Clinical Trials

❘❙❚■ Chapter 3 | Protocol DevelopmentIntroductionThe trial protocol is a formal document that specifies how a clinical trial is to beconducted (Table 1). It describes the objective(s), design, methodology, statisticalconsiderations, and administrative structure of the trial [1]. We can also regard theprotocol as a scientific, administrative, and organizational project guideline thatmay be the basis of a contractual relationship between an investigator and a trialsponsor [1]. Well-designed protocols are important for conducting clinical trialssafely and in a cost-effective manner. Different trial protocols will retain verysimilar key components. However, adaptations may be necessary for each trial’sparticular circumstances.In scientific research, the first step is to set up a hypothesis, and then to constructan appropriate study design to test that hypothesis. In clinical trials, the hypothesisis usually related to one form of therapeutic intervention that is expected to besuperior or equal to another in terms of specific outcomes.Once this hypothesis is developed, the study’s aims, design, methodology, statisticalmethods, and analyses should be formulated. The protocol should clearly addressissues related to the study’s conduct, set up, organization, monitoring,administrative responsibilities, publication policy, and timelines, in appropriatesections. Trial guidelines and regulatory requirements, such as the InternationalConference on Harmonisation guidelines for Good Clinical Practice (ICH–GCP)[1], the Declaration of Helsinki [2], the EU Clinical Trials Directive (EUCTD) [3],and the US Food and Drug Administration (FDA) Regulations Relating to GoodClinical Practice and Clinical Trials [4], should be followed as appropriate.Protocol writing in a clinical trialProtocol writing is a joint effort that typically involves a lead investigator (who isan expert clinician and researcher), along with his/her co-investigators, a clinicalscientist(s), and an expert medical statistician who is familiar (ideally) with thesubject matter. A group of experienced and renowned experts is chosen to peerreview the document; their consultations and opinions are sought as appropriate.Most common problems in protocol writing – such as incompleteness, ambiguity,and inconsistency – reflect an inefficient writing process [5]. Studies have shownthat protocol development is a collaborative scientific writing process, the aim ofwhich is to achieve consensus within a group of interdisciplinary clinical trialexperts [6,7]. Important characteristics of a good quality protocol are summarizedin Table 2.24