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ОглавлениеBefore Initiation
The study protocol is the basis of a clinical trial. The protocol addresses the quality, the ethical feasibility and the objectivity regarding the efficacy of the IMP.
The responsible authorities can only give approval when the operations and methodology are described exactly. For the clinical trial protocol, this means the intentions must be consistent, methodologically sound and every step repeatable for another research team.
Regulatory Reference
! ICH GCP Guideline, Chapter 6
! Declaration of Helsinki, B. 13, B. 14
! EU Directive 2001/20/EC, Art. 2 h, Art. 6.3 c, Art. 10 a, Art. 11 c
Responsibilities
Formal Requirements of the Study Protocol
The development of the protocol can be cumbersome; the sponsor-investigator must rely on his/her team, for instance, to collect all the important information (e.g. the required sample size from the statistician or essential laboratory data from the biochemist).
The authorities provide the sections and organization of the protocol. The main sections are:
1. General information
2. Background information
3. Trial objectives and purpose
4. Trial design
5. Selection and withdrawal of subjects
6. Treatment of subjects
7. Assessment of efficacy
8. Assessment of safety
9. Statistics
10. Direct access to source data/ documents
11. Quality control and quality assurance
12. Ethics
13. Data handling and record keeping
14. Financing and insurance
15. Publication policy
16. Supplements
see 1
Risk-Benefit Analysis
see 2
Study Types and Study Design
see 10
Informed Consent
see 22
Quality
see 17
Data Management
see 12
Insurance
Keeping with the protocol outline development and its required structure is not easy. In this chapter’s section ‘Forms and Templates’, the sponsor-investigator can use the template of a protocol outline for additional guidance.
Responsible Authorities
After writing the study protocol, the sponsor-investigator must send the completed document to the Ethics Committee(s) and health authorities to receive the approval for the study initiation.
Advice - Hints and Tips
The sponsor-investigator should not assume changes in the study protocol could be made a priori. Each change must be handled with care and, possibly, the amended protocol may need to be approved again.
Clinical trials often have tight time schedules. Bearing this in mind, every change in the study protocol needs adequate time to be implemented, time which could be better spent in getting the protocol right before submission.
Forms and Templates
Protocol Template (http://www.nia.nih.gov/NR/rdonlyres/57864169-734F-4B05-9DC0-A7B2E38C5A55/0/ProtocolTemplate_11_12_2007_Final.doc; accessed January 19, 2011)
During Study
After getting the approval of the Ethics Committee(s) and the health authorities, the sponsor-investigator must maintain the study protocol regarding its timeliness. Accordingly, the regulatory references allow changes only under well-defined conditions. The amendments of the trial protocol can be classified as either a change in substantial or non-substantial documents. Special forms are required for urgent (and substantial) amendments.
Regulatory Reference
! ICH GCP Guideline, Chapter 6
! EU Directive 2001/20/EC, Art. 10
! EU Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial
Responsibilities
Labelling the Amendment
The initial approval of the Ethics Committee and the health authorities is based upon the information contained in the clinical trial application, but does not include any later changes which may have been made. In case of any amendments, they must be attached to the latest version of the protocol. All amendment forms must be signed by the sponsor-investigator. All modifications to the protocol shall be added as an amendment and must be labelled with the date, initials of the authorized person and the signature in the original document.
Procedure for Notification
Substantial amendments must be reported to the competent health authorities and Ethics Committee(s) to obtain approval, or more often, an agreement of the changes.
see 13
Health Authority Approval
For the ‘Notification of a Substantial Amendment Form’, a template is available in the chapter ‘Health Authority Approvals’. A covering letter with a description of the modification and the relevant information related to the original application with a signature of the sponsor-investigator should be added to the notification form. An overview of the impact on the risk-benefit-analysis must also be included.
In contrast, non-substantial amendments do not require notification but must be recorded with the date of the change.
Advice - Hints and Tips
• The Ethics Committee gives an ethical opinion on the amendment within (not more than) 35 days from the date of receiving the correct notice of amendment.
• Where a negative opinion is given, the sponsor-investigator may submit a modified amendment. The Ethics Committee will give an opinion on the modified amendment within 14 days after receipt.
Forms and Templates
Protocol Amendment Covering Letter
Protocol Amendment Template
After Study
The study protocol and amendments, if any, also represent the basis of the Final Study Report at the end of the trial. The main topics of both documents are generally identical; this usually makes the necessary detailed and explanatory writing more comfortable for the sponsor-investigator.
see 26
Final Study Report and Publication
Regulatory Reference
! ICH GCP Guideline, Chapter 6.16
! ICH GCP Guideline E3: Note for Guidance on Structure and Content of Clinical Study Reports
Responsibilities
Study Completion
Within a year after the completion of the clinical aspects of a study, a summary of the study report must be sent to the Ethics Committee and the competent Health Authorities.
Often, the last regular ward round of the last participant (last patient, last visit) determines the completion date of the study, and therefore, of the protocol.
Further Actions
The sponsor-investigator has the responsibility to complete the trial in the manner stated in the study protocol. Responsibilities include the statistical analysis, data management, archiving, etc. as well as taking care of the observation of the study participants after the completion (patient follow-up period).
For more detailed instructions, please review the ‘After Study’ sections of the following chapters:
• IMPs (in particular, handling and disposal)
• Ethics
• Trial Master File
• Documentation and Data Management (archiving)
• Pharmacovigilance (care of the participants in subsequent study phases)
• Quality (standard operating procedures, etc.)
• Biometry (statistical evaluation)
• Final Study Report
see
After Study sections:
3. Investigational Medicinal Products
14. Ethics
15. Trial Master File, Updating and Archiving
16. Documentation
17. Data Management
19. Pharmacovigilance
22. Quality
24. Biometry
