Too often, IRBs review protocols that make scant mention of ethical questions and issues. If anything, these sections of a protocol are limited to standard language, which does not suggest that researchers have given ethics a thorough consideration. A multiple stakeholder group seeks to change this with a novel project involving a protocol ethics tool kit.

“There is almost always an ethics section in industry protocols, but it tends to be a boilerplate: ‘We’ll follow good clinical practice and IRB requirements and get consent from the legally authorized representative,’” says David Forster, JD, MA, CIP, chief compliance officer with WIRB-Copernicus Group of Princeton, NJ. Forster is one of 20 authors involved in a paper published about the tool kit.1

“We propose they go through all the issues we put into the tool and address them one by one,” Forster says. “It’d be a more robust and fact-based section.”

The ethics tool kit covers 11 essential elements, providing for each one a short explanation, specific points to consider, background information, practical examples, and references.1

While the ethics tool kit was designed to be used by investigators, it contains information that IRBs can use to make sure there is no missing information regarding ethics considerations in protocols, says Lindsay McNair, MD, MPH, MSB, chief medical officer and president of consulting services at WIRB-Copernicus Group. McNair is the physician editor for IRB Advisor.

“It’s a guide to what you have to think about and need included in the protocol,” McNair says.

Forster and McNair provide this information about the 11 essential elements that should be included in protocols:

1. Addressing the relevant question. “This item is sometimes addressed well and sometimes not addressed at all,” Forster says.

It’s about why the research is important and the knowledge gap that’s being addressed.

“It’s partly about the issue of the study’s design,” Forster says. “Maybe the study has been done and proven, and there is no need to put people at risk.”

2. Choice of control and standard of care. “This is one of the more important elements,” Forster says.

Sponsors make decisions about control regimens in light of existing standard of care. There can be a brilliantly designed protocol that puts people at risk, he adds. “What’s going to happen to potential subjects if they’re enrolled?”

For instance, certain placebo designs and wash-out periods can be too risky to ask people to participate in, he says.

“What we get in protocols is a description of the study design, but we never get a background statement of why this study design is OK,” Forster says. “And you need to look at the available standard of care; if a researcher’s doing a study in sub-Saharan Africa, there is a very different standard of care when compared with the studies done in the U.S.”

These kinds of issues can be addressed in protocols.

3. Choice of study design. “Usually there are a lot of discussions when a protocol is written about what is scientifically appropriate to do,” McNair says. “When researchers write a protocol, they write the conclusion and don’t show the work it took to get to that answer.”

When IRBs receive the given conclusion, they typically do not see the underlying decisions, explanations, and justifications, she adds. “These can answer a lot of the questions an IRB would have.”

Some larger academic research centers might have a separate study design review committee, but often there isn’t one, Forster notes.

The 11 essential elements were designed for all research settings, including those used in countries where there is a weak research structure, McNair says.

4. Choice of subject population. “This element is about using a population that could be considered vulnerable or selected for reasons of convenience,” McNair says.

Researchers need to say why they’re using that population for the study. For instance, if a researcher chooses to enroll prison inmates, is it because the study needs this particular population, or is it because they are convenient and largely willing to participate, she says.

Some of the past research abuses occurred because investigators chose to study vulnerable populations based on their convenience, Forster says.

“There is the Willowbrook study, which took place at a state institution for mentally disabled children,” he says.

At Willowbrook State School in Staten Island, NY, the mentally disabled children housed there had a 30% to 50% risk of contracting hepatitis A, according to the National Institutes of Health (NIH). (For more information on the study, visit

Researchers in the 1950s enrolled more than 700 Willowbrook children in a hepatitis study that included injecting protective antibodies into one group and withholding protection from the control group, and observing the children’s degree of immunity to hepatitis. But research ethicists point to how the study crossed ethical lines by deliberately infecting some newly admitted children with the hepatitis virus, the NIH paper says.

A more recent example of selecting subject populations based on convenience is when investigators do research in a location where no one has access to health insurance or care, so they enroll in the study to receive care, McNair notes.

5. Potential benefits and harms. “Sponsors clearly go through the thought process of minimizing risk, but all we’re left with at the IRB level is their conclusions,” Forster says. “The conclusion is embedded in the protocol, but we get no discussion about why a particular dose is acceptable risk or how benefits to community or subjects will be realized.”

6. Informed consent. “Usually, the protocol says we will obtain informed consent with good clinical practice,” Forster says.

But protocols say nothing about how participants’ capacity to provide informed consent could change over the course of study enrollment, he says.

For example, a study that enrolls patients with mild Alzheimer’s disease has subjects who may progress to dementia over a study’s three-year period, Forster explains.

It would be helpful to have sponsors think through this issue and include in the protocol specific actions that will ensure subjects maintain the capacity to provide consent, he adds.

7. Community engagement. This essential element is specific to research in developing countries and underserved communities in developed countries, McNair says.

“It’s about community engagement,” she says.

The idea also is to ensure that researchers consider the ethical implications of conducting research within a low-resource community and what it means to use that community and then take off as soon as the study is complete, McNair adds.

Community engagement means that researchers should have plans to meet with the community and be sensitive to a marginalized and socially sensitive community’s issues, Forster says.

8. Return of research results and incidental findings. This issue has become the focus of a working group of the Multi-Regional Clinical Trials Center (MRCT), which was involved in creating the protocol ethics tool kit, McNair notes.

The MRCT is developing detailed recommendations about what should be done after a study is over. “If you find things you didn’t expect, do you give the information to [professionals] who know what to do with it?” she says.

Research participants often want to know the findings of a study, so investigators could at least include information in the protocol about whether this information will be provided to them. They also could include information about how incidental findings are handled and whether participants have the ability to opt in or opt out of receiving incidental findings.1

9. Post-trial access. “It’s not that you have to give people access to a study drug after the study is over, but you need to have a plan before the study is over,” McNair says.

“Currently, protocols are silent on this issue,” Forster says.

Researchers should address the question of whether there is a plan in the protocol about providing post-trial access to medications, McNair says.

10. Payment for participation. “It’s the standard in the industry to not address this as part of the protocol and to leave it up to each site,” Forster says.

Although sponsors often include this information in the informed consent document, it also should be in the protocol, he adds.

“How much will you pay subjects to recruit them?” he says. “We might get a brief description, but no rationale, and we want them to say, ‘We’ll pay this amount because it’s a strain on their time or life.’”

11. Study-related injury. “This last essential element often is taken care of, but it’s just not included in the protocol,” Forster says. “Different countries have different requirements regarding insurance for clinical studies.”

Some nations require study participants to get insurance that will cover study-related injuries, for instance. “We want IRBs to see a full disclosure about this,” Forster says.


  1. Li RH, Wacholtz MC, Barnes M, et al. Incorporating ethical principles into clinical research protocols: a tool for protocol writers and ethics committees. J Med Ethics. 2016;42(4):229-234.