ICH ESSENTIAL DOCUMENTS

1

Good Clinical Practice Regulation Update 2005
Joan Perou GCP Trainer Consultant November
2005
2

Clinical Trial Regulation - Who makes the Rules?

3
U.S.A

• 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.

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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
  2004
• The European Commission demands that every Member
  State must appoint a Competent Authority to
  ensure compliance with the Directive

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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)

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What are the rules ?

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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 .

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The European Union25 Member States

• Austria
• Belgium
• Denmark
• France
• Finland
• Germany
• Greece
• Ireland
• Italy
• Luxembourg
• Netherlands
• Portugal
• Spain
• Sweden
• United Kingdom

• Cyprus
• Czech Republic
• Estonia
• Hungary
• Latvia
• Lithuania
• Malta
• Poland
• Slovenia
• Slovakia
• 400 million people
• 20 official languages

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GOOD CLINICAL PRACTICE

• 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

10
Milestones in Good Clinical Practice

• 1977 Federal Registers published in U.S. by FDA
• 1986 UK published guidelines Good Clinical
  Research Practice
• 1987 France and Nordic Countries published laws
• 1990 European GCP Guidelines published
• 1996 International Conference on Harmonisation
  produced ICH GCP E6 document.

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• 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 standard.

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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

13

THE EUROPEAN DIRECTIVE ON GCP IN CLINICAL
TRIALS 2001/20/EC
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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

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EU Directive (2001/20/EC)

• Makes GCP a legal requirement in European Member
  States
• 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

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EU Directive (2001/20/EC)

• Standardises
• 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 Database
• Information exchange between member states by
  means of a database of trial information
  (EudraCT database)

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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

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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.

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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

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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

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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

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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

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EU Guidance on the request for authorisation of
a clinical trial on a medicinal product for human
use to the competent authoritiesENTR/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

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SUBSTANTIAL AMENDMENTS

• 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

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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

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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

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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 riskbenefit
  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

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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 riskbenefit assessment ). For
  example concerning
• 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

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EU Directive (2001/20/EC)

• Non-substantial
• 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

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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.

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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 category.
• EudraCT will be developed in two stages. Simple
  version available now, more comprehensive version
  2005/2006

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EudraVigilance Website

• Maintained by The European Medicines Agency
• (previously called European Medicines Evaluation
  Agency)
• www.emea.eu.int
• The site provides useful information on
  pharmacovigilance, EudraVigilance, and reporting
  standards.

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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
  

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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

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THE EU GUIDANCE NOTES(to support Directive
2001/20/EC)
36
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 documents
• The 4 remaining GCP Guidance Notes were
  incorporated into a new GCP Directive
  (2005/28/EC) published 9 April 2005.

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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
  Database)
• Adverse reaction reporting for clinical trials
• Database of SUSARs on clinical trials
  (Eudravigilance)
• Website http//pharmacos.eudra.org

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EUROPEAN DIRECTIVE 2005/28/EC
39
Directive 2005/28/EC of 8 April 2005laying
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

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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.

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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 characteristics
• 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.

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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.

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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 sponsors 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

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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

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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 Guideline)
• 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 (GAFREC)

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Implementing the GCP Directives

• The Directives do not give us process
• The processes that we work to will come from a
  variety of sources
• ICH GCP E6 document (which must be taken into
  account)
• 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.

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SUMMARY

• 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 issues.
• Additional Guidance on the specific modalities
  referred to will also come from the MHRA

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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 different
• The only process that has been fully harmonised
  is the process for obtaining a Clinical Trial
  Authorisation