Document Sample
					 Good Clinical Practice
Regulation Update 2005

        Joan Perou
  GCP Trainer & Consultant

       November 2005
Clinical Trial Regulation
    - Who makes the

   1977 Food and Drug Administration (FDA) issued proposed
    rules for investigators, and sponsors.
   These were extended and became known as the Code of
    Federal Regulations; Title 21 Food & Drugs
   These FDA regulations laid down specific obligations for
    investigators, sponsors and ethics committees and were
    backed up by Federal Law
   FDA Inspectors conduct mandatory Inspections to ensure
    compliance with the Federal Regulations.
    The European Commission

   Controls legislation on pharmaceuticals throughout
    the EU
   Recent Directive 2001/20/EC makes GCP a legal
    requirement across 25 Member States from 1 May
   The European Commission demands that every
    Member State must appoint a ‘Competent Authority’
    to ensure compliance with the Directive
   The Medicines and Healthcare
products Regulatory Agency (MHRA)

   UK ‘Competent Authority’ (CA)
   Based in London
   Grants licences to conduct trials
   Monitors safety aspects of trials
   Provides enforcement - mandatory Inspections
    (started May 2004)
What are ‘the rules’ ?
           Good Clinical Practice
            The EU Standards
   ICH E6 Document
    Scientific Guideline - ‘Must be taken into account’

   EU Directive (2001/20/EC)
    Law across 25 Member States from 1st May 2004

   EU Directive 2005/28/EC
    European Law from 29 April 2005 – must be transposed
    into Member States own Laws from 26 January 2006

   National Laws
    Member States must transpose Directives into National
    Law and incorporate ‘choices’ .
           The European Union
            25 Member States

   Austria             Cyprus
   Belgium             Czech Republic
   Denmark             Estonia
   France              Hungary
   Finland             Latvia
   Germany             Lithuania
   Greece              Malta
   Ireland             Poland
   Italy               Slovenia
   Luxembourg          Slovakia
   Netherlands
   Portugal
   Spain               400 million people
   Sweden              20 official languages
   United Kingdom
An international ethical and scientific quality standard for
designing, conducting, recording and reporting trials that
involve the participation of human subjects. Compliance with
this standard provides public assurance that the rights, safety
and well-being of trial subjects are protected, consistent with
the principles that have their origin in the Declaration of
Helsinki and that the clinical trial data are credible.

ICH Guideline
Milestones in Good Clinical Practice

 1977   Federal Registers published in U.S. by FDA

 1986   UK published guidelines ‘Good Clinical Research

 1987   France and Nordic Countries published laws

 1990   European GCP Guidelines published

 1996   International Conference on Harmonisation produced
        ICH GCP E6 document.
   International Conference on Harmonisation
   of Technical Requirements for Registration
        of Pharmaceuticals for Human Use

ICH E6 GCP document
 one of 38 original documents - part of the ICH process
 The only document to cover Good Clinical Practice standard
 Signed off by U.S., Europe, Japan in July 1996
 Implemented on 17 January 1997
 The accepted standard for clinical trials from January 1997
  for registration studies
 Law in Japan
 Recognised in US for data generated outside U.S
 Adopted by many other countries outside the ICH region and
  incorporated into country laws by some - potential global
     ICH Good Clinical Practice
      Guideline (E6 Document)

This guideline should be followed when generating
clinical trial data that are intended to be submitted
to regulatory authorities.

The principles established in this guideline may
also be applied to other clinical investigations that
may have an impact on the safety and well-being of
human subjects
              EU Directive (2001/20/EC)

   Published in the Official Journal of the European
    Communities on 1 May 2001
   The Directive was implemented across Member States on
    1 May 2004
   The Directive is applicable to all clinical trials on human
    subjects involving medicinal products.
   The Directive does not apply to non-interventional trials
         EU Directive (2001/20/EC)

   Makes GCP a legal requirement in European Member
   Mandatory GCP inspections
   Added protection for vulnerable patients who are
    unable to give legal informed consent
   National ethics committees operating within a legal
    framework with firm deadlines for approval
   Applies to commercial and non-commercial clinical
    trials involving investigational medicinal products
           EU Directive (2001/20/EC)


   Regulatory approval system for clinical trials in the EU
   Manufacture and labelling of drugs in the EU must
    comply with GMP (Good Manufacturing Practice)
   Adverse event reporting in Europe via Eudravigilance
   Information exchange between member states by
    means of a database of trial information (EudraCT
        EU Directive (2001/20/EC)

Protection of the Trial Subject
 Legal Representative required for those patients
  unable to give legal informed consent
 Emphasis on Data Protection Directive (95/46/EC)
 Insurance/indemnity to cover the liability of the
  investigator and sponsor
 Medical care and medical decisions must be the
  responsibility of a qualified doctor or dentist
 Prior interview referred to for informed consent
 Contact point for all trial participants
 Additional protection for ‘vulnerable groups’
          EU Directive (2001/20/EC)

    Commencement of a Clinical Trial (Article 9)
    The sponsor may not start a clinical trial until:

   The ethics committee has issued a favourable opinion

   The Competent Authority of each Member State
    concerned has not informed the sponsor of any
    grounds for non-acceptance.
              EU Directive (2001/20/EC)

    Commencement of a Clinical Trial (Article 9)

   Prior to commencing a trial the sponsor must submit a
    request for authorisation to the Competent Authority of the
    Member State in which the sponsor plans to conduct the
    clinical trial.
   Competent Authority must consider application within 60
    days (maximum)
    (some exceptions apply for certain medicinal products)
   Competent Authority approval and ethics favourable
    opinion can run in parallel
           EU Directive (2001/20/EC)

Amendments :
 Sponsors may make amendments to the protocol at
  any time.
 Three categories of amendment have been identified
  under the Directive:

   substantial
   non-substantial
   safety issues

   Sponsor must assess on an individual basis whether or
    not amendment is substantial
            EU Directive (2001/20/EC)
            Substantial Amendments

    Defined as where they are likely to have a significant
    impact on:

   the safety or physical or mental integrity of the subjects
   the scientific value of the trial
   the conduct or management of the trial
   the quality or safety of any IMP used in the trial
            EU Directive (2001/20/EC)
            Substantial Amendments
    Implementation of Substantial amendments:

   Substantial amendments must be sent to Competent
    Authority and Ethics Committee
   Ethics Committee must give an opinion within 35 days
   Competent Authority must notify sponsor within 35 days if
    there are grounds for refusal.
   If the EC give favourable opinion and there is no
    communication from the CA within 35 days, sponsor may
    implement amendment
   If the CA notify the sponsor of their objection there is no time
    limit for CA to authorise amendment
                          EU Guidance on
    the request for authorisation of a clinical trial on a medicinal
        product for human use to the competent authorities
                       ENTR/CT 1 Revision 1

Examples of Substantial Amendments:

    The following five slides are examples of ‘substantial’
     amendments which need to be approved by the Competent
     Authority and/or Ethics Committee
Examples of Substantial Amendments:
(Amendments related to protocol)
   Purpose of trial
   Design of trial
   Informed Consent
   Recruitment procedure
   Measures of efficacy
   Schedule of samples
   Addition or deletion of tests or measures
   Number of participants
   Age range of participants
   Inclusion criteria
   Exclusion criteria
   Safety Monitoring
   Duration of exposure to the investigational medicinal product or comparator
   Change of posology of the IMP
   Change of comparator
   Statistical analysis
                   Substantial Amendments

Examples of Substantial Amendments:
(Amendments related to the IMP)
   Change or name or code of IMPs
   Immediate packaging material
   Manufacturer (s) of active substance
   Manufacturing process of the active substance
   Specifications of active substance
   Manufacture of the medicinal product
   Specifications of the medicinal product
   Specification of excipients where these may affect product performance
   Shelf-life including after first opening and reconstitution
   Major change to the formulation
   Storage conditions
   Test procedures of active substance
   Test procedures of the medicinal product
   Test procedures of non-phamacopoeial excipients
                Substantial Amendments

Examples of Substantial Amendments:
(Amendments related to the trial arrangements)

   Change of the principal investigator or addition of new ones
   Change of the co-ordinating investigator
   Change of the trial site or addition of new sites
   Change of the sponsor or legal representative
   Change of the CRO assigned significant tasks
   Change of the definition of the end of the trial
                 Substantial Amendments

Examples of Substantial Amendments:
(Changes to non-clinical pharmacology and toxicology data where this is
   relevant to the ongoing trials (I.e. altered risk:benefit assessment). For
   example concerning:

   Results of new pharmacology tests
   New interpretation of existing pharmacology tests
   Result of new toxicity tests
   New interpretation of existing toxicity tests
   Results of new interaction studies
                 Substantial Amendments

Examples of Substantial Amendments:
(Changes to clinical trial and human experience data where this is relevant to
   the ongoing trials (I.e. altered risk:benefit assessment ). For example
   Safety related to a clinical trial or human experience with the IMP
   Results of new clinical pharmacology tests
   New interpretation of existing clinical pharmacology tests
   Results of new clinical trials
   New interpretation of existing clinical trial data
   New data from human experience with the IMP
   New interpretation of existing data from human experience with
    the IMP
        EU Directive (2001/20/EC)

 Do not need to be sent to MHRA or ethics committee
 Must be logged (log may be requested by MHRA)

Safety Amendments
 Can be implemented by sponsor/investigator in
  emergency situations
 EC and MHRA must be notified within 3 days and
  ‘retrospective’ approval sought
                      EU Guidance on
        the European Clinical trials Database - EudraCT

Purpose of EudraCT Database (as quoted in Guidance Note)

   The European regulatory authorities require a database in
    order to provide each of them with an overview of clinical
    trials being conducted in the community.

   The database is needed to facilitate communication on these
    clinical trials between the authorities, to enable each to
    undertake better the oversight of clinical trials and to provide
    for enhanced protection of clinical trial subjects and patients
    receiving investigational medicinal products.
                     EU Guidance on
       the European Clinical trials Database - EudraCT

   Users will be Competent Authorities, European
    Commission and the EMEA

   EudraCT will provide users with information for a given
    product, trials conducted by a given sponsor, by
    patient population, by product type and by therapeutic

   EudraCT will be developed in two stages. Simple
    version available now, more comprehensive version
                 EudraVigilance Website

   Maintained by The European Medicines Agency
    (previously called European Medicines Evaluation Agency)


   The site provides useful information on
    pharmacovigilance, EudraVigilance, and reporting
        EU Directive (2001/20/EC)

   The EU Directive on GCP in Clinical Trials
    (provides a legal framework)

   The EU Guidance Notes (to support the Directive)
    (‘guidance’ on the processes)

Also allows:
 Flexibility for Member States to add their own
   legislation within the framework of the Directive
              EU Directive (2001/20/EC)

Legislation required by Member States:

   Definition of an Investigator
   National laws to define ‘legal representative’
   Establishment and operation of ethics review process
   Definition of the powers of the Competent Authority
   Procedure for establishing and maintaining Database for
    trial information to link up with EMEA databases
 (to support Directive 2001/20/EC)
     Guidance Notes relating to
       Directive 2001/20/EC

   9 GCP draft Guidance Notes were released for
    consultation (June 2002)
   5 of those GCP Guidance Notes were issued as final
   The 4 remaining GCP Guidance Notes were
    incorporated into a new GCP Directive (2005/28/EC)
    published 9 April 2005.
         Guidance Notes relating to
            Directive 2001/20/EC
The following are the 5 final Guidance Notes - issued in
  final form and revised again in April 2004:

   Ethics Applications/Documentation
   Clinical Trial Authorisation submission to CA
   European clinical trials database (EUDRACT
   Adverse reaction reporting for clinical trials
   Database of SUSARs on clinical trials (Eudravigilance)

               Directive 2005/28/EC
                  of 8 April 2005
    laying down principles and detailed guidelines for good
clinical practice as regards investigational medicinal products
 for human use, as well as the requirements for authorisation
     of the manufacturing or importation of such products

   Published in the Official Journal of the EU on 9 April 2005
   Entered into force on the twentieth day following its
    publication in the Official Journal
   Member States must bring into force laws to comply with this
    Directive by 29 January 2006
               Directive 2005/28/EC
                  of 8 April 2005

   Confirms ICH GCP as the basis of clinical research in the
    EU and EAA and states the ‘harmonised approach for
    Good Clinical Practice’ from the E6 document shall be
    taken into account

   Clinical trials shall be conducted in accordance with the
    1996 version of the Declaration of Helsinki

   Each individual involved in conducting a trial shall be
    qualified by education, training and experience to perform
    his tasks.
               Directive 2005/28/EC
                  of 8 April 2005

   Allows ‘specific modalities’ to be applied to some non-
    commercial trials, specifically those ‘with authorised
    medicinal products on patients with the same

   Allows simplified provisions for GMP procedures for non-
    commercial studies.

   Confirms that the principles of good clinical practice
    must still be applied to all studies and refers to additional
    Guidance being forthcoming.
                Directive 2005/28/EC
                   of 8 April 2005
   The sponsor may delegate any or all of the trial-related functions
    but shall remain responsible for ensuring that the conduct of the
    trial and the final data generated complies with Directive 2001/20
    and 2005/28

   The protocol must define the monitoring and publication policy.
   The information in the investigator brochure shall be presented
    in a concise simple objective, balanced and non-promotional
    form to enable a clinician to make an unbiased risk-benefit
    assessment of the proposed trial.
   If the IMP has a marketing authorisation a summary of product
    characteristics may be used instead of an IB.
   The investigator brochure must be updated at least annually.
             Directive 2005/28/EC
                of 8 April 2005

   The trial master file shall consist of essential documents which
    enable both the conduct of a clinical trial and the quality of the
    data produced to be evaluated.
   Those documents shall show whether the investigator and the
    sponsor have complied with the principles and guidelines of
    good clinical practice.
   The trial master file shall provide the basis for audit by the
    sponsor’s independent auditor and the inspection by the
    competent authority
   The content of the essential documents shall be in accordance
    with the specificities of each phase of the clinical trial.
   The Commission shall publish additional guidance to specify
    the content of these documents
            Directive 2005/28/EC
               of 8 April 2005
   Essential documents must be retained by investigator and
    sponsor for at least five years after trial completion.
   Documents must be retained for longer if specified in an
    agreement between sponsor and investigator
   Essential documents must be archived to be readily accessible
    by competent authorities
   Medical files of trial subjects shall be retained in accordance
    with national legislation
   Transfer of data shall be documented and the new owner shall
    assume responsibility for data retention and archiving.
   Sponsor shall appoint individuals within its organisation who
    are responsible for archives
   Access to archives shall be restricted to the named individuals
    responsible for the archives
GCP Documents - The standard
European - applicable to all Member States

   EU Directive 2001/20/EC
   The Guidance Notes to support the Directive (Good Clinical
    Practice and Good Manufacturing Practice)
   ICH Note for Guidance on Good Clinical Practice,
    CPMP/ICH/135/95 (E6 document - legal status of Scientific
   Directive 2005/28/EC
   Annex 13 of the GMP Guidelines (labelling requirements)

U.K. only
 Medicines for Human Use (Clinical Trials) Regulations 2004
 Governance Arrangements for Research Ethics Committees
             Implementing the
              GCP Directives
   The Directives do not give us process

   The processes that we work to will come from a variety of
      ICH GCP E6 document (which must be ’taken into
      Further official ‘Guidance’ from the EU and MHRA
      Standard Operating Procedures produced by each
       company or organisation must specify the process for
       implementing the Regulations
      Standard Operating Procedures must be compliant with
       EU and UK Law and ‘ Guidance’ issued.
   The EU Directive is now law across the 25 Member States
    of the European Union, plus 3 countries in the EEA, and
    Switzerland (29 countries in total)
   The Directive has achieved harmonisation in some areas
    but also gives Member States (limited) flexibility to ‘add in’
    their own local laws
   The supporting Directive (2005/28/EC) containing the four
    missing Guidance Notes has been finalised and must be
    transposed into U.K. Law by January 2006
   Directive 2005/28/EC promises further Guidance to give us
    details on the Trial Master File and other unresolved
   Additional Guidance on the ‘specific modalities’ referred
    to will also come from the MHRA
Summary of Differences with GCP
      Directive 2001/20
   Is Law and applies to all clinical trials with IMPs (except
    non-interventional trials)
   Legal requirement for every trial to have a Eudract number
   Every trial requires a defined sponsor (collaborative
    arrangements acceptable)
   The burdens of sponsorship are considerable and carry
    legal penalties if not complied with.
   Definition and process for dealing with amendments
   The only process that has been fully harmonised is the
    process for obtaining a Clinical Trial Authorisation