From Paradox to Paradigm: Working the Wisdom of Henry Beecher

APPI President, Chairman's Message | Greg Koski, PhD, MD, CPI

Having just assumed the responsibilities that accompany the presidency of APPI, I have inherited certain commitments and their associated deadlines. This bimonthly column for The Monitor represents one of them. In it, I will share with you a variety of ideas and perspectives regarding the many important issues facing APPI members in our various academic, industry, and government settings.

Serendipitously, perhaps, the deadline for this column caught up with me in the city of Udon Thani in Thailand, where I was participating in a conference on developing quality systems for health research that brought together stakeholders from the entire Asia-Pacific region. The conference offered a very clear reminder of the rapidity with which clinical trials and other health research activities are growing in that part of the world and in such regions as Eastern Europe, Latin and South America, and the Middle East.

The conference organizers invited me to discuss the role of investigators in protection of human subjects. This afforded me the opportunity to note that 40 years ago, Professor Henry Beecher, then chairman of the Department of Anesthesia at the Massachusetts General Hospital and one of the towering figures in human research ethics before research ethics committees (RECs) and institutional review boards (IRBs) were an accepted part of the clinical research landscape, Professor Henry Beecher wrote that the only true protection for the safety and well-being
of human subjects in research is a well-trained, conscientious investigator [Beecher HK. 1966. Ethics and clinical research. New England Journal of Medicine 274: 1354-60].

Regrettably, this message seems to have been largely ignored by much of the research community in the intervening decades. Much effort, time, and money have been devoted to building an elaborate process for review, approval, and oversight of human research by committees of individuals having no direct role in the research and, too frequently, no in-depth training in either research or ethics.

Few would deny that IRBs and RECs have reduced the likelihood that unethical, unsound, or unsafe research is done. However, many cite the lack of empirical evidence that the review process itself is effective in reducing harm to research subjects, and critics decry the excessive focus on procedural and regulatory compliance that characterizes the process today. Many in the research community, including investigators, view the process more as an obstacle to be overcome when trying to initiate research than as a critical part of its conduct.

Acknowledging these uncertainties, the message I delivered at the conference in Thailand emphasized Beecher’s Paradox—that the investigator is the individual best positioned to prevent harm to human subjects in research, while at the same time being the individual most likely to do harm. The paradox is readily resolvable by simply adopting Beecher’s Paradigm—that all investigators be well trained and well intentioned before they are permitted to engage in human studies.

At present, we are far from achieving this goal. Our core medical school curricula offer little or no training in clinical research, and most investigators still learn as apprentices to experienced mentors who may themselves have had little or no formal training in the responsible conduct of research, regulatory requirements, or research ethics. Alternatively, as is commonly the case outside of academic centers, they learn by the seat of their pants with the help of a research monitor or coordinator at an investigator orientation visit—hardly a recipe for thoroughness and excellence. Only within the past decade have some institutions and sponsors required that investigators acquire even minimal training in how to conduct research or research ethics, and frankly, many sponsors and contract research organizations are more interested in finding investigators (and IRBs) who will do things quickly than in selecting investigators committed to doing things well.

Reacting Defensively

If you happen to be a sponsor or investigator, you may already have taken offense at my characterization of the current state of affairs and reacted defensively to it. If so, stop for a moment and reflect on how you got to where you are today. Our late APPI president, Dr. Lou Sherwood, once confided to me how, upon leaving a stellar academic career in medicine and research for a high position in the pharmaceutical industry, he was stunned and, yes, humbled to find out how little he knew about the discipline that has come to be known as pharmaceutical medicine. Indeed, it was because of his humbling experience that Lou became such an ardent advocate of investigator training and certification, a hallmark of professionalism in clinical investigation and an essential part of APPI’s mission.

If you happen to be among those who felt that twinge of defensiveness when you read the paragraph above, take the challenge—that is, take the exam. Successfully sitting for certification exams is part and parcel of the life of medical professionals, so why not that of clinical investigators? Some who take the Certified Physician Investigator (CPI) exam will be rewarded to find that they know what they should and are able to apply that knowledge effectively; they will emerge from the process both confident and certified, having demonstrated their personal commitment to realizing Beecher’s Paradigm. Others may receive a needed wake-up call and opportunity to advance their knowledge while similarly demonstrating their commitment to achieving the highest standards of conduct in their activities. In time, both sponsors and the public will take note, and even greater rewards will ensue; but we must take the initial step toward excellence largely out of good will.

In Asia, the concept of yin and yang is well known; in keeping with it, the message from Udon Thani is at once both encouraging and worrisome. With the zeal and determination characteristic of this part of the world and its remarkably industrious people, the Asian clinical research community is striving to implement quality-focused systems for the protection of human subjects. At the same time, it is replicating a Western-style approach with all of the strengths and weaknesses that have become apparent since it was imposed upon the research community four decades ago. The consequences of doing so will also be both positive and negative. Yes, there will be a system for ethical review, approval, and oversight of research, along with regulations to enforce the process. There will also be a rush toward achieving the minimal goal of compliance without realizing the goal of excellence.

The Alternative

There is an alternative to this scenario, and APPI has an opportunity to take a leadership role in bringing it to fruition by showing the world that our commitment to responsible conduct of human research and protection of human subjects is aligned with the goals of RECs and IRBs. In this manner, we can work in concert to do more studies more efficiently without imposing more counterproductive regulatory impediments to our common goal, which is to bring the benefits of science and medicine to all the people of the world.

During the year ahead, ACRP and APPI will work vigorously to increase our engagement with our clinical research colleagues around the world, to expand our membership, and even more importantly, to promote professionalism and excellence. We will reach out to new partners and seek to expand recognition and acceptance of the standards, best practices, and tools of professional validation, accreditation, and certification. And we will call upon all of you who share these goals to help.

Though APPI can never be more than what its members bring to the organization, what we have to offer is extraordinary. To realize our goals, we need all of you to become more involved and to recruit your colleagues to join us in pursuit of excellence. As your president, I look forward to serving you as we work together, whether in Utah, Uruguay, Uppsala, or Udon Thani.