerning sponsor, CRO,

investigation sites and relevant staff are met Decide on archiving of the documents at the sponsor –

centralised (at Regulatory Affairs or at Clinical Development) or decentralised (at Regulatora Affairs and at Clinical Development and at Drug Safety etc)


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Training & Education

Assess available SOPs and adjust to new regulations appropriately

Compile a new Handbook of SOPs

Train relevant staff on new SOPs

Document training sessions … and outcomes!


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Contents


Project Management: Implementing German Drug Law and Regulations into Company Processes



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A case study experience

Single centre, bioavailability, asthma, drug for inhalation, CRO (after GCP-V 30 days) July 2004 – beginn of project Application on 8th October 2004

Confirmation of receipt on 21st October (>10 days) Meeting of the EC on 4th November Request for further information:

dated 5th November, received 8th November Reply to request on 11th November Positive vote on XXXXXX


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Request for further information

Confirmation by each investigator on received information on toxicological-pharmacological properties of the IMP

Explicit mentioning of Insurance sum Insurance conditions

Laboratory safety tests: Blood clotting TSH


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Documents with the application form

Information for the investigator: IB or SPC – document from the Co-ordinating investigator on successful information about toxicological-pharmacological properties of the IMP plus confirmation letter on the subject from each investigator

Justification for sex distribution of subjects

Compassionate use programme (after end of trial)

Agreement between sponsor and investigation site (use FDA forms)


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Tipps and advice

When cross-reference to documents – supply copies of referenced documents at that place in the file

No legal regulation for the EC Academic EC EC under the Federal Commissions of Medical Professionals

Formal check by the CA formalistic – new staff

No differentiation between formal check and content Mainly labeling and IMP dossier

Use additional documents for information on labeling 3. Bekanntmachung (draft) will regulate information for uniform

IMP dossier – no EU document yet available


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Thank you

Dr. Diana A. Taylor, MSc

DIA Conference Talk USA, The EU Directive - Germany

Health & Medicine

Transcript of DIA Conference Talk USA, The EU Directive - Germany