Clinical Trials

❘❙❚■ Chapter 3 | Protocol Developmentwith provision of the expected treatment effect, level of significance, and power areabsolutely critical to the success of the trial. The sample size is usually estimatedto test the primary hypothesis of no difference between the therapies to be tested.Statistical issuesIn this section, the statistical analysis plan is described; this is based on the studydesign, objectives, and outcomes (primary and secondary). The type of statisticalanalyses and their justification for use should be given, as appropriate – eg, thetype of analysis (such as intention-to-treat or per-protocol analysis) should bestated. The selection of the statistical methods will depend on the type of outcomemeasure variables and the study design.The protocol should specify how to deal with dropouts and missing data. If anadjusted analysis is planned, the protocol should specify the covariates to beincluded in the adjusted analysis. Similarly, subgroup analyses should be defineda priori on the basis of known biological mechanisms or in response to the findingsof previous studies.EthicsEthical considerations should be taken into account from the beginning of theprotocol design, addressing issues related to participants’ rights, confidentiality,and safety, as well as treatment efficacy issues for trials that evaluate the therapeuticeffects of an IMP.The main objective of this section is to establish that the study design conformswith ICH–GCP [1], the Declaration of Helsinki [2], and local ethical and legalrequirements. All research involving human participants must receive favorableapproval from the local research ethics committee or institutional review boardbefore its start. Before patients can be included in the study, they must read apatient information letter and sign a written informed consent form.Regulatory requirements and administrative considerationsThe development and sale of drugs and devices for human use is supervised bygovernment-appointed regulatory authorities, such as the MHRA in the UK andthe FDA in the US. These authorities ensure that the products or devices are safeand effective, and that all aspects of development, manufacturing, and clinicalinvestigation conform to agreed quality standards. The application to governmentauthorities for regulatory issues of the trial must be stated in the protocol.Furthermore, protocol amendments from previous versions and details of thetrial documentation, investigators, administrative structures, the investigator’sstatement, financial agreement, and issues related to trial discontinuation by thesponsor and by the clinical investigator should all be given.32