Clinical trials Cumulative

In leukemia, the intensified use of methotrexate and glucocorticoids is responsible for causing an increased frequency of neurotoxicity and, in older children and adults, avascular necrosis of bone. High cumulative doses of anthracyclines can cause cardiomyopathy. Cranial irradiation causes neuropsychologic deficits and endocrine abnormalities that lead to obesity, short stature, precocious puberty, and osteoporosis.3 As newer and more intensive treatments enter clinical trials, close observation for long-term side effects will assume even greater importance.24... 

Table 4.4 The clinical trial process. A drug must satisfactorily complete each phase before it enters the next phase. Note that the average duration listed here relates mainly to traditional chemical-based drugs. For biopharmaceuticals, the cumulative duration of all clinical trials is, on average, under 4 years...

MYKO 63 (P generation) was found to be significantly effective on all the animal tumors it was tested on and would have been really promising for clinical trials if it had not induced any cumulative toxicity when inoculated in daily polyinjections. In other words, the molecular structure of MYKO 63 was actually too stable to attack the tumor rapidly and to be excreted fast enough before a next injection would occur. 

In clinical trials the cumulative risk of death 35 days after starting treatment was 9% in the lepirudin-treated patients, compared with 18% in historical controls cumulative risk of new thromboembolic complications was 6% with lepirudin and 22% in historical controls... 

E. Therapeutic response Thrombin-dependent tests show dose dependency [aPTT rise proportionally to dose of Refludan]. The key criteria of efficacy in two pivotal clinical trials from a laboratory standpoint were platelet recovery and effective anticoagulation. Seven days after the start of treatment with Refludan in patients with HIT, the cumulative risk of death, limb amputation, or new thromboembolic complication was substantially lower than in a historical control group. 

While expenditure owing to expensive clinical trials grow more quickly for the accelerated pace, introduction to the market is reached more quickly (the goal is eight years in comparison to 12 years traditionally). Importantly, however, cumulative revenues between market introduction in, let us say, year 8 and patent expiration in year 18 to 20 tend to be considerably higher, as (i) more years under patent protection are available, and (ii) the initial market penetration and build-up phase is not as significant. 

Cumulative experience from 106 monkey-years and 23 human-years of retroviral gene therapy had revealed no side-effects or malignancies. Recently, however, three monkeys used in clinical trials developed T cell lymphomas which were traced to a helper virus-contaminated retroviral vector preparation (Anderson, 1992a). Contamination of defective viral vector stocks by infectious viruses produced in helper cells was a serious problem with the early version of the helper cells. New helper cell lines which greatly reduce the probability of virus production have been developed (Miller, 1990). Eurther, it is also imperative to test the lots of vector virus preparations used in therapy for the presence of other infectious viruses. The probability... 

Transient rises in serum AST also were observed in clinical trials of DCLHb in surgical and critically ill populations.f Serum amylase elevations were observed in clinical studies of DCLHb after single or cumulative doses of 20 g or more of DCLHb. These elevations are typically 2-3 times the upper limits of normal serum enzyme concentrations. The low incidence of acute pancreatitis observed in these trials was at the expected level for these patient populations. ... 

Pancytopenia is a rare but potentially fatal complication, and numerous reports have been published. The characteristics and incidence of pancytopenia have been carefully re-evaluated from case reports and clinical trials published from 1980 to 1995 (38). Of 70 reported cases, 12 patients died (17%). Impaired renal function was the most important contributing factor (54%), particularly in fatal cases (10/12). Other important susceptibility factors included advanced age (over 65 years), hypoalbuminemia, concurrent infection, and/or concomitant multiple medications (particularly co-trimoxazole). The mean cumulative dosage was 675 (10-4800) mg, and the minimal cumulative methotrexate dose leading to fatal pancytopenia was 10 mg. This confirms that pancytopenia can occur at any time during treatment, even in the absence of known susceptibility factors. Bone marrow biopsy showed megaloblastosis and hypocellularity. Eosinophilia and increased mean corpuscular volume were rarely observed. In an overall review of five long-term prospective studies (511 patients), the calculated incidence of methotrexate-induced pancytopenia was 1.4%. Although severe myelo-suppression sometimes required folinic acid, there are as yet no data to determine whether prophylactic folate supplementation can reduce the incidence of pancytopenia. 

The cumulation of all the data from the clinical trials of a new drug product, assuming a fairly orthodox regulatory strategy for a typical dossier or NDA, will form the largest fraction of the application. However, these data are also needed for derivative documents within the application, one of which is a benefit-risk analysis, which forms the last part of an Integrated Safety Summary (Section 9 of the NDA), and is a central objective of the expert report in European applications. These benefit-risk assessments must be derived from the clinical study reports and summaries elsewhere in the applications. 

Potentially harmful drug interactions may not be identified during controlled clinical trials, due to the exclusion of patients taking concomitant medications, which are not allowed to be taken during a study. For example, terfenadine, a novel nonsedating antihistamine which was found to cause a serious and potentially fatal cardiac arrhythmia, torsades de pointes, when administered with keto-conazole or erythromycin, and this could not realistically have been expected to be identified in the clinical trial setting. The mechanism of this adverse drug interaction was found to be due to cumulation of unmetabolized terfenadine, due to inhibition of cytochrome P-450 (CYP) by ketoconazole or erythromycin the parent terfenadine molecule is usually cleared very rapidly when there is no concomitant CYP inhibitor. 

FIG. 13.14. Initial clinical trials with Y-DOTATATE in Poland, patient No. 1 Treatment using four doses of Y-DOTATATE with a cumulative activity of 14.6 GBq. 

Figure 13.14 shows initial clinical trials of °Y-DOTATATE in patient No. 1, who was treated with four doses of Y-DOTATATE, using a cumulative activity of 14.6 GBq. The images show that liver deposits dominate the lesion with a high uptake of radiotracer. Tlie bremsstrahlung images after the four courses of therapy show significant decreases of uptake with each treatment session. 

Although the addition of dietary calcium can reduce diastolic blood pressure in healthy adults, it most visibly affects systolic blood pressure in patients with mild to moderate hypertension (Morris et al. 1984, McCarron and Morris 1985). Indeed, there is now cumulative evidence from more than 60 observational studies as well as randomized clinical trials, that low dietary calcium is a significant risk factor for primary hypertension, or, conversely, that calcium supplementation causes a consistent fall in blood pressure (McCarron and Reusser 1999). 

Agents - Phase I clinical trials of SOAz (1,3,3,5,5 penta-kis (aziridlno)-lX , 2,4,6,3X ,5X thiatriazadiphosphorine-1-oxide) have been completed. Cumulative myelosuppression was observed to be dose limiting-no responses were seen.25 Metabolic studies on cyclophosphamide and ifosfamide have indicated the necessity for metabolic activation at C4. 

Now suppose that a group of patients is included in a clinical trial because they have measured values in excess of some threshold k. We then have X > k. X now has a truncated Normal distribution. Let cJ)(m) be the probability density function of a standard Normal distribution and 0(m) be the distribution function (cumulative density function). Let a= k — iE)jcT- andZ = (X - then P(X>k) = P(Z >a) = l — 4>(a). 

HA has been used as a hydrophihc carrier to deliver diclofenac topically for the treatment of premalignant skin lesions such as actinic keratoses (AK) (106-112) and for colon-26 adenocarcinoma (113-115). HA is the preferred carrier for transdermal delivery of diclofenac, as it has been shown to enhance the partitioning of the drug into the skin compared to other vehicles (116). Furthermore, in a clinical trial, the safety and efficacy of 3% diclofenac in 2.5% HA gel have been evaluated as a topical treatment for actinic keratosis (108). Patients treated with HA-diclofenac showed significantly lower target and cumulative lesion number scores and lesion total thickness scores compared to the placebo group. The treatment with 3.0% diclofenac in 2.5% HA gel was effective when used for 60 days and was well tolerated in patients with AK. 

Trabectedin enters phase I clinical trial (table 1) due to its efficacy and therapeutic outcome in preclinical studies against several types of cancers. According to the obtained results, hepatotoxicity (elevation of alkaline phosphatase in half of patient receiving trabectedin treatment) and non-cumulative hematological toxicity were the most commonly reported adverse effeets [29]. However, vomiting, fatigue, asthenia, and reversible transaminitis were other dose-limiting toxicity of treatment in phase I (0.75 mg/m i.v. on day 1 every 3 weeks) [30, 31]. 

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