Ethical Principles in Clinical Research Part 4 of 4

Who speaks in this episode?

• Christine Grady (Main speaker)

What is discussed, and when

1. 0:00 – 5:00: Christine Grady, Belmont report, Common Rule
2. 5:00 – 10:00: Common Rule, Christine Grady, Belmont report, IRB
3. 10:00 – 15:00: IRB, Christine Grady, Belmont report, Common Rule

Notable quotes from "Ethical Principles in Clinical Research Part 4 of 4"

• Importantly, the Belmont report says, and this is important to keep in mind, that interests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research.

  about Belmont report · at 6:09

• One of the things that I've worked on in my career has been a payment to research participants.

  about Christine Grady · at 7:16

• In the United States, this is done by IRBs, and the criteria in both the Common Rule and the FDA regulations are the same.

  about Common Rule · at 8:51

• You also have oversight from the Office of Human Subjects Research Protection, or OHSRP, which holds the federal-wide assurance for the NIH intramural program.

  about NIH · at 9:50

• The same study reviewed by a number of different IRBs often, not often, but often enough, come out with varied interpretations and that's problematic.

  about IRB · at 11:15

• The Nuremberg Code starts with this tenet of voluntary consent of the human subject is absolutely essential.

  about Nuremberg Code · at 12:35

Who and what is mentioned in this episode?

People

• Christine Grady — Person · Main speaker · 3 mentions · first at 0:18
  She delivers an extended ethics lecture outlining principles for ethical human-subjects research (e.g., fair participant selection, risk-benefit, independent review, informed consent).

Companies & orgs

• NIH — Company · Business focus · 2 mentions · first at 9:46
  National Institutes of Health is mentioned as an entity conducting and overseeing research, with specific oversight mechanisms.
• Office of Human Research Protections — Company · Case study · 1 mention · first at 9:37
  Entity responsible for oversight of human subjects research under the Common Rule, discussed in the context of regulatory compliance.
  For those who are doing research under the Common Rule, there's oversight from the Office of Human Research Protections, which is OHRP, which is part of the Department of Health and Human Services.
• Department of Health and Human Services — Company · Headquarters · 1 mention · first at 9:44
  Parent organization of OHRP, mentioned in passing as part of the regulatory structure for human subjects research.
  For those who are doing research under the Common Rule, there's oversight from the Office of Human Research Protections, which is OHRP, which is part of the Department of Health and Human Services.

Concepts & topics

• Belmont report — Concept · Core topic · 3 mentions · first at 0:39
  Foundational document outlining ethical principles for human subjects research, frequently referenced in the discussion.
• Common Rule — Concept · Framework · 4 mentions · first at 3:13
  Regulatory framework governing human subjects research in the U.S., mentioned in relation to vulnerable groups and IRB review.
• IRB — Concept · Key argument · 3 mentions · first at 8:51
  Institutional Review Boards are central to the ethical oversight of research, discussed extensively in the context of participant protection.
• Nuremberg Code — Concept · Referenced work · 1 mention · first at 12:35
  Historical document setting ethical standards for research, cited as a foundational text in the discussion of informed consent.

Full transcript with timestamps

0:18 Christine Grady: The fourth principle is fair participant selection. And this is basically the idea that the scientific objectives of a particular study, in other words, what the question is and how it's designed, should guide the inclusion criteria, the recruitment strategies, and the selection of participants. And we should avoid, based on Belmont report recommendations, avoid privilege, driving who we select, or easy availability or vulnerability. I have a colleague who likes to think about this as flipping it on its head.

0:58 In other words, everybody should be included unless there's a justification to exclude. So no exclusion without justification. And when you think about those things, the kinds of things that might exclude somebody from a study would be that they're not scientifically appropriate. There may be risk-based exclusion justifications and more controversial but sometimes appropriate exclusion based on vulnerability, but scientific objectives driving the selection of participants is not the full story in terms of fair subject selection or fair participant selection.

1:36 There isn't also a need ethically to fairly distribute the harms and benefits of research. So not always ask the same people to accept the harms for benefits that may or may not go to them, and make sure that there is a sense of the distribution of the harms and benefits of research, both the conduct of it and the results of it. Interestingly, historically, if we look at the way research has been considered for a long, long time, and even still today in some respects, research has been considered a burden, and therefore we need to protect participants in the conduct of research, and that's the main emphasis.

2:19 But as I mentioned earlier, research can also be a benefit. And when thought of in that way, participants need and often want access, both for their own potential benefit in a research study, happens frequently, but also for their sense of contributing to projects that might help people like them in the future. So understanding, enrolling people with a certain serious illness so that even if they don't participate, they might be able to find answers that will help future generations of people with that illness. There are a number of challenges in participant selection.

3:05 I already mentioned the protecting of vulnerable groups. There have been debates about who exactly is vulnerable. You saw earlier the subparts to the Common Rule that for prisoners, pregnant women, and children, those are considered vulnerable and therefore have separate subparts to the Common Rule. However, there are other people who could be vulnerable in research. And if you look at lists of people who might be vulnerable -- Think about, for example, people at the end of their life. Think about people in the military.

3:42 Think about people who can't, adults who can't give their own consent. There's a lot of possible groups of people who are vulnerable. And we should think about when it's appropriate to include them and when it's appropriate to not include them in research. There's also interesting challenges in terms of trade-offs. So the second bullet here is, An example, is it preferable to test an early, potentially risky, early meaning early in the clinical trial process, potentially risky therapy in healthy affected adults who can consent but have milder disease because they've lived that long or test the same early potentially risky therapy in severely ill infants who are otherwise likely to die as infants and therefore if they do benefit could benefit a lot from the intervention.

4:36 That's a challenge that comes up and others like that. And then there are other examples like, you know, when should a study enroll pregnant persons? Something that people have been debating for years and the world has changed in terms of thinking that enrolling pregnant persons is a good thing, but it's not just straightforward about just enrolling them any old time. It's got to be thought through in terms of design and risk. The next principle is favorable risk-benefit. So the questions to ask are, are the risks to the participants or the subjects necessary in order to answer the question and minimized?

5:19 And then are they justified by benefit to the individual subjects or by the importance of the knowledge to society, or in other words, the social value, the valuable scientific question? Are the risks, can the risks be justified by that? And the answer is say sometimes can, But this requires a fair amount of careful judgment about what the risks are, how they can be minimized, and whether they're justified. The final question to evaluating favorable risk benefit is, are benefits enhanced? Can they be enhanced for the participants more than they are initially, or are they enhanced to the maximum extent?

6:03 This question, of course, is based on principles of nonmaleficence and beneficence. Importantly, the Belmont report says, and this is important to keep in mind, that interests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research. This basically is a way to point to the fact that research that has no prospect of benefit for the individuals in the project can be justified. If the social value is sufficient, and the subjects' rights and welfare have been protected.

6:42 Lots of interesting challenges in figuring out the risk-benefit ratio of any particular project. One is identifying the risks. What are the appropriate risks that should be counted in evaluating risks and benefits in a research study? And then how do we go about minimizing or limiting them? And there are lots of literature on this. There's lots of great examples. I'll give you one example. And it comes down to this question of direct versus indirect benefits. One of the things that I've worked on in my career has been a payment to research participants.

7:22 And payment is considered by most people an indirect benefit of research. And part of the reason it is, is because if payment was a direct benefit that allowed for the justification of risks, then you could just continually increase the amount of money to allow for an increase in the amount of risk. And that's not the way we generally think about this trade-off between risks and benefits. As I mentioned already, once risks are identified and benefits are identified, then there's a judgment that needs to be made both on the part of the investigator themselves, the team that they work with, the IRB and others who review the research, and the participants who decide whether or not they want to participate, there needs to be a judgment about whether or not the level of risk or the risks entailed in a particular study are worth it, given the prospect of either individual benefit or benefit to society.

8:31 The next principle is independent review, and this is basically done to ensure that ethical requirements have been fulfilled, including the regulatory requirements, to check investigator biases and potential conflicts, and to assure the public that research is not exploiting individuals or groups of people. In the United States, this is done by IRBs, and the criteria in both the Common Rule and the FDA regulations are the same. Basically, they require that risks are minimized to the extent possible, given the scientific design, that they're justified by anticipated benefits, if any, to the subjects or the importance of the knowledge to be gained.

9:15 In other words, again, the social value of the study. That subjects will be selected and treated fairly and that informed consent is adequate. And you'll see that all of these I've already covered in some of the principles that I'm talking about except for the last one, which I'll get to in a minute. For those who are doing research under the Common Rule, there's oversight from the Office of Human Research Protections, which is OHRP, which is part of the Department of Health and Human Services. And if you're at the NIH research, you also have oversight from the Office of Human Subjects Research Protection, or OHSRP, which holds the federal-wide assurance for the NIH intramural program.

10:02 And the links are there on this slide. Many challenges to IRB review. I should say that across the world, there are IRB entities. They are often not called IRBs. They're called often research ethics committees. Similar concept, sometimes follow similar rules, have different scope of authority in different jurisdictions. But the challenges still exist. There's questions about what is a good quality IRB review? There are a lot of people who are trying to measure that. Sometimes IRBs have an enormous amount of studies to review.

10:45 The volume is intimidating, and they don't get to spend much time on any one particular project. There are sometimes conflicts that need to be acknowledged and addressed, conflicts of interest between the reviewers and the researchers or sponsors or other kinds of conflicts that could come to bear. There's been data to show that IRB review sometimes is inconsistent. The same study reviewed by a number of different IRBs often, not often, but often enough, come out with varied interpretations and that's problematic.

11:26 Some of that had led to changes in the Common Rule and in the NIH policies about review for collaborative research or multi-site research. So that now, required by the Common Rule and by the NIH, when there's a study that's being done at multiple sites, it needs to be reviewed by one single IRB and other institutions should rely on that IRB for the review. This is not true when it's international sites, it's only domestic sites. And it's raised a lot of interesting, I think, efficiencies but also challenges in terms of how this review ought to be done and how it applies to different institutions.

12:09 The seventh principle in the framework is informed consent. Informed consent basically ensures that individuals have the opportunity to decide whether or not they want to participate in the research or continue to participate, and whether it's compatible with their own goals, their values, and their interests. And this is based on a principle of respect for persons. It shows up in almost all codes and regulations. These are just two selected ones. The Nuremberg Code starts with this tenet of voluntary consent of the human subject is absolutely essential.

12:43 And SEAMS also says investigator must obtain the informed consent of the prospective subject or authorized representative. The regulations that govern US-based research and US-funded research also very clearly say the informed consent of the prospective subject or authorized representative must be obtained. Belmont, of course, says to the extent capable Participants should be given the opportunity to choose what shall or shall not happen to them, but also goes on to recommend extra protections for those who have a limited capacity to consent.

13:24 And this is something that comes up in the regulations, which allow for a legally authorized representative or an LAR to consent for people who cannot consent for themselves, including children and adults who don't have the capacity of consent. Informed consent, meaningful informed consent, has a number of different sub-parts or elements to it. There's disclosure of information, which has to be adequate and clear. The person who's receiving the information has to have the capacity or the competence to both receive it and understand it.

14:04 They have to understand it to some level. And then they have to make a voluntary choice about whether or not they want to participate or continue to participate, and then demonstrate that choice in some way. In the United States, most of the time, informed consent is documented on a written form. These days, it's not always only paper. There are electronic means of documenting informed consent. but there needs to be some documentation that the person actually gave their voluntary informed consent based on understanding to some extent the information that was provided to them.

14:46 There are a number of challenges to informed consent. One of them is what I call the quality of informed consent. Again, there's been plenty of evidence to suggest that people who sign the forms and enroll in research don't always have a full understanding of the things that they should understand. There's debate about what should they understand. Certainly you would think that a person should understand the risks of what they're doing and the potential benefits. Certainly you hope they understand that this is a voluntary choice that they get to make.

15:19 But the data that exists suggests that that's not always the case. And so we have to do better at both providing information but also assessing understanding. There's lots of challenges around capacity to consent. We at the Clinical Center have a service which provides an assessment of a person's capacity to consent. There are tools out there that others at other institutions can use, but it's not a black and white kind of assessment. It requires some judgment and some clear evaluation of somebody's capacity. What we look for generally is understanding of what the choices that they're being asked to make, reasoning about that choice, and a voluntary choice whether or not to do it.

16:09 There are approaches to informed consent that are changing. There are things like people talk about broad consent, which is a way to give consent for the future use of your data or biospecimens that are not specified today, but you can give a broad consent for their future use. This is often monitored by some kind of an oversight body that looks at what the research is going to be done with those specimens. But it's something that has been contentious over the last decade or so. And there are lots of changing research methods, which I mentioned earlier.

16:51 I think challenging big data. How do we give consent? How do we know we've given consent for the use of big data? I also mentioned, for example, decentralized trials the issue of remote consent that's happening in a lot of cases. So there are different challenges that exist today that didn't exist long ago. The last principle on the framework is respect for enrolled participants. And this is a really important one that has really not been given a lot of attention in the ethics literature. We put it in the framework because way back then, people were saying, okay, you get a person's informed consent and then you have your, I mean, sorry, you get your research project approved by the IRB and then you get a person's informed consent, you're done with the ethics.

17:45 And that clearly cannot be the case because you're just beginning an engagement with a human being for the course of the research and whatever the research entails in the end. So there are lots of things that are required ethically as a research study is ongoing, including protecting the confidentiality of the participants, monitoring their welfare, recognizing the right to withdraw at any time, providing new information as it's relevant to their decision to continue, informing them of the findings at the end of a trial, and planning for what happens after the trial is over where people often need transition back to care or some access to the intervention that was studied in the trial.

18:33 There are lots of challenges under this principle. I'm just going to name two, because these are things that I think are really important, and we haven't given them enough attention. Providing information and results. People volunteer to participate in a study. They participate for a month, a year, 10 years, and they often never hear what happened, what the findings were, what the results were. I think that's ethically problematic. People should. be able to get information about what happened, what was learned from their participation, from their contribution. There are ways to do that.

19:09 We don't do it very well. The second thing on this slide is post-trial access to interventions. A huge issue in some trials where people are benefiting from the intervention that they're receiving in the trial, then the trial ends. How do we put into place mechanisms for them to have access to the intervention especially before it's approved and available in the commercial market. Something that many people have been working on for the last decade or so, and we've come a long way, but we still have a long way to go.

19:46 So again, the eight principles, collaborative partnership, social value, scientific validity, fair subject selection, risk benefit, independent review, informed consent, and respect for enrolled subjects. Following this framework allows someone to both put together a research study, evaluate a research study, and evaluate it as it's ongoing. This framework, as I mentioned, is systematic or meant to be systematic and sequential. You have to first figure out who the partners are and what the important question is to ask before you ask anybody for their consent, for example.

20:27 It's necessary to consider each of the eight elements of the framework. It's not necessarily true that every one of them is relevant to every study. And I wrote here, procedural requirements may be waived. There are examples of studies for which waiving informed consent is ethically justifiable, but it has to be thought through very carefully and justified. They're universal, and we say that meaning They apply to all kinds of research across designs, across methodologies, across time, and across jurisdictions. Yet sometimes the specifics of how it's applied need to be adapted and implemented according to the context in which the research is being done.

21:14 They often require balancing. In other words, in some cases, the scientific validity is really important, but it affects the risk-benefit ratio and so it requires some back and forth in terms of figuring out how to minimize risk without interfering with the validity of the science. Requires specification. How do you identify the risks? How do you identify the benefits? How do you weigh them? Requires judgment and it requires judgment from hopefully informed investigators, IRB members, and others. Here's some resources for further information, and thank you for your attention and your time.

Questions about this episode

Who speaks in "Ethical Principles in Clinical Research Part 4 of 4"?

Christine Grady (Main speaker).

What is discussed in "Ethical Principles in Clinical Research Part 4 of 4"?

In order: 0:00 Christine Grady, Belmont report, Common Rule; 5:00 Common Rule, Christine Grady, Belmont report, IRB; 10:00 IRB, Christine Grady, Belmont report, Common Rule.

What is mentioned in this NIH VideoCast episode?

8 people, works and ideas are mentioned, including Christine Grady, Belmont report, Common Rule, IRB, NIH, Nuremberg Code. Each one on this page links to its own page with every episode that mentions it.

How long is "Ethical Principles in Clinical Research Part 4 of 4"?

The episode runs 22 min; the transcript is about 3,049 words in 30 timestamped sections.

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