Microsoft PowerPoint - Set-up of a Phase III Trial SCT poster final by sdfsb346f


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									                         Site set-up of a large multi-centre, Phase III, randomised controlled trial:
                                             A UK post EU Directive experience.
                                  S Loi 1, AL Vallier2,3, A Willis1, H Earl2,3, L Hiller1, J Dunn1

1Warwick      Medical School CTU, University of Warwick, UK; 2Cambridge University Hospitals NHS Foundation Trust, UK; 3University of
                                                   Cambridge - Dept of Oncology, UK
                              Persephone is a Phase III national, multi-centre randomised controlled trial (RCT) trial of Trastuzumab duration (6 versus 12 months treatment) in HER-2 positive
                              early breast cancer in both the adjuvant and neo-adjuvant setting. This pragmatic study is funded by the National Co-ordinating Centre for Health Technology
                              Assessment (NCCHTA) in the UK. The study opened to recruitment in October 2007 and aims to accrue 4000 patients over 4 years.
                              The trial has received interest from over 100 UK hospitals of which over 50 are ready for recruitment and the rest are in the set-up phase. Management of such a
                              large trial under current UK legislation involves systems to be in place whereby records for each participating hospital can be easily maintained and retained up to
                              date in an orderly manner.

   The European Union Directive
The Medicines for Human Use (Clinical Trials) Regulations 2004 came into force on 1st May 2004 and implemented the European Union (EU) Clinical Trials Directive (2001/20/EC) in the UK.
The Directive, relating to implementation of Good Clinical Practice (GCP) for clinical trials of medicinal products, required Member States to adopt the laws, regulations and provisions as stated.
The aims of the Directive are:
              •     To protect the rights, safety and well being of trial participants
              •     To simplify and harmonise the administrative provisions governing clinical trials
              •     To establish a transparent procedure that will harmonise trial conduct in the European Union and ensure the credibility of results
The regulations are primarily concerned with:
              •     Identification of a sponsor
              •     Obtaining an favourable opinion from the ethics committee
              •     Obtaining an authorisation from the licensing authority

     The Persephone Experience
Persephone has been set up and continues to be conducted in accordance and compliance with the new regulations of the EU Directive. The processes undertaken during set-up have been
outlined below.
  Funding
    • Secured by National Co-ordinating Centre for Health Technology Assessment
  Identification of a sponsor and sponsor responsibilities:
    • The study has a joint sponsorship agreement between Cambridge Hospitals NHS Trust and University of Cambridge. In publicly funded trials such as Persephone the Co-Sponsors have
      delegated to the Chief Investigator a set of responsibilities. In addition the Co-Sponsors have sub-contracted certain responsibilities to the University of Warwick. However, under the EU
      Directive the Co-Sponsors of the study are mainly responsible for the following:

    Obtaining a Clinical Trial Authorisation
    The MHRA (Medicines and Healthcare products Regulatory Agency) is the competent authority for the UK in relation to the EU Directive and Medicines Devices Regulation 2002. As
    Persephone is a trial of an investigational medicinal product (IMP) the sponsors applied for and were granted a CTA to commence the trial. Notice must also be given to the MHRA for any
    amendments to the protocol or study related documents prior to implementing the changes. Amendments also include the addition of new principal investigators and centres.

    Obtaining a favourable opinion from the Ethics committee
    Regulation 16 (3) of the Medical Devices Regulations 2002 (No 618) states notification to the MHRA should be synchronised with the submission to the Multi-Centre Research Ethics
    Committee (MREC) for an ethical opinion. However, a clinical trial may only begin once the sponsor has received both a letter of no objection from the Competent Authority and the
    agreement of the MREC. In the case of Persephone a CTA was authorised in May 07 but the MREC gave a favourable opinion in August 07. It was only after the later date that the trial was
    able to open to multiple centres for patient recruitment. As with the MHRA, notice must be given to the MREC for any amendments to the protocol or study related documents prior to
    implementing the changes.

     Making arrangements to conduct the trial according to GCP principles
    GCP (Good Clinical Practice) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human
    subjects. Persephone has received a CTA and favourable opinion from the ethics committee for the protocol and related patient information sheets and consent forms which demonstrate
    compliance to GCP. Furthermore, ethical approval from the local research ethics committees for the NHS institution has been granted prior to commencement of the trial at that particular
    hospital. At each local NHS institution, a Persephone Clinical Trial Site Agreement has also been signed between the Co-Sponsors and the Directors at the respective institution to ensure
    the local investigator conducts the trial according to the responsibilities identified by the Sponsors. Research and Development approval has also been sought to ensure the institution has
    the appropriate facilities and adequate resources to conduct the trial locally and that local requirements are met as per the protocol and GCP regulations. Copies are of all these approvals
    and agreements are sent to the study office.

    Ensuring pharmacovigilance
    This involves retaining records of all serious adverse events (SAEs) reported by the local investigators, ensuring investigators are informed of suspected unexpected serious adverse
    reactions (SUSARs), SUSARs are recorded and promptly reported individually within the specified timeframes and also collectively on an annual basis to the MHRA and MREC. Electronic
    systems have been developed to enable all SAEs to be entered onto a trial specific database which allows reports and lists to be automatically generated for the aforementioned purposes.
  Indemnity and insurance
    • Sponsorship under the EU Directive requires that any clinical negligence claims are dealt with using standard procedures in the individual hospital where the patient concerned is
      treated. The Co-Sponsors of Persephone have a joint insurance policy in place to provide indemnity for injury caused by participation in the study. NHS Trusts also have a duty of care to
      patients treated whether or not the patient is taking part in a clinical trial. Compensation is therefore available in the event of injury caused by participation or through clinical negligence
      being proven as covered by the NHS.
  EudraCT number
    • The EudraCT number is a unique reference number for trials of an IMP and can be obtained from the EudraCT website. The number is the main identifier of the Persephone and is used
      on all correspondence to the MHRA and MREC, when reporting protocol amendments and in all SAE related correspondence.
  Trial management and monitoring systems
    • For a large scale study, it is of utmost importance to ensure that trial management systems are in place which enable management of core study documents, essential documents from
       hospitals and patient data. For the smooth management of Persephone, electronic tracking and data entry databases have been developed in addition to paper files. The systems
       together enables data to be sorted, manipulated and filtered in a way which allows “snap shot” views of records for each NHS institution and each patient participating in the study.
       Below are examples of the electronic database and paper filing system index as implemented by the University of Warwick.
                       The electronic database
                                                                                                      The paper filing system                                        Conclusion
                                                                               Site File Essential Document Checklist
                                                                                                                                                    •Strict regulations under the EU Clinical Trials
                                                                               Documents for Site Activation                    Date Received
                                                                                                                                                    Directive have been followed for the set-up and
                                                                               1. Ethics approval letter                        ____________
                                                                               2. SSI Application Form                          ____________
                                                                                                                                                    conduct of Persephone.
                                                                               3. R & D Trust approval letter                   ____________        •Electronic databases enable concise and
                                                                               4. Clinical Trial Site Agreement                 ____________
                                                                                                                                                    neat methods of tracking all essential
                                                                               Registration Forms:
                                                                                                                                                    documents for such a large trials. The system
                                                                               5. Site Registration Form                        ____________
                                                                                                                                                    can in fact be applied to any size trial and
                                                                               6. Principal Investigator Form                   ____________
                                                                               PI CV - current signed & dated                   ____________
                                                                                                                                                    allows for easy sorting and filtering.
                                                                               Co-Investigator Form                             ____________        •A recent audit has shown the study fully
                                                                               7. Research Nurse/Data Manager Form              ____________
                                                                                                                                                    complies to GCP standards.
                                                                               8. Pharmacy Contact Form                         ____________
                                                                               Pathology Contact Form                           ____________         For further information please contact:
                                                                               9. Site Signature & Delegation Log               ____________         Mrs Shrushma Loi, Clinical Trial Co-ordinator
                                                                               Any other documents                                                   : or visit:
                                                                               Patient Information Sheet on headed paper        ____________
                                                                               GP Information Sheet on headed paper             ____________

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