Clinical program development

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

Evidence from its initial clinical development program indicates that it works in patients who historically had not responded to TCAs (167). 

Mirtazapine like the other new antidepressants has a wide therapeutic index and is generally safe in overdose ( 470). Twelve overdoses occurred during the clinical development program with mirtazapine. The largest amount ingested in such an acute overdose was 975 mg per day, which is more than 20 times the maximal... 

Research and clinical development programs Osiris Therapeutics, Inc. Company World Wide Web Site. 2000, October 23. 

It should be noted that, as a protein, cetuximab has the potential to induce an immune response in individuals who receive it as a therapeutic agent During the cetuximab clinical development program, patient sera were monitored for induction of an anti-cetuximab or human anti-chimeric antibody (HACA) response. Although anti-cetuximab antibodies were identified in some patients, they were found not to interfere with the biological properties of cetuximab, such as its ability to bind EGFR (i. e., they are non-neutralizing). 

The hypothesis that Cox-2 inhibitors are less toxic than NSAIDs on the GI tract because of sparing Cox-l-dependent GI prostaglandin synthesis is born out by these data. Furthermore, data from the rofecoxib phase II and III studies have been combined in order to compare the effects of rofecoxib with those of NSAIDs on clinical outcomes relevant to GI toxicity. In this prespecified, combined analysis of the clinical development program, rofecoxib produced a significantly reduced incidence of clinical GI ulcers, bleeds, and perforations compared with the... 

The regulations pertaining to INDs are located in 21 CFR 312 and provide detailed guidance for both content and format. Interestingly, a sponsor does not hear from the FDA if the FDA s review is positive. The FDA reviewers have 30 days to respond to the sponsor following submission of the IND. If the sponsor has not been contacted in that window, they have implied permission to commence the clinical development program described in the IND. 

The standard deviation for change in SBP can be harder to determine. One way is to examine previously published data on similar outcomes (maybe other drugs in the same class). If few data are available from this source, consulting with experts in this research domain may be helpful. Another possibility is to conduct a small pilot study. In the later phases of a clinical development program, data from earlier studies may be informative. This often means that for confirmatory clinical drug trials there will be results from earlier trials, so information is readily available. From these two items, the standardized effect size can be calculated as the ratio CRD/SD. 

At each stage of the drug development program and for each trial within that stage, sponsors need to be aware of the implications of their choice of a and their choice of p and the acceptability of these implications. The implications of each choice and the acceptability of these implications may change throughout the course of a clinical development program. 

Understanding the metabolism of an investigative drug as early as possible in the clinical development program is important for several reasons, including the following ... 

Later in the clinical development program to demonstrate that the final commercial formulation to be marketed upon approval is equivalent to the formulation used in confirmatory trials. Issues of mass production and manufacturing scale-up can be relevant here (see Chapter 12). 

An entire clinical development program usually spans several years and includes many individual studies. Most sponsors will use CROs for some portion of the clinical development program, but rarely for creating the overall development plan. Nevertheless, if a particular CRO has established experience in a particular therapeutic area, it may be helpful in providing an independent assessment of draft plans prepared by the sponsor. 

Once a discovery compound has been identified with overall drug-like characteristics (good potency, selectivity, safety, and PK), that compound will be selected for advancement into clinical development. The next important PK activity is the quantitative projection of the human PK (20, pp. 207-228). Such information is useful for the planning of the preclinical and clinical development programs. Equation 6 can be used to estimate the clinical half-life if we can estimate CL and V. Two approaches can be used to estimate CL. 

This chapter is intended to provide the reader with a strategic overview of the manner in which an effective and efficient contemporary ciinicai deveiopment program is created. It is beyond the scope of a single chapter to be able to adequately cover all aspects of a clinical development program. More comprehensive... 

PHASES, SIZE, AND SCOPE OE CLINICAL DEVELOPMENT PROGRAMS... 

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