How the Seven Countries Study contributed to the launch and development of cardiovascular epidemiology in Italy. A historical perspective.

The Italian research group of the Seven Countries Study of Cardiovascular Diseases (SCS), through the independent use of the national cohorts and data, had the lucky opportunity, starting in the early 1960, to launch the Italian research in epidemiology of cardiovascular diseases (CVD). In this way, the Italian Section of that international study became the first investigation with baseline measurements in various cohorts, subsequent re-examinations, systematic search for morbid events, and follow-up for mortality up to 50 years. A large number of scientific aspects has been tackled including estimates of morbidity and mortality rates, the association of risk factors with cardiovascular events and total mortality, the role of risk factor changes, the use of multivariable models, the role of lifestyle behavior, the determinants of all-cause mortality including risk factors rarely measured in other studies, the identification of characteristics of a condition called Heart Disease of Uncertain Etiology (HDUE), the production of predictive tools for practical use and several other issues. All this has been enhanced by the availability of extremely long follow-up data rarely found in other studies. Field work organization, measurement techniques, diagnostic criteria, data handling and computing had the limitations and difficulties typical of those times, the mid of last century, when CVD epidemiology was at its beginning. All this represented anyhow the start of CVD epidemiology research in the country and was the stimulus to the start of other studies and a valuable collaboration with some of them.

Effective childhood cancer treatment: the impact of large scale clinical trials in Germany and Austria.

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.

Cooperative group trials in pediatric oncology: the surgeon's role.

The early history of the pediatric cooperative group trials is reviewed, and the surgeons who played a critical role in their formation are discussed. The vital information provided from the tumor specimens submitted as part of the protocols is presented, as well as how this information advanced our management of infants and children treated on current protocols of the Children's Oncology Group. Finally, a survey of the surgeons currently active in the clinical trials defined the "critical lessons" learned from the sequence of protocols by the cooperative groups which have advanced our surgical treatment of patients today.

What we have learned from the family of multicenter automatic defibrillator implantation trials.

Electrical device therapy began 50 years ago with the external defibrillator, and was followed subsequently with the introduction of implantable cardiac pacemakers, defibrillators, and resynchronization devices to prevent bradycardia, sudden arrhythmic death, and heart failure. During the past 20 years the Multicenter Automatic Defibrillator Implantation Trial (MADIT) research group has carried out a series of trials, including the MADIT-I, MADIT-II, and MADIT-III (MADIT-CRT), that have focused on improving the outcomes for patients with ischemic and nonischemic cardiac disease. The most recent MADIT-CRT trial showed that a cardiac resynchronization therapy device with defibrillator (CRT-D) was effective in reducing the risk of heart failure or death, whichever came first, in cardiac patients who were asymptomatic or minimally symptomatic (New York Heart Association class I or II) with reduced ejection fraction < or =0.30 and wide QRS complex > or =130 ms when compared with an implantable cardiac defibrillator (ICD) device. The family of MADIT ICD and CRT-D trials have provided a firm foundation for improving the clinical management of at-risk cardiac patients as the second decade of the 21(st) century begins.

Double-blind trial of recombinant gamma-interferon versus placebo in the treatment of rheumatoid arthritis. 1989.

One hundred five patients were enrolled in a 12-week, randomized, prospective, double-blind, placebo-controlled trial of recombinant human gamma-interferon (rHu gamma-IFN) for the treatment of rheumatoid arthritis. Fifty-four patients received rHu gamma-IFN and 51 received placebo. Forty-two patients in each group completed the 12-week trial. Some clinical improvement occurred in both groups of patients. Although the improvement with rHu gamma-IFN was greater than that with placebo, the differences were generally not statistically significant.

Critique of Falloon and the Optimal Treatment Project.

The Optimal Treatment Project advocated by Falloon has been demonstrated through the scientific research literature to be efficient and effective treatment strategies for people experiencing severe mental illness. For this reason, there is little critique of this approach. While the potential value of the project is acknowledged, it is important to identify the appropriateness of the model for specific services and to understand comprehensively the resources necessary for successful implementation. The aim of this paper is to review the literature in relation to the Optimal Treatment Project with a view to exploring the complexities associated with the model. It is concluded that the involvement of multiple stakeholders, including consumers of mental health services, should become an essential element of any implementation strategy.

Multicentre trials: a US regulatory perspective.

Multicentre trials are very common in the field of drug development. In recent years, multicentre trials have taken on a multinational and multiregional aspect. We provide a conceptual framework for the use of multicentre trials in the context of drug development, from the perspective of drug regulation in the United States. In this paper, we review some regulatory history, milestones and standards as they relate to multicentre trials. Special attention is given to the similarities and differences in the approaches to multicentre trials in the following documents; Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications, International Conference on Harmonization, Draft Guideline on Statistical Principles for clinical trials and the Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drug and Biologic Products. The paper includes a consideration of some of the issues in the analysis of data from multicentre trials.

Commentary: the 1944 patulin trial: the first properly controlled multicentre trial conducted under the aegis of the British Medical Research Council.

The 1948 report of the British Medical Research Council's randomized trial of streptomycin for pulmonary tuberculosis is widely regarded as marking the beginning of the modern history of controlled clinical trials. Four years earlier, however, a methodologically sophisticated multicentre trial conducted under the aegis of the Medical Research Council was reported, which assessed the effects of the antibiotic patulin on the course of common colds. Philip D'Arcy Hart and Joan Faulkner (later Joan Doll) were the secretary and assistant secretary, respectively, to the committee overseeing the trial, and they clearly recognized the importance of preventing foreknowledge of allocations from those admitting patients to the study. To do this and to 'muddle people up', they and Ruth D'Arcy Hart devised a scheme involving the use of two patulin groups and two placebo groups, allocating patients to one of these four groups using strict rotation. Philip D'Arcy Hart believes that this study has been overshadowed by the celebrated streptomycin trial (for which he was also secretary to the oversight committee) because no beneficial effect of patulin was detected, and because the report of the streptomycin trial referred to the use of random sampling numbers to generate the allocation schedule. This article makes clear why we agree with Philip D'Arcy Hart that the 1944 patulin trial deserves wider recognition as the first well controlled, multicentre clinical trial to have been conducted under the aegis of the British Medical Research Council. This status is reflected in the International Journal of Epidemiology's reproduction of the full text of the trial report in this issue of the journal.

Research design, organization, and sample characteristics of the Maternal PKU Collaborative Study.

OBJECTIVE: The Maternal PKU Collaborative Study (MPKUCS) was initiated in 1984 by the National Institute of Child Health and Human Development (NICHD). The purpose was to assess the efficacy of dietary restriction of phenylalanine in reducing morbidity in offspring of women with hyperphenylalaninemia (HPA). A contract was awarded to Childrens Hospital Los Angeles as the Coordinating Center to provide implementation of the research protocol, data collection, and analysis. METHODS: The Study included four regional contributing centers: Childrens Hospital Los Angeles (Western Region), Boston Children's Hospital (Northeast Region), University of Illinois (Midwest Region), and University of Texas Medical Branch, Galveston (Southeast Region). Within each region, many participating clinics were responsible for obstetric care, treatment, and monitoring protocols. In 1985, Canada joined the MPKUCS, and in 1992, Germany entered. They were selected because they provided dietary supplies and strong professional services. Acquisition began in 1984 and ended in October 1995. The study included 574 pregnancies in women with HPA and 100 control subjects matched on age, race, parity, and weeks of gestation. The sample included women with blood phenylalanine values >240 micromol/L, 66% of whom had classical PKU, 22% had atypical PKU, and 12% had mild HPA. Informed consents were obtained on all participants. The women ranged in age from 15 to 36 years of age, with a mean age at conception of 23 years. Teenage pregnancies accounted for 19%. Seventy-five percent graduated from high school. Offspring included 416 newborns, 317 of whom were evaluated at 4 years of age and 289 at 6 to 7 years. Follow-up involved medical, nutritional, psychosocial, and psychological assessments. CONCLUSION: Women with PKU treated before conception and in control of their blood phenylalanine levels between 120 and 360 micromol/L (2-6 mg) exhibited normal pregnancies and neonatal outcome. Surprisingly, women who achieved control in the recommended range by 8 weeks of pregnancy also had a normal fetal outcome.

Clinical research done by the Scandinavian Prostate Cancer Group during the first 20 years.

In 1981 the Scandinavian Association of Urology initiated the Scandinavian Prostate Cancer Group (SPCG) as one of eight collaborative groups representing different fields of urology. The task of the SPCG was to promote research, education and information concerning prostate cancer. In particular it became a forum for conducting clinical multicenter studies within the Nordic countries. This paper summarizes some aspects of the history of the SPCG and reviews the clinical trials initiated by the group on the occasion of its 20th anniversary.

The cystic fibrosis therapeutics development network (CF TDN): a paradigm of a clinical trials network for genetic and orphan diseases.

Clinical trials have become critical to the advancement of medical science and to the evolution of patient care in medicine. The science of clinical research has advanced from early studies in which treatment was assessed without controls to sophisticated multinational collaborative randomized, double-blind, placebo controlled trials of therapeutic interventions. To facilitate the advancement of clinical research, clinical trials networks have been developed to conduct multicenter studies. This review describes the history of clinical trials, clinical trials networks, and the goals of such networks in the United States. The Cystic Fibrosis Therapeutics Development Network, a network that represents the paradigm for genetic and orphan diseases, is described in detail. This network has been extremely successful in its first 3.5 years of existence conducting 18 different clinical trials in patients with Cystic Fibrosis. Unique aspects of the network include the use of internet applications for study conduct and communication, the development of statistical methodology to enhance the efficiency of clinical trial design, the development of outcome measures specific to Cystic Fibrosis, and the development of infrastructure necessary for expediting protocol development. In the current environment, clinical research faces significant challenges related to ensuring the safe and ethical conduct of clinical research while promoting fast and efficient clinical trials. To succeed and move forward to provide treatments and find cures for diseases, clinical trials networks must continue to evolve. The Cystic Fibrosis Therapeutics Development Network represents a network that has met this challenge and will continue to provide a venue for the safe and efficient conduct of clinical trials in Cystic Fibrosis.