As indicated in Section 1.4, the minimum requirements for the protocol of a clinical trial are provided in Section 312.23 of 21 CFR. In addition, Table 1.4.2 provides an example for format and contents of a protocol for a well-controlled clinical trial. A protocol cover sheet suggested by the FDA provides a tabular summary of information and characteristics for the trial. On the other hand, a protocol synopsis with a length of one to two pages can depict a narrative summarized description of a complicated and lengthy protocol. The table of contents of the protocol not only provides the structure and framework of the protocol, but also it serves as an index for each section of the protocol. Basically, a protocol can be structured into three major components: the scientific, ethical, and administrative parts. According to the ICH E6 guideline on Good Clinical Practice: Consolidated Guidance (ICH, 1996), the administrative parts consist of general information, organization of research teams, communication schemes among participants involved in the trials, shipping plan for specimen, data transfer network, obligations of clinical investigations, medical institutions, and sponsors, investigational drug accountability, case report forms, study registry, record retention, financing and insurance, publication policy, signature of investigators, confidential statements, and other administrative matters.
The research team of the clinical trial usually consists of the team of clinical staff at the study site, which includes clinical investigators, residents, research fellows, research nurse, pharmacists, laboratory technicians, and clinical assistants. The leader of this team is referred to as the principal investigator (PI). Individuals such as residents, research associates, and research fellows who are supervised by the principal investigator to perform critical trial related procedures and to make important trial related decisions are sometimes referred to as subinvestigators. If a clinical trial is sponsored by a pharmaceutical company, another research team is formed by the staff of the pharmaceutical company that may include project clinicians, a statistician, a pharmacokineticist, and a project manager. For a large-scale multicenter trial, a steering committee is usually formed to set up the research strategy, to make key decisions, and to oversee the activities of the trial. One of the principal investigators is usually selected as the chairperson of the steering committee. The steering committee is critical for successful management of large, long-term, and complicated clinical trials such as the PLCO trial discussed in Chapter 7. In practice, it is not uncommon to have a data and safety monitoring committee (DSMC) as another research team for clinical trials. As a matter of fact, the NIH requires that all clinical trials sponsored by the NIH have a DSMC. Furthermore, most phase 2 and phase 3 trials sponsored by the pharmaceutical industry also include DSMC. One key and crucial distinction between and DSMC and other research teams is that all members of the DSMC should not be involved with the conduct of the trials. In addition, the DSMC should function independently.
According to the ICH E6 GCP guideline, the general information provided by the protocol should include the following:
• Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment number(s) and date(s)
• Name and address of the sponsor and monitor (if other than the sponsor)
• Name and title of the person(s) authorized to sign the protocol and the protocol's amendment(s) for the sponsor
• Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when appropriate) for the trial
• Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s)
• Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable) who is responsible for all trial site-related medical (or dental) decisions (if other than investigator)
• Name and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial.
The scientific part contains the specific applications of the most methodological tools covered in the previous chapters of this book. They include background information, the objectives of the trials, definition of target patient population according to inclusion and exclusion criteria, the trial design, intervention or treatment under investigation for the trials, methods for evaluation of efficacy and safety, reporting procedures for serious and unexpected adverse events, and sample size determination, data collection, and a statistical plan for analyses. If the treatment under investigation is a pharmaceutical product, then the ICH E6 GCP guideline indicates that the following background information should be provided:
• Name and description of the product(s)
• A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial
• Summary of the known and potential risks and benefits, if any, to human subjects
• Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s) for the treatment evaluated in the trial
• A statement that the trial will be conducted in compliance with the protocol, GCP, and applicable regulatory requirement(s)
• A brief description of the population to be studied and its rationales
• References to literature and data that are relevant to the trial, and that provide background for the trial
The most important and yet difficult part during the development of a clinical trial protocol is the objective section that lays out the goals for the trial. From Example 3.2.1 to 3.2.7 of Section 3.2, the objectives of clinical trials are formulated through the experimental units, treatments, and evaluation in conjunction with the mechanism for data generation and the intentions of the trial. In the primary objective of Example 3.2.7, the experimental units are patients with atrial fibrillation. The treatments include the investigational product and the active comparator. In general, the dose and route of administration should be also given in the objective. The evaluation endpoint is the all-stroke (fatal and nonfatal) and systemic embolic events. The mechanism for data generation is the design used in the trial, which is a randomized parallel group design. Finally, the intention of the trial is to show that the investigational drug is not inferior to that of the active comparator for the prevention of all-stroke (fatal and nonfatal) and systemic embolic events. Therefore, this trial is a secondary prevention and noninferiority trial. Sometimes, it is useful to state the treatment duration and the length of follow-up period. It would be more complete if the expected event rate and noninferiority margin can be stated in the primary objective. However, the objective would become too long and yet confusing with too much information. Therefore, it is very difficult to reach a proper balance among comprehensiveness, completeness, clearness, and conciseness. A sound statement regarding the objectives of a clinical trial protocol, however, should at least include experimental units, treatment, evaluation, design, and intention.
Depending on the relative importance or priority of study endpoints, as shown in Example 3.2.5 to 3.2.7, the objectives of a clinical trial can also be classified into the primary, secondary, and tertiary objectives. In general, there should be only one primary objective and several secondary and tertiary objectives. The endpoint stated in the primary objective is the primary endpoint for the trial that is used for sample size calculation. In practice, there may be more than one primary objective, each with different primary endpoints. In such a case, the multiplicity issue discussed in Chapter 12 should be addressed in appropriate sections (e.g., the objective section and the statistical section) of the clinical protocol. In addition to inclusion and exclusion criteria discussed in Section 3.3 for the target patient population, the ICH E6 GCP guideline also provides the following subject withdrawal criteria:
• When and how to withdraw subjects from the trial/investigational product treatment
• The type and timing of the data to be collected for withdrawn subjects
• Whether and how subjects are to be replaced
• The follow-up for subjects withdrawn from trial treatment
As pointed out in the ICH E6 GCP guideline, the integrity of the trial and the credibility of the data obtained from the trial depend considerably on the design employed in the trial. Therefore, the ICH E6 GCP guideline suggests that the design section should include the following:
• A description of the type/design of trial to be conducted (e.g., double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures, and stage.
• A description of the measures taken to minimized/avoid bias, including randomization and blinding.
• A description of the trial treatment(s) and dosage and dosage regimen of the investi-gational product(s). Also includes a description of the dosage form, packaging, and labeling of the investigational product(s).
• The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
• A description of the stopping rules or discontinuation criteria for individual subjects, parts of trial, and entire trial.
• Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
• Maintenance of trial treatment randomization codes and procedures for breaking codes.
• The identification of any data to be recorded directly on the CRF's (i.e., no prior written or electronic record of data), and to be considered to be source data.
The treatment section should provide all relevant information of all treatments administered to the subjects during the trial. These include the name(s) of all the product(s), the dose(s), the dosing schedule(s), route/mode(s) of administration, treatment period(s), and follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial. In particular, quantity, frequency, time, and duration should be specified for the investigational products that are orally administered. For the IV investigational products, the preparation, reconstitution procedures, the infusion rate, loading, and maintenance doses should be also described clearly in this section. For the treatments that require titration, dose, schedule, criteria, and its based endpoints should be specified in this section. For the trials evaluating chemotherapy in cancer patients, schema for dose modifications due to adverse events or toxicities should also be described in detail in the treatment section. On the other hand, the treatment section should also include the procedures for monitoring subject compliance and methods for improving compliance. In order to avoid bias in estimation of treatment effects, the treatment section should describe the procedures to collect the
Table 14.2.1 Desirable Characteristics of Efficacy Parameters
1. Easy to administer
2. Rapid to administer
3. Little or no training necessary to administer
4. Easy to interpret
5. Rapid to interpret
6. Little or no training necessary to interpret
7. Sensitive to changes elicited by treatments under investigation
8. Insensitive to efforts brought about by treatments that might interfere with the efficacy parameter
9. Low rate of false-positive responses
10. Low rate of false-negative responses
11. May be used multiple times without a training effort
12. Results are reproducible
13. Results are valid
14. Interpretation is correlated with other efficacy parameters
Reproduced from Spilker (1991).
information on concomitant medications. In addition, medication/treatments permitted (including rescue medications) and not permitted before and/or during the trial should be specified in detail with prespecified time intervals.
Basically, the section of assessment of efficacy can be divided into two parts. The first part includes definitions and specifications of efficacy parameters. In this part, depending on clinical relevance and importance, efficacy parameters can be classified further in the primary, secondary, and tertiary efficacy parameters in accordance with the primary, secondary, and tertiary hypotheses specified in the objective section. Spilker (1991) gave a list of desirable features of efficacy parameters, which is reproduced with permission in Table 14.2.1. For each efficacy parameter, a precise definition should be clearly given in detail. In particular, the definitions of some derived efficacy parameters such as response rate should include the efficacy parameters on which they are based and their calculations. In addition, if some efficacy parameters are derived from some criteria or instrument scale, they should be validated for their validity, reliability, and reproducibility. Some examples include RECIST for evaluation of tumor response in caner chemotherapy (Therasse et al., 2000), Hamilton depression scale for evaluation of treatment in patients with depression, NIHSS for evaluation of treatment in patients with stroke (NINDS, 1995), and ADAS for evaluation of treatment in patients with probable Alzheimer's disease (Folstein et al., 1975).
The second part should provide a detailed narrative description for methods and timing for assessing, recording, and analyzing efficacy parameters. In addition to selection of reliable, valid, and reproducible efficacy parameters, the time points for measurement of efficacy parameters should be selected to demonstrate efficacy in relation to the time of administration of treatment under investigation described in the treatment section, e.g., just prior to dosing. In addition, it is crucial to define the times for evaluating inclusion/exclusion criteria that are based on efficacy parameters and for establishing the baseline values for efficacy parameters. Appendices should be provided for detailed narrative description of procedures if evaluations and measurements for some efficacy parameters require special equipments, training, or techniques. Some examples are bone densitometry for evaluation of bone mineral density and NIHSS, which requires additional training for neurologists in assessment of improvement by the treatment for the patients with stroke.
Similar to the section for assessment of efficacy, the section for assessment of safety can also be divided into two parts. The first part provides specifications of safety parameters that include adverse events, laboratory evaluations, vital signs, and some specific safety parameters. The second part includes the methods and timing for assessing, recording, and analyzing safety parameters. The definition of adverse events should be given in details. The information collected for adverse events should also be specified clearly in this section. This includes description of events, onset date and time in relation to the treatment, nature of the adverse events, its duration, intensity, seriousness, relationship to the treatment, actions taken, and resolution of adverse events. In addition, to avoid a possible overestimation of the incidence rate of an adverse event, the information of adverse events should be obtained by indirectly questioning using a nonleading question. One should not, in the protocol, prepare a list of all possible adverse events and ask patients whether they experience them. The coding system for adverse events described in Chapter 13 to be used in the trial should be also prespecified in this section. On the other hand, the time interval for collection of adverse events even after the completion of the trial treatment should be specified in this section.
Serious adverse events (SAE) and unexpected adverse events are the most important safety information to be collected and evaluated for a clinical trial that also require expedited reporting to the medical institute's IRB and health regulatory authority and the industry sponsors. Therefore, a detailed and precise narrative description of the definition and procedures for obtaining and reporting SAE should be provided in this section. Currently, the ICH definition of serious or unexpected adverse events is used for most of clinical trials sponsored by the pharmaceutical companies. Currently, the time frame for expedited reports of serious or unexpected adverse events suggested by the ICH is also adopted by most of the trials sponsored by the pharmaceutical industry. In addition, there should be a statement indicating that the principal medical monitor or sponsor should be notified promptly by phone of any death or serious or unexpected adverse event, even though they are not product-related. The name, address, business phone number, business hour, fax number, and email address of the principal monitor should be given in the protocol along with the same information for the physician on duty for nights, weekends, and holidays.
Other safety parameters include laboratory evaluations, vital signs, and some special safety parameters. In general, routine laboratory evaluations include hematology, blood chemistry, and urinalysis. The time and procedures for collecting, labeling, and shipping the blood and urine samples should be described in this section. For multicenter trials, whether a central laboratory is used for analyzing the blood or urine samples should be specified. If samples are to be analyzed at site laboratories, a standardization procedure among different laboratories should also be depicted in this section. Vital signs usually include systolic and diastolic blood pressures, heart and respiratory rates, and sometimes body temperature. Examples for special safety evaluations include ECG and pap smears tests. Again, the protocol should specify the procedures and time points for evaluation of these safety parameters.
However, there should be another section on other clinical evaluations that include medical history, medication history, and physical examination. A section on the conduct of the study can be very helpful. In this section, narrative descriptions for every evaluation of all efficacy and safety parameters performed at each visit for all visits are provided by visit. In addition, a flowchart is given in appendices to provide a summary of all evaluations by time points. In this flowchart, columns represent the visits or time points; the rows represent the evaluations of efficacy and safety parameters. Therefore, each entry in the flowchart indicates a particular efficacy or safety evaluation to be performed at a specific time point.
The section on statistics should include the following parts: statistical hypotheses and sample size determination, definition of analysis set, analysis of demographic data and baseline characteristics, analysis of efficacy parameters, and analysis of safety parameters. First, the objectives in the beginning of the protocol should be translated into statistical hypotheses. Based on the expected difference on primary efficacy parameter between treatment arms and their corresponding anticipating variability, the sample size for the trial can be determined by the corresponding statistical method used for analysis of the primary efficacy parameter to achieve a predetermined level of power at a prespecified significance level. Clinical relevance for selection the difference between treatment arms or equivalence/noninferiority margin for determination of sample size should be justified. The sample size calculation should also take dropout rate into consideration. If the trial is a multicenter trial, the number of subjects projected for each site should be specified. In addition, the projected accrual rate and anticipated completion of enrollment should be provided.
The statistics section should clearly define the analysis sets from which the conclusions of the trial are derived. The definition of analysis sets and the criteria for selection of subjects into analysis sets should be clearly described and specified in this section. The methods for analysis of each efficacy and safety parameters should be provided with relevant references if necessary. If interim analyses are planned for the trial, the timing of interim analyses and the methods for determination of spending significance level at various time points for interim analyses and the corresponding stopping boundaries should also be provided in detail. The procedures for early termination of the trial based on planned interim analyses should also be prespecified in the protocol. Furthermore, if necessary, the methods for sample size reestimation should be also given. However, the procedures to avoid or eliminate bias due to the planned or unplanned interim analyses and sample size reestimation should be specified in the protocol to protect the integrity of the trial. The statistics section should provide the procedures for addressing the issues of multicenter trial, use of covariates (both subject-specific covariates and time-dependent covariates), missing values, and multiplicity.
The last component of the protocol is the ethical section. Because the experimental units in clinical trials are human subjects, the ethical section is probably the most important component in the protocol for protection of the trial subjects. This component should include the detailed review procedures both internally and externally. In addition, a copy of the proposed informed consent form should be included as one of the appendices. Other procedures for elimination of any unnecessary risk from the trial subjects should be provided in this section.
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