Biomedical research ethics

Biomedical research is needed for the development of medicine. It provides the scientific evidence to improve health care by providing knowledge and information on the usefulness and effectiveness of diagnostic, therapeutic and preventive procedures. Moreover, biomedical research contributes to increase our understanding of the etiology, pathophysiology and risk factors of diseases.

In other words, biomedical research is the careful, meticulous, systematic, diligent inquiry or examination of current knowledge, undertaken to establish facts or principles. Researchers strive to better understand the causes of disease, expand knowledge to discover better ways to prevent ill health, and to develop beneficial medications, and procedures to treat and cure diseases and conditions that cause illness and death. For all these reasons biomedical research should be considered a moral obligation for all physicians and health professionals (37% of you answered correctly via the clickers).

Ethical biomedical research encompasses not only the attainment of moral aims or purposes but also the application of morally acceptable means to obtain them. Therefore, scientific rigor is a necessary condition but not a sufficient one; not all what is scientifically feasible may be acceptable from an ethical standpoint.

Ethics is a set of moral obligations that define what is right and wrong in our practices and decisions. Scientists have long maintained an informal system of ethics and guidelines for conducting research, but documented ethical guidelines did not develop until the mid-twentieth century, after a series of well-publicized ethical breaches and war crimes.

 

During World War II, Nazi scientists launched, among others, a series of studies designed to test the limits of human exposure to the elements with the final aim of better preparing German soldiers. For instance, some experiments addressed the effects of hypothermia in humans. During these experiments, concentration camp prisoners were forced to sit in ice water or were left naked outdoors in freezing temperatures for hours. Numerous victims were left to freeze to death while others were eventually re-warmed with blankets or warm water, or underwent experimental rewarming attempts that left them with permanent injuries. War crimes during World War II led to the Nüremberg Code (1947).

In 1932 the U.S. Public Health Service started the “Tuskegee Study”, an experiment on black men in the late stages of syphilis. These men, for the most part illiterate sharecroppers from one of the poorest counties in Alabama, were never told what disease they were suffering from or of its seriousness. They were only informed to be treated for “bad blood”, and their doctors had no intention of curing them of syphilis at all. The experiment was aimed to collect data from autopsies of the participating men, and they were thus deliberately left to degenerate under the ravages of tertiary syphilis, which can include tumours, heart disease, paralysis, blindness, insanity, and death.

The following video summarizes the atrocities of the “Tuskegee Syphilis Study” and has served us to reflect on the ethical implications and consequences.

Infamous cases of fraud and misconduct highlight the need for a system of ethics to ensure proper behaviour and reliable research in science. As a result of the Tuskegee Syphilis Study (1932-1972), the U.S. Congress passed the National Research Act in 1974. The Act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to oversee and regulate the use of human experimentation and defined the requirements for Institutional Review Boards. To assure that research is conducted in accordance with basic ethical principles, the Commission considered:

1. the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine,
2. the role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects,
3. the establishment of appropriate guidelines for the selection of human subjects for participation in such research, and
4. the nature and definition of informed consent in various research settings.

The Belmont Report

The work of the National Commission led to The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research which was presented in 1978 and published in 1979 that states that “persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well being”. The Belmont Report summarized and defined the basic ethical principles of respect, justice and beneficence, thereby representing the origins of modern research ethics.

 
Basic Ethical Principles

1. Principle of autonomy: recognizes the rights of individuals to self-determination. The respect for persons incorporates at least 2 ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection.
This principle of respect for persons thus translates into two separate moral requirements:
(i) to acknowledge autonomy and
(ii) to protect those with diminished autonomy.
To respect autonomy is to give weight to the person’s autonomous considered opinions and choices while refraining from obstructing their actions unless they are clearly detrimental to others. Withholding information necessary to make a considered judgment, when there are no compelling reasons to do so represents a lack of respect.

However, it has to be highlighted that not every human being is capable of self-determination. The capacity for self-determination matures during an individual's life, while some individuals lose this capacity wholly or in part as a consequence of illness, mental disability, or circumstances that severely restrict liberty. Respect for the immature and the incapacitated requires protecting them as they mature or while they are incapacitated. Respect for persons demands that subjects enter into the research voluntarily and with an adequate information (informed consent).

2) Principle of justice: refers to the ethical obligation of fairness and equality in health resources and treatment. The conception of justice is especially relevant to protect vulnerable groups. In this regard, the selection of research subjects needs to be scrutinized in order not to be discriminatory. It should be determined whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the research condition being studied. Furthermore, justice demands that when research leads to the development of therapeutic devices and procedures, these not provide advantages only to those who can afford them as well as that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research.

3) Principle of beneficence: means the obligation to act in the best interest of patients maximizing possible benefits and minimizing possible harms. Individuals are treated in an ethical manner not only by respecting their decisions, but also by making efforts to secure their well-being. This principle establishes the need to carefully evaluate the risk-benefit relation; learning what will in fact be beneficial may require exposing persons to risk. The imperative posed by this principle is to decide when it is justifiable to seek certain benefits despite the risks involved, and when the benefits should be foregone because of the risks. Moreover, this principle implies the professional competence of the researchers involved to warrant maximization of benefits and the reduction of risk that might occur from the investigation.

The concept of non-maleficence considers that it is more important not to harm your patient, than to do them good; this is embodied by the Latin expression “primum non nocere”, "first, do no harm".

The Declaration of Helsinki

The Declaration of Helsinki represents one of the most relevant documents in the history of research ethics as the first significant effort of the medical community to regulate research itself. With the primary purpose to set international ethical principles for research involving human participants the World Medical Association (WMA), the Declaration of Helsinki was originally enacted in 1964 and forms the basis of most subsequent documents. It has undergone various revisions (the most recent at the General Assembly in October 2013) since its first promulgation. Given that 2014 marked the 50th anniversary of the Declaration of Helsinki, the WMA developed its eighth version of the Declaration updating and revising the 2008 version with the core aim of the working party to preserve the unique character and status of the document. The first draft was out for public consultation until June 15th, 2013 while the final revised and updated version was published in JAMA in November 2013. Major changes with respect to the 2008 version were carried out regarding both its structure and content. Noteworthy, the duty of physicians expands not only to promote and safeguard health but also well-being. The articles pertaining to vulnerable populations have also been changed to better capture several important ethical principles. Although the WMA has been congratulated for the work performed and the transparency of the process, it was agreed that the declaration has not undergone radical change representing “an evolution rather than a revolution”. Additional distinctive aspects contemplated in the 2013 version include appropriate access of underrepresented groups to participation in medical research, the need for compensation for study participants who are inadvertently harmed, and attempts to further clarify the role of placebos, the need to register every study involving human subjects in a publicly accesible database before recruitment of the first subject, provision for post-trial arrangements in advance of study start, and the ethical obligation to publish and disseminate the study results, even if they are negative or inconclusive.

• Understand and remember the basic ethical principles of respect, justice and beneficence derived from the Belmont Report.
• Study in detail the 2013 revision of the Declaration of Helsinki together with the changes introduced as compared to the 2008  version (pdfs available at ADI).
• Learn the characteristics and content of the written informed consent.

The scientific method

We have conducted a survey asking who, in your opinion, was the greatest scientist in history. These are the exact figures obtained via the clickers’ responses:

Although the question is subjective to some degree, 40% of the class matches the thinking of the majority of the Scientific Community. Surprisingly, a higher percentage (41%) states that Galileo was the most important scientist. Although Einstein (voted by 15%) has been considered the greatest scientist of the twentieth century, the Scientific Community identifies Isaac Newton as the most relevant scientist of all times.

The scientific method can be defined as the sequence of steps pre-established by a discipline in order to achieve valid knowledge through reliable instruments. In other words, the scientific method consists of a series of steps that we take to improve our knowledge in a reliable manner. It is described in an "informal" way in this video:

Chemistry music video on the steps of the Scientific Method. All music and lyrics copyright 2005, Mark Rosengarten. All rights reserved.

Development of science & scientific thinking

Before going straight into the topic we have carried out an opinion toll on the use of mobile phones, tablets and similar gadgets. I also wanted to know your use of social networks. These are new communication tools and it is interesting to know that you use them on a regular basis.
Most of you (87%) use social networks, and a huge proportion does it on a regular basis during the course (63%). Almost all of you (97%) use WhatsApp! Only 3% of you has no mobile phone at all, while the majority has either a smartphone or several different similar gadgets. In over a third of you (36%) the amount of time (expressed in hours per day) that you are connected is 10-15 hours per day or more, which is quite high.

"The Marshmallow Experiment" 

The very funny video of "The Marshmallow Experiment" has served us to reflect on the current use of mobile phones and networks and the temptation of being continously distracted by them. The original Marshmallow Experiment was conducted back in the late 1960s and early 1970s by the psychologist Walter Mischel, then a professor at Stanford University. It refers to a series of studies on delayed gratification, i.e. the ability to wait to obtain something that one wants. In these studies, a preschool child was offered a choice between one small reward (for example, a marshmallow) provided immediately or two small rewards if he or she waited until the experimenter returned (after an absence of approximately 15-20 minutes). Some kids could wait, but others could not.

Most interestingly, in the follow-up studies the researchers found an unexpected correlation between the results of the marshmallow test and the success of the children many years later. Noteworthy, in the first follow-up study, performed in 1988, preschool children who had delayed gratification longer in the self-imposed delay paradigm were described by their parents as “adolescents who were significantly more competent". A second follow-up study, carried out in 1990, further showed that the ability to delay gratification also correlated with higher SAT scores (the Scholastic Aptitude Test, then the Scholastic Assessment Test, a standardized test for most college admissions in the United States).

Science Works in Specific Ways
  
The joy of science emanates from the freedom to explore and wonder. However, in order to maximize the probability of obtaining correct answers, science needs to follow specific guidelines. It is important to keep in mind certain fundamentals:

• Science relies on evidence from the natural world and this evidence is examined and interpreted through logic.
• Creative flexibility is essential to scientific thinking, however science follows a process guided by certain rules.
• Science is embedded within the culture of its times.

Instead of offering narrow solutions scientists across the different centuries have encouraged critical thinking based on intellectual rigour and open-mindedness. Scientific thinking is characterized by scepticism, objectivity, an appreciation of uncertainty and the flexibility to alter one's beliefs in the face of conclusive evidence. Within the scientific community, this appraoch stimulates open debate and ensures rigorous analysis of data and generation of hypotheses.

The Scientific Revolution

Kuhn's theory identifies three stages of the scientific revolution as follows:

1) "Pre-paradigm" stage where a new paradigm appears as the most promising theory among several equally co-existing at the time.

2) Stage of "normal science" where it progresses within the existing paradigm accumulating knowledge corresponding to the conceptual framework.

3) "Scientific crisis" where the prevailing paradigm is not able to explain some important observations and a new paradigm challenges the previous one by encompassing explanations and a broader scope of known facts.

Shneider's classification of the four evolutionary stages of a scientific discipline:

1) Introduction of a new language to adequately describe the subject matter.

2) Development of a toolbox of methods and techniques for the new discipline.

3) Generation of most of the specific body of knowledge of the new discipline via publication of original research.

4) Passing on and revision of scientific knowledge generated during the previous stages.

Andreas Vesalius (1514-64) is one of the most important figures in the history of anatomy. He was the author of De Humani Corporis Fabrica a revolutionary study of the human body famous for its detailed and beautifully drafted illustrations showing the complex formations of the muscles, nervous system, blood vessels, viscera and skeleton. As a young student, Vesalius was so fascinated by the human anatomy that he stole the body of an executed criminal from a scaffold, taking it home to study the amazing structure of the body. At that time, medical students did not have to attend dissections as they do today. Instead they were expected to learn from the teachings of the Greek physician Galen. Vesalius' work translated into a number of important changes to the study of anatomy. Also while working on his masterpiece the Fabrica, Vesalius discovered that a number of Galen's teachings were wrong. 

During the Renaissance, the focus, especially in the arts and sciences, was on representing as accurately as possible the real world. This required two things. The first was new methods for drawing and measuring. The second, relevant to this topic, was careful observation.

Standing on the Shoulder of Giants is the fourth studio album by the English rock band Oasis, released on 28 February 2000. The album's title was taken from the words made famous by Sir Isaac Newton: "If I can see further than anyone else, it is only because I am standing on the shoulders of giants". The rock star Noel Gallagher saw the quote on the side of a £2 coin while in a pub and used it to name their new album.

The following short video nicely summarizes some of the relevant turning points in history focusing in particular on the scientific revolution.

• Study the main philosophical and scientific movements (names and time period) that led to the development of science.

• Understand and remember the stages that characterize the scientific revolution according to Thomas Kuhn and Alexander Shneider.



Getting started

Classroom 14 was packed full!

First of all, we have introduced ourselves... We wanted you to put the face to the name of the teachers that will guide you through the diverse topics of "Introduction to Research" during this semester.

Cartoon of the "Intro teachers" (Note: Andoni in the bottom right of the cartoon has been replaced by Leire this year) [Reproduced with permission of the artist (María Mouzo) and the owner of the cartoon (Ana Pérez); both students currently attending the 5^th year at our Med School].

Making use of the "clickers" we have asked you about your interest on the subject - which is your opinion on the usefulness of this course, and whether you would like to devote your professional career exclusively to research or preferred to combine it with clinical work. Not surprisingly, approximately a third of you (36%) were unsure about the usefulness of this course. We hope to be able to raise your curiosity, interest and respect for science, as a whole, and for research, in particular, during the coming months by sharing with you the experience, passion and enthusiasm of many of the scientists that preceded us and paved the way to develop the knowledge that is being taught and applied nowadays. Also as expected, most of you (77%) would like to combine clinical work with research, while a minority (5%) expressed their interest of dedicating themselves exclusively to research. 

Subsequently, we have outlined why this subject is important to any medical student. What you are being taught and what you will learn throughout your medical career, and thereafter, is due to the research effort of many physicians and scientists that asked themselves questions in order to improve their knowlege to better help their patients.

We also want to "demystify" the image of the "boring researcher" working alone in his/her laboratory. In the following Lady Gaga parody videoclip you have a nice example of how funny scientists can be:

Research lies at the heart of all medical knowledge, activities and applications.

Attendance to practical sessions is mandatory.

There will be written short questions throughout the year that will have a 10% impact on your final score.

You will have to form a working group to prepare a topic to be presented in front of your classmates.

Additionally, as an individual you will have the chance to perform an optional or voluntary work consisting in a written essay on the book entitled "Bad Pharma" by Ben Goldacre.

It is important that you read the teaching guide of "Introduction to Research" to be aware of all the details of what is expected from you and how it will be evaluated.