Inclusion of minorities and women in cancer clinical trials, a decade later: Have we improved?

BACKGROUND: Inclusion of diverse groups of participants in cancer clinical trials is an important methodological and clinical issue. The quality of the science and generalizability of results depends on the inclusion of study participants who represent all populations among whom these treatment and prevention approaches will be used. METHODS: We conducted a systematic review using OVID as the primary source of reports included. Based on 304 peer-reviewed publications, diversity in the inclusion and reporting of study participants during a decade of cancer treatment and prevention trials (2001-2010) is summarized. Recommendations are made for improvements in the science and reporting of cancer clinical trials. RESULTS: Of the 277 treatment trials and 27 prevention trials included in this report, more than 80% of participants were white and 59.8% were male. In the recent decade, race and sex are rarely used as selection criteria unless the trial is focused on a sex-specific cancer. CONCLUSIONS: Women and racial/ethnic minorities remain severely underrepresented in cancer clinical trials, thus limiting the generalizability of cancer clinical research.

Toxicity testing in the 21st century: a vision and a strategy.

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

Cancer and reproductive risks in the semiconductor industry.

Although many reproductive toxicants and carcinogens are used in the manufacture of semiconductor chips, and worrisome findings have been reported, no broad epidemiologic study has been conducted to define possible risks in a comprehensive way. With few exceptions, the American semiconductor industry has not supported access for independent studies. Older technologies are exported to newly industrialized countries as newer technologies are installed in Japan, the United States, and Europe. Thus there is particular concern about the many workers, mostly in countries that are still industrializing, who have jobs that use chemicals, technologies, and equipment that are no longer in use in developed countries. Since most countries lack cancer registries and have inadequate reproductive and cancer reporting mechanisms, industry efforts to control exposures to carcinogens are of particular importance. Government agencies, the courts, industry, publishers, and academia, on occasion, collude to ignore or to downplay the importance of occupational diseases. Examples of how this happens in the semiconductor industry are presented.

IBM, Elsevier Science, and academic freedom.

Elsevier Science refused to publish a study of IBM workers that IBM sought to keep from public view. Occupational and environmental health (OEH) suffers from the absence of a level playing field on which science can thrive. Industry pays for a substantial portion of OEH research. Studies done by private consulting firms or academic institutions may be published if the results suit the sponsoring companies, or they may be censored. OEH journals often reflect the dominance of industry influence on research in the papers they publish, sometimes withdrawing or modifying papers in line with industry and advertising agendas. Although such practices are widely recognized, no fundamental change is supported by government and industry or by professional organizations.

FIOH-sponsored newsletter misrepresents asbestos hazards in Zimbabwe.

The Finnish Institute of Occupational Health (FIOH) has received support from the World Health Organization (WHO) and the International Labor Office (ILO) to publish the African Newsletter on Occupational Health and Safety. The African Newsletter on Occupational Health and Safety should not be a medium for industry propaganda, or the source of misinformation among the workers of Africa. Instead, FIOH should provide the same level of scientific information in Africa that it does in Finland and other developed countries.

Redefining the confidence interval.

The confidence interval, its close cousin the p-value, and other statistical summaries of data are widely used in science, including the occupational and environmental health sciences, but they are almost as widely misused. My purpose here is to review some basic matters that should be covered in every introductory statistics course, but are generally omitted. More specifically, some of the many assumptions that are needed in the usual forms of analysis are reviewed.

Firm measures are required to effect any significant decrease in the Japanese age-adjusted mortality rate from malignant neoplasms for the 21st century.

The Japanese have the longest lifespan worldwide, but this has been mostly due to reductions in the mortality rates from diseases other than malignant neoplasms. Changes in the age-adjusted mortality rates (AMRs) for malignant neoplasms in Japan from 1950 to 2000 are analyzed to elucidate the overall trend. The overall AMRs for all malignant neoplasms in men increased from 1950 to 2000, and decreased slowly in women during the same period. Changes since 1990 have been small in both genders, but show a hopeful trend towards a decrease in the total AMR since 1995. These trends reflect a balance between the decreased AMR from gastric (both male and female) and uterine cancers and increases in many other malignant neoplasms. However, in the period 1990-2000, the decrease in the AMR from gastric and uterine cancers has shown a trend towards leveling off. Therefore, improving the trend towards reductions in cancer incidence and mortality in the 21st century and beyond will depend on achieving changes in other cancer sites, which can only be realized through the twofold approach of preventative medicine and research as well as improvements in the levels of diagnosis and therapy. Much more emphasis must therefore be placed on primary prevention, in particular on anti-smoking campaigns, as well as stepping-up research into the etiology of, and novel treatments for other malignant neoplasms, especially colorectal and breast cancers.

Influenza-like symptoms in the college dormitory environment: a survey taken during the 1999-2000 influenza season.

The effect of dormitory environments on the transmission of the influenza virus in college students is not well understood. During the 1999-2000 flu season, dormitory residents at a college campus in Chicago were surveyed about their living conditions and influenza-like symptoms (ILS). The survey had a 42 percent response ratio (721 of 1,704). Students who had > or = 50 percent carpeting in their room were at significantly lower risk for ILS (p = .02). Although the risk of ILS increased for roommates who shared sleeping quarters compared with those who slept in different rooms (RR = 4.3), the difference was not statistically significant. No evidence was found that ILS risk was affected by washroom, laundry, or dining settings, or by demographics, including gender or year in college. The survey instrument detected strong relations between ILS and the dormitory room environment, in contrast with other settings in the dormitory. Further research on transmission may focus on the room environment.

Implications of the Precautionary Principle in research and policy-making.

The Precautionary Principle (PP) has recently been formally introduced into national and international law. The key element is the justification for acting in the face of uncertainty. The PP is thereby a tool for avoiding possible future harm associated with suspected, but not conclusive, environmental risks. Under the PP, the burden of proof is shifted from demonstrating the presence of risk to demonstrating the absence of risk and it is the responsibility of the producer of a technology to demonstrate its safety rather than the responsibility of public authorities to show harm. Past experiences show the costly consequences of disregarding early warnings about environmental hazards. Today, the need for applying the PP is even greater. New research is needed to expand current insight into disease causation, to elucidate the full scope of potential adverse implications resulting from environmental pollutants, and to identify opportunities for prevention. Research approaches should be developed and strengthened to counteract innate ideological biases and to support our confidence in applying the PP for decision-making in the public policy arena.

Associations between ambient air pollution and daily mortality among persons with congestive heart failure.

We conducted a mortality time series study to investigate the association between daily mortality for congestive heart failure (CHF), and daily concentrations of particles and gaseous pollutants in the ambient air of Montreal, Quebec, during the period 1984-1993. In addition, using data from the universal Quebec Health Insurance Plan, we identified individuals >/=65 years of age who, one year before death, had a diagnosis of CHF. Fixed-site air pollution monitors in Montreal provided daily mean levels of pollutants. We regressed the logarithm of daily counts of mortality on the daily mean levels of each pollutant, after accounting for seasonal and subseasonal fluctuations in the mortality time series, non-Poisson dispersion, weather variables, and other gaseous and particle pollutants. Using cause of death information, we did not find any associations between daily mortality for CHF and any air pollutants. The analyses of CHF defined from the medical record showed positive associations with coefficient of haze, the extinction coefficient, SO(2), and NO(2). For example, the mean percent increase in daily mortality for an increase in the coefficient of haze across the interquartile range was 4.32% (95% CI: 0.95-7.80%) and for NO(2) it was 4.08% (95% CI: 0.59-7.68%). These effects were generally higher in the warm season.

Selection and description of cancer clinical trials participants--science or happenstance?

BACKGROUND: The selection of clinical trials participants is a critical step in study design, because it affects the generalizability of recommendations made on the basis of trial results and public acceptance of medical research. The authors assessed the heterogeneity of subgroups in cancer treatment and prevention trials and the analysis of subgroups in the evaluation of trial outcomes. METHODS: The authors reviewed published reports (1990-2000) of cancer prevention and treatment trials from 11 journals. They report here on all Phase III cancer treatment and prevention trials that had at least 100 participants and were conducted among adults in the United States. A structured abstract was developed and used to extract data from the 261 published reports. Descriptive summaries of the abstracted data provided the information included in this systematic review. RESULTS: Age and gender of study participants were reported in more than 90% of these trials, whereas fewer than 30% of the trials reported race or ethnicity. Gender was reported as an explicit criterion for participant selection primarily in studies of gender specific malignancies. Race and ethnicity were reported as explicit selection criteria for participant selection for five of the prevention trials and for none of the cancer treatment trials. The 105 treatment trials that reported including both men and women had 42,355 participants, and 38.6% of those participants were women. The 26 prevention trials that reported including both men and women had 73,995 participants, and 34.7% of those participants were women. Fifty-seven treatment trials reported participant ethnic diversity: There were 45,815 participants, with 10.5% African-American participants and with less than 1% Hispanic, Asian, or Native American participants. Seventeen prevention trials reported participant ethnic diversity: There were 91,741 participants, with 5.5% African-American participants, 1.7% Hispanic participants, and less than 1% Asian or Native American participants. CONCLUSIONS: Cancer treatment and prevention trial reports provide scant information about participant race and ethnicity. Such studies use participant selection criteria that do not define diverse subgroups, and few subgroup analyses are conducted. Improvements in the selection, reporting, and analysis of clinical trials participants are needed.

Review of assessments of the human health risk associated with the use of antimicrobial agents in agriculture.

To our knowledge, no comprehensive risk assessment of agricultural uses of antimicrobial agents has been published. The published risk assessments of antimicrobial use in farm settings are all subject to multiple, serious limitations in scope, including (1) limitation to one species of microorganism; (2) limitation to one or a very few related antimicrobial agents; (3) limitation to a single outcome (death, hospital days, number of illnesses, etc.); (4) limitation to one species of farm animal (e.g., chicken or swine); and (5) limitation to therapeutic use, despite reason for concern about misstated, off-label, or illegal use. In addition, all of the risk assessments reviewed overlooked important issues by accepting 2 further limitations: (6) limiting the scope of the analysis to what has already happened and ignoring the effects of continuing the practices of recent years; and (7) examining only the effects on the species of microorganism that was initially affected and ignoring the cross-species spread of resistance by plasmid transfer. After our review of the risk assessments now available, we propose a comprehensive scheme for organizing existing knowledge and dealing with critical gaps.