UK Legal Requirement for Notification of Serious Breaches of Good Clinical Practice or The Trial Protocol John Poland, PhD Senior Director, Regulatory Policy Covance Clinical Development Services October 2009

Protocol deviations and violations v GCP violations ICH GCP guidance E6 (sections 3.3.7 and 4.5.4) No deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when change(s) involve only logistical or administrative aspects of the trial The implication is that deviations from the protocol not meeting these criteria are considered to be protocol violations

Protocol deviations and violations v GCP violations ICH Clinical Study Report guidance E3 (section 10.2 and Appendix 16.2.2) All important deviations related to study inclusion or exclusion criteria, conduct of the trial, patient management or patient assessment should be described “Important” is not defined (= an impact on interpretation of the study results?) An individual protocol deviation/violation is not necessarily considered to be a violation of Good Clinical Practice – but systematic use of protocol deviations/violations would be

Protocol deviations and violations v GCP violations EMEA Questions & Answers on GCP matters “Sponsors and investigators should not use systems of prospectively approving protocol deviations, in order to effectively widen the scope of a protocol.   Protocol design should be appropriate to the populations required and if the protocol design is defective, the protocol should be amended………..GCP inspectors have observed a number of sponsors implementing systems where the investigator can contact the sponsor, usually the Medical Monitor, and request a prospective approval to deviate from the inclusion and/or exclusion criteria.  The use of such systematic waiver systems in clinical trials is not considered to be appropriate and studies using such a system might be regarded as non-compliant with GCP”

Protocol deviations and violations v GCP violations MHRA guidance for the notification of serious breaches of GCP or of the trial protocol “Deviations from clinical trial protocols and GCP occur commonly in clinical trials. The majority of these instances are technical deviations that do not result in harm to the trial subjects or significantly affect the scientific value of the reported results of the trial. These cases should be documented e.g. in the case report form for the trial or trial master file, in order for appropriate corrective and preventative actions to be taken. In addition, these deviations should be included and considered when the clinical study report is produced, as they may have an impact on the analysis of the data. However, not every deviation from the protocol needs to be reported to the MHRA as a serious breach”

UK Law (Statutory Instruments) SI 2004 No. 1031: The Medicines for Human Use (Clinical Trials) Regulations 2004 Effective 1 May 2004 Implemented European Clinical Trial Directive (2001/20/EC) and most aspects of Directive 2003/94/EC on GMP for IMPs Amended by SI 2006 No. 1928: The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 Effective 29 August 2006 Implemented European Directive 2005/28/EC (GCP) and remaining aspects of Directive 2003/94/EC

Reporting Serious Breaches of GCP or of the Trial Protocol The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 (SI 2006/1928) Regulation 29A requires: The sponsor of a clinical trial shall notify the licensing authority in writing of any serious breach of (a) the conditions and principles of good clinical practice in connection with that trial; or (b) the protocol relating to that trial (including amendments) within 7 days of becoming aware of that breach. Failure to comply established as a criminal offence MHRA guidance document published February 2007

Purpose of the Regulation To enhance the safety of trial subjects/patients by seeking to ensure that the competent authority (MHRA) is promptly informed of such serious breaches, in order to take appropriate action in response to the breach To allow the MHRA to take 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

Notification of Serious Breaches Who should notify? The sponsor or a person legally authorised by the sponsor. A CRO is legally responsible for compliance with the law in relation to functions delegated by the sponsor to the CRO Who should be notified? MHRA GCP Inspectorate

When Should Notification be Made? Within 7 days of the sponsor becoming aware of the breach - if the notification function has been delegated to a CRO, the 7 day timeline applies to the CRO If there is clear and unequivocal evidence of a breach, notify the MHRA within 7 days If a breach is suspected but the evidence is not unequivocal, notify the MHRA within 7 days and investigate simultaneously or after notification Agreements between the sponsor and other parties involved in the trial (e.g., CROs, contractors, co-development partners, investigators) should state that the other party will promptly notify the sponsor (or other party responsible for notification) when they become aware of a potential serious breach Inspectors will review the process for notification during MHRA GCP inspections and delays in notification will be classified as a non-compliance

What Needs to be Notified? A breach of GCP or of the trial protocol that is likely to affect to a significant degree: (a) the safety or physical or mental integrity of the subjects of the trial and which is relevant to trial subjects in the UK; or (b) the scientific value of the trial anywhere in the world

What Needs to be Notified? It is the responsibility of the sponsor to assess the impact of the breach for UK patients or on the scientific value of the trial This assessment should be documented The appropriateness of the decisions taken by the sponsor may be examined during MHRA inspections If the sponsor is unclear about the potential for a breach to have a significant impact on UK patients or on the scientific value of the trial, the sponsor should contact the MHRA to discuss the issue

What is a Serious Breach of GCP or of the Protocol? Examples provided by MHRA in 2006 Violations of eligibility criteria that put trial subjects at risk or invalidate trial design Systematic failure to adhere to schedule of events for patient visits Routine failure to follow instructions for handling of IMP Systematic use of incorrect informed consent information/forms Routine failure to follow safety instructions in protocol Routine failure to follow data recording/handling instructions in protocol

What is a Serious Breach of GCP or of the Protocol? Further examples provided by MHRA in 2007 A breach of GCP or of the protocol leading to death, hospitalisation or permanent disability of a trial subject in the UK Proof of fraud relating to clinical trial records or data, if the fraud is likely to have a significant impact on the integrity of trial subjects or the scientific value of the data (includes fraud outside the UK if it is likely to significantly impact UK trial subjects or the overall scientific value of the trial) 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 (eg, widespread and uncontrolled use of protocol waivers affecting eligibility criteria, repeated failure to reduce or stop the dose in response to a trigger defined in the protocol)

What is a Serious Breach of GCP or the Protocol? Examples of serious breaches (continued) Failure to report adverse events, serious adverse events or SUSARs in accordance with law such that trial subjects or the public in the UK are put at significant risk A breach at any site (including those outside the UK) where the cause is such that the breach may occur at other trial sites (e.g., incorrect administration of IMP resulting from erroneous protocol instructions) Irretrievable loss of original Trial Master File documentation (including archived documentation after the trial has finished)

Implications Evaluate any potential serious breach of GCP or of the protocol, occurring anywhere in the world, for possible implications for the safety or physical or mental integrity of subjects in the UK or on the scientific value of the trial Establish processes for the investigation of potential serious breaches of GCP or of the protocol, and for notification of confirmed breaches to MHRA within 7 days if they impact UK trial subjects or the scientific value of the trial: Ensure contracts between sponsors, investigators and other parties involved in the trial (e.g., CROs) contain appropriate wording to ensure potential serious breaches of GCP or of the protocol are immediately reported to the party responsible for evaluation and reporting

References EMEA Q&A statement on use of protocol waivers http://www.emea.europa.eu/Inspections/GCPQaA.html SI 2004 No. 1031 http://www.opsi.gov.uk/si/si2004/20041031.htm SI 2006 No. 1928 http://www.opsi.gov.uk/si/si2006/20061928.htm MHRA guidance for the notification of severe breaches of GCP or of the trial protocol http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2030355&ssTargetNodeId=387