1. Research Guidelines Research Governance
EU Directive on Clinical Trials
ICH-GCP:
Informed Consent
Safety & Adverse Events
Documentation - Audit

2. ICH definition - GCP
"A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected"
ICH E6 1.24

3. ICH-GCP
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
ICH-GCP - Good Clinical Practice guidelines agreed at the conference
This module will cover what is GCP; the major milestones in its development ; where we are to date and finally an overview of the responsibilities GCP outlines for those involved in clinical trials. These responsibilities will fall in to the 4 categories of consent, safety, data handling and study product. These 4 categories will be covered in more depth in the other 4 modules.
Liz - I understand that you are producing the slides to introduce the other four modules.

4. The objectives of ICH GCP Guidelines
Developed with consideration of the current good clinical practices of the European Union, Japan & USA, plus those of Australia, Canada, the Nordic countries & World Health Organisation.
Provide a unified standard for the European Union, Japan & USA to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
This module will cover what is GCP; the major milestones in its development ; where we are to date and finally an overview of the responsibilities GCP outlines for those involved in clinical trials. These responsibilities will fall in to the 4 categories of consent, safety, data handling and study product. These 4 categories will be covered in more depth in the other 4 modules.
Liz - I understand that you are producing the slides to introduce the other four modules.

5. Good Clinical Practice - GCP
What is GCP?
“Ethical and scientific quality standards for designing, conducting, recording and reporting trials that involve participation of human subjects”
Why is it needed?
To ensure that the RIGHTS, SAFETY and WELLBEING of the trial subjects are protected
Ensure the CREDIBILITY of clinical trial data
Why has it developed into formal guidelines?
Public disasters, serious fraud and abuse of human rights
Liz - the bits in blue need to be ‘flashed’ in - I don’t know how to do it.
Good clinical practice:
“A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.”
ref: ICH-GCP June 1996.
In order to be able to unpack this slightly wordy explanation a little, we need to be aware of why GCP guidelines have come into existence and why these guidelines have become formal and soon be be integrated into legislation. ? Add here the latest EU directives?

6. ICH GCP Guidelines cover…
Ethics Committee
/IRB
Sponsor
Investigator
Investigator’s
Brochure
Essential
Documents
for conduct
of a trial
Clinical Trial
Protocol &
Amendments
EU directive will ensure the same level of patient protection, scientific standards, it will rationalise administrative procedures across member states
it is unlikely that the above timeframes will be upheld - more likely that it’s adopted 2001, implemented the following year.

7. Responsibilities of the Investigator
Agreements
Compliance
Ethics
Informed Consent
Investigational drug
Qualifications
Medical care of trial subjects
Randomization
Records
Reports
Resources
Safety reporting
Unblinding
EU directive will ensure the same level of patient protection, scientific standards, it will rationalise administrative procedures across member states
it is unlikely that the above timeframes will be upheld - more likely that it’s adopted 2001, implemented the following year.

8. World Medical Association Declaration of Helsinki
Adopted by 18th WMA Assembly, June 1964 (Helsinki, Finland)
Covers all “medical research”
Most recent amendment October 2000
changes include:
Peer review of protocol,supervision of research, results to be made available, test against “gold standard”, access to best proven treatment at end of research.

9. Research Governance Framework

10. Scope of the Framework
Research by staff with Trust and Honorary Trust Contracts
Research involving patients, service users, care professionals, volunteers or their organs, tissues or data
Research funded by the NHS
Research using facilities funded by the NHS

11. Aims of the Framework set out in legislation and regulations
To promote a quality research culture
To promote excellence
To provide strong leadership for research
To implement standards:
set out in legislation and regulations
required by the Department of Health
established as good practice

12. Research Governance domains
Ethics
Science
Information
Health, Safety and Employment
Finance and Intellectual Property

13. Ethics - key points
Independent review of research involving patients, service users, care professionals, volunteers, or their organs, tissues or data
Consideration of the dignity, rights, safety and well being of participants
Informed consent
Data protection
Consumer involvement
Diversity of human culture
Avoidance of animal experiments

14. Science - key points
Peer review – commensurate with the scale of research
Regulation by the MHRA and MDA
Data retention to allow further analysis and support monitoring

15. Information - key points
Free access to information on research being conducted and research findings
Publication of results in a format understandable to the public
Making findings available to participants

16. Responsibilities of the Researcher
Developing proposals
Seeking ethical committee approval
Conducting research according to the agreed protocol
Ensuring participant welfare
Feeding back results to the participants

17. Responsibilities of the Sponsor
Assuring scientific quality (peer review)
Ensuring research ethics committee approval
Ensuring arrangements for the management and monitoring of research

18. Responsibilities of the Care Organisation
Ensuring that research using their patients, users, carers or staff meets the standards in the Research Governance Framework
Ensuring ethics committee approval
Retaining responsibility for research participants’ care

19. Sanctions
“the assumption will be that there is full compliance (or else research is stopped)”

20. The Medicines for Human Use (Clinical Trials) Regulations 2004
The EU Clinical Trials Directive 2001/20/EC
The Medicines for Human Use (Clinical Trials) Regulations 2004

21. Aims of the EU Directive
To simplify and harmonise the administrative provisions governing clinical trials in the EU
To facilitate the internal market in medicinal products
To maintain appropriate protection for public health

22. ICH-GCP is to be the GCP standard
Application of GCP
ICH-GCP is to be the GCP standard
(EU GCP Directive 2005)
All drug trials will need:
an ICH-GCP compliant protocol
an investigator brochure
case report forms
a site file
to report SAEs

23. The regulations cover:
All medicinal products – medicinal by function or presented as treating or preventing disease in human beings (including health products)
All phases of trials - including Healthy Volunteer Trials
Trials sponsored by industry, government, charities, universities, NHS organisations
Trials recruiting participants after 1st May 2004 – the regulations are RETROSPECTIVE
Devices are exempt if looking at mode of delivery (comparing devices) rather than dosage
  Further guidance is still awaited

24. EU Directive & Informed Consent
Standards currently adopted in the UK comply with the Directive
However, the Directive states that a “legal representative” may act for a trial subject that is not able to give informed consent
A formal mechanism to appoint a legal representative for incapacitated adults will be introduced

25. Indemnity/Compensation
Provision must be made for compensation for non-negligent harm for all trials e.g
The clinical negligence scheme for Trusts
University Public Liability Insurance
Specific Clinical Trials insurance
ABPI model indemnity agreements to used for industry sponsored trials

26. Licensing Authority Approval
UK “competent authority” will be the Medicines and Health-care products Regularity Agency (MHRA)
Prior authorisation is required for all trials and substantial amendments
Consideration the MHRA within 30 days, extendable to 60 days
SAE reporting protocols
Report to the MHRA within 90 days of trials conclusion
If trial is terminated or ended prematurely notification required within 15 days

27. EU Directive & Ethics Committees
60 day time limit for decisions
A single request for additional information
Approval or Rejection decisions
Approval to take place in parallel with licensing authority approval
Extended time limits for gene therapy, somatic cell therapy, medicinal products containing Genetically Modified Organisms and xenogenic cell therapy trials
35 day time limit to review amendments
If trial is terminated or ended prematurely notification required within 15 days
Substantial amendments to be notified

28. Substantial Amendments
Amendments are considered to be substantial if they are likely to impact on:
Subject safety
Scientific value of the trial
Conduct or management of the trial
Quality or safety of the IMP
Duration of the trial
- anything other than minor administrative amendment

29. EU Directive & Competent Authority - Information to Support Approval
Core information - Required by the Directive
Covering letter
EUDRACT form - register via MHRA
Protocol
Investigator Brochure
Investigational medicinal products dossier - Ph1 trials
List of CA to which an application has been made
EC opinion if available
Member State Specific
Local information: consent forms, information sheets, recruitment, indemnity, manufacturing of IMPs

30. EU Directive & Good Manufacturing Practice and Investigational Medicinal Products
Manufacture or importation from countries outside the European Economic Area will require prior Licensing Authority authorisation
All products to be approved by a “Qualified Person” (QP) as compliant with GMP
Labelling requirements
Unlikely that Manufacturer’s licence and QP will be required to cover reconstitution and packing of IMPs by hospital Pharmacists

31. GCP and GMP Inspections
Inspections to be undertaken (by MHRA) of trial sites, manufacturing sites, laboratories used for analysis and sponsors premises
Charges to be levied, amount still to be determined
Inspections will be of two types:
Cyclical, systems based inspections of sponsors
Triggered inspections as required

32. Safety Reporting PI to identify category
Complete Safety Report Form (s)
Forward as appropriate to Trust and Sponsor within 24hrs
If SUSAR Sponsor to forward to REC, MHRA and relevant CA outside UK if applicable (EUDRAVIGILANCE database).
N.B. It is relevant to report events that may be related to placebo or reference drugs
N.B. If SAE for non-CTIMP report within 15 days using non-CTIMP SAE form (COREC/UHL website)

33. Timelines for Sponsor for further reporting
Fatal /life threatening report within 7days to MHRA
‘Other’ report within 15 days to MHRA
Further information to MHRA or/and REC within 8 days if requested
Annual Safety Report listing all SARs and SUSARs for the study on anniversary of CTA approval (PI responsibility)

34. The Medicines for Human Use (Clinical Trials Regulations) 2004
Order came into force in the UK on 1 May 2004 following the EU Directive on Good Clinical Practice in clinical trials 2001/20/EC (The Clinical Trials Directive).
Clinical Trials Authorisation has now replaced the DDX / CTX

35. The MHRA have produced a short description of the (the UK order which implements the EU Directive) which aims to help those involved in the conduct of clinical trials to follow and understand the Regulations

36. GOOD CLINICAL PRACTICE
Consent

37. What is Informed Consent?
"Informed consent is a process by which a subject voluntarily confirms his or her willingness to participate in a particular clinical trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate”
ICH 1.28

38. Who can consent a subject?
A medically qualified person (usually) - however, Declaration of Helsinki states “physician”
UHL has a policy for Nurses & AHPs obtaining consenting for clinical trials – each study assessed and training package implemented as necessary. Not automatic right
Consent may be delegated to a sub investigator (needs to be documented) – must have be approved by LREC
The investigator retains overall responsibility
Consent must be documented in the medical notes

39. When should a subject be consented?
Prior to participation in a trial
Before ANY trial procedure - including the taking of blood to screen patients if it is not part of normal clinical practice or a questionnaire to access health etc

40. How should someone be consented?
The consent form must have been approved by the Ethics Committee
There should be no coercion to enter the trial
Non-technical language must be used
The information must be presented to the subject in the most appropriate way
The subject must have “ample” time to consider their decision

41. How should a consent form be completed?
Subject must sign & date the form (& preferably write their own name)
Original PIL & consent form - site file
Copies of PIL & consent form - Patient notes and to the patient
The consent form & patient information leaflet should always be kept together

42. GOOD CLINICAL PRACTICE
Safety & Adverse Events

43. Safety Data collected in Clinical Trials
Adverse Events
Serious Adverse Events
Adverse Reactions
Suspected Unexpected Serious Adverse Reaction
Pregnancy
Lab data
Vital Signs
Project specific data
Explanatory - essentially, all data collected in a trial can be considered safety data.
Ask audience – “Can anybody tell me what safety data is collected in clinical trials”

44. Adverse Event Any untoward medical occurrence
Not necessarily causal relationship with treatment
Unfavourable /unintended sign ICH (1.1)
ICH GCP definition of an adverse drug reaction - ADR's reported in clinical trials before AEs

45. Adverse Reaction Untoward or unintended response to IMP ICH (1.2)
ICHGCP definition of an adverse event - can be deemed positive response as well as negative e.g. increased libido.
Ensure everyone understands the differences between AEs and ADRs

46. Suspected Unexpected Serious Adverse Reaction
Unexpected-not consistent with information already available in the protocol and the IB
Imperative that ALL prescribers (doctors, dentists, coroners and pharmacists) report any suspected toxicity.
“Does anyone know how we go about this in the UK?
The yellow card system – yellow card (found at back of BNFs, compendium of data sheets, prescriptions….) allow all prescribers to report any suspected ADRs to the MCA (Medicines control agency)/CSM (Committee on safety of medicines) – essential for monitoring drug safety. The system is still being developed – nurses used it during the meningitis C campaign and in fact the MCA are looking to extend the use of nurse reporting.
 Yellow card requires details of the reporting prescriber, patient, the suspected drug (dose, dates of use) and the suspected reactions. This card scheme is in the process of changing in that personal details (name and DOB) are no longer requested, instead patients age, sex and a reference number is asked for, which enables identification – this change is to ensure that the scheme is in line with current guidelines on confidentiality. Electronic yellow cards are being piloted at the moment to make it even easier to report suspected ADRs. To help prescribers a black triangle symbol (upside down triangle!) is placed onto the drug label of a medicine that is under intensive safety monitored by the MCA/CSM. These medicines can either have been recently introduced into the UK or can be a product containing previously licensed active substances. For these drugs all suspected ADRs should be recorded. It should be noted however, that it is recommended that all ADRs in children are reported to the MCA even if there is no black triangle (from 2001 BNF 41).
 For drugs that don’t have a black triangle only serious suspected ADRs should be recorded to the MCA/CSM. The black triangle drugs are monitored closely for a minimum of two years and the black triangle symbol is not removed until the safety of the drug is well established.
Post market surveillance - needs to be encouraged as drug are prescribed to huge numbers of patients when marketed in comparison to during the clinical trial phase.

47. SAE,SAR or SUSAR is SERIOUS and requires reporting if it:
Results in death
Is life threatening
Requires hospitalisation or prolongation of stay
Results in persistent or significant disability/incapacity
Consists of congenital anomaly or birth defect
Other
Exacerbation – Asthma attacks
Increase in frequency and intensity – Migraines
Diagnosis of condition after trial started that may have been present before the trial started – cancer/tumours
Continuous disease worsens – symptoms of a condition that was not excluded by the study protocol that worsens.

48. Continued Results in death
- Record the event that lead to death as the SAE
- “Death” is the outcome
Life threatening
- “The patient was, in the view of the investigator, at immediate risk of death from the event as it occurred. It does not include an event that, had it occurred in a more serious form, might have caused death”

49. Continued Prolonged hospitalisation - Record diagnosis NOT procedure
- Hospitalisation = in-patient admission
- Not out-patient appointments or A & E visits
Disabling or incapacitating
- Event which is disabling or incapacitating or causes a disruption of one’s ability to carry out normal life functions or daily activities

50. Continued Congenital anomaly
- Diagnosed in the offspring of a subject who received study drug
Other
- Additional option given by some pharmaceutical companies
- Event not covered by SAE categories but in the investigator’s opinion, should be considered serious

51. Pregnancy - what and when to report
Protocol specific - report on SAE or pregnancy reporting form
All need reporting - don’t forget the female partners of men participating in the trial too!!
All need to be followed up - Length of follow-up depends on drug
Pregnancies can be reported as an SAE or on a pregnancy report – dictated by the Sponsor Company.
Pregnancies are usually followed up throughout the pregnancy until approx. 3 months after birth (dictated by sponsors) – pharmaceutical companies tend to send out questionnaires at birth, 3 months and later if needed.
Important to report and follow up if a partner of a subject participating in a clinical trial becomes pregnant.
E.g. If partner becomes pregnant of someone participating in a HIV trial it is likely that the child will have HIV – need to know the combination of the drug that the child would have been exposed to be able to provide the new born child with the correct combination of medication.

52. GOOD CLINICAL PRACTICE
Documentation
&
Audit

53. Essential Documents
“Are those documents, which permit evaluation of the conduct of the trial and the quality of data produced.
These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of GCP and with all regulatory requirements”
ICH (8 .1)
Slide 4 – Essential Documents
This is ICH GCP definition (read).

54. Minimum list - see ICH section 8
Essential Documents
Documents which…
are audited by the regulatory authorities or sponsor company to confirm the validity of the data & integrity of the data collected
are contained in the files established at the beginning of the trial at sponsors office and investigators site
Minimum list - see ICH section 8

55. Essential Documents - source data
Records should be accurate, complete, legible & timely ICH (4.9.1)
Data should be consistent with source documents (or discrepancies explained) ICH (4.9.2)
Any changes should be initialled, dated & explained
Document all deviations from protocol and explain ICH (4.5.3)
Document all dose/therapy modifications, visits and tests not conducted
ICH has a whole section dedicated to Essential Documents. Basically, the study file, as provided by the sponsor should contain all the essential documents and is your evidence of compliance with GCP, the protocol and requirements of the MCA or FDA. It will contain ALL the information required to verify the results of the study for the patients you have recruited.
“Can anyone suggest the types of documents I mean by essential documents?”

56. What needs to be recorded in the patient notes?
Copy of signed and dated Consent Form and PIL
Title of the trial including the drug to be received
Study and patient number
Visit dates
Concomitant medicines taken
Any adverse events
A letter informing the GP that the patient has been enrolled in the clinical trial
Meaning of source data is the ORIGINAL record, or the first place data is recorded, or written down.
“Anyone give me some examples of source data?” (X-ray, lab report, writing BP in notes etc)
Whatever form this takes, it MUST be kept. This is because every CRF entry should be verifiable against source data, known as Source Data Verification (SDV). This is mainly what your monitor will be doing. (Joanne’s example: Investigator who was called by a patient with an AE while he was at dinner, so wrote it all down on a paper napkin, which is still filed in the study file!)
Explain bullets of slide e.g. timely is very important, as is initialling and dating changes. This will prevent a long list of data queries at the end of the study and ensures the data is robust.

57. Essential Documents continued
Essential documents should be retained for 2 yrs following last approval of marketing application in the ICH region (taken to be 15yrs) ICH (4.9.5)
All records must be made available (direct access) for monitors, auditors & regulatory authorities ICH (4.9.7)
Pharma companies should tell you this, some now archive for you. Is likely to be at least 5 years.

58. ICH definition - Audit
"a systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analysed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s)"
ICH E6 1.6)

59. Common audit findings Patients do not fulfil the entry criteria
Incomplete/incorrectly completed consent forms
Drug accountability inadequate
Hidden entry envelopes opened during study
Many pharma companies now have audit departments, but you may also be audited by the MCA or FDA.
“Has anyone been through an audit?”
Very detailed and thorough process that will go back and check everything, every signature etc. (Joanne’s example: audit that picked up that the oxygen was out of date, many people don’t know oxygen has a shelf life.) MCA and FDA have very different approaches to auditing; FDA are distant, you won’t be allowed to give them coffee, they have a “20 minute rule” – if you cannot produce any document or information within 20 minutes of being asked, the FDA assumes it doesn’t exist, and won’t accept it after this time. This is why filing is so important.
These are some common audit findings, all related to documentation, which have consistently been found for years, ie we’re not learning the lesson, and we need to….

60. Audit can be conducted to:
EU GCP Directive
EU Clinical Trials Directive
Protocol

61. Clinical Trial Audits
Sponsor Audits - Independent & separate from routine monitoring or quality control functions and evaluate trial conduct & compliance with the protocol, SOPs, GCP & applicable regulatory requirements
FDA Audits - In USA inspections occur without notice. In Europe, carried out with notice (about 14 days)
MHRA Audits – increasingly common and at short notice

62. Audit of the SITE FILE will check ….
Approvals & correspondence – Ethics approval, all correspondence to & from Ethics /Trust , MHRA notification
Laboratory – normal ranges, reports, procedures, etc
Documentation – protocol & amendments (signed), Information Leaflet & Consent, signed consent forms, Investigator Brochure, Indemnity, all correspondence between sponsor & investigator

63. Audit of the SITE FILE will check ….
Personnel – CVs of those working on the study, training records (such as GCP)
Drug – shipping records, drug receipt - but these may be in pharmacy
Patient details – screening / enrolment / identity logs, SAE reports

64. Audit of the PATIENT NOTES will check ….
Data verification –Case report forms, looking at data queries, lab results, ECGs, x-rays etc
Data verification patient notes – protocol details/number in the notes, date of birth, vital signs, all visit dates, concomitant medication & changes, medical examination, study specific procedures

65. An audit may also look at-
Drug storage – accountability, temperature logs, security, dispensing, labelling,
Laboratories – procedures, handling samples, accreditation
Other study specific procedures

66. The Inspection Report Contains details of all finding
Each finding labelled “Critical”, “Major”, “Minor” or “For Note”
Each finding is referenced to the particular regulation / guideline to which it is attributable
A reply to the report is required

67. Common Audit Findings
Patient or Investigator signature on consent form not dated
No version / date on consent form
Staff CVs not on file
Ethics Committee member list not up to date
Ethics Committee letter did not list all docs reviewed
Ethics Committee letter did not contain statement of GCP compliance
Drug not temperature monitored (was required)
Signatures not dated
Investigator failed to report SAEs

68. Write it down– if it’s not written down it didn’t happen
In summary
Legislation will affect us all - we all have to work to GCP and Research Governance guidelines
The legislation aims to improve standards and build public confidence
Ensure that:
The site file and filing is up to date – have a complete “paper trail”
The PIL & consent form in use are the most up to date and approved by LREC
People obtaining informed consent have been “approved”
Write it down– if it’s not written down it didn’t happen

69. Remember…..
“ the assumption will be that there is full compliance (or else research is stopped)”

70. Useful Contacts in Research and Development at LGH
Office Manager - Nicky Turner 4109
Programme Board Co-ordinators - Jill Horsley 8239 Gemini Davda Marlene Chapman 8246
Clinical Trials Pharmacist – Claire Khalil 8241
Clinical Trainer - Sarah Nicholson 8180