Abstract:
:The overall response rate (ORR) is a largely adopted outcome measure in early-phase oncology trials. ORR is highly relevant in cancer drug development at the time of deciding whether to move to confirmatory phase 3 trials; moreover, ORR is gaining increasing relevance in fast-track registration procedures. No systematic analysis has been conducted so far to investigate whether a discrepancy exists between ORR assessed by local investigators and those assessed by blinded reviewers in phase 2 oncology trials. In this study, we carried out a search in the clinicaltrials.gov and EudraCT databases, looking at the trials reporting the results of both investigator-assessed and independently-assessed ORR. A discrepancy index was obtained by calculating the ratio of each investigator-assessed ORR on the corresponding independently assessed ORR, so that a discrepancy index >1 indicates that the investigator was "more optimistic," whereas a discrepancy index <1 indicates the opposite. We also analyzed different subgroups (by tumor type, by drug type, by year). Twenty trials met the search criteria; in some cases, >1 comparison was conducted in the trial, so that the total number of comparisons analyzed was 33. The estimated mean discrepancy index was 1.175 (95% confidence interval, 1.083-1.264; n = 33). In conclusion, local investigators significantly overestimate ORR compared to paired blinded reviewers in phase 2 oncology trials. This may represent a risk in drug development, when deciding whether to move to confirmatory, more expensive phase 3 trials. Blinded independent central review should be used in ORR assessment if a more conservative estimate of treatment efficacy is required, as in the case of fast-track drug developments leading to accelerated approvals of cancer therapies.
journal_name
J Clin Pharmacoljournal_title
Journal of clinical pharmacologyauthors
Dello Russo C,Cappoli N,Pilunni D,Navarra Pdoi
10.1002/jcph.1790subject
Has Abstractpub_date
2020-11-26 00:00:00eissn
0091-2700issn
1552-4604pub_type
杂志文章abstract::Quinapril, a nonsulfhydryl ACE inhibitor, was evaluated in ten New York Heart Association (NYHA) functional class (FC) II-III CHF patients to determine its effects on regional blood flow [effective renal plasma flow (ERPF), renal blood flow (RBF), renal vascular resistance (RVR), hepatic blood flow (HBF), hepatic vasc...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1992.tb03791.x
更新日期:1992-01-01 00:00:00
abstract::To investigate whether methyldopa alters digoxin disposition, eight healthy subjects received methyldopa titrated to 250 mg t.i.d. or placebo in a double-blind, cross-over manner for 16 consecutive days, with 0.25 mg intravenous digoxin coadministered on day 5 and 0.25 mg oral digoxin on days 9 to 16. Digoxin concentr...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1984.tb02791.x
更新日期:1984-08-01 00:00:00
abstract::A pediatric population pharmacokinetic model including covariate effects was developed using data from 2 clinical trials in pediatric patients with epilepsy (SP0847 and SP1047). Lacosamide plasma concentration-time data (n = 402) were available from 79 children with body weights ranging from 6 to 76 kg, and a balanced...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1340
更新日期:2019-04-01 00:00:00
abstract::Nine healthy subjects received 400 mg sodium valproate orally in the fasting state. Binding parameters of valproic acid to serum proteins were determined by Scatchard analysis for individual series of valproic acid data. Total and unbound (intrinsic) clearances (CLt and CLu) were calculated by dividing the dose by the...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1993.tb03932.x
更新日期:1993-02-01 00:00:00
abstract::Experiments were performed on humans to study the blunting on the diuretic action of furosemide by prostaglandin synthetase inhibitors. Maximal water diuresis was instituted. At the peak of urine flow, clearance periods were performed during baseline conditions and repeated after the injection of aspirin and, subseque...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1980.tb01718.x
更新日期:1980-07-01 00:00:00
abstract::Lemborexant is a novel orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia. This article describes the population pharmacokinetics (PK) of lemborexant and the relationship of its daily steady-state exposure (Cav,ss ) to the probability of most frequent treatment-emergent ad...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1683
更新日期:2020-12-01 00:00:00
abstract::The effects of propafenone on the pharmacokinetics and pharmacodynamics of propranolol were evaluated in 12 healthy male subjects. Both propafenone and propranolol were each administered alone for one week followed by concomitant administration for an additional week. Blood samples, obtained at steady-state, were anal...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1989.tb03373.x
更新日期:1989-06-01 00:00:00
abstract::To determine if ordinary doses of nitrates produce a significant increase in methemoglobin, methemoglobin levels were measured in 59 randomly selected patients with coronary artery disease and unstable angina pectoris who were receiving organic nitrate therapy. Patients were taking isosorbide dinitrate, 2% nitroglycer...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1984.tb01825.x
更新日期:1984-04-01 00:00:00
abstract::In patients with renal insufficiency, dose adjustments based on creatinine clearance and body weight have been a component of imipenem dosage instructions. The objective of the current analysis was to provide revised dosing recommendations by evaluating the impact of creatinine clearance and body weight on the pharmac...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1002/jcph.1356
更新日期:2019-05-01 00:00:00
abstract::Twenty healthy volunteers (age ranging from 19 to 72) were studied for their aldosterone response to oral administration of 10 mg cisapride, a serotonin-4 receptor agonist. The participants were studied after minimum of 4-hour ambulation (high basal renin) and a repeated test after overnight bed rest (low basal renin)...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1997.tb04299.x
更新日期:1997-12-01 00:00:00
abstract::It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynam...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1177/0091270011408611
更新日期:2012-07-01 00:00:00
abstract::The purpose of this study was to evaluate the pharmacokinetics of sulindac, a purported "renal sparing" nonsteroidal anti-inflammatory drug, and its effects on renal function and prostaglandin excretion in patients with reduced glomerular filtration rate. Twelve female patients (glomerular filtration rate 37 +/- 4 mL/...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1989.tb03275.x
更新日期:1989-11-01 00:00:00
abstract::Disease states such as liver cirrhosis and chronic kidney disease can lead to altered pharmacokinetics (PK) of drugs by influencing drug absorption, blood flow to organs, plasma protein binding, apparent volume of distribution, and drug-metabolizing enzyme and transporter (DMET) abundance. Narrow therapeutic index dru...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1709
更新日期:2020-10-01 00:00:00
abstract::In 14 patients with congestive heart failure (CHF) of various grade (NYHA class 2-4) the effects of zofenopril calcium (SQ 26,991) on blood pressure and forearm circulation were studied by venous occlusion plethysmography. Changes in plasma renin activity (PRA), aldosterone, Atrial natriuretic factor (ANF) and arginin...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1989.tb03282.x
更新日期:1989-12-01 00:00:00
abstract::The authors evaluated the effect of high-dose aspirin at a therapeutic dose, using chlorzoxazone as a probe for CYP2E1 enzyme activity. In a randomized, open-label, 2-way crossover study, 10 healthy men were treated 3 times daily for 6 days with 1 g aspirin or placebo. On day 7, 1 dose of 400 mg chlorzoxazone was admi...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1177/0091270005282635
更新日期:2006-01-01 00:00:00
abstract::A double-blind, randomized trial was carried out in patients suffering from pain after removal of an impacted lower wisdom tooth. The analgesic effects of a codeine preparation (Staralgin), a dextropropoxyphene preparation (Doleron novum), and paracetamol were compared in a multiple-dose study of 94 patients. The asse...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1002/j.1552-4604.1981.tb01744.x
更新日期:1981-10-01 00:00:00
abstract::The new antidepressant nomifensin (Hoechst 36984), a drug which showed less cardiotoxicity than tricyclics, was compared in a single-blind comparative trial with viloxazine. Forty elderly depressed patients were treated during four weeks. Nomifensin, N=21, 75 mg/day; viloxazine, N=19, 150 mg/day). Antidepressant effec...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1002/j.1552-4604.1977.tb04589.x
更新日期:1977-01-01 00:00:00
abstract::The peritoneal clearance of gentamicin was studied in 11 chronic uremic patients who undergoing intermittent peritoneal dialysis. Gentamicin was significantly removed by peritoneal dialysis with a clearance value of 9.75 +/- 3.78 ml/min. The serum half life was 14.08 +/- 3.57 hr, a value significantly less than that o...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1989.tb03302.x
更新日期:1989-02-01 00:00:00
abstract::Transporters play an important role in drug absorption, disposition, and drug action. The evaluation of drug transporters requires a comprehensive understanding of transporter biology and pharmacology. Physiologically based pharmacokinetic (PBPK) models may offer an integrative platform to quantitatively evaluate the ...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1002/jcph.740
更新日期:2016-07-01 00:00:00
abstract::The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German drug regulation authority, issued guidelines for determining whether bioavailability/bioequivalence studies are required for certain drugs. This decision tree is based on pharmacodynamic, pharmacokinetic, and physicochemical criteria. Details ...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1998.tb04385.x
更新日期:1998-10-01 00:00:00
abstract::Amiodarone is a unique antiarrhythmic agent originally developed as a vasodilator. Classified electrophysiologically as a Type III antiarrhythmic, it also has both nonspecific antisympathetic and direct, fast channel-membrane effects. Hemodynamic effects of orally administered amiodarone (a negative inotropic agent) a...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,评审
doi:10.1002/j.1552-4604.1991.tb03673.x
更新日期:1991-11-01 00:00:00
abstract::Ofatumumab is a human monoclonal antibody that binds to a unique CD20 epitope on the surface of B lymphocytes, resulting in efficient lysis of CD20-expressing cells via complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The potential effect of ofatumumab on cardiac repolarization and ...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1002/jcph.376
更新日期:2015-01-01 00:00:00
abstract::The availability of poisoning information from the pharmaceutical industry was evaluated. Manufacturers of the top 50 drugs were surveyed. Information that was received was classified by established criteria for evaluation. Compendia on poisoning information was evaluated based on 11 components ranging from toxicity i...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1979.tb02474.x
更新日期:1979-02-01 00:00:00
abstract::The disposition of nalmefene, an opioid antagonist intended for the reversal of opioid-induced respiratory depression, and its primary metabolite nalmefene glucuronide, were characterized in adult volunteers with normal renal function and in patients with end-stage renal disease (ESRD). The effect of hemodialysis on t...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1996.tb04179.x
更新日期:1996-02-01 00:00:00
abstract::The relationship between indenolol (an investigational agent) plasma levels and the drug's effect on blood pressure and heart rate was investigated after single and repeated once daily administration at two dosage levels (60 mg and 120 mg) in two different groups of patients with first or second stage hypertension, ac...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1985.tb02851.x
更新日期:1985-07-01 00:00:00
abstract::Cyclosporine (CsA) dosing is based on CsA plasma or blood concentrations measured 12 to 24 hours after drug administration (trough levels). This study evaluated the relationship between the timing of CsA concentrations and subsequent pharmacokinetic parameters to predict an optimal sampling period. Plasma samples were...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1992.tb03798.x
更新日期:1992-11-01 00:00:00
abstract::Sinbaglustat (ACT-519276), a brain-penetrating inhibitor of glucosylceramide synthase and nonlysosomal glucosylceramidase, is developed as a new therapy for lysosomal storage disorders. In the first-in-human study, sinbaglustat was primarily excreted unchanged in urine. This study was conducted to evaluate the effect ...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/jcph.1808
更新日期:2020-12-23 00:00:00
abstract::ReN1869 (NNC 05-1869) is a novel, selective H1 receptor antagonist that has been developed for analgesic purposes. In a first human dose administration study, the safety and pharmacokinetics of seven single oral doses in the range of 3.5 to 95 mg ReN1869 were studied. The study was a randomized, double-blind, placebo-...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1177/0091270002239708
更新日期:2003-01-01 00:00:00
abstract::The possible effect of oral flecainide acetate on steady-state digoxin levels was assessed in 15 healthy men. Each volunteer received digoxin 0.25 mg daily (8 AM) for 22 consecutive days and flecainide 200 mg bid (8 AM and 8 PM) on days 11 through 15. Plasma digoxin and flecainide levels were measured by radioimmunoas...
journal_title:Journal of clinical pharmacology
pub_type: 杂志文章
doi:10.1002/j.1552-4604.1986.tb02898.x
更新日期:1986-01-01 00:00:00
abstract::ABT-761 is a second-generation 5-lipoxygenase inhibitor in clinical development for the treatment of asthma. The effects of ABT-761 on the pharmacokinetics of an oral contraceptive were assessed in 21 female adult volunteers in a phase I, multiple-dose, open-label study. Subjects received a single dose of oral contrac...
journal_title:Journal of clinical pharmacology
pub_type: 临床试验,杂志文章
doi:10.1002/j.1552-4604.1998.tb04472.x
更新日期:1998-07-01 00:00:00