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PubMedDate not supplied

A rational regulatory approach for positron emission tomography imaging probes: from "first in man" to NDA approval and reimbursement.

We propose a new regulatory approach for positron emission tomography (PET) molecular imaging probes, essential tools in today's medicine. Even though the focus of this paper is on positron-emitting labeled probes, it is also justified to extend this proposed regulatory approach to other diagnostic nuclear medicine radiopharmaceuticals. Key aspects of this proposal include: (1) PET molecular imaging probes would be placed in a "no significant risk" category, similar to that category for devices in current Food and Drug Administration (FDA) regulations, based on overwhelming scientific evidence that demonstrates their faultless safety profile; (2) the FDA-sanctioned Radioactive Drug Research Committee (RDRC) will oversee all diagnostic research with these probes. The newly defined RDRC should approve "first in man" use; supervise a broader spectrum of diagnostic research protocols, including those looking to demonstrate initial efficacy, as well as multicenter clinical trials and the use of molecular imaging probes as a screening tool in drug discovery. The current investigational new drug (IND) mechanism is thus eliminated for these diagnostic probes; (3) when a molecular imaging probe has demonstrated diagnostic efficacy, FDA approval (i.e., NDA) will be sought. The review will be done by a newly constituted Radioactive Drug Advisory Committee (RDAC) composed of experts chosen by the professional societies, who would provide a binding assessment of the adequacy of the safety and efficacy data. When the RDAC recommends its diagnostic use on scientific and medical grounds, the molecular imaging probe becomes FDA approved. After a molecular imaging probe is approved for a diagnostic indication, the existing mechanism to seek reimbursement will be utilized; and (4) the FDA would retain its direct oversight function for traditional manufacturers engaged in commercial distribution of the approved diagnostic molecular imaging probes (i.e., under NDA) to monitor compliance with existing US Pharmacopeia (USP) requirements. With abbreviated and more appropriate regulations, new PET molecular imaging probes for diagnostic use would be then rapidly incorporated into the mainstream diagnostic medicine. Equally importantly, this approach would facilitate the use of molecular imaging in drug discovery and development, which would substantially reduce the costs and time required to bring new therapeutic drugs to market.

Animals↗

PubMed2005

Exchange of beta-blockers in heart failure patients. Experiences from the poststudy phase of COMET (the Carvedilol or Metoprolol European Trial).

BACKGROUND: The Carvedilol or Metoprolol European Trial (COMET) reported a significant survival benefit for carvedilol, a beta1-, beta2- and alpha1-blocker, vs. metoprolol tartrate, a beta1-selective blocker, in patients with mild-to-severe chronic heart failure (CHF). Patients on treatment with metoprolol might benefit from switching to carvedilol. AIM: To investigate the safety and tolerability of switching beta-blockers in CHF. METHODS: At the end of COMET, the Steering Committee recommended that study medication was stopped without unblinding, and patients were commenced on open-label beta-blockade at a dose equivalent to half the dose of blinded therapy, with subsequent titration to target or maximum tolerated dose. Patients were followed for 30 days. RESULTS: 1321 out of 1440 patients were transitioned to open-label treatment (76.8% to carvedilol). Serious adverse and CHF-related events were respectively 9.4% and 4.7% in those switching from carvedilol to metoprolol and 3.1% and 1.5% in patients switching from metoprolol to carvedilol. Patients who switched from carvedilol to metoprolol showed the highest mortality or hospitalisation rate (12.3%) in comparison with those who switched from metoprolol to carvedilol (3.1%, p<0.001) or who stayed on the same drug (carvedilol: 2.5%, p<0.001; metoprolol: 4.2%, p=0.04). Reducing the initial dose of the second beta-blocker maximised the safety of this strategy. Event rate was higher in patients with more severe heart failure and in those withdrawing from beta-blockade. CONCLUSION: Our data show that switching beta-blockers is a practical, safe and well-tolerated strategy to optimise treatment of CHF. Patients who switched to carvedilol showed the lowest rate of adverse events. A closer clinical monitoring is recommended during transition in high-risk patients.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

The CHART trials: Bayesian design and monitoring in practice. CHART Steering Committee.

In this paper we describe the design and monitoring of two large randomized trials being conducted through the British Medical Research Council (MRC) Cancer Trials Office. In particular we discuss the issues involved in the design of the trials, specifying the null and alternative hypotheses and how the design has influenced the monitoring procedure used. From these two examples, and some other MRC experiences, we suggest some basic considerations which could be applied to many MRC and other trials.

Bayes Theorem↗

PubMedDate not supplied

[The SMILE study: the rationale, design, organization and definition of the objectives. Survival of Myocardial Infarction Long-term Evaluation].

The rationale, design, organization and outcome definitions of the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study are described in detail. The recruitment of a total of 1500 patients (750 per treatment group) has been planned for this multicenter, double-blind, randomized, placebo-controlled study to investigate the effects of oral treatment with zofenopril calcium (7.5-30 mg twice a day) on the combined short-term total mortality and occurrence of severe refractory congestive heart failure in patients with acute anterior myocardial infarction (AMI). Secondary end-points of the study include recurrent myocardial infarction, angina, progression of congestive heart failure as well as long-term mortality. Patients are initially treated in hospital within 24 hours from the onset of symptoms of AMI and their active follow-up continued for 6 weeks. In addition, the patients will be passively followed for a total of 12 months from the index AMI to assess their vital status and the occurrence of congestive heart failure. The study data will be analyzed on an intention to treat basis. An international independent Policy and Safety Monitoring Board is acting as the overall supervisory body and is responsible for the ethical conduction of the trial. A Scientific Committee is responsible for the scientific aspects of the trial and for the regular review of the progress of the study. We assume that the rationale and design of the SMILE trial will provide reliable information on the ability of ACE-inhibitors to reduce the occurrence of major cardiovascular events in patients with acute myocardial infarction.

Administration, Oral↗

PubMed1998

Are safety committees really safe?

In an increasing number of recent major clinical trials, independent safety committees or safety monitors have been involved. Their role and function is not yet defined and continues to evolve. The aim of this paper is to discuss the role and tasks of safety committees as a result of our collective experience as members of three safety committees of studies evaluating antithrombotic prophylaxis against postoperative deep vein thrombosis. We believe that the type of pharmacological intervention used is of less importance than the general experiences gained, which can be extrapolated to other studies and should stimulate a more general debate.

Clinical Trials as Topic↗

PubMed2002

Azithromycin for acute bronchitis: a randomised, double-blind, controlled trial.

BACKGROUND: The value of azithromycin for treatment of acute bronchitis is unknown, even though this drug is commonly prescribed. We have investigated this question in a randomised, double-blind, controlled trial. METHODS: Adults diagnosed with acute bronchitis, without evidence of underlying lung disease, were randomly assigned azithromycin (n=112) or vitamin C (n=108) for 5 days (total dose for each 1.5 g). All individuals were also given liquid dextromethorphan and albuterol inhaler with a spacer. The primary outcome was improvement in health-related quality of life at 7 days; an important difference was defined as 0.5 or greater. Analysis was by intention to treat. FINDINGS: The study was stopped by the data-monitoring and safety committee when 220 patients had been recruited. On day 7, the adjusted difference in health-related quality of life was small and not significant (difference 0.03 [95% CI -0.20 to 0.26], p=0.8). 86 (89%) of 97 patients in the azithromycin group and 82 (89%) of 92 in the vitamin C group had returned to their usual activities by day 7 (difference 0.5% [-10% to 9%], p>0.9). There were no differences in the frequency of adverse effects; three patients in the vitamin C group discontinued the study medicine because of perceived adverse effects, compared with none in the azithromycin group. Most patients (81%) reported benefit from the albuterol inhaler. INTERPRETATION: Azithromycin is no better than low-dose vitamin C for acute bronchitis. Further studies are needed to identify the best treatment for this disorder.

Acute Disease↗

PubMed1982

Organization and management of recruitment.

Recruitment of participants to a multicenter study is complex. Considerable attention must be given to management and organization. In either a multi- or single-center study, a data-based management system is a sensitive and responsive means of monitoring participant flow. This system gives rapid feedback, encourages ongoing evaluation of strategies and permits centers to mark their own progress. In a multicenter study, an effective organizational framework for recruitment should include the central functions of administration, data management, monitoring progress and providing consultation concerning recruitment strategies, and public relations activities; and the recruitment team at each center, composed of counterparts of these central functions at the local level and the screening staff. The central staff is responsible for developing strategies, monitoring recruitment performance and providing consultation at the collaborative level. Staff from the central functional areas and local center recruitment teams can communicate effectively by using a central coordinating committee composed of representatives of each major component. This system is effective and applicable to most multicenter clinical research studies. In a single-center study, coordination may be provided through the recruitment team with equivalent representation to that described for this component in multicenter studies.

Clinical Trials as Topic↗

PubMed2002

A national survey of provisions in clinical-trial agreements between medical schools and industry sponsors.

BACKGROUND: Concerned about threats to the integrity of clinical trials in a research environment increasingly controlled by private interests, the International Committee of Medical Journal Editors (ICMJE) has issued revised guidelines for investigators' participation in the study design, access to data, and control over publication. It is unclear whether research conducted at academic institutions adheres to these new standards. METHODS: From November 2001 through January 2002, we interviewed officials at U.S. medical schools about provisions in their institutions' agreements with industry sponsors of multicenter clinical trials. A subgroup of the respondents were also asked about coordinating-center agreements for such trials. RESULTS: Of the 122 medical schools that are members of the Association of American Medical Colleges, 108 participated in the survey. The median number of site-level agreements executed per institution in the previous year was 103 (interquartile range, 50 to 210). Scores for compliance with a wide range of provisions--from ensuring that authors of reports on multicenter trials have access to all trial data (1 percent [interquartile range, 0 to 21]) to addressing the plan for data collection and monitoring (10 percent [interquartile range, 1 to 50])--demonstrated limited adherence to the standards embodied in the new ICMJE guidelines. Scores for coordinating-center agreements were somewhat higher for most survey items. CONCLUSIONS: Academic institutions routinely engage in industry-sponsored research that fails to adhere to ICMJE guidelines regarding trial design, access to data, and publication rights. Our findings suggest that a reevaluation of the process of contracting for clinical research is urgently needed.

Clinical Trials as Topic↗

PubMed2003

ABI 007.

ABI 007 is an albumin-stabilised nanoparticle formulation of paclitaxel designed to overcome insolubility problems encountered with paclitaxel. This then eliminates the need for toxic solvents like cremophor, which limits the dose of paclitaxel that can be administered and hence effect overall drug efficacy. ABI 007 is being developed for the treatment of a variety of tumour types by American Pharmaceutical Partners. In addition to the standard infusion formulation of ABI 007, oral and pulmonary delivery formulations are also being investigated. American Pharmaceutical Partners, a subsidiary of American BioScience, secured exclusive North American marketing and manufacturing rights to ABI 007 from American BioScience in November 2001. American BioScience completed a phase III study in the US in metastatic breast cancer patients in early 2003. An indication for which ABI 007 was granted fast track status in January 2003. The phase III study directly compared the efficacy of ABI 007 260 mg/m(2) with paclitaxel 175 mg/m(2). Both agents were administered every 3 weeks. ABI 007 was administered as a 30-minute infusion without steroid pretreatment. Paclitaxel-treated patients received steroid pretreatment and the drug was administered over 3 hours. In October 2002, a Data Monitoring Committee concluded that a sample size adjustment of the phase III trial would not be required and that the study can be continued to completion. Enrolment was completed in December 2002 with 460 first- and second-line metastatic breast cancer patients enrolled. The results were expected to be unblinded in mid-2003. A phase II trial of ABI 007 is also underway in metastatic breast cancer patients who have failed taxane therapy. The trial is evaluating a weekly rather than 3-weekly regimen of ABI 007. Earlier, in May 2003, American Pharmaceutical Partners reported that ABI 007 is also being evaluated for the treatment of non-small cell lung cancer, ovarian cancer, melanoma and cervical cancers. However, the phase of development for these indications remains unclear.

Albumin-Bound Paclitaxel↗

PubMed2002

Lifeline Registry of Endovascular Aneurysm Repair: Registry data report.

PURPOSE: The goal of the Lifeline Endovascular Registry is to provide a minimal, yet comprehensive, data set of patient follow-up that can evaluate the long-term safety of endovascular grafts used in abdominal aortic aneurysm repair. METHODS: Follow-up data have been collected on 1757 patients for this first report, including 1646 endovascular graft recipients and 111 surgical patients receiving treatment for abdominal aortic aneurysm. RESULTS: Logistic regression of 1-year survival indicates that the factors most likely to decrease 1-year survival for the surgical group are renal failure and larger aneurysm size. For the endovascular graft recipients, the presence of renal failure, chronic obstructive pulmonary disease, congestive heart failure, larger aneurysm size, and increased age demonstrates a decrease in 1-year survival. Approximately 80% (1309) of the endovascular recipients have been followed for 1 year. Of these 1309 patients, 17% (222) have incurred an endoleak, and enlargement of the aneurysm has occurred in 4.6% (60). There was a total of 80 (4.9%) endovascular graft recipients converted to surgery. The most prevalent factors causing conversion to surgery were an increase in aneurysm diameter, aneurysm rupture, and the presence of a proximal endoleak. CONCLUSIONS: Although the data collected by the Registry thus far are limited, we anticipate rapid expansion of the Registry to include data from other manufacturers and investigators. Nevertheless, early data analysis does demonstrate the importance of surveillance of endovascular graft recipients. Through the collection and analysis of Registry data, adverse events continue to be captured, enabling the monitoring of long-term safety of endovascular grafts and the evaluation of graft performance. Data on comorbidities and postoperative factors, collected and evaluated for their effect on survival of the graft recipients, also provide information on optimal patient selection and management. We expect that the next report will support and expand on these findings, providing continuing evidence of the value of a national endovascular registry.

Aged↗

PubMed2004

PENTA guidelines for the use of antiretroviral therapy, 2004.

There have been few major advances in paediatric HIV management over the last 2 years. Decisions about starting antiretroviral therapy can now be based on a recent large meta-analysis of the predictive value of CD4 and HIV RNA viral load (VL) in nearly 4000 untreated children, which is discussed in these updated guidelines. Risk estimates for progression to AIDS and death using surrogate markers can now be broken down by age, allowing more accurate discussion with families. In addition, there is increasing recognition of the problems of long-term adherence, drug resistance and cumulative toxicity in adults and children. The controversy over whether to treat asymptomatic infants continues. For older children more data on the efficacy of ritonavir boosted protease inhibitor (PI) regimens suggests that these may be the PI option of first choice. There is still no adult or paediatric trial evidence on which to base decisions about whether to start with PI- or non-nucleoside reverse transcriptase inhibitor (NNRTI)- based regimens, but the PENPACT 1 trial, which is addressing this question, is ongoing. There are increasing moves to provide simpler antiretroviral therapy (ART) regimens, including once daily dosing, but these lag behind adult regimens because of the paucity of pharmacokinetic data. Resistance assays should now be performed in all HIV-infected infants exposed to ART in pregnancy. Therapeutic drug monitoring may be very important in children because of high between- and within-child variability in drug absorption and metabolism. A trial to evaluate this should start shortly in Europe (PENTA 14 trial). The value of resistance tests for choice of second-line and subsequent choices of ART regimens remain unproven (the PERA trial will report late in 2004), but resistance assays are increasingly being used. The issue of when to switch therapy also remains unanswered and is being addressed within the PENPACT 1 trial. Regular formal assessment of adherence is now the standard of care, and routine monitoring in the clinic for lipodystrophy syndrome (LDS) and other ART toxicities is increasingly important. These guidelines will be updated again in 2006.

Anti-HIV Agents↗

PubMed2005

Standards of evidence: criteria for efficacy, effectiveness and dissemination.

Ever increasing demands for accountability, together with the proliferation of lists of evidence-based prevention programs and policies, led the Society for Prevention Research to charge a committee with establishing standards for identifying effective prevention programs and policies. Recognizing that interventions that are effective and ready for dissemination are a subset of effective programs and policies, and that effective programs and policies are a subset of efficacious interventions, SPR's Standards Committee developed overlapping sets of standards. We designed these Standards to assist practitioners, policy makers, and administrators to determine which interventions are efficacious, which are effective, and which are ready for dissemination. Under these Standards, an efficacious intervention will have been tested in at least two rigorous trials that (1) involved defined samples from defined populations, (2) used psychometrically sound measures and data collection procedures; (3) analyzed their data with rigorous statistical approaches; (4) showed consistent positive effects (without serious iatrogenic effects); and (5) reported at least one significant long-term follow-up. An effective intervention under these Standards will not only meet all standards for efficacious interventions, but also will have (1) manuals, appropriate training, and technical support available to allow third parties to adopt and implement the intervention; (2) been evaluated under real-world conditions in studies that included sound measurement of the level of implementation and engagement of the target audience (in both the intervention and control conditions); (3) indicated the practical importance of intervention outcome effects; and (4) clearly demonstrated to whom intervention findings can be generalized. An intervention recognized as ready for broad dissemination under these Standards will not only meet all standards for efficacious and effective interventions, but will also provide (1) evidence of the ability to "go to scale"; (2) clear cost information; and (3) monitoring and evaluation tools so that adopting agencies can monitor or evaluate how well the intervention works in their settings. Finally, the Standards Committee identified possible standards desirable for current and future areas of prevention science as the field develops. If successful, these Standards will inform efforts in the field to find prevention programs and policies that are of proven efficacy, effectiveness, or readiness for adoption and will guide prevention scientists as they seek to discover, research, and bring to the field new prevention programs and policies.

Clinical Trials as Topic↗

PubMed2006

A phase I/II trial of a WT1 (Wilms' tumor gene) peptide vaccine in patients with solid malignancy: safety assessment based on the phase I data.

OBJECTIVE: We conducted a phase I study to investigate the safety of a weekly WT1 tumor vaccine therapy in patients with solid tumors that had been refractory to all other anti-cancer therapies. METHODS: Skin-test-negative patients were intradermally injected weekly for 12 weeks with 3.0 mg of an HLA-A*2402-restricted modified 9-mer WT1 peptide emulsified in Montanide ISA51 adjuvant. We estimated the Bayesian posterior probability of the occurrence of grade 3 or 4 toxicity when receiving the weekly WT1 vaccination. This analysis provided the basis for making a decision to terminate the phase I study and switch to phase II. Moreover, we performed an exploratory assessment of the anti-tumor effects of WT1 treatment. RESULTS: Ten patients received 114 vaccinations with WT1 on a weekly schedule. No grade 3 or 4 toxicities were observed. Based on the Bayesian approach, it was highly likely that the probability of grade 3 or 4 toxicity was below 20% (the posterior probability = 0.914). Fifteen grade 2 and two grade 1 toxicities were observed; all of these incidents, however, were determined by the Independent Data and Safety Monitoring Committee to be unrelated to the WT1 treatment. One patient exhibited a partial response; five additional patients had stable disease while receiving weekly WT1 treatment. CONCLUSION: This paper confirms that the potential toxicities of the treatment schedule of weekly WT1 vaccination are acceptable and suggested a potential anti-tumor effect. Consequently, we validated the decision to continue to the phase II trial.

Adolescent↗

PubMed1999

A phase 3 randomized study of radiotherapy plus procarbazine, CCNU, and vincristine (PCV) with or without BUdR for the treatment of anaplastic astrocytoma: a preliminary report of RTOG 9404.

PURPOSE: This study was an open label, randomized Phase 3 trial in newly diagnosed patients with anaplastic glioma comparing radiotherapy plus adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy with or without bromodeoxyuridine (BUdR) given as a 96-hour infusion each week of radiotherapy. METHODS AND MATERIALS: Only patients 18 years or older with newly diagnosed anaplastic glioma were eligible; central pathology review was accomplished, but was not mandated prior to registration. The study had initially opened as a Northern California Oncology Group (NCOG) trial in 1991, becoming an Intergroup RTOG, SWOG, and NCCTG study in July 1994. Total accrual of 293 patients was planned as the sample size, using survival and time to tumor progression as the primary endpoints. The experiment arm (RT/BUdR plus PCV) was to be compared to the control arm (RT plus PCV) using an alpha = 0.05, one-tailed, with a power of 85% for detecting an increase in median survival from 160 to 240 weeks, assuming a 3-year follow-up after completion of enrollment. RESULTS: As of July 1996, 281 patients had been randomized; 53 (20%) were ineligible, primarily based upon central pathology review, and another 39 cases were canceled. In total, 30% of cases were excluded from analysis. The treatment arms were well balanced despite this rate of exclusion. The RTOG Data Monitoring Committee recommended suspension of enrollment in July 1996 based upon a stochastic curtailment analysis which strongly suggested that the addition of BUdR would not be associated with increased survival. In February 1997, the study was closed prior to full enrollment. At that time, the 1-year survival estimates were 82% versus 68% for RT plus PCV and RT/BUdR plus PCV respectively (one-sided, p = 0.96). The conditional power analysis indicated that even with an additional 12 months of additional accrual and follow-up the probability of detecting the prespecified difference was less than 0.01%. The differences in the two arms seem to be due to early deaths in the BUdR arm, not related to toxicity of the treatment. CONCLUSIONS: Despite encouraging Phase 2 results with BUdR, it is unlikely that a survival benefit will be seen. A final study analysis will not be done for at least 3 more years.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1988

The European Cooperative Study Group trial of intravenous recombinant tissue-type plasminogen activator (rt-PA) and conservative therapy versus rt-PA and immediate coronary angioplasty.

This report describes the organization and results of the European Cooperative Study Group trial of intravenous recombinant tissue-type plasminogen activator (rt-PA) plus conservative therapy versus intravenous rt-PA plus immediate intervention (coronary angiography with a view to angioplasty) in patients with acute myocardial infarction. One hundred eighty-four patients were allocated to noninvasive treatment and 183 to an invasive/intervention policy. Immediate angioplasty was attempted in 168 patients (92%) of the latter group. The trial was terminated after a data review by the ethical monitoring committee showed no benefit in the "invasive" group in terms of enzymatic infarct size or left ventricular function, and a trend (although not statistically significant) toward increased mortality in the intervention group. Analysis of coronary patency and residual stenosis at the time of discharge showed no difference in patency rate, but less residual stenosis in the intervention group. The study differed from the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) and the Thrombolysis in Myocardial Infarction Phase-IIB (TIMI-IIB) trials in that the philosophy of intervention to produce the earliest and most complete reperfusion resulted in a high incidence of angioplasty procedures in vessels not yet reperfused. The reasons for the failure of this philosophy to show benefit are uncertain, but may include an increased risk of reocclusion after angioplasty or reperfusion damage, or both.

Angioplasty, Balloon↗

PubMed1990

[Preliminary study and clinical evaluation method of ioversol in angiocardiography--establishment of safety evaluation parameters and reliability of radiographic quality evaluation].

A multi-center clinical study of a new nonionic iodinated contrast medium (ioversol) was performed in 26 patients undergoing left ventriculography (LVG) and coronary angiography (CAG) at four centers. The aims of this study were to try to establish a clinical evaluation method on contrast media in angiocardiography and to determine radiographic efficacy and safety of ioversol. The reliability of the method evaluating the radiographic quality of the contrast medium was also examined with statistical analysis. Excellent radiographic efficacy was observed with ioversol and morphological diagnosis was possible in all cases. The electrocardiograms (ST-segment deflection, T-wave amplitude, QT interval, corrected QT interval, arrhythmia and heart rate) and the hemodynamic parameters (left ventricular systolic and end diastolic pressures, left ventricular dp/dt max, aortic systolic and diastolic pressures) indicated no clinically significant changes. This study suggested that the monitoring of the ECGs and hemodynamic parameters for up to three minutes after injection of the contrast medium is sufficient for the evaluation in LVG and CAG, and that the monitoring in CAG during the first injection into each left and right coronary artery is also sufficient for the purpose. Heat sensation during injection was mild. A patient had a symptom of nausea after ioversol administration, but it was mild and transient and resolved spontaneously. There were no abnormal clinical laboratory data related to ioversol. The reliability of the radiographic quality evaluated by the individual clinical investigators was considered to be high and adaptable. However, the evaluation in the blinded cinefilms by the committee members involving all investigators would be more preferable for the higher objectivity. The study results suggest that ioversol is considered to be the efficacious and safe contrast medium for the cardiovascular angiography.

Adolescent↗

PubMed2005

Guidelines for vaginal birth after previous Caesarean birth.

OBJECTIVE: To provide evidence-based guidelines for the provision of a trial of labour (TOL) after Caesarean section. OUTCOME: Fetal and maternal morbidity and mortality associated with vaginal birth after Caesarean (VBAC) and repeat Caesarean section. EVIDENCE: MEDLINE database was searched for articles published from January 1, 1995, to February 28, 2004, using the key words "vaginal birth after Caesarean (Cesarean) section". The quality of evidence is described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam. RECOMMENDATIONS: 1. Provided there are no contraindications, a woman with 1 previous transverse low-segment Caesarean section should be offered a trial of labour (TOL) with appropriate discussion of perinatal risks and benefits. The process of informed consent with appropriate documentation should be an important part of the birth plan in a woman with a previous Caesarean section (II-2B). 2. The intention of a woman undergoing a TOL after Caesarean section should be clearly stated, and documentation of the previous uterine scar should be clearly marked on the prenatal record (II-2B). 3. For a safe labour after Caesarean section, a woman should deliver in a hospital where a timely Caesarean section is possible. The woman and her health care provider must be aware of the hospital resources and the availability of obstetric, anesthetic, pediatric, and operating-room staff (II-2A). 4. Each hospital should have a written policy in place regarding the notification and (or) consultation for the physicians responsible for a possible timely Caesarean section (III-B). 5. In the case of a TOL after Caesarean, an approximate time frame of 30 minutes should be considered adequate in the set-up of an urgent laparotomy (III-C). 6. Continuous electronic monitoring of women attempting a TOL after Caesarean section is recommended (II-2A). 7. Suspected uterine rupture requires urgent attention and expedited laparotomy to attempt to decrease maternal and perinatal morbidity and mortality (II-2A). 8. Oxytocin augmentation is not contraindicated in women undergoing a TOL after Caesarean section (11-2A). 9. Medical induction of labour with oxytocin may be associated with an increased risk of uterine rupture and should be used carefully after appropriate counselling (II-2B). 10. Medical induction of labour with prostaglandin E2 (dinoprostone) is associated with an increased risk of uterine rupture and should not be used except in rare circumstances and after appropriate counselling (II-2B). 11. Prostaglandin E1 (misoprostol) is associated with a high risk of uterine rupture and should not be used as part of a TOL after Caesarean section (II-2A). 12. A foley catheter may be safely used to ripen the cervix in a woman planning a TOL after Caesarean section (II-2A). 13. The available data suggest that a trial of labour in women with more than 1 previous Caesarean section is likely to be successful but is associated with a higher risk of uterine rupture (II-2B). 14. Multiple gestation is not a contraindication to TOL after Caesarean section (II-2B). 15. Diabetes mellitus is not a contraindication to TOL after Caesarean section (II-2B). 16. Suspected fetal macrosomia is not a contraindication to TOL after Caesarean section (II-2B). 17. Women delivering within 18 to 24 months of a Caesarean section should be counselled about an increased risk of uterine rupture in labour (II-2B). 18. Postdatism is not a contraindication to TOL after Caesarean section (II-2B). 19. Every effort should be made to obtain the previous Caesarean section operative report to determine the type of uterine incision used. In situations where the scar is unknown, information concerning the circumstances of the delivery is helpful in determining the likelihood of a low transverse incision. If the likelihood of a low transverse incision is high, a TOL after Caesarean section can be offered (II-2B). VALIDATION: These guidelines were approved by the Clinical Practice Obstetrics and Executive Committees of the Society of Obstetricians and Gynaecologists of Canada.

Breech Presentation↗

PubMed1993

Data monitoring boards in the pharmaceutical industry.

This paper describes the characteristics and responsibilities of data monitoring boards (DMBs) employed in clinical trials sponsored by pharmaceutical firms. These DMBs are compared with DMBs in clinical trials sponsored by the National Institutes of Health (NIH). All trials discussed are assumed to be phase III pre-market clinical trials. It is seen that DMBs in pharmaceutical industry trials have more limited responsibilities than DMBs in NIH clinical trials. Pharmaceutical industry DMBs are employed to add credibility to trials by certifying critical clinical trial processes such as patient evaluability, interim analyses, evaluation of efficacy endpoints, and safety monitoring. An example of a pharmaceutical industry DMB's charter and operations is presented for a clinical trial for the prevention of stress ulcers. The specific problems encountered when a pharmaceutical industry clinical trial is conducted by NIH under the auspices of an NIH-appointed DMB are discussed. New uses for DMBs in the pharmaceutical industry are introduced and future trends in the industry with respect to DMBs are examined.

Clinical Trials as Topic↗