The Clinical Study Protocol

Buncher and Tsay (2006a) listed just some of the detailed requirements of a study protocol  

Inclusion and exclusion criteria are a very important component of clinical trials. A study s inclusion and exclusion criteria govern the subjects who may be admitted to the study. Criteria for inclusion in the study may include items such as the following  

Criteria for exclusion from the study may include items such as the following  

While inclusion and exclusion criteria are typically provided in two separate lists in regulatory documentation, exclusion criteria can be regarded as further refinements of the inclusion criteria. Meeting all the inclusion criteria allows a subject to be considered as a study participant, while not meeting any exclusion criteria is also necessary to allow the subject to become a participant. In the language of mathematics, meeting the stated inclusion criteria is necessary but not sufficient to gain entry to the study. 

Inclusion and exclusion criteria strictly define the nature of the subject sample that participates in a clinical trial. Accordingly, they also strictly define the study population to which statistical inferences may be made (see Chapter 7 for discussion of statistical inference). For now, this statement can be expressed as follows The inclusion and exclusion criteria strictly define the study population to whom the results of the clinical trial can reasonably be generalized. This study population may or may not be a good representation of the entire population of patients with the disease or condition of interest. Chapter 11 provides more detailed discussion of the implications of this statement. (See also www.clinicaltrials.gov for examples of inclusion and exclusion criteria in clinical trials.) 

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.  

The following are some of the fundamental components in a study protocol for a therapeutic confirmatory trial for an investigational antihypertensive drug  

A study protocol is often supplemented with another very important document called the statistical analysis plan (sometimes referred to by similar names such as a data analysis plan or reporting analysis plan). The statistical analysis plan often supplements a study protocol by providing a very detailed account of the analyses that will be conducted at the completion of data acquisition. The statistical analysis plan should be written in conjunction with (and at the same time as) the protocol, but in reality this does not always happen. At the very least it should be finalized before the statistical analysis and breaking of the blind. In many instances (for example, confirmatory trials) it may be helpful to submit the final statistical analysis plan to the appropriate regulatory authorities for their input. 

---

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. 

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 ... 

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... 

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. 

Inspectors will visit the investigator site and may possibly wish to visit the sponsor s office. They will review the documentation of the study file (see Box 7.1). Approval documents of the lEC will be compared with any amendments made to the protocol or to the subject s information sheet/ICR Consent forms for the study subjects will be inspected to establish who actually gave consent and whether this was before entry into the clinical study. A thorough source data verification of the CRF with the source documents, including the medical records, will be undertaken. Documentation relating to drug accormtability wiU be matched with each subject s CRF The facilities wiU be reviewed and the site staff interviewed. Further information can be obtained from... 

A revised sample size may then be calculated using suitably modified assumptions, and should be justified and documented in a protocol amendment and in the clinical study report... The potential need for re-estimation of the sample size should be envisaged in the protocol whenever possible. ... 

Today, clinical trials must adhere to nationally and internationally agreed codes of good clinical practice, which define ethical and scientific standards. Good clinical trial design and conduct should apply scientific methods. Skilful analysis can never correct for poor design. The purpose of the trial should be defined and specific hypotheses stated in the written study protocol, which will also include details of how the trial will be conducted. Errors in the data have two components, purely random errors and systemic errors or bias, which are not a consequence of chance alone. Randomisation of subjects is important both to avoid observer bias and to prevent or minimise the influence of unknown factors that might influence the results. 

IRBs approve the clinical trial protocols, which describe the type of people who may participate in the clinical trial, the schedule of tests and procedures, the medications and dosages to be studied, the length of the study, the study s objectives, and other details. IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm. 

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. 

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 ... 

Be prepared to provide the following items for the end-of-phase 2 conference, representing each protocol under which the clinical studies have been performed ... 

Copies of the protocol and clinical record form must be attached to the clinical study report. 

The clinical trial protocols have to be approved beforehand as do the results of the study prior to final marketing authorisation. (See also Figure 3)... 

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. 

The IND differs in a number of ways from its European counterparts. First, it is much longer a typical IND is of at least 1000 pages, and for dmgs with foreign human experience, often many multiples of this number. The UK Clinical Trials Certificate, used very rarely for this reason, and not the Clinical Trials Exemption ( CTX ), would be the nearer comparison. Second, an IND is required for all human exposure to INDs, and this includes normal volunteer studies. Third, all being well, there is only a 30-day wait between filing and commencement of the clinical study no news from FDA after this time period has elapsed is presumptive evidence that the study may proceed (most FDA divisions will, in fact, issue affirmative letters that this is the case, within 30 days). Fourth, once an IND has become active, there is no subsequent 30-day wait when further clinical protocols are submitted. 

Fasting and meals should be adequately controlled during the study days, as food intake can significantly affect the absorption of drugs. Standardized meals, snacks and drinks should be planned and provided to study subjects in accordance with the clinical trial protocol. 

---