Some of the practices that are believed to enhance the quality of science may produce bias. Studies with unexciting results may never be published, or results are selectively reported to highlight positive outcomes. Investigators often measure multiple outcomes while only reporting those with statistically significant findings. The best remedy for this problem is to require prospective declaration of study plans through study registration, such as the primary and secondary outcome variables and data analysis plans. Failure to report results of completed studies remains a serious problem. Further, results from many studies remain unpublished and the probability of publication is higher for positive results, leading to overestimates of treatment benefit. It is possible that some encouraging clinical trial findings are actually false positive results. For US Food and Drug Administration evaluations, data from a significant portion of relevant completed trials remain undisclosed at the time the pharmaceutical products are under evaluation.

Clinical research is expensive: In 2024, the US National Institutes of Health will spend about $49 billion on research projects. Requesting sufficient resources to conduct a high-quality investigation must be balanced against a desire to use public funds prudently. Most studies are underbudgeted. In addition to funds for study personnel and the costs of evaluation and treatment, there may be costs associated with regulatory and scientific oversight, such as a research ethics committee, community advisory boards, information technology, study registration, and funds for study dissemination. Clinical research is a heterogeneous enterprise that usually requires personnel with a range of complementary expertise. This chapter offers guidance on constructing realistic budgets. In addition, we address the complicated issue of paying study participants, which raises important ethical issues. It is important to compensate participants for their time and discomfort. We review models on which to base participant compensation.

This book is about the science and ethics of clinical research and healthcare. We provide an overview of each chapter in its three sections. The first section reviews foundational knowledge about clinical research. The second section provides background and critique on key components and issues in clinical research, ranging from how research questions are formulated, to how to find and synthesize the research that is produced. The third section comprises four case studies of widely used evaluations and treatments. These case examples are exercises in critical thinking, applying the questions and methods outlined in other sections of the book. Each chapter suggests strategies to help clinical research be more useful for clinicians and more relevant for patients.

In the middle of the last century, Archie Cochrane, one of the founding fathers of evidence-based medicine, argued that understanding healthcare treatments required the consideration of three questions: “Can it work?”, “Does it work?” and “Is it worth it?” Each of these questions addresses a different aspect of the problem and requires different assumptions and different research methodologies. Understanding if a treatment can work establishes proof of principle derived from efficacy studies that control who takes the treatment, how it is administered, and how outcomes are measured. The question “Does it work?” is about effectiveness that is evaluated under conditions of the usual care. Randomized controlled trials, which form the core of efficacy research, are difficult to employ in the evaluation of effectiveness. Even if interventions are shown to be efficacious and effective, people need to decide if accepting the treatment is worth it. Healthcare can be expensive, inconvenient, painful, and sometimes of little value. This introductory chapter reviews the three questions and prepares the reader for the in-depth discussion of these issues in the following 16 chapters.

In order to examine our three questions, we need objective research methods. Estimating whether a treatment can work, does work, and has value requires a wide range of research strategies. Evidence establishing that a treatment works under controlled conditions does not necessarily assure benefits when the intervention is applied in clinical practice. This chapter considers the development of a research protocol, and biases that might be attributable to participant recruitment, enrollment, retention, and dissemination of findings. In practice, establishing the value of a treatment should consider an examination of the existing literature, development of thorough research plans, recognition of the strengths and weaknesses of the chosen research methods, and integration of study results within a wider body of knowledge. We challenge beliefs in a hierarchy of methods that assumes some methods, such as the RCT, are free from bias.

Antidepressant medications are widely prescribed for depression and other uses. They are considered a first-line treatment for major depressive disorder. We examine the lack of support for the mechanistic idea that neurotransmitters affect and are affected by these medications. Few people experience significant benefit from their use when compared with the effects of placebos. We consider several ethical issues associated with antidepressants, including conflicts of interest among the committees recommending their use, and examine a study that suffered from spin and other issues of integrity. The chapter examines potential alternatives to antidepressant medications for those with depression.

We use healthcare in an effort to live longer or feel better. Yet many evaluations do not consider these outcomes, which are of high importance to patients. Instead, they concentrate on variables that are considered surrogates for what treatment is attempting to achieve. Prevention of heart disease, for example, might be estimated from changes in LDL cholesterol levels. These surrogate markers are often poorly correlated with the outcomes of most importance to patients. Understanding the basic biological mechanisms is valuable, but sometimes irrelevant. The chapter reviews patient-reported outcomes that are becoming more commonly used to evaluate health care. These measures are used to create indexes that combine how long people live with the quality of life during the years that precede death. The measures are generic and can be used to compare the value of investing in interventions that have different specific objectives. Cost-effectiveness analysis can directly compare health gain associated with treatments as different as exercise training versus organ transplantation. The public policy implications associated with these metrics are discussed.

Gastroesophageal reflux disease is a common condition that can be controlled with proton pump inhibitors such as omeprazole. We examine randomized controlled trials (RCTs) of omeprazole and find stronger evidence of efficacy among RCTs with industry support than without. The participants in these trials were unlike most people who take proton pump inhibitors, raising questions about the external validity of RCTs. Furthermore, use of these medicines is associated with short- and longer-term adverse effects. Healthy behavior change, such as weight loss, holds promise as an alternative to proton pump inhibitors.