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PubMed2006

The impact of the 'Clinical Trials' directive on the cost and conduct of non-commercial cancer trials in the UK.

BACKGROUND: The UK Medicines for Human Use (Clinical Trials) Regulations 2004 implemented the European 'Clinical Trials' Directive (2001/20/EC) (EUCTD) into UK law and came into effect on 1(st) May 2004. In the period leading up to the implementation of the EUCTD in the UK there were serious concerns that it would have major cost implications for academic units running non-commercial clinical trials. METHODS: Directors and senior staff in 8 Clinical Trials Units (CTUs) were contacted and invited to participate in the study; arrangements were made for face-to-face interviews and the units were sent a questionnaire in advance of the meeting. The questionnaire was divided into six sections covering their involvement in non-commercial cancer clinical trials, and their perceptions of the EUCTD and its impact on all stages of trial development and conduct. Detailed cost data were also collected. FINDINGS: The findings from the questionnaire and interviews indicate that the EUCTD has resulted in a doubling of the cost of running non-commercial cancer clinical trials in the UK and a delay to the start of trials. The lack of central guidance, lack of clarity regarding the interpretation of the guidance notes, and increase in essential documentation and paperwork were causes of major concern for experienced staff who were anxious about whether they were interpreting the Directive correctly. Moreover, the CTUs were unable or unwilling to open trials in non-UK centres because of the different interpretation of the EUCTD by member states. INTERPRETATION: The EUCTD has both increased the cost and caused delay to non-commercial cancer clinical trials run by major public sector Clinical Trials Units in the UK. Staff have felt that they were working beyond capacity and were feeling demoralised in many CTUs. Finally, rather than harmonising and simplifying the regulatory environment, the Clinical Trials Directive has stopped many units from running trials in international centres. The UK has taken action to address some of the problems identified by this and other research, but problems remain.

Attitude of Health Personnel↗
PubMed2002

Endocrinology trial design: adverse event reporting in randomised controlled trials of recombinant human GH in GH-deficient adults.

We have evaluated the reporting of withdrawals due to adverse effects and specific adverse effects in randomised controlled trials of recombinant human GH in adults. A systematic review was carried out of randomised controlled trials of the clinical effectiveness of recombinant human GH in adults with GH deficiency in relation to impact on quality of life. Trials were identified from searching electronic databases, bibliographies of related articles and consulting experts. There was reporting of withdrawals due to adverse effects and specific adverse effects. Rates of oedema and arthralgia were reported in included trials. Seventeen randomised controlled trials, published between 1990 and 1999, met the inclusion criteria for the review. Nine trials reported data on the effectiveness of GH on quality of life in adults. Only five trials (29%) reported both withdrawals from the study because of adverse events and specific adverse events with numbers per study arm and per type. Six further trials (35%) reported either withdrawal details or specific adverse event details or partial data on specific adverse events. Six trials (35%), however, did not report information on either withdrawals or specific adverse events. Ten of the 17 studies (59%) reported the number of patients who withdrew from the study due to adverse events per study arm and type of adverse event per study arm. Seven of the 17 trials (41%) reported the number of specific adverse events per study arm and six (35%) reported the type per study arm. The reporting of adverse events in randomised controlled trials of GH is variable and not consistent across trials. It is not possible to assess the impact that adverse events may have had on unblinding patients, and therefore the extent to which the effects of GH may have been overestimated. Therefore those conducting endocrinology trials in the future need to pay attention to the reporting of withdrawals due to adverse events and specific adverse events.

Adult↗
PubMed1987

Two randomised phase II trials of intermittent intravenous versus subcutaneous alpha-2 interferon alone (trial 1) and in combination with 5-fluorouracil (trial 2) in advanced colorectal cancer.

Sixty-five patients with advanced colorectal cancer were randomised to one of two schedules of recombinant alpha-2 interferon (IFN). In the first study, 36 patients received single-agent IFN, either 50 X 10(6) U/m2 intravenously on 5 consecutive days every 4 weeks, or 20 X 10(6) U/m2 subcutaneously three times per week. No tumour responses were seen and toxicity was unacceptable. In the second study, 29 patients received IFN in two similar schedules, but the dose of IFN was reduced to 20 X 10(6) U/m2 per day in the intravenous arm and to 5 X 10(6) U/m2 per day in the subcutaneous arm. In addition these patients were administered intravenous 5-Fluorouracil (5-FU), 250-500 mg/m2 per day on the first 5 days of each 4-weekly cycle. Although the toxicity of this second study was tolerable, only one short-lived partial remission was observed. Alpha-2 interferon, alone or in combination with 5-FU, is ineffective in advanced colorectal cancer.

Adenocarcinoma↗
PubMed2000

Prophylactic implantable cardioverter defibrillator trials: MUSTT, MADIT, and beyond. Multicenter Unsustained Tachycardia Trial. Multicenter Automatic Defibrillator Implantation Trial.

MUSTT and MADIT have clearly shown the survival benefit of an implantable cardioverter defibrillator (ICD) in patients with previous myocardial infarction, left ventricular ejection fraction < or = 0.40, and nonsustained ventricular tachycardia (VT), and who have had sustained VT induced at electrophysiology study. Progress in primary prevention of sudden cardiac death (SCD) depends on a concerted effort by clinicians to identify and appropriately treat MUSTT/MADIT-type patients; further research to more precisely define patient subgroups at risk for SCD and the willingness of industry to develop a lower priced ICD for prophylactic use are needed.

Clinical Trials as Topic↗
PubMed2000

A phase II trial of 5-fluorouracil, leucovorin, and interferon alpha 2A (IFN-alpha 2a) in metastatic pancreatic carcinoma: a Penn Cancer Clinical Trials Group (PCCTG) trial.

A phase II study was performed to evaluate the activity and toxicity of 5-fluorouracil (5-FU), leucovorin, and inteferon alpha-2a in metastatic pancreatic carcinoma. Twenty-three patients were entered in this study. Four patients withdrew before receiving treatment and one patient was nonevaluable for response because of treatment-related toxicity. The most common significant toxicity was nausea and vomiting. Treatment-related hospitalization was significant. Of 18 evaluable patients, 4 maintained stable disease and 14 had disease progression. None had an objective clinical response. We conclude that this biochemically modulated 5-FU regimen is ineffective treatment for advanced pancreatic carcinoma, with significant toxicity even in highly selected patients with an ambulatory performance status.

Adult↗
PubMed2003

Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741.

PURPOSE: Using a 2 x 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. PATIENTS AND METHODS: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A x 4 (doses) --> T x 4 --> C x 4 with doses every 3 weeks, (II) sequential A x 4 --> T x 4 --> C x 4 every 2 weeks with filgrastim, (III) concurrent AC x 4 --> T x 4 every 3 weeks, or (IV) concurrent AC x 4 --> T x 4 every 2 weeks with filgrastim. RESULTS: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P =.010), and OS (RR = 0.69; P =.013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. CONCLUSION: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.

Adult↗
PubMed2005

Randomized trial of two intravenous schedules of the topoisomerase I inhibitor liposomal lurtotecan in women with relapsed epithelial ovarian cancer: a trial of the national cancer institute of Canada clinical trials group.

PURPOSE: Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study. PATIENTS AND METHODS: Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m(2)/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m(2)/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior. RESULTS: Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B. CONCLUSION: The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.

Adult↗
PubMed2000

Extubation from low-rate intermittent positive airways pressure versus extubation after a trial of endotracheal continuous positive airways pressure in intubated preterm infants.

BACKGROUND: Failure of extubation and subsequent reintubation may result in additional stress and trauma to the premature infant. Testing infants about to be extubated with a period of endotracheal CPAP has been suggested as a method of demonstrating readiness for extubation. However, this process has been criticized as increasing the neonate's work of breathing and perhaps increasing the likelihood of extubation failure. OBJECTIVES: In premature infants having their endotracheal tube removed, is direct extubation from low rate intermittent positive pressure ventilation (IPPV) more successful than that following a period of endotracheal continuous positive airway pressure (CPAP)? SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group as outlined in the Cochrane Library was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Controlled Trials Register, MEDLINE, previous reviews including cross references, abstracts, conferences, symposia proceedings, expert informants and journal hand searching mainly in the English language. SELECTION CRITERIA: All trials using random or quasi-random allocation of premature infants to endotracheal CPAP or direct extubation following a period of IPPV were included. DATA COLLECTION AND ANALYSIS: Data were extracted using standard methods of the Cochrane Collaboration and its Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author and synthesis of data using relative risk. MAIN RESULTS: Direct extubation from low rate ventilation is associated with a trend to increased chance of successful extubation when compared to extubation after a period of endotracheal CPAP, RR 0.45 (0.19,1.07), RD -0.103 (-0.200,-0.006), NNT 10 (5,167). When only truly randomized trials are considered, this result becomes both statistically significant and clinically important, RR 0.10 (0.01,0.78), RD -0.201 (-0.319,-0.083), NNT 5 (3, 12). Similar differences are seen for the secondary outcome, apnea. REVIEWER'S CONCLUSIONS: Preterm infants no longer requiring endotracheal intubation and IPPV should be directly extubated without a trial of ETT CPAP.

Humans↗
PubMed1998

Who should provide routine antenatal care for low-risk women, and how often? A systematic review of randomised controlled trials. WHO Antenatal Care Trial Research Group.

Many activities, the timing and the frequency of visits of conventional antenatal care provided to low-risk pregnant women have most often been introduced without proper scientific evaluation. Few trials, to date, have been conducted to evaluate the effectiveness of antenatal care programmes for low-risk women with varied number of antenatal visits and type of care providers. We have performed a systematic review of these randomised controlled trials. Five randomised controlled trials were identified in which the effectiveness of a schedule of reduced number of antenatal visits (n = 12,883) was compared with the existing practice (n = 9438). Four of these trials were carried out in developed countries. The difference in the number of visits between intervention and control arms of the trials was moderate. Only one trial achieved a reduction in the median number of visits, from six in the standard care to four in the intervention group, that could be considered to be of health-care relevance for the study population. No significant differences were observed in the two arms of the trials when low birthweight, small-for-gestational-age, Caesarean section, induction of labour, antepartum haemorrhage and postpartum haemorrhage were considered as outcome measures. However, there was a tendency towards an increased rate of preterm delivery in the intervention group in three of the trials. Conversely, the largest trial in Harare, Zimbabwe, demonstrated a statistically significant reduction in preterm delivery in the intervention group (relative risk [RR] 0.88; 95% confidence interval [CI] 0.80, 0.96). Neither the individual studies nor the review had the statistical power to evaluate mortality outcome variables. When perception of care was assessed, women participating in two trials expressed less satisfaction with frequency of visits in the experimental group. In the London, UK, trial, some women in the reduced number of visits group felt that their expectations were not completely fulfilled. However, an opposite trend was reflected when women were asked for their preference of the type of care for any future pregnancy. We also identified three trials that compared midwife/general practitioner-managed care vs. obstetrician/gynaecologist-led shared care. The results were indicative of similar clinical efficacy of the two groups. However, women's response regarding the continuity of care favoured midwife-led care. From the health economics perspective, there is evidence of cost reduction if antenatal care was provided by staff other than the obstetrician/gynaecologist. The available data demonstrate no significant differences in selected perinatal outcomes for low-risk women receiving care according to a reduced frequency (approximately two visits fewer) of prenatal visits vs. those following the existing practice. However, there are differences in satisfaction with the prenatal care provider and the prenatal care system. There is evidence that a midwife's clinic for provision of antenatal care for low-risk pregnancies is feasible and therapy reduction in costs achievable.

Appointments and Schedules↗
PubMed2003

Clinical trials in orthodontics II: assessment of the quality of reporting of clinical trials published in three orthodontic journals between 1989 and 1998.

AIMS: To test the hypothesis that the quality of reporting of orthodontic clinical trials is insufficient to allow readers to assess the validity of the trial. DESIGN: A retrospective observational study. SETTING: The American Journal of Orthodontics and Dentofacial Orthopedics (AJODO), the British Journal of Orthodontics (BJO) and European Journal of Orthodontics (EJO). DATA SOURCE: Clinical trials published between 1989 and 1998. METHOD: A hand search was performed to identify all clinical trials. The concealment of allocation, whether the trial was randomized, double blind, and whether there was a description of withdrawals and dropouts was recorded. RESULTS: One hundred and fifty-five trial reports were identified of which 4 (2.6%) were adequately concealed, 85 (54.8%) were described as being randomized, 10 (6.5%) as double-blind, and 44 (28.4%) gave a description of withdrawals and drop-outs from the trial. The type of randomization was considered appropriate in 78 (50.3%) reports and in 57 (36.8%) reports the level of blinding was considered appropriate. When assessed for the risk of bias in the reported trials,(1) one trial (0.6%) had a low risk of bias, 17 (11%) a moderate risk, and 137 (88.4%) a high risk. CONCLUSIONS: In general the quality of reporting orthodontic clinical trials was insufficient to allow readers to assess the validity of the trials. Reporting of clinical trials could be improved by orthodontic journals adopting the CONSORT statement(2,)(3) to ensure that all relevant information is provided.

Chi-Square Distribution↗
PubMed2002

The transitive fallacy for randomized trials: if A bests B and B bests C in separate trials, is A better than C?

BACKGROUND: If intervention A bests B in one randomized trial, and B bests C in another randomized trial, can one conclude that A is better than C? The problem was motivated by the planning of a randomized trial, where A is spiral-CT screening, B is x-ray screening, and C is no screening. On its surface, this would appear to be a straightforward application of the transitive principle of logic. METHODS: We extended the graphical approach for omitted binary variables that was originally developed to illustrate Simpson's paradox, applying it to hypothetical, but plausible scenarios involving lung cancer screening, treatment for gastric cancer, and antibiotic therapy for clinical pneumonia. RESULTS: Graphical illustrations of the three examples show different ways the transitive fallacy for randomized trials can arise due to changes in an unobserved or unadjusted binary variable. In the most dramatic scenario, B bests C in the first trial, A bests B in the second trial, but C bests A at the time of the second trial. CONCLUSION: Even with large sample sizes, combining results from a previous randomized trial of B versus C with results from a new randomized trial of A versus B will not guarantee correct inference about A versus C. A three-arm trial of A, B, and C would protect against this problem and should be considered when the sequential trials are performed in the context of changing secular trends in important omitted variables such as therapy in cancer screening trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Who wants to join preventive trials?--Experience from the Estonian Postmenopausal Hormone Therapy Trial [ISRCTN35338757].

BACKGROUND: The interest of patients in participating in randomized clinical trials involving treatments has been widely studied, but there has been much less research on interest in preventive trials. The objective of this study was to find out how many women would be interested in a trial involving postmenopausal hormone therapy (PHT) and how the women's background characteristics and opinions correlated to their interest. METHODS: The data come from recruitment questionnaires (n = 2000) sent to women in Estonia in 1998. A random sample of women aged 45 to 64 was drawn from the Population Registry. The trial is a two-group randomized trial comparing estrogen-progestogen therapy with placebo or no drugs. A brief description of the study was attached to the questionnaires. Women were not told at this stage of the recruitment which group they would be assigned to, however, they were told of the chance to receive either hormone, placebo or no treatment. RESULTS: After two reminders, 1312 women (66%) responded. Eleven percent of the women approached (17% of the respondents) were interested in joining the trial, and 8% wanted more information before deciding. When the 225 women who stated clearly that they were interested in joining and the 553 women who said they were not interested were compared, it was found that interested women were younger and, adjusting for age, that more had given birth; in other respects, the sociodemographic characteristics and health habits of the interested women were similar to those of the non-interested women. The interested women had made more use of more health services, calcium preparations and PHT, they were more often overweight, and more had chronic diseases and reported symptoms. Interested women's opinions on the menopause were more negative, and they favoured PHT more than the non-interested women. CONCLUSION: Unlike the situation described in previous reports on preventive trials, in this case Estonian women interested in participating in a PHT trial were not healthier than other women. This suggests that trials involving PHT are more similar to treatment trials than to preventive trials. In a randomized controlled trial, more information should be obtained from those women who decline to participate.

Age Factors↗
PubMed2006

Increasing recruitment to randomised trials: a review of randomised controlled trials.

BACKGROUND: Poor recruitment to randomised controlled trials (RCTs) is a widespread and important problem. With poor recruitment being such an important issue with respect to the conduct of randomised trials, a systematic review of controlled trials on recruitment methods was undertaken in order to identify strategies that are effective. METHODS: We searched the register of trials in Cochrane library from 1996 to end of 2004. We also searched Web of Science for 2004. Additional trials were identified from personal knowledge. Included studies had to use random allocation and participants had to be allocated to different methods of recruitment to a 'real' randomised trial. Trials that randomised participants to 'mock' trials and trials of recruitment to non-randomised studies (e.g., case control studies) were excluded. Information on the study design, intervention and control, and number of patients recruited was extracted by the 2 authors. RESULTS: We identified 14 papers describing 20 different interventions. Effective interventions included: telephone reminders; questionnaire inclusion; monetary incentives; using an 'open' rather than placebo design; and making trial materials culturally sensitive. CONCLUSION: Few trials have been undertaken to test interventions to improve trial recruitment. There is an urgent need for more RCTs of recruitment strategies.

Culture↗
PubMed2006

A substudy protocol of the hypertension in the Very Elderly Trial assessing cognitive decline and dementia incidence (HYVET-COG) : An ongoing randomised, double-blind, placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Randomised, controlled trials and population studies have suggested a link between hypertension and the development of dementia (vascular dementia and Alzheimer's disease) although the results are not conclusive. The very elderly are at highest risk for both hypertension and dementia but have been underrepresented in studies to date. The Hypertension in the Very Elderly Trial (HYVET), an international, randomised, double-blind, placebo-controlled trial of antihypertensive medication for those > or =80 years of age, is currently underway. The protocol for the assessment of cognitive decline and detection of incident dementia cases is described in this article. The objective of this protocol is to determine whether treatment of hypertension in this very elderly group affects the incidence of dementia and decline in cognitive function during the period of the HYVET trial. METHODS: Cognitive function in all HYVET trial participants is assessed at baseline and annually thereafter using the Mini-Mental State Examination (MMSE). An MMSE score that decreases more than three points per year or decreases to <24 prompts further investigation for possible incident dementia. This includes use of the Diagnostic and Statistical Manual-IV criteria, the modified Hachinski scale and CT scanning. In cases where a CT scan cannot be obtained the full Hachinski scale is used. Additional information is provided when available from the clock drawing test and Geriatric Depression Scale. Data are also gathered from all trial participants with regard to education, blood pressure, alcohol use, co-morbidities and concomitant treatments. At the end of the trial, changes in cognitive function and incident dementia cases will be compared in those receiving active treatment (indapamide slow-release +/- perindopril) and those receiving matching placebo. RESULTS: The protocol has been applied successfully and the data collection phase is underway. DISCUSSION: Previous population studies have been unable to study antihypertensive use in a controlled manner and randomised, controlled trials suggest a positive or mixed picture regarding an association between use of antihypertensive therapy and reduction in incident cognitive decline and/or dementia. No such trial has yet been performed exclusively in subjects > or =80 years of age with hypertension. The HYVET trial is placebo controlled and while investigating the cardiovascular effect of treatment also assesses cognitive function and quality of life in both the placebo and actively treated arms of the trial. The HYVET cognitive substudy trial (HYVET-COG) design has been successfully applied and the instruments chosen appear to be appropriate, valid and pragmatic. CONCLUSION: HYVET-COG provides the first opportunity to examine the effect of antihypertensive treatment on incident dementia in a high-risk very elderly population.

Aged, 80 and over↗
PubMed2006

Improving the quality of randomized controlled trials in Chinese herbal medicine, part I: clinical trial design and methodology.

OBJECTIVE: To discuss the quality of randomized controlled trials (RCTs) in Chinese herbal medicine (CHM) with respect to design and methodology, and provide suggestions for further improvement in future clinical trials. METHODS: A search of the Cochrane Library was conducted to identify RCTs of CHM on line in July 2005. Quality of the RCTs was assessed using a 11-item checklist modified from the revised CONSORT statement, with 2 items specific to CHM (i.e. herb preparation form and quality control of herbs). RESULTS: The search yielded 167 RCTs that were selected for assessment. All trials included statements about the interventions, objectives, primary outcome design, statistical methods, and herb preparation form. Although 163 (97.6%) trials reported inclusion criteria, exclusion criteria were only reported in 26 (15.6%) trials. Fewer than 10% of trials clearly stated the random allocation sequence generation methods, and only 2.4% mentioned allocation concealment. The vast majority (86.8%) of trials were open-label, while only 13.2% used blinding. Almost half (45.5%) administered the CHM intervention as a tea or decoction. Only one trial (0.6%) reported a sample size calculation, and a single trial (0.6%) discussed quality control of the CHM intervention. CONCLUSION: The overall methodologic quality of RCTs in CHM was poor. It is essential to improve the design of future RCTs in this clinical area. RECOMMENDATIONS: (1) Investigator conducting RCTs should have formal training about clinical trial design; (2) A flow chart is recommended to ensure that all essential steps of clinical trial design are included. (3) Conducting pilot studies prior to RCTs may help improve their design; (4) Registration of clinical trials and publishing their protocols prior to enrollment may reduce publication bias and solicit peer reviews of the proposed design; (5) Collaboration between CHM investigators and traditional medicine academic research centers interested in integrative medicine may lead to quality improvement of RCTs of CHM.

Humans↗