The Audit and Inspection Process
What is the Difference Between the Audit and the Inspection Process?
‘Audit is where there is 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, Good Clinical Practice and the applicable regulatory requirements.’ ICH 1.6
‘Inspection is the act by a Competent Authority of conductIng an official review of documents, facilities, records, quality assurance arrangements and any other resources that are deemed by the competent authority to be related to the clinical trial and that may be located at the site of the trial at the sponsor’s and/or contract research organisation’s facilities or at other establishments which the competent authority sees fit to inspect.’ ICH 1.29
Selection for Inspection
Selection tends to be from data submitted from CTA applications which then forms the basis of a pre risk assessment. The assessments incorporates :
- the number of CTAs,
- the nature of the CTAs
- the number of clinical trials involving a CT IMP
- the percentage of estimated trials involving a CTIMP compared to the total clinical trial population
- the inspection history
- any previous findings
- the extent of a researcher's involvement in clinical trials.
The Scope of the Inspection
A routine inspection tends to focus on:
- ICH Note for Guidance on Good Clinical Practice
- Annex 13 of the GMP Guidelines (labelling)
- The EU Directive 2001/20/EC
Categories of Inspections
Inspections tend to fall into three categories:
- routine
- triggered
- requested
The key regulatory frameworks used to inspect compliance are generally:
- The EU Directive 2001/20/EC
- UK SI 2004/1031 The Medicines for Human Use (Clinical Trials) Regulations 2004
- The EU Directive 2005/28/EC detailed guidance for GCP for implementation by 29th May 2006
- The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006
Inspectors are generally looking to ensure that there is evidence of compliance with regulations and that there are Total Quality Management Systems in place that include:
- documentation (data trials, dates and version numbers on documents, evidence of circulation and receipt for documentation, clearly labelled files, clear systems for indexing and systematic filing systems).
- standard operating procedures (that reflect current working practice, that are controlled, updated, and managed but most importantly that are implemented after training).
Routine Inspection
Key areas of interest in a routine inspection may be:
- personnel arrangements (contract management (e.g.contracts of employment, inc. honorary contracts) arrangements for insurance & indemnity)
- monitoring procedures and processes (e.g.products, patients)
- pharmacovigilence reports
- data management (documentation, analysis of statistics, storage, files, archiving etc.)
- regulatory submissions
- quality assurance processes
- personnel training records
- computer IT systems (n.b. validation of systems and backup processes, disaster plans)
- inspection of support departments (laboratories, Pharmacy- review of logs for whole process, data protection, transport arrangements, equipment validation )
- arrangements for IMPs (blinding, release, storage facilties, monitoring, accountability etc.)
- equipment (maintenance and calibration e.g. thermometers etc.)
Prior to Receiving Formal Notification of an Inspection
What if a CTIMP is involved?
Key areas when an CTIMP is involved, will be details of the audit trial for the CTIMP.
Some initial work should be undertaken to ensure that the following questions can be addressed.
How is the CTIMP identified?
Is there a CTA application?
Does the label on the IMP encompass all relevant information?
Is the packaging suitable?
How can the supplier be identified?
What documentation is there for the trial?
Is there a dispensing log for the specific trial?
Is there a trial prescription?
What is the trigger for release of the CTIMP?
Is the product manufactured or assembled?
Is the ML licence available?
Is the product randomised?
What is the procedure for the unblinding of the CTIMP?
What is the quality of the information available about the product?
Does manufacturer have ML?
Do they comply with GMP?
Is there a certificate of analysis for the product?
If e.g. imported, Is there any 'shipping' information for the product?
What are the arrangements for accountability of the medicines?
Are there documents of receipt?
What are the storage arrangements?
How is the CTIMP to be stored, both within the pharmacy and immediately prior to administration?
(e.g. fridge,frozen, space for storage, segregation, temp. monitoring).
What process and procedures are in place to monitoring the CTIMP?
What is the procedure for recall of a defective CTIMP?
Would the full history of the product be able to be tracked? (e.g. are temperature logs available that would identify if the defective CTIMP was in storage for the defined period over which the CTIMP is being recalled?)
What are the transport arrangements and audit trail, should the CTIMP require to be transported to another site? (n.b. should only be in exceptional circumstances, with robust accompanying documentation for delivery and communication of receipt by other site)
12 weeks Prior to a Routine Inspection
The organisation will receive a letter from the MHRA, informing of the intention to inspect and requesting the development and submission of an inspection dossier.
For pharmacy staff some considerations may be:
Clinical Trial Activity
What are the number of trials currently in process and how many are commercial compared to non - commercial (academic)?
Which trials are classified as high risk trials?
Can the sponsor for each trial be identified?
Regulatory Considerations
What were the arrangements for DDX roll over and introduction of CTAs? Do you have documentation to show how this was handled?
Do the files contain management approval documents, CTAs. for trials? i.e. is the legislation being followed (favourable opinion by ethics committee), Has authorisation by the MHRA been granted? Is Research Governance being followed and is 'management approval ' available?
Are the trials GCP compliant ?
What are the informed consent procedures and patient eligibility. Do you agree
with what is detailed in the patient information leaflet? Do you have a copy of the
leaflet with each trial?
What documentation is available?
Do the pharmacy procedures (SOPs) reflect current practice?
Are monitoring documents (environment and for medicines) up to date and available for consultation? Are they available for the past year?
Does monitoring enable a product to be identified should there be a product recall ?
Is there documentation should the IMP require to be destroyed or returned to a source at the end of the trial? (i.e. procedure and destruction log)
What have been the communications re closure of the trial and that trial has been archive according to written procedure? What happens if the trials needs to terminate early? Are there processes and procedures with time lines stipulated?
What is the amendment process for e.g. protocols ? Is there a written procedure for staff to follow? Do you have file notes that highlight amendments?
What are the procedures for the purchase, monitoring and management of IMPs?
How are the trials monitored?
Is safety information being captured?
Is there a procedure should the safety information relating to the medicine require to be updated ?
Have there been any adverse incidents that you are aware of?
Is there a procedure for the reporting of problems with equipment and a log to enable monitoring of progress with such issues?
What were the actions from the most recent local audit and is there an action plan developed following the audit?
Are the staff involved in the trial trained?
Are CVs up to date, are training records up to date?
Are all staff trained in GCP?
Have staff had specific training for the trial?
is the SOP training log up to date?
8 weeks prior to a routine inspection
Pre inspection dossier to be prepared for MHRA by organisation
(inc. company details, size, nature of activities, organisational charts, contact name
list of clinical trials dating back to one year, SOP index and procedures in specific areas)
Inspector reviews dossier and prepares for inspection
4 weeks prior to a routine inspection
Organisation receives confirmed date for inspection and agenda (for agreement), prior to inspection.
Contract management
Monitoring
Pharmacovigilence
Medical advisors
Data management
Statistics analysis
Regulatory submissions
Quality assurance
Training
Computer systems
Report writing
Archives
Laboratories
0 weeks prior to a routine inspection
Inspection of organisation occurrs.
Process: Open meeting, interview sessions with staff, visits to facilities, review of documentation, selection of investigator site inspections, closing meeting ;where inspectors will give verbal feedback of their initial findings.
Definition of findings: critical, major, other where clarification may be sought from which an action plan should be developed that details what has been done to correct any deficiencies and how will they be prevented in future (n.b. response required within 30 calendar days from despatch of the inspector’s report).
6 weeks post inspection
Further inspection of other sites (if required).
At this stage a report should have been received from the MHRA. The MHRA will request a response from the organisation.
Inspection Findings as detailed above may be classified as:
Critical - evidence exists that safety, well-being or confidentiality of trial subjects has been (or has significant potential to) be jeopordised, and/or where serious doubt exists relating to the accuracy or credibility of the trial data. Critical findings are referred to the Inspection Action Group at the MHRA.
Major - where there is evidence of significant and unjustified departure from the UK GCP Regulations or where there are a number of minor departures from the UK GCP Regulations or other relevant established guidance, suggesting a systematic assurance failure and/or that reveals a failure to comply with the relevant legislative requirements.
Observations may also be noted within the report along with recommendations for action.
14 weeks post inspection, within 30 days with response time of 28 days by organisation
Inspection closing letter issued and GCP statement issued so long as any issues have been satisfactorily resolved.