Early phase clinical trials limitations

Discussions in this chapter emphasize statistical considerations in early phase clinical trials. These include study designs employed, the types of data collected, and the usefulness and limitations of these data. 

In this chapter we have discussed the importance, and the strengths, of early phase clinical trials. Before moving on to later phase clinical trials, it is also appropriate to consider their limitations. The word "limitations" should not be seen as a negative assessment in this context. As we will discuss in Chapter 12, later-phase preapproval clinical trials also have their limitations. Acknowledgment of the strength and the limitations of any method of inquiry is legitimate and helpful As Katz (2001, p xi) noted, "to work skillfully with evidence is to acknowledge its limits."... 

Unlike with kidney injury biomarkers, where between 2008 and 2010 the FDA, the EMA and the PMDA qualified the use of seven urinary biomarkers for GLP rat studies to support the safe conduct of early phase clinical trials, GI injury is stiU in its infancy with regard to discovery, development, and implementation of biomarkers. The challenges of developing biomarkers are even greater when the complexity of GI injuries is looked upon more carefully. These injuries include, but are not limited to, nausea, vomiting, ulceration, inflammation of the intestine, mucositis, altered fecal output, abdominal pain/discomfort, GI bleeding, and/or perforation which can be inflicted by various dmg classes, chemical classes, or therapeutic areas. 

Similar MAT may enter clinical trials in a variety of other rheumato-logic conditions, including scleroderma, for which the success of current treatments is extremely limited. Another autoimmune disease that has already been studied, though not extensively and only in early phases, is psoriatic arthritis, and it appears as if this disease will respond to similar measures as rheumatoid arthritis. 

Seventy-five percent of drug candidates do not reach the clinical trial phase mainly due to poor pharmacokinetics in animal studies (1). Since so many compounds fail in late stage testing, the current trend is to study the pharmacokinetics of lead compounds as early as possible. One of the most important elements of pharmacokinetics is lipophilicity, or a compound s affinity for fat. Usually, the more water soluble a compound is, the lower its lipophilicity. Low water solubility (high-lipophilicity) compounds have a limited oral bioavailability but are usually easily metabolized. On the other hand, low-lipophilicity compounds have poor membrane permeability since membranes are partly composed of fat. 

In summary, the findings of early Phase I and II clinical trials suggest subjective and objective improvements in patients with ischemic lower-extremity or myocardial disease, and merit further investigation in additional Phase II, and pivotal Phase III and IV clinical studies. Issues that need to be addressed in these studies include limitations and safety profiles, definition of the populations that would benefit from this therapy, determination of... 

---