Guidance for Trial Design

SEND

Purpose

The Trial Design Model in the SENDIG provides a standardized way to describe those aspects of the planned conduct of a nonclinical study, as shown in the study design diagram examples within this section. The Trial Design Model in the SENDIG is equivalent to the Trial Design Model within the SDTMIG for clinical trials. Trial Design datasets contain study-level, rather than subject-level, information. Note that generally the term "trial" is equivalent to "study" in the nonclinical context. In addition, "subjects" are equivalent to "animals."
The Trial Design Datasets will allow:

Clear and quick understanding of the design of nonclinical studies (or trials)
Comparison of the designs of different studies (or trials)
Comparison of planned and actual treatments and sponsor-defined groups for subjects (or animals) in a study (or trial)

Modeling a nonclinical study in this standardized way requires the explicit statement of certain decision rules that may not be addressed or may not be as explicit in the textual description of the approved study protocol (or study plan). Prospective modeling of the design of a study could contribute to a more complete and wholly representative protocol. Retrospective modeling of the study design provides a Reviewer with a clear description of how the study was conducted.

Trial Design Concepts

A nonclinical study is a scientific experiment, typically involving animal subjects, which is intended to address certain scientific questions that are the objectives of the study.

Branch:	In a study with multiple Arms, the protocol plans for each subject to be assigned to one Arm. The time within the study at which this assignment takes place is often the point at which Arms with common Elements diverge into uncommon or nonshared Elements, and is referred to as a branch point. Many studies have a single branch point. Subjects are assigned to an Arm all at the same time. For other studies, there may be two or more branches that collectively assign a subject to individual Arms. The process that makes this assignment may be a randomization, but this is not always the case, as branch points are protocol-defined.
Element:	An Element is a basic building block in the study design. All Elements are related to the administration of planned interventions, which may involve treatment or no treatment, during a period of time. Elements for which the planned intervention does not involve treatment would include screening, washout, and recovery.
Epoch:	As part of the design of a study, the planned periods or phases of subjects' participation in the study are divided into Epochs. Each Epoch is a period of time that serves a purpose in the study as a whole. Typically, the purpose of an Epoch will be to expose subjects to a treatment, or to prepare for such a treatment period (e.g., pretreatment or screening period, wash out previous treatments) or to gather data on subjects after a treatment has ended (e.g., recovery phase). It is possible for Epochs to span multiple Elements for some or all Trial Arms present on a study. For example, there may be two sequential (but different) treatment Elements planned for a group; the sponsor might choose to include both of these in a single treatment Epoch.
Treatments:	The word "treatment" may be used in connection with Epochs or Elements, but has somewhat different meanings in each context:

Since Epochs cut across Arms, an Epoch involving treatment is a higher-level concept that may not specify anything that differs between Arms. For example, in a three-period crossover study of three doses of Compound X, each treatment Epoch is associated with Compound X, but not with a specific dose. In this case, EPOCH may be populated as "Study Treatment."
An Element may be fairly detailed. For example, for an Element representing repeated dosing, an Element treatment might specify twice-daily dosing of 100-mg/kg doses of Compound X. In this case, ELEMENT may be populated as "Study Drug 100 mg/kg Administered Twice Daily."

Trial Arm:	A Trial Arm is a planned path through the study based upon a planned sequence of Elements. This path covers the entire time of the study. Each sponsor-defined protocol group may contain subjects from several Arms, one Arm, or part of an Arm. Each subject is assigned to one and only one planned Arm.
Trial Design:	The design of a study is a plan outlining the activities subjects will experience and what data will be collected during the course of the study in order to address the study's objectives.
Trial Group:	A group describes the sponsor-defined protocol structure commonly used in nonclinical studies, where study subjects are allocated to study groups within the study protocol. These groups may be defined for a variety of experimental purposes. Groups are frequently defined to separate subjects receiving different treatments, but there may be other considerations involved in the design of any particular study. For purposes of SEND, a Trial Group is a collection of subjects which have been designated with the same sponsor-defined protocol group code. A Trial Group consists of one or more Trial Sets.
Trial Set:	A Trial Set is a collection of subjects that have a common set of parameters defined in the protocol, where those parameters include experimental parameters (such as diet restriction), treatment parameters, and/or sponsor-defined attributes (such as control group designation). There should be no planned parameters of interest that could further subdivide a Trial Set. Each subject must be assigned to one and only one Trial Set. Each Trial Set should be assigned to a single Group. Each Set should be assigned to a single Trial Arm.
Trial Summary:	As part of the Trial Design datasets, Trial Summary provides important or key study-level information.

SDTM

Concept	Definition
Trial design	The design of a clinical trial is a plan for what will be done to subjects and what data will be collected about them, in the course of the trial, to address the trial's objectives.
Epoch	As part of the design of a trial, the planned period of subjects' participation in the trial is divided into epochs. Each epoch is a period of time that serves a purpose in the trial as a whole. That purpose will be at the level of the primary objectives of the trial. Typically, the purpose of an epoch will be to expose subjects to a treatment or to prepare for such a treatment period (e.g., determine subject eligibility, washout previous treatments), or to gather data on subjects after a treatment has ended. Note that at this high level, a “treatment” is a treatment strategy, which may be simple (e.g., exposure to a single drug at a single dose) or complex. Complex treatment strategies could involve tapering through several doses, titrating dose according to clinical criteria, complex regimens involving multiple drugs, or strategies for adding or dropping drugs according to clinical criteria.
Arm	An arm is a planned path through the trial. This path covers the entire time of the trial. The group of subjects assigned to a planned path is also often colloquially called an "arm." The group of subjects assigned to an arm is also often called a "treatment group"; in this sense, an arm is equivalent to a treatment group.
Study cell	Each planned path through the trial (i.e., each arm) is divided into pieces, 1 for each epoch. Each of these pieces is called a study cell. Thus, there is a study cell for each combination of arm and epoch. Each study cell represents an implementation of the purpose of its associated epoch. For an epoch whose purpose is to expose subjects to treatment, each study cell associated with the epoch has an associated treatment strategy. For example, a 3-arm parallel trial might have a treatment epoch whose purpose is to expose subjects to one of 3 study treatments: placebo, investigational product, or active control. There would be 3 study cell associated with the treatment epoch, 1 for each arm. Each of these study cells exposes the subject to 1 of the 3 study treatments. Another example involving more complex treatment strategies would be a trial comparing the effects of cycles of chemotherapy drug A given alone or in combination with drug B, where drug B is given as a pretreatment to each cycle of drug A.
Element	An element is a basic building block in the trial design. It involves administering a planned intervention, which may be treatment or no treatment, during a period of time. Elements for which the planned intervention is "no treatment" would include elements for screening, washout, and follow-up.
Study cells and elements	Many (perhaps most) clinical trials involve a single, simple administration of a planned intervention within a study cell. For some trials, however, the treatment strategy associated with a study cell involves a complex series of administrations of treatment. In such cases it may be important to track the component steps in a treatment strategy operationally; secondary objectives and safety analyses also might require that data be grouped by the treatment step during which it was collected. The steps within a treatment strategy may involve different doses of drug, different drugs, or different kinds of care (e.g., preoperative, operative, and post-operative periods surrounding surgery). When the treatment strategy for a study cell is simple, the study cell will contain a single element, and for many purposes there is little value in distinguishing between the study cell and the element. However, when the treatment strategy for a study cell consists of a complex series of treatments, a study cell can contain multiple elements. There may be a fixed sequence of elements, or a repeating cycle of elements, or some other complex pattern. In these cases, the distinction between a study cell and an element is very useful.
Branch	In a trial with multiple arms, the protocol plans for each subject to be assigned to 1 arm. The time within the trial at which this assignment takes place is the point at which the arm paths of the trial diverge, and so is called a branch point. For many trials, the assignment to an arm happens all at one time, so the trial has 1 branch point. For other trials, there may be 2 or more branches that collectively assign a subject to an arm. The process that makes this assignment may be a randomization, but it need not be.
Treatments	The word "treatment" may be used in connection with epochs, study cells, or elements, but has somewhat different meanings in each context: Because epochs cut across arms, an epoch treatment is at a high level that does not specify anything that differs between arms. For example, in a 3-period crossover study of 3 doses of drug X, each treatment epoch is associated with drug X, but not with a specific dose. A study cell treatment is specific to a particular arm. For example, a parallel trial might have study cell treatments placebo and drug X, without any additional detail (e.g., dose, frequency, route of administration) being specified. A study cell treatment is at a relatively high level, the level at which treatments might be planned in an early conceptual draft of the trial, or in the title or objectives of the trial. An element treatment may be fairly detailed. For example, for an element representing a cycle of chemotherapy, element treatment might specify 5 daily 100 mg doses of drug X. The distinctions between these levels are not rigid, and depend on the objectives of the trial. For example, route is generally a detail of dosing, but in a bioequivalence trial comparing IV and oral administration of drug X, route is clearly part of study cell treatment.
Visit	The notion of a visit—a clinical encounter—derives from trials with outpatients, where subjects interact with the investigator during visits to the investigator's clinical site. However, the term is used in other trials, where a trial visit may not correspond to a physical visit. For example, in a trial with inpatients, time may be subdivided into visits, even though subjects are in hospital throughout the trial. For example, data for a screening visit may be collected over the course of more than 1 physical visit. One of the main purposes of visits is the performance of assessments, but not all assessments need take place at clinic visits; some assessments may be performed by means of telephone contacts, electronic devices, or call-in systems. The protocol should specify what contacts are considered visits and how they are defined.

SDTM

ICH E3, Guidance for Industry, Structure and Content of Clinical Study Reports (available at http://www.ich.org/products/guidelines/), Section 9.1, calls for a brief, clear description of the overall plan and design of the study, and supplies examples of charts and diagrams for this purpose in Annex IIIa and Annex IIIb. Each Annex corresponds to an example trial, and each shows a diagram describing the study design and a table showing the schedule of assessments. TOBA-2 DONE The Trial Design Model provides a standardized way to describe those aspects of the planned conduct of a clinical trial TOBA-3 DONE shown in the study design diagrams of these examples. The standard Trial Design Datasets will allow reviewers to:

Clearly and quickly grasp the design of a clinical trial
Compare the designs of different trials
Search a data warehouse for clinical trials with certain features
Compare planned and actual treatments and visits for subjects in a clinical trial

Modeling a clinical trial TOBA-4 DONE in this standardized way requires the explicit statement of certain decision rules that may not be addressed or may be vague or ambiguous in the usual prose protocol document. Prospective modeling of the design of a clinical trial should lead to a clearer, better protocol. Retrospective modeling of the design of a clinical trial should ensure a clear description of how the trial protocol was interpreted by the sponsor.

From SENDIG v4.0 (and earlier) + additional text in green - strikethrough text

The goal of the Trial Design Model is to provide a brief, clear description of the overall plan and design of a study. It ~~The Trial Design Model in the SENDIG~~ provides a standardized way to describe ~~those~~ aspects of the planned conduct of a ~~nonclinical~~ study, as shown in the study design diagram examples within this section. ~~The Trial Design Model in the SENDIG is equivalent to the Trial Design Model within the SDTMIG for clinical trials.~~ Trial Design datasets contain study-level, rather than subject-level, information. Note that generally the term "trial" is equivalent to "study" in the nonclinical context. In addition, "subjects" are equivalent to "animals."

The Trial Design Datasets will allow:

Clear and quick understanding of the design of clinical or nonclinical ~~studies~~ trials
Comparison of the designs of different trials
Comparison of planned and actual treatments and sponsor-defined groups for subjects (or animals) in a study (or trial)

Modeling a ~~nonclinical study~~ trial in this standardized way requires the explicit statement of certain decision rules that may not be addressed or may not be as explicit in the textual description of the approved study protocol (or study plan). Prospective modeling of the design of a ~~study~~ trial could contribute to a more complete and wholly representative protocol. Retrospective modeling of the ~~study~~ design of a trial provides a ~~Reviewer with a~~ clear description of how the ~~study~~ trial was conducted.

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Guidance for Trial Design