Ellen van Bavel, PhD

	There are many misconceptions regarding the development of clinical trial protocols, the most common being that it requires only about a day’s work to develop the protocol synopsis, and that a half-page synopsis is sufficient to fully develop the research protocol. It is often thought that the clinical trial study design is not really the concern of statisticians and that it takes only about one week in total to develop the complete protocol document. 

, a clinical trial protocol is “a document that describes the objective(s), design, methodology, statistical considerations, and organization of a study.” Typically, protocol development starts with a description of the study concept on what and how will be studied, which is then further refined and confirmed, leading to the development of a protocol synopsis. 

	In going from study concept to protocol synopsis, the aim of the study is translated into objectives and design. This step of development is of crucial importance given its implication on other items in the protocol, such as the type of assessments to be undertaken, the number of doses of the investigational drug to be tested, the mode of administration of the investigational drug, and the subject selection criteria. Thoughtfully defining the objectives and the design, so that these elements remain unchanged throughout further development, increases the efficiency of the writing, and avoids inconsistencies in the final document. Furthermore, the sample size calculation (if applicable) by the statistician is based on the primary objective, which should, therefore, be carefully selected from the objectives that were initially defined. Thereafter, any additional objectives can be categorized as secondary or exploratory. 

	Knowledge of what assessments to perform and their relevant timing within the study to characterize the objective(s), taking into account the indication and the characteristics of the investigational drug itself, is of equal importance. Having a clear schedule of assessments--often referred to as the flow chart--that identifies all necessary visits and study periods, and also groups ‘related’ assessments together, such as all laboratory assessments, enhances the feasibility assessment of the necessary activities to be performed at given time points within the study. Using a clear table for the schedule of assessment and minimizing the use of footnotes greatly assists project planning and can identify potential bottlenecks.

	Given that the protocol synopsis is the basis to write the complete protocol, spending time to achieve a stable, final version with all elements as discussed below, will improve the development process. 

	Development of the protocol synopsis can be done by the sponsor, or the sponsor in conjunction with the CRO. As the complete protocol document is the basis to write the methods section of the Clinical Study Report (CSR), one should also keep in mind the ICH E3 guideline

, which provides far more detail than the ICH E6 guideline on what information should be provided. Designing the protocol corresponding to the methods described in ICH E3 ensures that it contains the text required for the CSR and simplifies the writing process of the latter. To facilitate the writing process of the protocol synopsis and the complete protocol document, ICH E6 and ICH E3 compliant templates should be used to ensure all elements that are required are addressed and to ensure consistency across studies

	The technical and administrative elements of the protocol synopsis that need to be included are the study title, the product, which clinical phase the study covers, the protocol number, the disease indication of the drug, its EudraCT or IND number, plus information on the sponsor, the Principal/Coordinating Investigator, and the clinical center(s) where the study will take place.

	The protocol synopsis will list the primary and secondary objectives of the clinical study and provide an overview of the study design, specifying, for example, whether it is open-label or double-blind, or whether treatment arms are performed in a parallel or crossover fashion. Equally important are the details of the treatment(s), including the dose regimen, the drug formulation, the duration of the treatment, and also the nature of the control â whether the performance of the drug is being compared to that of a placebo, an active control or to no treatment at all.

	Once these features of the study have been described in the protocol synopsis, further information on the study population (such as “healthy male volunteers” in a Phase I), the number of subjects to be enrolled, and the detailed eligibility criteria for a subject’s inclusion or exclusion need to be described. Another essential part is the type and timing of assessments to be performed, based on the objective(s), to evaluate, for example, the safety and pharmacokinetic characteristics of the investigational drug, and the creation of a schedule of assessments.

	After finalizing the protocol synopsis, complete protocol development can commence, which entails more topics than the synopsis. In addition to the elements of the protocol synopsis described above, the complete protocol also needs to include an introduction, which comprises the indication and its current management, the investigational drug, and nonclinical and clinical data (if available). The introduction can be written based on the information provided in other protocols and/or the Investigator’s Brochure of the investigational drug. Any recent and relevant literature regarding the indication or new insights of current knowledge can be included as background. A description of the rationale behind the clinical study design (an ICH E3 requirement) and a more elaborate description of the assessments are also included. Data analysis methodologies (statistical methods) need to be described, as does any other medication relevant to the study procedure, i.e., any prior or concomitant treatments. Furthermore, the conditions under which the study would need to be suspended or cancelled need to be specified, and any procedures with respect to replacement of subjects.

	The actual writing of a protocol is a team effort with contributions from a medical expert, a statistician, a pharmacokinetics expert, the clinical research coordinator, and the project manager, who all provide input to the medical writer to produce the final document. 

	The medical expert is a major contributor in producing the protocol, including the design of the study, its objectives and endpoints, and determining selection criteria and assessment procedures. Furthermore, he/she is also involved in the selection of which concomitant therapies are permitted or disallowed, the definition of any stopping rules for dose escalation or the study, and the information provided in the introduction. Without the input of a medical expert, the period between subsequent dosing in single ascending dose studies chosen could be too short to evaluate sufficient safety data; the use of a sentinel cohort based on the safety profile of the investigational drug could be overlooked; or the timing of any follow-ups may be incorrectly scheduled, for example, adverse events from a drug with a long half-life may be missed if follow ups are planned too soon.

	The statistician calculates the sample size and power of the study (if applicable), and determines its objectives and endpoints. Needless to say, the statistician is responsible for determining and implementing the statistical procedures used, and without one, the determined sample size could be too low to allow detection of a clinically meaningful difference between treatment groups. The statistician also ensures that the design reduces the potential variability of the study and that the appropriate number of interim analyses are performed; if too many are planned, the chance increases to detect a difference between treatments while there is none.

	Pharmacokinetics is an essential part of any clinical study where the primary objective involves evaluation of the pharmacokinetic properties of the investigational drug. The pharmacokinetic expert contributes to developing all the major elements of the protocol, from the determination of objectives and endpoints and dosing procedures (e.g., single ascending dose, multiple ascending dose), to specifying the core pharmacokinetic requirements. These include the timing of pharmacokinetic samples and assessment of pharmacokinetic parameters. The pharmacokinetic expert is also involved in determining the statistical procedures for pharmacokinetic data evaluation, and if not involved, potential issues may arise when determining the dosing frequency of an investigational drug going from the single to multiple ascending dose part of the study.

	The clinical research coordinator’s responsibilities include determining the practical feasibility of the assessments by means of the schedule of assessments and the description of assessments in the complete protocol document. He/she contributes to some of the more detailed features of the management and logistics of performing the clinical study, including laboratory safety and sample logistics. He/she reaches out to the pharmacist in case the study drug needs to be prepared at the clinical site or to the laboratory technician to assess the feasibility of a complicated sample handling. If a clinical research coordinator would not be involved in the development, for example, more assessments can be planned around the same time point than could be performed in practice, leading to protocol deviations and/or amendments. 

	The project manager is essential in the process to map out the sponsor’s expectations, develop detailed timelines for the protocol and the requirements for the set-up of the study, and will oversee among others the data management part of the study.

	Other stakeholders with a contribution in producing the protocol are Regulatory Affairs, who ensure compliance with regulatory guidance and liaise with the Health Authority, as well as being responsible for submission of the Investigational Medicinal Product Dossier. Laboratory staff manage sampling handling procedures, Secure Data Office provides input on the randomization procedure (if applicable), and the Medical Affairs (Pharmacovigilance) department ensures (serious) adverse event reporting is accurately described. 

	All of these contributions are then finally streamlined and compiled into a single document by the medical writer, who ensures that questions raised during the protocol review are resolved by addressing them to the right contributors and ensures consistency of information throughout the synopsis and body of the complete document, and the schedule of assessments.

	The stability of the protocol synopsis is an important factor in how smooth the CTP writing process goes.

	In this case, the first stage is to produce a ‘stable’ protocol synopsis. Initial assumptions to this are that the study design is fixed and is endorsed by upper management and other important stakeholders of the client, and that the elements of the protocol synopsis are defined and clear with a schedule of assessments in place.

	The medical writer then develops the complete CTP document, starting from the protocol synopsis. This includes review of the sponsor and study sites. Writing a complete CTP document takes at least six weeks for a simple early-phase study (first-in-human plus two weeks).

	There are also unstable protocol synopsis situations. When there are no counterparts at the sponsor’s side of the major CTP contributors, the study design has to be fully developed by the CRO undertaking the study. As a consequence, developing a complete CTP document for a simple Phase I pharmacokinetic study without a (stable) synopsis requires an additional four weeks. 

	Sufficient time needs to be invested in the development of the protocol synopsis, with particular attention needed regarding the study objective(s), design, and type and timing of assessments, to ensure a more efficient writing process and avoiding potential inconsistencies in the final CTP document. To facilitate the writing process of the protocol synopsis and complete CTP document, ICH E6 and ICH E3 compliant templates should be used to ensure all elements that are required are addressed, and to ensure consistency across studies. The actual writing of a CTP is a team effort with contributions from a medical expert, a statistician, a pharmacokinetic expert, the clinical research coordinator, and the project manager all providing input to the medical writer to produce the final document. 

		Guideline for Good Clinical Practice E6(R1), International Conference on Harmonisation, 10 June 1996.

		Structure And Content Of Clinical Study Reports E3, International Conference on Harmonisation, 30 November 1995.

	Ellen van Bavel, PhD, is Senior Medical Writer for SGS - Life Sciences

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