Clinical studies, phase

A major goal of pharmacogenetic and pharmacogenomic analyses in early-phase clinical studies is to identify subpopulations of subjects with an improved safety and efficacy profile. However, there are various views on how pharmacogenetics and pharmacogenomics could be used in the design of clinical trials. Some examples are as follows ... 

Early-phase clinical studies involve relatively small numbers of subjects. However, this does not mean that design, methodology, and analysis are any less critical. Machin and Campbell (2005) noted that these early-phase clinical studies... 

The usual decay process of heavy nuclei is a-particle emission. An a particle is a helium ion containing two protons and two neutrons. Alpha particles are heavy particles that have a very short range in matter due to their mass, and radiopharmaceuticals labeled with a emitters are used only with therapeutic purposes. Their clinical use is very limited, and they are mainly used for research purposes or in early phase clinical studies. 

General comments on study designs in early phase clinical studies... 

Section (g) of this section indicates that the drug product used for investigation does not need to follow cGMP providing that the company will meet their specifications set by stability testing of clinical materials. However, many companies choose to follow cGMP for their late-phase clinical studies. 

Darpo B, Ferber G, Garnett G, liu J, Stockbridge N (2015) Topic of timely interest - decision criteria for negative QT assessment using exposure response analysis of data from early-phase clinical studies letter to the Editor Ther Innov Regul Sci 49 717-719... 

This chapter will discuss the role of the analytical chemist in the preformulation process and highlight the methods that will need to be developed, validated and utilized to support these studies. An assortment of analytical techniques is needed to measure a number of critical quality attributes of the new molecular entity such as solubility, purity, and crystalline habit. The methods will be used to make important decisions such as the choice of salt form, or which sohd oral dosage form has the best probability of providing adequate exposure in an early phase clinical study. These analytical tools are critical to the decision that a pharmaceutical development organization uses to evaluate the first round of solid dosage form development prior to the availability of clinical data. 

Aniracetam (6), launched in 1993 in both Japan and Italy for the treatment of cognition disorders, is in Phase II trials in the United States as of this writing. In clinical studies it has been shown to cause some improvement in elderly patients with mild to moderate mental deterioration (63), and in geriatric patients with cerebral insufficiency (64). In a multicenter double-blind placebo-controUed trial involving 109 patients with probable AD, positive effects were observed in 36% of patients after six months of treatment (65), a result repeated in a separate study of 115 patients (66). A review of the biological and pharmacokinetic properties, and clinical results of aniracetam treatment in cognitively impaired individuals is available (49). 

Phase II. Initial clinical studies for therapeutic safety and efficacy are performed in volunteer patients who are suffering from the disease for which the dmg has therapeutic promise. Recognition of toxic symptoms and side effects are vital at this point because these may occur here, even when not observed in animal studies or in Phase I. 

An hplc assay was developed suitable for the analysis of enantiomers of ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory dmg (NSAID), in plasma and urine (59). Following the addition of racemic fenprofen as internal standard (IS), plasma containing the KT enantiomers and IS was extracted by Hquid-Hquid extraction at an acidic pH. After evaporation of the organic layer, the dmg and IS were reconstituted in the mobile phase and injected onto the hplc column. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (chiral AD) with hexane—isopropyl alcohol—trifluoroacetic acid (80 19.9 0.1) as the mobile phase pumped at 1.0 mL/min. The enantiomers of KT were quantified by uv detection with the wavelength set at 254 nm. The assay allows direct quantitation of KT enantiomers in clinical studies in human plasma and urine after adrninistration of therapeutic doses. 

Research on an hCG vaccine has been conducted over the past 15 years. WHO has conducted a phase I clinical study in AustraUa, using a vaccine based on a synthetic C-terminal peptide (109—141) of P-hCG conjugated to Diptheria Toxoid (CTP-DT), that showed potentially effective contraceptive levels of antibodies were produced in vaccinated women without any adverse side effects. Phase II clinical studies are under consideration to determine if the immune response, raised to its prototype anti-hCG vaccine, is capable of preventing pregnancy in fertile women volunteers (115). While research on the C-terminal peptide from the P-subunit of hCG has been carried out under the auspices of WHO, research supported by the Population Council and the National Institutes of Health has involved two alternative vaccine candidates (109,116,118). 

MK-677, an orally active spiroindoline-based growth hormone secretagogue (GHS) agonist, discovered by Merck and currently in Phase II clinical studies, was synthesized with a Fischer indolization as a key step. The synthesis of this agonist involved a Fischer indole/reduction process and was achieved in 48% overall yield from the relatively cheap starting material, isonipecotic acid 72. ... 

OPG has been shown to reduce bone turnover in postmenopausal women. More recently, Denusomab, an anti-RANKL mAb, has been tested for its ability to increase BMD and to reduce bone turnover. Results were promising and clinical phase III studies with fracture endpoints are presently under way. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

The clinical trial that resulted in FDA approval of bevacizumab (February 2004) was a randomized, double-blind, phase III study in which bevacizumab was administered in combination with bolus-IFL (irinotecan, 5FU, leucovorin) chemotherapy as first-line therapy for previously untreated metastatic colorectal cancer [3]. Median survival was increased from 15.6 months in the bolus-IFL + placebo arm to 20.3 months in the bolus-IFL + bevacizumab arm. 

The majority of non-clinical studies are undertaken in the pre-clinical phase of drug development. These studies serve both to guide the developer and satisfy the regulatory authorities. The objectives of this phase can be summarised as follows ... 

Safety and quality aspects are the main topics that must be addressed from a regulatory perspective at the pre-clinical phase of drug development. Indicative efficacy data will also be obtained, but authoritative data can be obtained only from clinical studies conducted with humans. Safety and preliminary efficacy indications... 

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