Transcript EU Clinical Trials Regulation 536/2014

Good Clinical Practice (GCP)
A whistle stop tour!
St George’s University of London, UK
Debbie Rolfe
Regulatory Assurance Manager, Joint Research & Enterprise Office
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What is GCP?
Good Clinical Practice (GCP) is an
international ethical scientific quality
standard for designing, conducting,
recording and reporting trials that involve
the participation of human subjects..
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What is GCP?
The objective of ICH GCP is to provide a
unified standard for
- USA
- European Union
- Japan
To facilitate the mutual acceptance of
clinical data by the regulatory authorities in
these jurisdictions.
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13 Principles of GCP
1.
Ethical Principles of Declaration
of Helsinki
8.
Researcher training, education and
experience
2.
Benefit justifies risk
9.
Freely given informed consent
3.
Rights, safety, wellbeing
10. Accurate data handling and storage
4.
Adequate information to support
trial
11. Data Protection and confidentiality
5.
Clear, scientifically sound
protocol
13. Quality assurance systems
6.
Favourable ethics approval
7.
Qualified Chief Investigator
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12. Good Manufacturing Practice
ICH GCP Section 2
What is a clinical trial?
ICH GCP 1.13:
Any investigation in human subjects intended to discover or verify the
clinical, pharmacological and/or pharmacodynamic effects of an
investigational product and/or to identify any adverse reactions to an
investigational product, and/or to study absorption; distribution;
metabolism; and excretion of an investigational product with the object
of ascertaining its safety and efficacy.
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Principle 1
• Clinical Trials should be conducted in
accordance with the ethical principles that
have their origin in the Declaration of
Helsinki, that are consistent with GCP and the
applicable regulatory requirements
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DECLARATION OF HELSINKI
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Leading international ethical standard 1st adopted in 1964 – 7 revisions
current 2013
The Declaration provides guidance for research on humans, their material
and/or their data:
– Safeguarding research participants
– Adhering to an approved research protocol
– Benefits > risks
– Full informed consent, including assent where appropriate
– Publishing findings
– Use of placebos
– Post-trial access to treatment
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Clinical Trials
Pre-Clinical
Tissue samples
Computer simulation
In vitro tests
Animal testing Toxicology
IMPD for Regulatory
submission
Phase I: Healthy volunteers/
Oncology patients MTD/DLT
Testing for safety, PK and PD,
tolerability
Phase II: Exploratory Selected
people with relevant illness
Testing for clinical efficacy
Phase III: Confirmatory Large
number of people with relevant
illness
Testing against “gold
standard” or placebo
Marketing Authorisation
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Post Marketing
Phase IV: Post marketing
surveillance. Wider testing in a
more generalised population,
reporting further side effects and
long-term risks and benefits
Principle 2
• Before a trial is initiated, foreseeable risks and
inconveniences should be weighed against
anticipated benefit for the individual trial
subject and society. A trial should be initiated
and continued only if the anticipated benefits
justify the risks
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Principle 3
• Rights , safety and well-being of the trial
subjects are the most important
considerations and should prevail over
interests of science and society
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Principle 4
• The available non-clinical and clinical
information on an investigational product
should be adequate to support the proposed
clinical trial
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Principle 5
• Clinical trials should be scientifically sound,
and described in a clear, detailed protocol
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Principle 6
• A trial should be conducted in compliance
with the protocol that has received prior
institutional review board (IRB)/ Independent
ethics committee (IEC) approval/ favourable
opinion.
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Principle 7
• The medical care given to, and medical
decisions made on behalf of, subjects should
always be the responsibility of a qualified
physician or, where appropriate, of a qualified
dentist.
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Principle 8
• Each individual in conducting a trial should be
qualified by education, training, and
experience to perform his or her respective
tasks.
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Role of the IRB/REC
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Who are the ethics committee/ Review board?
 At least 5 members with at least 1 non-scientific member, at least 1
member independent of trial site or institution can be clinicians,
nurses, pharmacists and other interested parties
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Ethical approval:
 Gives balanced independent view of research following review of the
trial protocol, information provided to the subjects, subject recruitment
procedures e.g. advertisements, informed consent forms and proposed
process and available safety information
 Ensures Investigator suitable qualified and experienced
 Clear documented approval listing documents and version numbers
approved for use
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Principle 9
• Freely given informed consent should be
obtained from every subject prior to clinical
trial participation.
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Informed Consent
“a process by which a participant voluntarily confirms his
or her willingness to participate in a particular trial, after
having been informed of all aspects of the trial that are
relevant to the participant’s decision to participate.
Informed consent is documented by means of a written,
signed and dated consent form”
ICH GCP Section 1.28
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Must be obtained before any research related activity occurs
Copy to participant, copy in ISF and original in medical notes
Continuous process throughout the study.
What if consent is withdrawn?
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Requirements for valid consent
• Who should obtain consent?
– CI/PI or suitably qualified individual
• Must ensure:
– Sufficient opportunity to read and consider information
• Time given (preferred) >24 hrs
• To reflect on implications of participation
• To ask questions & discuss with family
– Capacity, i.e. consideration of age, maturity, cognitive ability
• Illiteracy – use impartial witness
– Thumbprint
– Name and date of witness entered by witness and signed
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Adults without Capacity
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Mental Illness / Mental Disability / Brain Damage
Country-specific regulations
– Legally designated person to give consent for another adult
– Hierarchy:
1. Personal legal representative
• Suitable by virtue of relationship
• Willing
2. Professional legal representative
• Not connected with study
• Primarily responsible for person’s medical care OR
• Nominated by relevant health care provider
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Requirements for valid
Unconscious Patients
consent
• Research should relate directly to life-threatening condition of
participant
• Legal representative (personal or professional) to give consent
• Waiver accepted if allowed by IEC/IRB
• Emergency research should be re-consented
– Follow-up
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Assent of Minors
• Only research that directly relates to the child’s clinical condition
should be conducted
• Parent’s signature sufficient in law
– Best practice: assent of child (if deemed competent)
– Assent is not legally binding, however, favoured by ethics
committees
• Child should be involved as much as possible – use of age related
information sheets
• Parental consent should reflect wishes of the child, these may
overrule parents’ wishes
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Inspection Findings
• Missing consent forms – not possible
to verify subjects had consented
• Lack of subject or Investigator
signature to demonstrate agreement
to participate
• Unapproved consent form used
• Consent form referencing wrong
Patient information sheet
• Consent taken by persons not listed
on delegation log – therefore no
evidence of training to obtain consent
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Principle 10
• All clinical trial information should be
recorded, handled, and stored in a way that
allows its accurate reporting, interpretation
and verification
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Essential
Documents
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What are Essential Documents?
“Essential documents are those which individually and collectively permit
evaluation of the conduct of a trial and the quality of the data produced.
These documents serve to demonstrate the compliance of the investigator,
sponsor and monitor with the standards of Good Clinical Practice and with
all applicable regulatory requirements.”
Filing essential documents in a timely manner greatly assists in the
successful management of a trial by the investigator, Sponsor and monitor.
Normally it will be these documents that are inspected by the regulatory
authorities as part of the process to confirm the validity of the trial conduct
and integrity of the data collected
ICH GCP Section 8
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Why Bother?
• First thing inspectors, auditors & monitors look at
• Organises the paperwork
– Saves time
– Saves effort
– Facilitates organisation of the study
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Trial Master File
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Trial master files should be established at the beginning of the trial
BOTH at the Investigator site and at the Sponsor office
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Essential documents are generally grouped in 3 stages of the trial
(normally where generated)
– Prior to Clinical phase
– Clinical conduct
– Following completion/ trial termination
• Description & purpose of each document and whether kept at Sponsor
office or Investigator site or both is described in ICH GCP Section 8.2-8.4
• All documents described should be subject to and available for audit by the
Sponsor’s monitor and inspection by the regulatory authorities
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Principle 11
• Confidentiality of records that could identify
subjects should be protected, respecting the
privacy and confidentiality rules in accordance
with the applicable regulatory requirements
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Data Protection Directive 95/46/EC
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Was created to regulate the progression of personal data within the European
Union and is part of the EU privacy and human rights law.
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New EU data protection regulation (draft)
To harmonise current data protection laws across the EU member states.
Regulation means it will be directly applicable to all EU member states without
need for national implementing legislation.
2012/0011(COD) Awaiting council 1st reading position
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http://www.europarl.europa.eu/registre/docs_autres_institutions/commission_europeenne/co
m/2012/0011/COM_COM%282012%290011_EN.pdf
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Investigator Site File
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Contact Lists
Protocol and any Amendments
Ethics and Regulatory Approvals
Participant Information Sheets and Consent forms
Agreements and contracts
Delegation & duty Logs
Participant master file – Participant ID log
Data Management
Case Report Forms
Serious Adverse Events
Correspondence and Communication (both Sponsor and
Internal Team meetings)
Study specific SOPs & Training logs
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Protocol
A document that describes the objective(s), design, methodology,
statistical considerations and organisation of a trial. The protocol usually
also gives the background and rationale for the trial, but these could be
provided in other protocol referenced documents.
ICH GCP 1.44
Contents of a protocol are suggested in
ICH GCP Section 6
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Document Control
• All documents should have:
– Version number
– Date
• Standard numbering system
– Ensures only current ethically approved version in use
– Format consistent
• e.g. v1.1; 27/09/2010 DRAFT
– Method/ approved procedure for amending version numbers
• Approval and distribution procedures defined
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Amendments
Substantial
An amendment to the protocol or any other supporting documentation that is likely to
affect to a significant degree the:
1.
2.
3.
Safety or physical or mental integrity of the trial subjects
Scientific value of the trial
Conduct or management of the trial
Non-substantial
• Requires notification only (e.g. typos, amending members of research teams except CI
& PIs)
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Retain all documents in the ISF/TMF – documents that are no longer approved for use
MUST be clearly marked as superseded
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Pharmacy MUST be included on the circulation list of approved Protocols, updated
Reference Safety Information
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Inspection Findings
• Lack of essential docs e.g. IMP
shipment receipt, blood sample
shipments to central labs
• Incomplete trial subject screening lists
• Missing source documents
• Discrepancies between source data and
data reported in Clinical Study Report
• Lack of evidence of Sponsor SOP use
• Poor document control – documents
not superseded/removed from
circulation upon update
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Principle 12
• Investigational products should be
manufactured, handled and stored in
accordance with applicable good
manufacturing practice (GMP). They should
be used in accordance with the approved
protocol.
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PHARMACY !
• All IMPs (including comparators and placebo) is manufactured in
accordance with any applicable GMP and is coded, labelled in a manner
that protects the blinding and in accordance with applicable regulatory
requirements.
• Decoding/unblinding of treatment in case of medical emergency
• Storage temperatures, storage conditions e.g. Protect from light,
reconstitution fluids and procedures and stability information.
• IMP accountability and chain of custody details
Sponsors responsibility
ICH GCP 5.12-5.14
Recommend to include your Pharmacy department early on!
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Pharmacy Site File
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RSI -IB IMPD or Summary of
Product Characteristics (SmPC)
Protocol and Amendments
Submission and approval
documentation in accordance with
local & regional requirements
Approved label (Annexe 13)
Template
Certificate of Analysis
IMP QP release
Instructions for Use
Dose & administration
Approved prescription template &
copies of participant prescriptions
Approved prescribers signature
samples
Recommended storage conditions
Training log
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Delivery notes
Drug accountability forms
Chain of Custody
Treatment AllocationParticipant lists
Drug destruction procedure
Drug destruction log
Code break Procedure
Pharmacy delegation log
Contact Lists
Correspondence &
communications
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Product Accountability
• Should determine:
– Storage temperatures
– Storage conditions
ICH GCP Section 5.19
– Storage times
– Reconstitution fluids and procedures
– Devices for infusion
• Site should receive appropriate instructions
• Document shipment, receipt, delivery, distribution- dispensing, Subject returned
IMP and destruction
ICH GCP Section 5.13-5.14
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Risk Adaptive Approach ~(UK)
• Type A – Routine prescribing on licensed IMPs (or
established off-label use supported by published
evidence/guidelines)
• Type B – licensed IMP – new indication, substantial
dose modifications, combinations in which
interactions are suspected
• Type C – Unlicensed IMPs in any EU MS
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Principle 13
• Systems with procedures that assure the
quality of every aspect of the trial should be
implemented.
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Trial Management Group (TMG)
• Every trial should have a TMG
• Normally includes individuals who are responsible for the day to day
management of the trial
– CI
– Trial manager
– Statistician
– Research nurse
– Data manager
• Role is to:
– Monitor conduct and progress of the trial
– Ensure that the protocol is adhered to
– Take appropriate action to safeguard participants
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Data Monitoring Committee
• aka DSMB, IDMC, DMEC
• Role is to:
– Interim analyses to monitor the progress of the trial, the safety data,
and the critical efficacy endpoints
– Recommend to the sponsor whether to continue, modify, or stop
– Assess whether there are any safety issues that should be brought to
participants’ attention
• Should be considered for all trials
– DAMOCLES charter
• Strongly recommended for blinded studies
– Should be the only body that has access to unblinded data
• Independent from study AND study team
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Trial Steering Committee (TSC)
• Role is to:
– Provide overall supervision of the trial
– Ensure that it is being conducted in accordance with the principles of
GCP and the relevant regulations
• Should agree the trial’s protocol and any protocol amendments
• Provide advice to the investigators on all aspects of the trial
• The TSC may have members who are independent of the investigators, in
particular an independent chairperson
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Compliance with GCP provides public
assurance that the rights, safety and wellbeing 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
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Safety Reporting
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Pharmacovigilance (PV)
is the process and science of monitoring the safety of
medicines and taking action to reduce the risks and
increase the benefits of medicines
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What's it all about?
Collect and manage data on safety of medicines
Interrogate data to detect ‘signals’ (new or changing issues)
Evaluation and decision making with regards to Safety Issues
Pro-active risk management to minimise potential risk associated with
medicine use
• Acting to protect public health (including regulatory action)
• Communication with and informing stakeholders & the public
• Audit, both outcomes of actions taken & processes involved
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Acronyms
• AE
– Adverse Event
• AR / ADR/ADE
– Adverse Reaction / Adverse Drug Reaction/Adverse Device Event
• SAE/SADE
– Serious Adverse Event/Serious Adverse Device Event
• SAR/SADR
– Serious Adverse Drug Reaction
• SUSAR
– Suspected Unexpected Serious Adverse Reaction
• USADE
– Unanticipated Serious Adverse device effect
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AEs and ARs/ADRs
ADE/SADE
Any untoward medical occurrence in a patient or clinical trial participant
administered a medicinal product
• AE: Does not need to be related to a drug
• AR: Related to any dose administered of medicinal product
For Non-CE marked devices or CE marked devices used outside the
Intended use covered by the CE marking
• ADE: Includes any events resulting from
insufficiencies or inadequacies in instructions
for use, deployment, installation the
operation, or any malfunction. It also includes
user error or intentional misuse
• SADE: Adverse device event has
resulted in any consequences
characteristic of an SAE
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SAEs
• Any AE that at any dose:
– Results in death
– Is life threatening
– Requires hospitalisation, or prolongation of existing inpatients’
hospitalisation
– Results in persistent or significant disability or incapacity
– Is a congenital anomaly or birth defect
– Is otherwise considered medically significant
by the investigator
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SARs/SADRs
• Any adverse reaction that is classed as serious AND is consistent* with
the information about the IMP listed in the Reference Safety Information
(SmPC or IB or IMPD) *i.e. it is expected
• Investigator Brochure should be reviewed & updated annually to include
aggregated safety information – PI should ensure all study team
members are updated and familiar with new information – record on
training log kept in the TMF– ensure all participating sites receive
updated information especially participating pharmacy departments
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SUSARs
Any adverse reaction that is classed as serious
and is suspected to be caused by the IMP and is
NOT consistent with the information about the
IMP in the Reference Safety Information e.g.
SmPC/IB/IMPD
Suspected and Unexpected
USADE (Unanticipated Serious Adverse Device
Effect
Serious adverse device effect which by its nature,
incidence, severity or outcome has not been
identified in the current version of the risk
analysis report.
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Causality
Factors to consider:
• Nature of the reaction
– ARs commonly caused by medicines, eg skin reactions
• Timing
– e.g. anaphylaxis usually occurs within minutes
• Relationship to dose
– Positive dechallenge
– Positive rechallenge
• Disagreement between CI and PI then reporting weighted in favour of
greatest risk
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Causality
Description of relationship of IMP with SAE
Definitely
Clear evidence of causal relationship & other possible
factors can be ruled out
Probably
Evidence suggests causal relationship and other
possible factors is unlikely
Possibly
Some evidence to suggest a causal relationship as
event occurred within a reasonable time following
IMP administration however, other factors cannot be
ruled out.
Unlikely
Little evidence as the event did not occur within a
reasonable time frame and another reasonable
explanation exists
Unrelated
No evidence of causal relationship
Not Assessable
NB: If this description is used the Sponsor will assume
event IS related until subsequent follow up
information suggests otherwise
Recording AEs and ARs
• Trial Planning
– In the protocol list expected SAEs & SARs
- in relation to known IMP side effects,
- in relation to the disease
- State which expected SAEs will not be reported or do not require
immediate reporting but do state when and how they will be
reported (outcome data or within x days of event)
- Reference procedures to be followed in event of SAE
- Clearly state responsibilities
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Recording AEs and ARs continued
• Data Collection
– Maintain listing of all AEs/ARs that occur during the study
– AEs/ARs do not need to be reported but may require notification to
the Sponsor in accordance with the monitoring plan & protocol.
– AE logs should be clinically reviewed by the CI to rule out
trends/increase in frequency or severity- Document any reviews in
TMF and adverse findings should be reported to the Sponsor within
24 hours.
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Reporting SAEs and SARs
• Assess AE for
– seriousness
– causality
– Expectedness
• Report to CI/Sponsor within 24 hrs on specific form
– Except when listed in protocol as not requiring immediate reporting
ICH GCP Section 4.11 & 5.17
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Reporting SAEs/SUSARs
• Assess AE for
– seriousness
– causality
– expectedness
• If serious, suspected causally related and NOT expected
• Expedited reporting to CA and REC
– fatal or life threatening = 7 days, follow-up in 8 days
– other = 15 days
– Report even if occurred outside MS
– Follow up until resolution
– Included on DSUR in line listing
ICH GCP Section 4.11 & 5.17
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DEVICES- Reportable Events
under Annex 7 & X of directives 90/385/EEC
and 93/42/EEC respectively
• The following events are considered reportable
– Any SAE
– Any Investigational Medical Device Deficiency that may have led to
an SAE if
• a/ suitable action had not been taken
• b/ intervention had not been made
• c/ if circumstances had been less fortunate
– New findings/updates in relation to already reportable events
• Reportable events occurring in 3rd countries in which a clinical
investigation is performed under the same clinical investigation plan
have to reported as above
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DEVICES- Reportable Events
under Annex 7 & X of directives 90/385/EEC
and 93/42/EEC respectively
• Report to CI/Sponsor & Manufacturer within 3 days after occurrence
on specific form supplied by manufacturer
– Except when listed in protocol as not requiring immediate reporting
• Reported by Sponsor simultaneously to each National CA & NB where
investigations have occurred immediately (or no later than 2 calendar
days) where death or imminent risk of serious injury has occurred, any
other reportable events no later than 7 days following awareness of
event
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Special Situations
• Pregnancy or impregnation
– Follow up to birth (& beyond if stipulated in protocol)
• Lack of efficacy
– May be a significant hazard to the subject population if IMP used to
treat life threatening disease
• Overdose / abuse / misuse
– Protocol should include guidance
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Special Situations
• Expected SAE, but unexpected outcome
• Increase in frequency or severity of SAE (hence regular AE log review by
CI encouraged for signal detection)
• URGENT SAFETY MEASURES
Can be implemented immediately for the protection of trial subjects
however IRB/REC/CA must be notified within 3 days via submission of
amendment
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Why do we need to monitor safety post
marketing?
REAL LIFE IS NOT LIKE A CLINICAL TRIAL
• Clinical trials only encompass a very TIGHTLY CONTROLLED section of a
population
• No pregnancy
• Concomitant medications are controlled
• Long term use
UK
• Yellow card scheme via the MHRA website https://yellowcard.mhra.gov.uk/
Report – Side effects for a medicine, vaccine, herbal or
homeopathic remedy
Report - Medical Device adverse incident
Report – Defective medicines of unacceptable quality
Report – Counterfeit or fake medicine or medical device
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Common Inspection Findings
• Failure to report SUSARs
• Failure to follow up pregnancy
outcomes
• Subject confidentiality – i.e. SAE
reports in the TMF with Subject names
• Failure to submit ASR’s/DSUR’s in a
timely fashion
• Inadequate instruction or procedure
contained in the protocols to ensure
Adverse Events recorded or reported
appropriately
• Lack of sponsor oversight/process to
ensure and monitor compliance of
SUSAR reporting and ASR/DSUR
submissions
Source MHRA GCP Inspections Metrics
Reports 2009-2012
DSURs
Replaces Annual Safety Reports
– Anniversary of first international birth date (regulatory approval)
=DIBD
– Paediatric studies may require 6 monthly reports
– If listing multiple studies – then Data Lock Point (DLP) Include each
study until declaration of end of that study
– DSUR per IMP to the MHRA (although for some investigator led
studies MHRA may accept report on anniversary of MHRA CTA)
– Aggregate Reporting - Ensure all SAEs and SUSARs for that
reporting period are line listed/tabulated in suggested format
– Check for any new information/publications during that reporting
period and updates on SmPC’s if using licensed medicines
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Progress Reports, Declaration of End of Study and
Final Report
Annual progress reports to IRB/REC
 Within 30 days of Anniversary of IRB/REC approval
 Until end of study
Declaration of End of Study to IRB/REC
 Appropriate form within 90 days of the end of the study
 Or within 15 days if the study is terminated early
Final report on the research to IRB/REC
 Within 12 months of the end of the study
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End Of Study
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Archiving principles
Retained for minimum
of 5 years (non CTIMP)
or 15 years (CTIMP)
after study end
Until
when?
Who?
Stored in a
Where?
secure,
environmentally
controlled area
Following Archive SOP
–Sponsor & siteseparately
Sponsor, CI
What?
All essential
docs in TMF
How?
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When?
Following End of
study Report
EU Directives & the new EU Regulation
EU Clinical Trials Directive
2001/20/EC
GCP Directive 2005/28/EC
GMP Directive 2003/94/EC
EU Clinical Trials Regulation
536/2014
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EU Clinical Trials Directive 2001/20/EC
• Simplify and standardised Clinical Trial applications for
both commercial & academic Sponsors across EU
• To protect safety and well being of participants and
improve quality of emerging data
However
• Increased documentation burden for academic partners
• Increased financial burden for academics & their host
institutions acting as Sponsor
• One size fits All ?
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EU Clinical Trials Directive 2001/20/EC
EFGCP compared data between 2003 and 2007
– Commercial studies submitted and conducted
increased by 11% and 30% respectively
– Academic studies submitted remained
unchanged but studies conducted decreased by
25%
• EORTC
– New trials fell by 63% between 2004-5
• Academic CT fell by 75% in Finland, 70% in Ireland,
25% in Sweden and 66% in Austria1
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Why?
• CT directive intended to harmonise process
across Europe
• Each MS interpretation has led to need for
country specific document requirements
increasing administrative burden and Europe
seems increasingly less attractive
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EU Clinical Trials Regulation 536/2014
Regulation removes “ interpretation” and
introduces true uniformity
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EU Clinical Trials Regulation 536/2014
Highlights
 Will not apply to non-interventional studies
 Clinical Study = investigation in relation to humans intended::
 To discover or verify the clinical, pharmacological or other
pharmacodynamic effects of one or more medicinal products
 To identify any adverse reactions to one or more medicinal
products or
 To study absorption, distribution, metabolism and excretion of
one or more medicinal products with the objective of
ascertaining safety and efficacy of those medicinal products
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EU Clinical Trials Regulation 536/2014
What is covered
 Clinical Trial :
 Assignment of a subject to a particular therapeutic strategy
decided in advance and does not fall within normal clinical
practice in MS concerned (in a non interventional study the
patient is usually treated within normal clinical practice)
Or
 decision to prescribe the IMP is taken together with decision to
include the subject in the clinical study (in a non interventional
study the decision to prescribe a treatment is taken before
entry into the study)
Or
 diagnostic or monitoring procedures in addition to normal
clinical practice are applied to the subjects (this would be noninterventional and so is a Clinical Trial)
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EU Clinical Trials Regulation 536/2014
Low Intervention Trial
 IMPs excluding placebos are authorised according to the protocol of
the Clinical Trial,
 The IMPs are used in accordance with the terms of the
marketing authorisation
Or
 The use of the IMPs is evidence based and published by
scientific evidence on the safety and efficacy of those IMPs in
any MS concerned;
and
 The additional diagnostic or monitoring procedures do not pose
more than minimal additional risk or burden to the safety of the
subjects compared to normal practice in any MS
 In the UK CA-(MHRA) already using “Risk adaptive
approach”
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EU Clinical Trials Regulation 536/2014
A single electronic application will be submitted via EU portal
Sponsor can propose a Reporting Member State (RMS) to conduct
assessment in co-ordination with other CMS
2 part application
- Part I – Scientific – to include
Application form, Protocol, IMPD, Investigator’s brochure,
examples of trial labels, Manufacturing authorisation/QP
declaration, copy of scientific advice or paediatric investigation
plan, proof of fee, cover letter and Statement of compliance
with the EU data protection Regulation
- Part II – Country specific – feasibility & Ethics
- Recruitment arrangements, Patient information sheet, Informed
consent Form, Investigator/site information, proof of insurance,
Financial arrangements
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EU Clinical Trials Regulation 536/2014
Part I
RMS to prepare initial draft assessment report to circulate to CMS for
comment & a co-ordinated review.
Final assessment report issued to Sponsor
Validation = up to 15 days
Validation to reporting date = 45 days
Only RMS can request further info (consideration given to issues
raised by CMS) if further info required of Sponsor additional 31 day
extension = 76 days total
Includes 12 days for Sponsor to respond to Questions, 12 days for coordinated review and 7 days for RMS to finalise assessment report.
Acceptable
Acceptable subject to conditions
Not acceptable
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EU Clinical Trials Regulation 536/2014
Part II
National assessment – can be conducted simultaneously as Part I
Each CMS to assess compliance with Data protection compliance,
recruitment, consent and use and storage of biological samples*
(*national laws).
Currently performed by REC/IRB not clear if Part II will be in addition to
and REC/IRB submission
if Part I and Part II submitted in parallel the final decision on Part II
must be within 5 days of Part I decision – so could be interesting!
However if Part I submitted separately - Part II can be submitted up to
2 years following Part I assessment BUT cannot be submitted until Part
I decision reached.
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EU Clinical Trials Regulation 536/2014
• Substantial Amendments
• Part I – 38 days +31 days if questions raised &
decision within 5 days of assessment report
• Part II – 38 days (plus extension for questions)
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EU Clinical Trials Regulation 536/2014
Notifications via the portal
• Sponsor required to notify via portal within 15
days
–
–
–
–
–
–
–
–
Recruitment start
FPFV
End of recruitment
LPLV
Final end of trial (LPLV last country)
Suspension
Temporary halt
Early termination
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EU Clinical Trials Regulation 536/2014
Other Notifications Required by the Sponsor
– SUSARs to the EMA via the Eudravigilance
database.
– Annual Safety Reports. EMA will forward reports
to the MS
– 3rd country inspection reports
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EU Clinical Trials Regulation 536/2014
Headline Trial Management Changes
• All previous trial data in the submission must be registered on a
database e.g. EudraCT or clinicaltrials.gov
• Public access to EU CT database- results must be available in lay
summary – subjects must be told how to find results
• Serious breaches to be reported within 7 calendar days
• TMF archived for 25 years minimum
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EU Clinical Trials Regulation 536/2014
Implementation
• Timetable dependant on EU submission portal set up
• Planned 6 months after but no earlier than 28th May 2016
• Transition period to allow anything submitted before effective date to
continue under the existing directive for 3 years
• 1 year overlap of 2 systems so current submissions until at least 28th
May 2017 governed by directive for up to 42 months from declaration of
portal being ready
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Thank you for listening
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