Human Subjects Research Protection Expert
Have you ever heard the catchphrase “Not All Heroes Wear Capes”? Well, this motto applies to everyday IRB members who engage in courageous conversations and make important decisions for people who choose to participate in clinical trials. This task is often done with little to no recognition.
Institutional Review Boards (IRBs) are granted the authority to review and approve research studies to protect the rights, safety, and welfare of those brave participants, who choose, to participate.
What does it mean “to choose”? According to Merriam-Webster “to choose” means to allow someone or something to either decide, pick out or select a course of action, typically after rejecting alternatives.
When it comes to conducting clinical trials in populations that are very sick, I can’t help but wonder are these people actually “choosing to participate” or are they merely “out of choices”?
Researchers design clinical trials to answer specific research questions related to medical products. Although a lot of information is discovered about how drugs, devices and biologics work during preclinical research done in labs, this does not substitute how these discovered agents interact within the human body.
Typically, clinical trials follow a series from early (small-scale) to late (large scale) models during the investigational process.
In Phase I studies, researchers test a new treatment in about 20-80 volunteers who may be “normal” (healthy people) or have a disease/condition. Participants are closely monitored as researchers gather information about how the investigative treatment interacts with the human body. During this phase researchers may adjust treatment to participants based, on animal data, to find out how much a human body can tolerate and what its side effects are.
With Phase II studies, researchers may examine a new treatment in up to several hundred of people with a disease/condition for a period of time, to examine safety information and how effective the treatment is in a disease/condition. However, it is important to understand, Phase II studies are no longer enough to show whether a treatment will be beneficial.
Whereas, Phase III studies researchers continue to assess how effective the treatment is by monitoring side effects. This phase may include thousands of volunteers who have a disease/condition which lasts longer. During this phase, researchers may examine whether a treatment offers a benefit to a specific population.
There are some Phase IV studies which are carried out once the treatment has been approved by the Food and Drug Administration (FDA) during the post-market safety monitoring. This phase may include several thousand volunteers who have a disease/condition.
Now that we’re all caught up on the different phases of clinical trials lets discuss desperately ill patients in research.
The way I see it, if you are “desperate”, you are in such a bad situation that you are willing to try anything to change it. Now, combine that with being “ill”, which is the suffering from a disease or a health problem. Therefore, for the sake of this blog, let’s describe someone that is “desperately ill” as a person who may be willing to try anything to help their medical condition.
Questions an IRB member may have; what is the mindset of a patient who is desperately ill? How literate are they in their situation, and how this may differ from their emotional state?
According to psychotherapist “Claude Steiner” Emotional literacy is having the ability to handle your emotions in a way that improves your power and the quality of life around you.
When I think about this, I can only imagine the thought process of someone who is dealing with a severe sickness and considering participation in a clinical trial.
As IRB members, we must consider how we can use this information in conjunction with the criteria for IRB approval of research.
In thinking about IRB approval, which criteria stand out the most to you? For myself, I consider the following: (a) The risks to subjects being reasonable in relation to anticipated benefits, (b) Informed consent will be sought and (c) Vulnerability, coercion, or undue influence to protect the rights and welfare of these subjects.
IRBs try to address concerns in the informed consent document with language such as “you are being asked to participate in a clinical trial”, “this is research”, “your participation is voluntary and you may choose not to participate”, “you may not benefit from participation”, “you have alternative options such as palliative care (explain palliative)”, etc. However, let’s break down these criteria a little further.
The “risks/benefit” ratio for this study population may be both emotional and physical. We already know that the primary goal for the majority of phase I trials is to examine safety. We also know that there are very little breakthrough responses for these participants with less than a 5% curative and/or life expectations rate. This begs the question, are the risks worth the anticipated benefit?
Considering the mindset and/or emotional literacy of the study participant, an IRB member may consider whether the design of the study is scientifically sound, that the inclusion/exclusion criteria is well defined, and most importantly that the informed consent document clearly states there is little to no benefit from participating on this study.
IRBs know that the Informed Consent Form is not just a document but a process in which investigators educate the potential participants about the study. The Informed Consent Form is an ethical obligation of the researchers, to make it clear to participants, to know their rights about what happens to their body, to be involved in the decision-making process and to avoid making participants feel forced to agree by adhering to the basic Belmont principle of “respect for persons”.
It is also important to understand that an Informed Consent Form IS NOT A CONTRACT! Participants can stop involvement at any time and the decision to stop will not affect their care.
So, we know the words are there, but how are those words received and/or perceived by potential participants? For decades, ethicists have argued that informed consent to participate in research should include clarification of the difference between research and standard clinical care.
Standard Clinical Care is a treatment that experts agree is appropriate, accepted, and widely used. Standard of Care may be used interchangeably with “best practice”, “standard medical care”, and “standard therapy”. Whereas, research involves new ways to screen, prevent, diagnose, and treat the disease.
Oftentimes, the line is unclear, and it is important not to confuse research with standard of care because standard of care is not necessarily research.
The terms “practice” or “standard of care” refers to interventions designed solely to benefit an individual patient and have a reasonable expectation of success. To the contrary “research” is an activity designed to test a hypothesis and contribute to generalizable knowledge.
With that being said, the IRB must balance this information because the responsibility is not only to the subjects in front of the researcher but to the patients we never get to meet.
Patients that a desperately ill may have the misconception that the “research” is treatment and may literally think they are getting clinical care.
This is why it is important for IRB members to be cognizant of therapeutic misestimation, which is a person’s belief that the clinical trial will bring them a cure or health benefit. Therapeutic misestimation may be a result of low literacy or driven by the mindset of “this is the end of my life and what do I have to lose”. And, if this is the case, is participation in a phase one clinical trial even a choice? How is the informed consent process even helpful, and is there an argument to be made about whether these patients are making a choice in an autonomous way?
I find that often there are more questions than answers. For example, there is the notion of unrealistic therapeutic optimism, which essentially implies “hope”. Hope that even with all the information provided about the clinical trial and the understanding that most phase one studies have less than a 5% cure rate, desperately ill patients will hold on to the belief that they will be different, and that the treatment could likely cure them.
A research attorney once said to me “why does the motivation to participate on a clinical trial matter”? As an IRB member my head nearly exploded!
The goal of an IRB is to ensure protection of the rights and welfare of human research subjects. Yes, this includes physical well-being but also IRB’s must consider the importance of quality of life, spiritual benefit, psychological state, social conditions, as well as scientific benefit. This is challenging because it may not always be about how patients may benefit, but what they may be giving up.
The reason I enjoy IRBs is because when you consider the first principles of thinking, the fundamentals, and at the core of what they are designed for it is really about evoking a conversation rather than the rule.