Background or Rationale

Sufficient information should be given in this section to set the stage for the clinical trial for which the protocol is being developed. This requires in- tegrating the results (with references) of previous studies that have bearing on the current protocol. The section should end with a paragraph explaining why the current protocol is needed or why it is being developed.

2.4.2

Objective

The objective or research question of the protocol should be defined so that it is unambiguous. For example, in an investigation about the antihy- pertensive efficacy of drug D in some defined population, the statement: “The objective of this investigation is to assess the efficacy of drug D” is ambiguous. It provides only general information as to the question (“Is D efficacious?”). The statement: “The objective of this investigation is to assess whether drug D is superior to placebo P in the treatment of hypertensive patients with diastolic blood pressure (DBP) between 90 and 105 mm HG for six months” is better as the hypertensive population to be treated and what is meant by efficacious in a comparative sense are specified.

However, the data or endpoint(s) upon which antihypertensive efficacy will be based is (are) not specified. DBP is stated, but how will it be measured? Using a sphygmomanometer or a digital monitor? Will DBP be measured in the sitting, standing or supine position? Further, what function of the DBP will be used? The change from baseline to the end of the treatment period? Or whether the patient achieves a therapeutic goal of normotension (DBP ≤ 80 mm HG) by the end of the treatment period?

If there is more than one question or objective, one should identify which is primary versus which is secondary.

22 Clinical Trial Data Analysis Using R

2.4.3

Plan of Study

The plan of study entails all that is to be done in order to enroll and treat patients, monitor the study, ensure patient safety, and collect valid data. The study population has to be specified. Design aspects of the study, including all procedures to be used in the diagnoses, treatment or management of patients must be delineated.

2.4.3.1 Study Population

Characteristics of the population of patients to be entered into the proto- col must be specified. This is typically accomplished by specifying inclusion and exclusion criteria appropriate for the disease and drug under study. In specifying these criteria, one has to be cognizant that patients entered must have the disease under study, that the condition of the patient must not com- promise patient safety by participating in the protocol, and that the patients entered should enable the efficacy of the drug under study to be determined (absence of masking or confounding factors).

The inclusion criteria specify the demography of the patient population, their disease characteristics, acceptable vital signs ranges, acceptable clinical laboratory tests ranges, etc. Exclusion criteria are generally the complement of the inclusion criteria, with delineation of a subset that specifically excludes patients from entry. For example, non-menopausal females who are pregnant or who do not agree to practice an acceptable form of birth control during the intervention period are excluded; as are patients who do not agree to abstain from using concomitant medications that may mask or interfere with the ac- tivity of the drug under study. Inclusion/exclusion criteria essentially define the population to be studied. Therefore they provide general descriptors of the population to which inferences from analyses of the data collected pertain. 2.4.3.2 Study Design

The study design subsection should identify: the type of study; the treat- ment or intervention groups and how patients who qualify for the protocol will be assigned to treatment groups; what measures will be taken to ensure the absence of bias; requirements relative to patients taking medications other than those constituting the assigned intervention; and all procedures that are required by the protocol in order to diagnose, treat, ensure patient safety, and collect data.

1. Type of Study. The type of study should be described. Is the study prospective? What type of control (placebo, positive, historical, etc.) will be used? Is it single or multi-center? Is the study parallel, crossover, stratified, or some other type?

2. Treatment Group Specification and Assignment. The treatment groups and the interventions (drug, dose, etc.) that patients in the groups

Overview of Clinical Trials 23 will receive should be specified. Then how patients will be assigned to the treatment groups to remove assignment bias should be articulated. The gold standard is to randomly assign patients to the groups in bal- anced fashion. Minor departures from balance are acceptable and may be more ethical. For example, for a placebo control trial of a new drug, our preference is to recommend that twice as many patients be ran- domly assigned to the drug than to placebo. This reduces the number of patients assigned to placebo by 1/6 and ensures that twice as many patients are assigned to the drug group as to the placebo group. A 2-to-1 departure from balance has a relatively small impact on power.

3. Packaging to Achieve Blinding. Intervention group medications should be packaged so that neither the patient nor personnel (physician, research nurse or assistant) who will either treat, assign medication, draw blood, administer procedures, or collect data knows the identity of the interventions. This requires interaction between the protocol biostatisti- cian (who will generate the randomization schedule) and the formulation or packaging chemists (who will package the medication). Both have to thoroughly know the protocol, particularly the drug, dose and frequency of dosing of intervention medications, when patients are at the clinic for medication dispensing, and how many days are between visits.

4. Concomitant Medication. The protocol should indicate whether any medications other than those comprising the treatment or intervention groups are permitted while the patient is participating in the protocol. Generally any medication, prescription or over the counter (OTC), that would mask, cloud or otherwise interfere with the effect of the interven- tion medications should be excluded.

5. Procedures. All procedures required for enrolling, diagnosing, treat- ing, or medically monitoring patients should be clearly identified and described. This applies to all phases: pre-treatment, during treatment, or post treatment, of the protocol. Providing a study schema at the end of the protocol that identifies procedures to be administered by day of study is helpful.

Observers (personnel who see patients that result in data collection and recording) should be specified. The assignment of observers to patients should be made to try to eliminate or minimize the introduction of observer variability into the trial. For example, in hypertension studies, different observers for different patients are permitted; but each patient should have the same observer throughout the trial.

Procedures for recording the data to be collected in the trial should be specified. Whether data are to be recorded on paper data collection forms (DCFs) or electronically requires protocol sponsor personnel to interact with site personnel to ensure proper and valid recording of data.

24 Clinical Trial Data Analysis Using R 2.4.3.3 Problem Management

In this subsection of the protocol, criteria for dealing with problems related to patient safety or that may compromise study objectives if left unattended, should be specified. For example, clinically significant changes in clinical lab- oratory parameters; criteria for discontinuing study drug including severe ad- verse events; actions to be taken for protocol deviations or violations, includ- ing taking prohibited drugs, missed visits, dropouts, etc. should be specified. Contact information from the investigational sites to the protocol sponsor for problem management should be clearly delineated.