Serious Breaches. Ian Gravenor. Senior Clinical Project Manager Novo Nordisk Ltd

Serious Breaches Ian Gravenor Senior Clinical Project Manager Novo Nordisk Ltd

Serious Breaches of GCP or the Trial Protocol Agenda Why report? The legislation MHRA Guidance document Timelines Actions Identifying breaches and examples What did Novo Nordisk do? Slide no 2 Serious Breaches ICR Northwest Forum 13th May 2010

EU GCP Directive 2005/28/EC Builds on EU Clinical Trials Directive 2001/20/EC Put into UK law as an amendment by means of a Statutory Instrument (2006/1928) Article 29A of this SI contains a requirement for the notification of serious breaches of GCP or the trial protocol Slide no 3 Serious Breaches ICR Northwest Forum 13th May 2010

Serious Breaches Article 29A 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 Slide no 4 Serious Breaches ICR Northwest Forum 13th May 2010

Serious Breaches Article 29A Article 29A (2) For the purpose of this regulation, a serious breach is a breach which is likely to affect 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 Slide no 5 Serious Breaches ICR Northwest Forum 13th May 2010

Serious Breaches why? Enhance the safety of trial subjects by seeking to ensure that the licensing authority is promptly informed of such serious breaches, in order to take appropriate action in response to the breach and/or, To take the information regarding serious breaches into account when assessing future applications for clinical trial authorisation, and applications for marketing authorisation, which include data from trials affected by serious breaches Slide no 6 Serious Breaches ICR Northwest Forum 13th May 2010

Guidance on Serious Breaches MHRA Guidance document that: outlines the practical arrangements for notification provides advice on what should and should not be classified as a serious breach and what must be reported outline possible actions that may be taken by the MHRA in response to notifications of serious breaches Serious Breaches Guidance Version 2 (Final, 15/10/09) Article from CRFocus that summarises the MHRA guidance document (Vol 18, No. 4, April 2007 23-26) Slide no 7 Serious Breaches ICR Northwest Forum 13th May 2010

Timelines Notification has to be made within 7 days of the Sponsor becoming aware of the breach If this function has been delegated by the Sponsor the 7 day timeframe applies to whoever has been delegate the task The Sponsor should obtain written agreement from others, i.e. CRO, investigators, etc that they will promptly report serious breaches Slide no 8 Serious Breaches ICR Northwest Forum 13th May 2010

Timelines The Sponsor should define the requirements in their SOPs As with SUSAR reporting, the clock starts when the Sponsor becomes aware of the serious breach Sponsors might need to investigate the deviation to be able to assess whether or not a breach is serious Once identified as a serious breach this triggers the 7 days in which to notify the MHRA However, the Sponsor should not wait for ALL details of the breach prior to notification Slide no 9 Serious Breaches ICR Northwest Forum 13th May 2010

Timelines If an inspector considers the notification to have been inappropriately delayed, this might also be classed as non-compliance The MHRA GCP group are willing to discuss whether a particular breach needs to be notified. Slide no 10 Serious Breaches ICR Northwest Forum 13th May 2010

Actions The matter does not stop once notification is made The Sponsor must take and document appropriate corrective and preventative actions in response to the serious breach The actions and documentation will be reviewed during an MHRA inspection Slide no 11 Serious Breaches ICR Northwest Forum 13th May 2010

Identifying Serious Breaches Not all deviations from the protocol are considered serious Deviations from the protocol and from GCP do occur; most are regarded as technical deviations which do not result in harm to the trial subjects or affect the scientific value of the study These are usually documented and commented upon in the final study report Slide no 12 Serious Breaches ICR Northwest Forum 13th May 2010

Identifying Serious Breaches 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 Slide no 13 Serious Breaches ICR Northwest Forum 13th May 2010

Identifying Serious Breaches The difficulty is judging whether or not a given breach is serious This judgement can be complex, depending on a variety of factors, such as type of trial, complexity of the study etc. Inaccurate judgement can lead to problems in audit/inspection or in later regulatory submissions It is the responsibility of the Sponsor to assess the impact of the breach on the scientific value of the trial Slide no 14 Serious Breaches ICR Northwest Forum 13th May 2010

Examples A breach of GCP or protocol deviation leading to the death, hospitalisation or disability of a trial subject in the UK. Not all SAE/SUSARs would routinely be regarded as serious breaches, but those that are a result of GCP or protocol non-compliance might. If a SUSAR is notified as a serious breach, it will still need to be reported and submitted to the EudraVigilance database Slide no 15 Serious Breaches ICR Northwest Forum 13th May 2010

Examples Failure to report AEs, SAEs or SUSARs in accordance with the UK legislation, such that subjects are put at risk Proof of fraud relating to clinical trial records or data that impacts on the integrity of trial subjects or scientific value of the data Slide no 16 Serious Breaches ICR Northwest Forum 13th May 2010

Examples Persistent or systematic non-compliance with GCP or the protocol that has a significant impact on the integrity of trial subjects in the UK or on the scientific value of the trial. Failure to control investigational medicinal product such that subjects or the public are put at risk or the scientific value of the trial is compromised. Serious breaches in non-uk sites that impact on UK subject integrity and/or that affects the scientific value of the trial Slide no 17 Serious Breaches ICR Northwest Forum 13th May 2010

What Did Novo Nordisk do in response to the requirement to report serious breaches? Started local in the UK affiliate set up mailbox to report cases set up quorum to review cases quickly to decide whether to report or not wrote local UK SOP Going global expanding SOP across the company globally in progress. Slide no 18 Serious Breaches ICR Northwest Forum 13th May 2010

Local SOP Mailbox set up to report breaches avoids reliance of one person to pick up email and act on it Quorum to review each case reported 5 members, of which minimum of 3 will make decision Quorum to consist of 2 x PM, 2 x CRA, 1 x CRM Quorum to consult other experts e.g. Safety dept, DM dept where needed If no consensus reaches seek advice from MHRA or report as a potential serious breach Slide no 19 Serious Breaches ICR Northwest Forum 13th May 2010

Documentation Database of cases maintain a DB of all cases reported and not Keep a file of each case so that there is an audit trail particularly important to have documentation on when it was first identified within the company and when it was reported Summary list of each case for quick review/identification Inspections Inspectors will want to see procedure and list of all cases to date NN provided the list and brief summary of each case and cases were chosen to look at in more detail Slide no 20 Serious Breaches ICR Northwest Forum 13th May 2010

Deciding is it or isn t it??? Cases are not straightforward Guidance is grey and vague Timelines are very short Information available at the time is limited Slide no 21 Serious Breaches ICR Northwest Forum 13th May 2010

Completing the Form what is the breach why you think it s a breach what action you have taken what action you are currently taking what action and follow up you will take provide updates to the MHRA as new information becomes available and document the impact of this information on the case Slide no 22 Serious Breaches ICR Northwest Forum 13th May 2010

Cases at NN To date 11 cases have been reviewed by NN quorum 5 were reported as serious breaches or potential serious breaches cases included temperature monitoring of trial products, informed consent, trial product handling, source data issues, trial data issues NN were inspected by the MHRA in 2008 reporting procedure was praised cases looked at were well documented and reported correctly minor comment one case that involved Ireland as well as UK it was recommended that the IMB could have notified of the breach as well as the MHRA however no formal requirement Slide no 23 Serious Breaches ICR Northwest Forum 13th May 2010

Experience to date.. Inspectors are very helpful and approachable about cases Always good to report potential breaches and state following up on the case Shows that you are pro-active and monitoring your procedures Interested in the procedure that you have in place Always interested in documentation! If in doubt either discuss with MHRA or report as potential breach Slide no 24 Serious Breaches ICR Northwest Forum 13th May 2010

Thank You!