PREFACE

This fourth edition of Clinical Trials represents renewed effort to describe foundational methods for advanced clinical trials. My goal is not to describe trends, but valid principles that invariably underlie useful new methods. Clinical trial topics do not divide neatly into simple versus advanced subjects, and I have made no attempt to do so. All topics have intertwined foundational and advanced aspects. This is evident for technical topics like bias, randomization, power, and analyses but also true for non-technical subjects like ethics, authorship, and misconduct to name a few. No aspect of clinical trials is perfectly simple.

A good aspect of teaching clinical trials is that there are many illustrative examples. Difficulties are due to mixed audiences, inconsistent teaching venues, student knowledge gaps, and little standardization. Such problems arise partly because there is no consistent home for clinical trials as a discipline despite over 80 years of evolution. Where trial methods are housed, how they are taught, to whom and by whom, are inconsistent even within single institutions. There is no standard body of knowledge or core competencies for clinical trials. The subject has diverse experts and neophytes, theory and practice, teachers and trainees, and no shortage of opinions about methods and conduct. This book does not fix those issues, but does represent evolved content and a benchmark for consistent instructional material.

A premise of my approach has been that newly minted clinicians are not well prepared to be clinical investigators. Some basic research skills may be added to fellowship training but are too limited to create fully prepared clinical investigators. Topics like research design, statistical methods, and study management are often lacking. When clinical researchers declare themselves and want to develop their own trials, clinic and other early faculty responsibilities severely restrict their time. A common solution to this problem at academic medical centers is to construct didactic and mentored training programs for selected young investigators. Formal degrees or certifications in clinical investigation are usually awarded based on curricula cherry-picked from institutional courses originally created for other purposes—typically public health training. Such programs usually do not design and construct clinical investigation programs based on a body of required knowledge or skills, but assemble them from local resources. Individual courses usually comprise lectures by topical experts with coordination by a course director, but not necessarily tailored to a given body of knowledge. In contrast, this book is designed to cover and integrate essential topics under a single voice. I have used it mostly in year two of training programs following introductory courses on research design, clinical trials, and basic biostatistics.

Meanwhile, clinical trials training for non-physicians remains poorly defined at many institutions. Structured programs are rare and most curricula can offer only a course or two. It has always been mysterious to me why skills so integral to therapeutic research are not universally nurtured and taught in the environment they serve. Clinical trials are interdisciplinary science and do not need to be specialty restricted, a view I hope this book displays. They should be embraced within all therapeutic settings and owned by medicine as well as public health.

One hundred years ago, an emerging discipline of public health understood its need for biostatistics, itself a new science, gave it an academic home, and made it a core competency. Medicine and therapeutic research had yet to realize how essential biostatistics would become, so resistance and skepticism to it persisted for decades. Biostatistics has now proved its necessity for laboratory and therapeutic research, especially in clinical trials, yet is not embraced as a core discipline in medicine. Methods for clinical trials are central to scientific medicine—an essential specialty without a universal administrative or instructional home. With further definition of the field and core curricula that literature can help create, a home for clinical trial science may emerge.

Many biostatistics trainees gravitate toward genomic sciences instead of clinical trials. Clinical investigation understandably seems unfamiliar to many biostatisticians, and they are not taught explicitly how to communicate well with clinicians or laboratory scientists. Those attracted to clinical research are often unappreciated. Some researchers mistakenly assume that statisticians are meant to work under their direction, for example. This is alienating and damages collegiality. Statistics is a mature science with its own scope and legitimacy, as public health has always recognized. Many researchers in biological science and especially clinical trials recognize how statistics is relevant, essential, and synergistic with their discipline, but engagement can be inhibited by disciplinary and departmental silos. Such restrictions do not exist within these pages.

It is humbling to look back at writing begun years ago, expect it to make sense, but realize some concepts are poorly explained or incorrect in places. That has happened: mistakes were made. Most likely some errors remain and there is new material to spawn more. It is best to use a classroom for clarity as I have done since before the first edition.

Sadly, I owe much progress on this fourth edition to SARS-CoV-2. Pandemic mandates for remote work, social distancing, and travel restrictions freed time that otherwise might have gone into social, pleasurable, or frivolous activities. This version benefited from those recovered times. COVID-19 brought forward acts of heroism and selflessness by many colleagues in clinical care, first response, and related roles. Lesser fear felt outside emergency rooms, hospitals, and intensive care units can only be used to measure bravery in those tending to the sick and dying. I hope this work contributes to education and preparedness for a future that will again depend on clinical trials at some point. Some colleagues turned to me for help in study design and execution during the pandemic, and this text supported some of my responses. Other practical questions contributed to new topics.

The pandemic revealed a mindset of stupidity and selfishness in many people. Ordinarily, one would politely label this as ignorance. But ignorance in an honorable person can be corrected, which clearly did not happen for many people during this pandemic. As its grip deepened and deaths rose, many political leaders pointed in directions that would sacrifice elderly, frail, vulnerable, and health care workers, under pretenses of rapid economic normality. Population subsets behaved similarly, sporting on beaches, jetting off to spring break, scorning masks, or crowding into bars, rallies, churches, or colleges—and ultimately refusing safe and effective vaccines. A relatively small fraction of fools can kill a sizable population.

News media simultaneously drove panic, doubt, and denial by focusing on emotional extremes. Daily we witnessed a ravenous appetite for higher and higher death numbers, amplification of pains of unemployment, initially dwindling reserves of ventilators and protective equipment, all served up with heaps of partisan politics. A year later, seesaw reporting covered vaccination access and rates. It was beyond news that we were caught unprepared, that more people died today than yesterday, that nursing homes and hospital intensive care units were scenes of horror, that testing for a new disease is imperfect, and that tragedy reveals victims with faces of good and bad. News media probably should have reported our long-sought desire to time travel had come true—we now visit what we did and did not do 2 weeks ago, last month, and last year. And we will see today again in coming weeks, months, or years, because we did not remain disciplined enough to stop spreading coronavirus.

Early in the pandemic when weather permitted, I walked in a park near my Boston apartment where most people were still not covering their faces even out of respect for others. Bare faced joggers and cyclists would blow past exhaling heavily while dodging walkers speckled along paths. Only geese who wintered there were behaving appropriately, socially distanced, and soon departed. Later in Chapel Hill and Emerald Isle, NC, I encountered a few people who suggested coronavirus was a hoax. What kind of human being does not understand hundreds of thousands of deaths? When U.S. deaths reached half a million, I wondered if deniers were still untouched by reality. The floundering presidential administration that was voted out of office in 2020 bears responsibility for denials, misinformation, and numerous preventable deaths. Even after 800,000 U.S. deaths, over a fourth of the population refused vaccination. After 1 million people had died by 2022, much of the population remained willingly unvaccinated or incompletely vaccinated.

Writing for this edition tapered as the pandemic waned, which is not to say that either has run its course. A new coronavirus variant or mutation could arise; further advances in clinical trial methods will certainly happen and will be chronicled by new colleagues. Perhaps these two threads will disentangle over time. Either way, we now have more good and bad experiences on which to base judgment. Lessons for both viruses and trials will be needed again.

Edition four of Clinical Trials fixes none of it. A silver lining might be that new historic clinical trials have been performed and are discussed herein. A handful of brilliant vaccine ideas followed by...