Clinical study protocols

In 10 studies the corresponding clinical study protocol stipulated that cetuximab was to be given in combination with a chemotherapeutic agent (irinotecan, paclitaxel, gemcitabine, cisplatin, carboplatin, or doxorubicin) or in combination with radiation therapy. 

The statisticians conducting the review of an NDA evaluate the statistical relevance of the data presented so that they can provide the medical officers with information concerning how well the findings are likely to generalize to the larger patient population in the country. They evaluate the extent of any deviations from the protocols submitted in the IND in the conduct of the study as well as the overall quality of the data collected. All clinical study protocol amendments are reviewed to see what deviations from the original study design have occurred and how these (and deviations that were not detailed in protocol amendments) may have influenced the data. 

Several summary tables are commonly presented to report safety data. Two examples of typical formats are provided here. Table 10.3 shows the format for the overall summary of adverse events falling within several adverse event categories. Such table shells are typically prepared by medical writers in advance of the study results being available and are based on the clinical study protocol and/or the statistical analysis plan written before the study started. Preparation in advance of the availability of the data saves time during the preparation of the clinical study report once the data are available. 

Because the framework of every clinical research study relies on a number of interdependent disciplines, the development of a clinical study protocol is ideally a multidisciplinary task. Teamwork, coordinated by one experienced person in clinical research with good knowledge of the regulatory requirements for new drug development, is essential. The protocol design team should also include input, recommendations, and review by the following ... 

The structure of an IND application is contained in the regulation and is quite easily followed. Almost all pharmaceutical companies, contract research organizations and universities have templates for the writing of these documents. All the animal data, the proposed clinical study protocol, a clinical investigators brochure and the chemistry and manufacturing controls must be described. 

As the IND progresses further clinical study protocols and the results of completed studies (manufacturing, nonclinical, and clinical) are submitted, and the IND grows accordingly. 

At the point where an IND would be submitted to the FDA, a clinical trial application (CTA) is submitted by the sponsor. We noted earlier that an IND grows in size as additional clinical study protocols in a clinical development program are submitted to the FDA, each being incorporated into the overall IND. In contrast, CTAs are protocol specific and one CTA must be filed for each clinical study protocol. Hence, in this case, the number of individual CTAs increases during a clinical development program. CTAs are based on summary information only no full study reports are submitted. 

When the clinical research team has decided on their research question, and the appropriate study design and methodology to acquire optimum quality data with which to answer this question, all this information needs to be documented. The clinical study protocol is the document that is written for this purpose. Chow and Chang (2007, p 1) noted that the study protocol is "the most important document in clinical trials, since it ensures the quality and integrity of the clinical investigation in terms of its planning, execution, conduct, and the analysis of the data."... 

A table, usually located in an appendix to a clinical safety subsection, is to list all deaths occurring while subjects/patients are on study, including deaths that occurred shortly following (e.g., within 30 days) treatment termination. Only deaths that are clearly disease-related as described in a clinical study protocol and are not related to the administration of a drug candidate can be excepted from this table. All deaths should be examined for any unexpected patterns between study treatment arms and further analyzed if unexplained differences are noted. Deaths are to be examined individually and analyzed on the basis of rates in individual clinical trials and appropriate pools of trials, considering both total mortality and cause-related deaths. Potential relationships of death to demographic, intrinsic, and extrinsic factors should also be considered. 

The IND contains information regarding the drug s composition and synthesis and lists all specifications that have been set for the drug substance. Specifications are set for many tests, which may include trace metals. All subsequent batches of the drug that will be used in clinical studies must meet these specifications before their release. The IND contains information regarding animal toxicology study data and protocols for clinical trails. The IND clinical study protocol for a new drug candidate consists of three clinical phases (Table 2). 

The clinical trial protocol is a detailed written plan that outlines how the study procedures are to be carried out and how the data are to be collected and analyzed. It insures the quality and integrity of the trial, particularly when multiple research sites are participating in data collection (Chow and Liu, 1998). The purposes of the protocol are to outline ... 

Clinical trials are costly to conduct, and results are often critical to the commercial viability of a phytochemical product. Seemingly minor decisions, such as which measurement tool to use or a single entry criterion, can produce thousands of dollars in additional costs. Likewise, a great deal of time, effort and money can be saved by having experts review the study protocol to provide feedback regarding ways to improve efficiency, reduce subject burden and insure that the objectives are being met in the most scientifically sound and cost-effective manner possible. In particular, I recommend that an expert statistician is consulted regarding sample size and power and that the assumptions used in these calculations are reviewed carefully with one or more clinicians. It is not uncommon to see two studies with very similar objectives, which vary by two-fold in the number of subjects under study. Often this can be explained by differences in the assumptions employed in the sample size calculations. 

When conducting a clinical trial, the well-being of the study subjects is primary. Subjects must be treated fairly and with respect. The two primary methods of ensuring fair treatment of study subjects are review of the study protocol by an Institutional Review Board (IRB) or Ethics Committee and... 

The establishment of performance criteria for a given tumor marker test is not a simple process because accuracy and precision are unique for each type of analyte and its application. Establishing methodological limits for accuracy, precision, sensitivity, and specificity often requires standard reference materials, quality control materials, comparative studies, and actual clinical specimens. Accuracy and precision must be measured over the analyte reportable range for which the device is intended to be used. Sensitivity and specificity must be considered with respect to the intended clinical use of the device. Also, the indications for use should be carefully considered in the design of the study protocol. The indications for class II should be to monitor residual tumor after surgery (or radiation), the recurrence of tumor, or response to therapy. A 510(k) must provide clear evidence that the device is accurate, safe, effective, and substantially equivalent to a device legally marketed in the United States. 

Administration of the Drug. As it is with accurate identification of a drug, so it is that its administration must at times be held in question. Subject compliance with the study protocol is not a rare problem in clinical trials. Complete noncompliance sometimes occurs. 

Clinical trials. A subset of those clinical studies that evaluates investigational medicines in Phases I, II, and III. Phase IV evaluations of marketed medicines in formal clinical trials using the same or similar types of protocols to those used in Phases I and III are also referred to as clinical trials. 

The earlier clinical studies of ECT in the nineteenth century1"6 clearly showed the considerable potential of this technique, although standarized protocols could not be established ECT thus faded away without being integrated into the practice of surgery. 

Name and description of the clinical trial protocol Summary of results from nonclinical studies Potential risks and benefits to human subjects Description and justification for route of administration, dosage, and treatment plan Compliance to GCP... 

Regulatory authorities play an important and active role to ensure regulatory compliance in the conduct of a clinical trial. Agencies such as the FDA inspect clinical studies. An inspection of a trial may reveal that the protocol is not being followed strictly, the Investigator may not be involved with the project as much as is expected, there may be a lack of patient care, changes to the protocol may not have been relayed to the IRB, and so on. In such cases, corrective actions have to be implemented immediately and the FDA must be satished before the trial can continue. Deficiencies found are reported on Form 583. 

Satellite pharmacokinetic or special study groups Deviations from original study protocol Statistical methods Observations and times Clinical signs Body weights Food consumption Flematology Clinical chemistry Organ weights... 

Should a study subject suffer any deterioration in health or well-being caused by participation in a study, the sponsors of the clinical research must provide appropriate compensation without regard to the question of legal liability. A statement to that effect should be present in the protocol. Frequently, the insurance policy of the sponsor includes the pharmaceutical company, clinical investigators and the institution where the clinical study is being undertaken. 

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