The “Three-legged Stool Principle” for Clinical Research Trials and Protection of Human Research Subjects

The proper design, conduct, analysis and evaluation of clinical research trials in humans can be compared to a properly constructed three-legged stool. The proper design, conduct, analysis, and evaluation of clinical research trials requires the integration of principles from three perspectives:

1)       Clinical science and practice,

2)       Biometrics (biostatistics),

3)       Human ethics and protection of research subjects.

We may consider that each of the three perspectives represent one leg of a properly leveled three-legged stool. Thus each must have equivalent emphasis and importance in the design and implementation of a properly “balanced” clinical trial to meet today’s good clinical practice guidelines.

As clinical trials have evolved during the past 3 decades, advances in clinical trial design and conduct have occurred principally in clinical science and practice and in biometrics. Advances in clinical science and practice have, for example, defined proper study population groups, proper clinical measurements for efficacy and safety parameters for outcome evaluation, and skilled care of subjects including adherence to a well-designed study protocol. Biometrics have gained primary ascendancy and importance to clinical science through such things as implementing measures to minimize bias and developing sophisticated statistical models for probability to minimize uncertainties in the interpretation of results in human trials.

Unfortunately, as evident from recent Office for Human Research Protections (OHRP) compliance determinations communications (http://ohrp.osophs.dhhs.gov/detrm_letrs), the third perspective, protection of research subjects and further development of ethical principles for human research have not advanced as far as the other two perspectives, resulting in an unbalanced three legged stool.

At present, fulfilling processes for construction of informed consent forms and submission of the protocol to under-staffed and overworked Institutional Review Boards (IRB) or Institutional Ethical Committees are considered sufficient for human ethics and protection of research subjects. Though highly important, these are only minimum requirements. As present and future biological research advances, principles for human ethics and protection of research subjects must also advance. These advances are by no means easy and can be contentious without arriving at consensus as these principles, unlike that of clinical science and biometrics, are not easily quantified. The following are some suggestions for investigators and clinical research directors who wish to contribute to advancing human ethics and protection of human subjects to provide for a properly integrated clinical research trial:

1.        Be thoroughly familiar and constantly reminded of the fundamentals for human research found in the Helsinki and the Belmont Reports.

2.        Become knowledgeable of the history and continue to reflect on past failures of human trials that were not only unethical but also harmful to humans- all justified in the name of science.

3.        Before, and while designing and implementing a clinical trial, satisfy yourself that you have given thoughtful and independent considerations to some basic questions: Is this clinical trial in human subjects the only or best way to obtain the answers for the purpose and objectives? Is the use of a placebo as one of the comparative limbs justified (see Helsinki Conference discussion on withholding of accepted therapy or management)?

4.        Provide for training (and retraining) of investigative team and staff members, including laboratory technicians, etc on the history and principles of protection of human subjects.

5.        Assure that the ethical principles are integrated with clinical science and biometrics perspectives in the design and conduct a trial that will maximize benefits while minimizing risks for all subjects (see Belmont Report on “Beneficence”).

6.        Be responsive to IRB’s needs.  Provide assistance to IRB’s with clearly written reasons and justification that this clinical trial is in compliance with the three basic ethical principles of the Belmont Report for 1) Respect for persons, 2) Beneficence, and 3) Justice. In the placebo-controlled trial include why accepted or alternative comparison groups are not appropriate.

We believe as Research Professionals that our duty is clear, to make sure the stool remains stable and supportive for all that use it.  We hope this discussion helps stimulate your thoughts and leads to continually improving research.