Clinical trials limitations

Eor multi-centre clinical trials limited to the territory of a single Member State, Member States shall establish a procedure providing, notwithstanding the number of Ethics Committees, for the adoption of a single opinion for that Member State. 

Treatment Pharmacology and positive attributes Efficacy (clinical trials) Limitations... 

For the past few years, however, there has been a hiatus in the pace of discovery of novel medicinal agents. It has been postulated by some that the field has now slowed down due to the limitations of the almost strictly empirical approach that has been applied to date to drug development. It is possible, too, that the higher standards of efficacy and safety that a new drug must meet today, combined with the enormously increased costs of clinical trials, have acted to keep all but the most promising new drugs off the market. 

It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants of the compound tested preclin-ically that is intended for use in clinical trials. The maximum level of impurities in a stereoisomeric product used in clinical studies should not exceed that in the material evaluated in nonclinical toxicity studies. This point is expanded in the ICH impurities guideline (Section 13.5.3). 

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

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. 

There have been few reports on the cUnical use of albumin microspheres for the delivery of drugs. The limited clinical trials, using chemotherapeutic agents, employ a technique referred to as arterial chemoembolism in which the drug-containing microspheres... 

For the treatment of lung surfactant deficiency in premature human infants suffering from respiratory distress syndrome, limited clinical trials were performed showing that liposomes in the lung-instilled intratracheally either as an aerosolized mist (Ivey et al., 1977) or as a suspension via an endotracheal tube (Fujiwara et al., 1980)—rapidly improved lung function. No adverse effects were observed as a result of the supplementation with surfactant-like material. It appears, therefore, that liposomes are a suitable system for the delivery of major phospholipid components of endogenous lung surfactant. 

The first issue lies in the whole realm of the human disease process itself. Many adverse drug events mimic diseases and vice versa. Is an adverse event really an adverse event, or is it merely a natural occurrence of a disease process that is entirely independent of drug exposure The science of drug safety is often complicated by the lack of objective markers of drug toxicity that can systematically separate a disease process from an adverse drug event process [2]. Clinical trials, often viewed as the gold standard to assess efficacy, are simply too limited in scope to answer safety questions in a systematic way. 

Limited Knowledge of Exposure and Reporting Rates in Postmarketing Data. Unlike clinical trials and electronic medical records in clinical practice, postmarketing voluntarily reported data contain limited information about the total number of patients exposed and the duration of exposure. This problem is compounded by the fact that adverse events are often underreported [2,9]. 

Randomized, controlled clinical trials reduce bias and variability by a process of selection, randomization and standardization of treatment, and often take place under artificial conditions isolated from those of routine clinical practice (Freemande et al, 1993 Simon et al, 1995b). Yet it is the uncontrolled interactions of a dmg technology with patients, health-care workers and the system of health care that ultimately lead to much of the variability in outcomes and expenditures in clinical practice. Thus the value of RCTs in evaluating cost-effectiveness in clinical practice maybe limited (Reeder, 1995 Simon et al, 1995b Hotopf et al, 1996). 

Once a suitable strain is available, the prachce is to grow, often ftom a single organism, a sizeable culture which is distributed in small amounts in a large number of ampoules and then stored at 70°C or freeze-dried. This is the seed lot. From this seed lot, one or more ampoules are taken and used as the seed to originate a limited number of batches of vaccine which are first examined exhaustively in the laboratory and then, if found to be satisfactory, tested for safety and efficacy in clinical trials. Satisfactory results in the clinical trials validate the seed lot as the seed from which batches of vaccine for routine use can subsequently be produced. 

The number of study sites to be used for a clinical trial depends on the characteristics and number of subjects that need to be recruited. Often, a sufficient number of participants cannot be enrolled from a single site, especially if the study inclusion criteria are restrictive and the timeframe for recruitment is limited. In order to complete the study within a reasonable period of time, an inclusion of multiple research centers is often necessary (Chow and Liu, 1998). The selection of study sites depends on several factors including ... 

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