Presentation is loading. Please wait.

Presentation is loading. Please wait.

MHRA GCP Inspection 21st – 24th June 2011

Similar presentations


Presentation on theme: "MHRA GCP Inspection 21st – 24th June 2011"— Presentation transcript:

1 MHRA GCP Inspection 21st – 24th June 2011
Afternoon – we are all here because in 6 weeks time Emma & Mark, 2 inspectors from the MHRA will be visiting the university to conduct a GCP Inspection to examine the systems used by the university in the conduct of clinical trial research. UoA have been working to ensure that there are systems in place so that the organisation has oversight of all clinical trials. Been doing this in conjunction with NHSG so that there is no or very little duplication. Medicines and Healthcare products Regulatory Agency

2 What do the MHRA inspect?
University systems that support conduct of CTIMPs in compliance with regulations and GCP. Areas of interest include: Approval processes and regulatory submissions Contract management Trial file and data management Quality assurance and monitoring Training IT systems Pharmacovigilance Archiving Laboratories Pharmacy So they are very interested in the machinery of the university and how much oversight we have of things.

3 What do the MHRA inspect?
Specific examples of CTIMPs that demonstrate those systems UoA sponsors or co-sponsors 8 CTIMP studies UoA hosts 33 CTIMP studies MHRA have chosen 4 to look at in depth However…….they can change their minds before the visit or decide to look at other studies during the visit….we must all be prepared! One of the best ways for them to do that is to look at…………..

4 Aims of this session Brief researchers on what the inspectors will be looking at in your CTIMP study - Qualifications & training - Study files & documentation - Pharmacovigilance - Serious breaches - Informed consent - Communication Describe new overarching SOP’s Prepare researchers for interviews with inspectors

5 Preparation for MHRA Inspection Regulations, Qualifications & Training

6 Legislation: Letter from MHRA:
“The main references used for the inspection will be EU Directives 2001/20/EC and 2005/28/EC and supporting guidance documents as incorporated in UK National Legislation, Statutory Instrument 2004, Number 1031, the Medicines for Human Use (Clinical Trials) Regulations 2004 and subsequent amendments.”

7 Legislation: 2001 EU Clinical Trial Directive: Directive 2001/20/EC
2004 Medicines for Human Use (Clinical Trials) Regulations (SI: 1031) 2005 EU Directive on Good Clinical Practice 2005/28/EC 2006 The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 (SI:1928) 2006 The Medicines for Human Use (Clinical Trials) Amendment (No.2) Regulations 2006 2008 The Medicines for Human Use (Clinical Trials) and Blood Safety and Quality (Amendment) Regulations 2008 2009 MHRA GCP guideline - Laboratories Good Idea to read the regulations – most of you will be adhering to these, but it will allow you to put your practice into the context of the regulatory documents and be able to speak confidently about your work, knowing that you are following the regulation.

8 Medicines for Human Use (Clinical Trials) Regulations 2004 (SI:1031)
“Each individual involved in conducting a trial shall be qualified by education, training, and experience to perform his or her respective task(s)”

9 Qualifications and Training:
Delegation Log Training Record The MHRA inspectors will pay particular attention to the management of informed consent within your trial. Consent procedures will be specific to each trial but you must ensure they are the same as what you have ethical approval for.

10 Delegation of Duties: Delegation log should be established, documenting which tasks are undertaken by each member of the research team These should be signed by each team member to confirm that they agree to undertake the task they have been delegated

11 MHRA Inspection: Those listed on the delegation log should be qualified to carry out their specific task(s) CV GCP Training Training Record For CIs / PIs they will be looking on the CVs to see how much experience you have in leading a trial. Informed consent – will wish to see that your GCP training is up to date. Taking bloods etc – have you documented your venepuncture training etc If there has been any in house training (e.g. using a specific piece of equipment) sometimes the reps from the manufacturers come round to instruct you how to use the new equipment – is this documented.

12 SOP: Establishing and Maintaining a Training Record UoA-NHSG-SOP-016
Applies to all staff conducting or supporting clinical research sponsored or co sponsored by UoA / NHSG Responsibility of the individual to create an update their own training record

13 Contents of the Training Record:
Current CV Job Description(s) Certificates of training Training Log: ongoing list of all internal and external training - may include training from previous post (training courses, conferences, seminars, relevant meetings) Keep copies of handouts / agendas If a staff leave – take original training record, but leave a copy with the study file Add in the fact that you have been to this talk today – going over the contents of the SOPs

14 Possible Questions Tell me about your qualifications
What is your clinical experience / experience on clinical trials What type of GCP training have you had / who was the provider How do you assess that your team are competent to complete their delegated tasks – Is this documented GCP training for CTIMPs is provided by staff from Glasgow Clinical Trials Unit – based on Medicines for Human Use (Clinical Trials) 1031. Can do online training for CTIMP studies – see Carol Should be updated every 2 years – will look at certification for this. If someone is being trained to do informed consent – how do you teach them this – - you do informed consent - watch them a couple of times to make sure they are ok with it and you are happy. Have you done any other research training

15 Study Files and Documentation:
Trial Master Files Investigator Site Files

16 Medicines for Human Use (Clinical Trials) Regulations 2004 (SI:1031)
“All Clinical Trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification” “The confidentiality of records that could identity subjects shall be protected, respecting the privacy and confidentiality rules in accordance with the requirements of the Data Protection Act 1998 and the law relating to confidentiality” Specifically refers to: Data Protection Act – 8 Principles: Fair and Lawful Used only for specified and lawful purposes Adequate, relevant and not excessive to need Accurate and kept up to date Not kept for longer than necessary Processed in accordance with participant data rights – including rights of access Kept secure and protected against accidental disclosure, loss or damage Not transferred outside the EEA.

17 Study Files and Documentation:
Chief/Principal Investigators are required to keep, and maintain, a CORE set of documents for EACH research project they manage Should be kept in a designated file called a Investigator Site File (ISF) and/or Trial Master File (TMF)

18 SOPs: Establishing and Maintaining a TMF: UoA-NHSG-SOP-008
UoA-NHSG-TMP-003 – TMF Checklist Establishing and Maintaining an ISF: UoA-NHSG-SOP-009 UoA-NHSG-TMP-002 – ISF Checklist (If single centre: both can be combined to save duplication) Applies to all staff conducting or supporting CTIMPs sponsored or co sponsored by UoA / NHSG

19 TMF / ISF Maintaining TMF / ISF is the responsibility of the CI/PI – can be delegated to research team Use file index / checklist. Alternative version can be used, but must retain all the listed documentation as minimum standard If documents stored elsewhere – add in file note Updates / amendments added to TMF / ISF and reviewed by sponsor. Stored in a secure environment – but remain accessible to trial staff The TMF and ISF lists are the minimum standard of information we would wish you to have. Can keep more detailed documents if you

20 Possible Questions: Who has access to your files
Who is managing your TMF / ISF Do you keep electronic versions of documents How do you ensure the security of your records

21 Archiving: What Where How For how long

22 SOP: Archiving Clinical Research Data: UoA-NHSG-SOP-021
Not yet finalised Applies to all staff conducting or supporting CTIMPs sponsored or co sponsored by UoA / NHSG Responsibility of the sponsor and CI to ensure essential documents are retained for an appropriate period of time - and made available for monitoring and audit

23 What: Essential Documents / Source Documents: TMF / ISF Data
Hospital Records Clinical and office charts Lab notes Memoranda Subjects diaries Case Report Forms Evaluation checklists Recorded data from automated instruments Copies of transcriptions Records kept at pharmacy / Labs X-Rays / reports Photographs / microfilm Other – if appropriate TMF / ISF – contains all your essential documents and some of your source documents: So – everything listed in the TMF / ISF checklists plus:

24 Hospital Records: Hospital records and source data therein should be retained throughout the archiving period: Adhere sticker to inside of all medical records documenting: Study Title Study ID no – R&D/ EudraCT Name of local CI or PI Department name / contact number Date to which notes should be retained

25 Where: Suitable for type of archived material
Building / room / fireproof safe / locked cabinet Environmental conditions (avoid extreme fluctuations in temp and humidity) Risk of fire / flood Pest control Secure – accessible only to delegated staff

26 Where: UoA- sponsored / co-sponsored CTIMPs – Health Sciences Building. NHSG Sponsored CTIMPs – The Vault Box (Removal Services Scotland Ltd) Multicentre trials may have site files and relevant records archived at host sites. Should be agreed by sponsor / CI / host site at the beginning of the trial

27 How: After the trial closeout visit:
CTIMPs sponsored / co-sponsored by UoA – CI should contact Technical Resource Manager (School of Medicine and Dentistry) CTIMPs sponsored by NHSG – QA Manager will contact re Archiving arrangements

28 For How Long: At least 5 years after the conclusion of the trial (or at least 2 years after the last approval of a marketing application in the EU) Duration of Archiving - agreed by Sponsor / CI at the beginning of the trial Approved by Ethics (require ethical approval if these require to be kept for longer) Do not destroy early or take with you if you leave – must be retained within the Sponsors locality

29 Possible Questions: What happens with the archiving at other sites
What happens to the study material and patient medical notes at the end (archiving arrangements, who, where, how long) What will be forwarded to the TMF for archiving How does general correspondence, e.g. s get into the file Are these meeting minuted and where is this documented

30 Preparation for MHRA Inspection Pharmacovigilance
30

31 Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031) Part 5 Pharmacovigilance Notification of adverse events 32. (1) An investigator shall report any serious adverse event which occurs in a subject at a trial site at which he is responsible for the conduct of a clinical trial immediately to the sponsor. (2) An immediate report under paragraph (1) may be made orally or in writing. (3) Following the immediate report of a serious adverse event, the investigator shall make a detailed written report of the event. (4) Paragraphs (1) to (3) do not apply to serious adverse events specified in the protocol or the investigators' brochure as not requiring immediate reporting. This is the legislation we have to follow which indicates…… 31

32 Key components of the regulations :
Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031) Part 5 Pharmacovigilance Notification of adverse events 32. Key components of the regulations : Notification of serious adverse events to sponsors Immediate reporting of SUSARs Annual reporting of serious adverse reaction To summarise 32

33 Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031)
Amendment 2006 (SI1928) Condition which applies to all clinical trials: Rights, safety, and well being of trial participants are the most important considerations and shall prevail over interests of science and society Principles contained within SI1031 are guided by ICH – GCP principles. 33

34 SOP: Procedure for Reporting Serious Adverse Events and Suspected Unexpected Serious Adverse Reactions (UoA-NHSG-SOP-014) Not yet finalised “describes the correct procedure for reporting SAEs to the sponsor and expediting reports to ethics and the MHRA when required.” 34

35 CI pharmacovigilance responsibilities
Timely collection of data recording and notification to sponsor Appropriate assessments undertaken data completeness seriousness relatedness expectedness Expedited and periodic reporting REC, MHRA, Sponsor (& others as appropriate). Additionally may need to inform additional PIs, drug manufacturers etc of SAEs/SUSARs. 35

36 Requirements for Pharmacovigilance
All protocols must have a PV section. Risk to participants is dependent on the clinical trial. Responsibilities and systems to deal with recording, assessment and reporting must be clearly stated. Time frames for notification, assessment and reporting are critical. SOPs are required. Extent of recording & notification of adverse events will vary depending on the drugs under study and the aims of the trial. 36

37 Requirements for Pharmacovigilance
CI’s need to understand their responsibilities with respect to adverse event recording and notification Reports SAEs to the sponsor immediately (in practice 24 – 48 hours). Report SUSARs to the MHRA within 7 days if fatal/life threatening otherwise within 15 days. Urgent safety measures implemented, notify MHRA within 3 days. Assessment of adverse events: Seriousness Relatedness/causality Expectedness 37

38 Current Procedure for Pharmacovigilance
CI/delegate to report serious adverse event to the Research Governance Manager (RGM) ( Initial report may be by telephone (Ext: 55076) Detailed written report by within 24 hours CI/delegate to report SAEs/SUSARs to REC and MHRA (as required). CI to forward copy of eSUSAR report to RGM. 38

39 Current Procedure for Pharmacovigilance
RGM to provide guidance/support for SUSAR reporting on MHRA electronic reporting site. Website for SUSAR reporting: https://esusar.mhra.gov.uk/? CI/delegate will require registration to the eSUSAR website. RGM will facilitate. 39

40 Possible questions What is the process for reporting SAEs?
Would CI report to MHRA if a SUSAR? Who assesses SUSARs? Where do you send the annual safety report? (How) Does the protocol permit for any non-escalated SAES? What is the process for reporting SUSARs?

41 Preparation for MHRA Inspection Serious Breaches
41

42 Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031) Amendment 2006 (SI1928) Notification of serious breaches 29A (1) The sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach of - (a) the conditions and principles of GCP in connection with that trial; or (b) the protocol relating to that trial, as amended from time to time in accordance with regulations 22 to 25, within 7 days of becoming aware of that breach. (2) For the purposes of this regulation, a “serious breach” is a breach which is likely to effect to a significant degree – (a) the safety or physical or mental integrity of the subjects of the trial; or (b) the scientific value of the trial”. This is the legislation we have to follow which indicates…… 42

43 Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031)
Amendment 2006 (SI1928) Condition which applies to all clinical trials: Rights, safety, and well being of trial participants are the most important considerations and shall prevail over interests of science and society Principles contained within SI1031 are guided by ICH – GCP principles. 43

44 SOP: Procedure for Reporting Serious Breaches of the protocol or GCP
(UoA-NHSG-SOP-015) Not yet finalised “describes the correct procedure for reporting serious breaches to the sponsor, ethics and to the MHRA.” 44

45 Examples of serious breaches
Principal Investigator unable to provide training log. Study protocol not peer-reviewed. It started with a simple case of peer review

46 Examples of serious breaches
No trial specific SOPs. Investigator unaware of the Declaration of Helsinki.

47 Examples of serious breaches
Protocol does not contain a section on the exclusion criteria for study participants. Failure to report an SAE to study sponsor.

48 Examples of serious breaches
CRFs contain patient identifiers. After trial commences new data concerning IMP safety not taken into account.

49 Examples of serious breaches
No statement of patient eligibility signed by medically qualified individual No CTA in place before study start.

50 Examples of serious breaches
Patient identifiable data on laptop stolen from investigator’s car. Inadequate insurance cover in place.

51 Current Procedure for Serious Breaches
CI/delegate to report serious breaches to the Research Governance Manager (RGM) ( If unsure a breach has occurred contact the RGM for advise within 24 hours of event. Initial report may be by telephone (Ext: 55076) Detailed written report by within 7 days CI/delegate to report serious breaches to REC and MHRA within 7 days CI to forward copy of report & to MHRA to RGM. 51

52 Current Procedure for Reporting Serious Breaches to the MHRA.
RGM to provide guidance/support for serious breach reporting to REC and MHRA. MHRA notification of serious breach form available at: Notification form to be sent to: 52

53 Current Procedure for Reporting Serious Breaches to the REC.
RGM to provide guidance/support for serious breach reporting to REC and MHRA. No specific REC notification of serious breach form. RECs will accept the MHRA notification of serious breach form. Forward letter/ to REC to the RGM. 53

54 Possible questions Have there been any deviations from the protocol?
What do you class as a deviation? Have there been any breaches of GCP? Have there been any persistent deviations of GCP or the protocol?

55 Preparation for MHRA Inspection Informed Consent
The MHRA inspectors will pay particular attention to the management of informed consent within your trial. Consent procedures will be specific to each trial but you must ensure they are the same as what you have ethical approval for.

56 Medicines for Human Use (Clinical Trials) Regulations 2004 (SI1031)
For the purposes of this Schedule, a person gives informed consent to take part, or that a subject is to take part, in a clinical trial only if his decision— (a) is given freely after that person is informed of the nature, significance, implications and risks of the trial; and (b) either — (i) is evidenced in writing, dated and signed, or otherwise marked, by that person so as to indicate his consent; or (ii) if the person is unable to sign or to mark a document so as to indiacte his consent, is given orally in the presence of a at least one witness and recorded in writing. This is the legislation we have to follow!!

57 SOP: Obtaining Informed Consent from Competent Adults for Research Studies (UoA-NHSG-SOP-010)
“describes the correct procedure for obtaining written informed consent for clinical research studies” This SOP is for competent adults only and is superseded by any trial specific SOP for informed consent. If your trial involves either children or adults with incapacity you must be aware of how current legislation covers these groups of people.

58 SOP: Responsibilities of PI
Ethical approval for : consent form PIS adverts Remember all changes need ethical approval! Delegation log Training of staff in informed consent No tests, procedures, data collection before consent Substantial amendments need to go to Gail sponsor, ethics & r&d

59 SOP: Procedure - providing information
RCT: Pink or Blue Pill for Chocolate Addiction? Version 3, 25 June 2010 You need to be able to answer patients questions about the study as well Give enough time for the participant to decide whether to take part…………….if it says you post PIS’s out to folk in the protocol/ethics application then that how you must do it!!

60 Who can obtain informed consent?
                                                      'Thanks for telling me your entire medical history but I'm the hospital barber.' Your ethical submission & protocol states who will be taking consent……you may just have put down ward doctors, research nurse but on the delegation log you need to specify who these individuals will be. Investigators/Co-investigators & staff named on delegation log

61 Checks prior to obtaining signature
the participant’s identity and eligibility (there is no new or undisclosed information that would exclude them from the study) the participant’s understanding of the study is adequate and they are happy to continue with entering the study the participant knows that they can withdraw at any time without giving a reason the participant has had sufficient time to consider taking part in the study The inspectors may ask you about the process of informed consent, what do you check for etc (usually 24 hours unless otherwise agreed by the REC) So what should the consent form look like & what is the patient signing………………………..

62 Consent Form Must be signed and personally dated by participant and the person taking consent Must be obtained prior to initiation of any screening procedures and before any changes are made to patient’s medication Filing Original -> investigator study file Copy -> to participant/legal representative (Copy -> patient’s notes along with PIS) Printed on university/hospital/surgery headed paper Dated, version number, pages numbered Ethics committee approval of consent form & information sheet before study starts May be revised (needs Ethics approval & send to R&D)

63 Unit & dept conducting the trial
Headed Paper Participant must initial not tick boxes Signed & personally dated by participant Person taking consent must sign also Telephone or verbal consent is not permitted for CTIMPS Version no Eudract no

64 Vulnerable Participants
1. Difficulty reading/writing - Impartial witness - Read PIS to participant - signature of witness 2. Minor – child under 16 - consent of parent required 3. Adult – unable to give informed consent due to physical or mental incapacity - Adults with Incapacity (Scotland) Act 2000 - consent by a legal representative So that was the process, what if your research involves vulnerable participants? The regulationsstate that certain groups require additional protection and you as the researcher need to work to these additional requirements.

65 Common MHRA findings They will check source data from medical notes!
No record of study visit in medical notes No records of consent being taken – medical notes or ISF Poor version control Inconsistencies with protocol Missing elements e.g. signature Unclear process So that has been a whistle-stop tour of the consent process and because it is at the heart of research ethics & research governance, please be aware that it is something that is always checked by inspectors.

66 Possible questions How have other clinicians been told about the trial? How do you approach patients? Who tells participants about the trial Where do you store PIS & Consent form Talk me though the consent procedure Can all participants consent on their own?

67 Preparation for MHRA Inspection Communication

68 Inspectors will look for evidence that a study team communicates well
Communication Inspectors will look for evidence that a study team communicates well “if it isn’t written down, it didn’t happen” Research teams are usually very good at communicating, but you have to ensure this is documented so that the inspectors can see this for them selves. Site File Index

69 Communication – with who?
Research team Clinical team (e.g. ward nurses/doctors) Pharmacy Labs – internal & external Sponsor Ethics/R&D

70 Communication – how? Internally: Research team
Regular meetings – dates, agenda, minutes updates Written correspondence All must be filed appropriately in the TMF/ISF

71 Communication – how? Externally: Clinical team
Ward staff: presentations/posters New staff/rotational staff – documented procedure of how the are informed of study External clinicians – e.g. labels on notes Keep a record of everything & file in TMF/ISF

72 Communication – how? Externally: pharmacy, sponsor, ethics, R&D, MHRA etc updates Written correspondence Amendments – inform correct people Keep a record of everything & file in TMF/ISF

73 Possible questions How is communication maintained?
Do you have regular team meetings? What do you cover in these meetings – are they minuted? How do staff on call (not part of core team) know what to do? How do clinicians know this patient is part of a study? How have other clinicians been told about the trial?

74 Summary Review your trial documentation and training files for staff.
Have evidence of training (GCP certificate, CV) Ensure you can explain your role in the trial Review the typical questions and answers provided Familiarise yourself with new SOPs Be confident of your trial and processes. Remember that you know your trial better than anyone else!

75 Main Contacts: Prof Phil Hannaford – Prof Alison MacLeod – Dr Gail Holland – Tel: Lynda Sime – Tel:


Download ppt "MHRA GCP Inspection 21st – 24th June 2011"

Similar presentations


Ads by Google