. (Agathe Guillot - GCP Inspector, 14 July 2014) MHRA view of responsible Sponsorship

Content Sponsor Basis for Oversight Investigator Oversight: o Contracting/delegating o Plans for oversight o Evidence of oversight o Retention of evidence Common findings MHRA Expectations

Sponsor An individual, a company, institution or organisation that takes responsibility for the initiation, management, and/or financing of a clinical trial (Reg 3(1) of SI 2004/1031) Established in the EEA (or legal representative in EEA) Types of sponsor seen in the UK: o Commercial pharmaceutical companies, o Research councils, o Medical charities, o and Other non-commercial bodies (Trusts & Universities)

Oversight Watchful and responsible care Supervision Watchful management Management of the performance or operation of a person/group

Basis for oversight Sponsor Responsibilities: Global:Guidance ICH GCP E , and EU:Directive 2005/28/EC article 7, EU Regulation 536/2014 Chapt 8 UK:Reg.3(12) of SI2006/1928 Quality Systems: Global :Guidance ICH GCP E6 2.13, and EU:Directive 2005/28/EC article 2(4) UK:Reg.28(2) of SI2006/1928, Schedule 1 part 2 (4) & (9)

Basis for oversight Trial Master File: Global :Guidance ICH GCP E6 2.10, 5.5.3, 5.5.4, 5.5.6, and 8.1 EU:Directive 2005/28/EC articles 5 and 16 to 20 UK:Reg.31A of SI2006/1928, Schedule 1 part 2 (9)

Sponsor Oversight Summary

Trials Complexity of trials: o New technology, more specialised/niche vendors o More vendors within the trial to provide necessary expertise o Involvement of CTUs o Outsourced work (specialised labs, image analysis, CRF)

Co-sponsorship Reg.3(2) of SI2004/1031 – joint responsibility No reference to contract information in the TMFs, as contracts are not at a trial level No evidence in the TMF of what aspects of the delegated “function” was undertaken by each party Although all staff were on the delegation log, it was not apparent from any trial documents who were sponsor or co-sponsor staff especially if they have an honorary contract Training logs were incomplete, as these were split between the sponsor and co-sponsor, so not everything was available.

Delegation

Sponsor can delegate a task or role, but not the responsibility under the legislation (Reg.3(12) of SI2006/1928) The sponsor/vendor relationship (delegation of whole departmental functions) o CTUs (Data management/statistics/project management)

Delegation Expectations Delegation of tasks must be in writing Sufficiently detailed: who does what Routinely reviewed throughout the trial lifecycle Regular well-defined communication (documented Reg.31A(4) of SI2006/1928) Escalation process Assessment program

Delegated Parties Examples include: o Investigators o Clinical Trials Units (CTU) o Third parties e.g. laboratories

Common Issues Sponsor and delegated parties (DP): Sponsor or DP not undertaking their responsibilities DP undertaking activities not formally delegated Inadequate detail of the activities delegated Partnership agreement for function not considered formal delegation, so no clarity in trial documents that activities performed by vendor Responsibility of reporting of SUSARs to CA not clear

Oversight

Mechanisms for oversight Monitoring (on site or remote) and audits Review of monitoring reports & co-monitoring visits Minuted meetings with study team Review of progress reports (e.g.ASR/APR/Organisation Report) Spot checks (processes and trial documents) Documentation to support key decision making Plan for review of vendors performance Defined process for escalation and resolution of issues

Expectations Formal procedures for addressing oversight Proactive & ‘up front’ determination of the levels of oversight needed for a trial/project Justified rationale for levels of oversight Flexible oversight plans to permit changes Risk assessment and oversight mitigation plan

Expectations Then: Documentation of what has been performed Contemporaneous evidence of compliance Retained in the TMF

Issues Documentation to reconstruct appropriate oversight No evidence of TMF issues addressed/closed when raised by sponsor No evidence of sponsor review of status reports Informal meetings so not documented: attendance and decisions unclear

Retention of documentation Oversight documentation: contemporaneously retained TMF = o individual to the organisation (index) o story of the trial o all documentation produced during the trial (what happened and compliance with SOPs)

MHRA Expectations Follow current Regulations Procedures in place and being followed Follow protocol, follow randomisation procedure Mechanism for non-compliances – appropriate management of issues Staff appropriately trained Oversight of contracting or outsourcing

Contracting

TMF/ Documentation

Expectations Formal process: vendors identification and assessment Mechanisms for assessment depending on GCP criticality Assessment and decision documented Retention – where/how is this referenced if not in the TMF

Common Issues Sponsors No/inadequate assessment Commitment prior to any issues being resolved Not considered trial data, so not in TMF or referenced No awareness of third party outsourcing Vendors Unable to deliver to a required standard (e.g. laboratory being unable to comply with GCP)

Issues for sponsors to be aware of Pressure on study team: o time o funding Academic qualifications: o CI, rotating registrars conducting different parts of the trial, pressure to write up publication

Sponsorship responsibility Awareness of what is to be done Clear who/what responsibility Appropriate mechanisms to ensure oversight Use of tools to manage risk: o sponsor audits, visibility to trial team, presence of sponsor on project team/copied into minutes Management of data, close out and publication: o no review on outputs from trial, no process for publication review despite claims of compliance

Summary Basis for sponsor oversight Delegations and our expectations Oversight and the various mechanisms that can be used Contracting and our expectations Sponsor responsibilities

29 Questions ?

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