University Times

Regenerative medicine and similar new biotechnologies are changing the role of subjects in human research, raising numerous moral and policy questions that must be addressed.

Nancy M.P. King

In a recent talk on campus, ethicist Nancy M.P. King said: “Most of what’s going on in regenerative medicine is first-in-human or early phase research. And what that means for the research subjects is starting to change because of the nature of regenerative medicine research.”

Regenerative medicine is a complex and diverse area of research that aims to understand the basic mechanisms of how living organisms grow and develop, she said.

“There’s a lot of discussion of ‘first-in-human’ trials and early-phase research, which focus on things other than being able to promise the possibility of direct benefit to patients who are research subjects,” said King, co-director of Wake Forest’s Center for Bioethics, Health and Society and graduate program in bioethics, and a professor in the Department of Social Sciences and Health Policy at the Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine.

Her Nov. 12 talk, “Ethics in Regenerative Medicine: What’s Old, What’s New, What’s Borrowed & What’s Blue Sky?” was part of the annual Nordenberg Lecture in Law, Medicine and Psychiatry series sponsored by Pitt’s School of Law and Center for Bioethics and Health Law.

King drew on the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research’s 1978 Belmont Report, which outlined ethical principles for human subjects research.

Its three basic principles — respect for persons; beneficence and non-maleficence; and justice — “all have to be balanced, but they carry equal moral weight, so there’s expected and inevitable tension,” King said.

Striving to balance the three “leads to lots of good-faith judgment calls,” she said. “This is what (institutional review boards) are hashing out with investigators all the time. And reasonable people may disagree about the proper way of cashing out all these principles in a given research setting. That’s why it’s absolutely essential to have good discussion,” King maintained. “That’s why conversation between investigators, oversight bodies like IRBs, potential subjects and their families and the general public is so critical.”

One area that must be addressed in translational research is “the point at which one goes from bench to the bedside, when one goes from doing research in the laboratory or animals to human subjects,” King said.

“How you decide when to do that and how to do that is an extremely important decision for the research process,” she said, suggesting that time may come when a researcher can answer ‘yes’ to the following questions:

• Do you have enough preclinical information so that the only way to learn more is to go to humans?

• Have you done enough to reduce the risks of harm to humans and to maximize the likelihood that the intervention is going to ultimately show benefit?

• Have you reached the point of irreducible uncertainty? “You can never eliminate uncertainty,” she said. “Is the amount of irreducible uncertainty small enough that it’s fair to offer human subjects research participation?”

• Do you have a design where you can learn both about whether it works and how it works?

• Is it possible to do adequate monitoring and long-term follow-up to gather the kind of information you need about the balance between harms and benefits?  “Long-term follow-up is way more important in novel biotechnologies than it may be in ordinary pharmacological research,” King said, citing recent news that a gene-transfer intervention for the blood disorder beta thalassemia began losing effectiveness seven years after patients had received the intervention: “For seven years, it worked really well then the effect started to degrade,” she said.

• Can you do informed consent properly? Can you make sure that the human subjects have reasonable expectations about what’s going to happen in their participation?

The path from the bench to the bedside often is not a straight one, King stressed. Despite the desire to move as quickly to human subjects as possible, responsible research may take U-turns and detours. “You have to be able to think about when it’s time to go back to the preclinical stage in order to learn more. Your funders and oversight bodies and the public have to understand that’s not a failure. That’s the way research happens,” she said.

“Early-phase research is at this very liminal point between preclinical and clinical work and you may have to go back to the lab. It’s important to realize that.”

She noted that the list of questions contains multiple value-laden terms: “Has enough information been reached? Is the uncertainty irreducible? Can we do adequate things? Can we have reasonable expectations? All of those are more evidence that there are value choices embedded in moving along a research trajectory. That’s again why it’s really important to have dialog and real conversation between investigators, oversight bodies, funders, potential subjects and the public.”

First-in-human trials involve beginning proof of concept, she said. “Gathering preliminary data that potentially signal efficacy is not the same thing as providing direct benefit to research subjects,” King said, alluding to stem-cell tourism that arises when some institutes encourage patients to come to them for treatment via patient-funded trials.

“There are a lot of places willing to say that research is going really slowly because the powers that be want to control answers that are already out there and they want to control the money and the outcome,” King said. “There are stem cell institutes that will give you stuff that you shouldn’t be able to have available to you,” she said. “That blurs the line between research and treatment and causes a great deal of confusion.”

Who should participate?

Another question is who should be the first subjects and why, she said.

Seeking the subjects who are most likely to benefit from the intervention often is the question that’s asked but is the wrong approach to early-phase studies, she said. “Potential for benefit is, at best, secondary in early-phase research … if you talk about who’s likely to benefit then you’re going in the wrong direction,” she said.

“Your human subjects are your partners in producing generalizable knowledge,” she said. “You want subjects for whom you can reduce the risk of harm and get really good data.”

Selecting healthy volunteers is the typical model for traditional drug-development research. Although the risk of harm can be minimized more easily and the data gleaned may be reliable, these subjects “may be too healthy to provide the data” researchers need in order to make the next step forward.

Using the sickest patient model, typical in oncology trials, seeks out subjects whose treatment possibilities have been exhausted. “These are folks who are not being asked to give up something that might work in order to enroll in research. And they may value the small possibility of benefit very highly and be less worried about the risks. But they may be at greater risk of harm because they’re so sick,” King said.

“It may be very hard to untangle the effects of their disease, the effects of their prior treatment and the effects of the experimental intervention in order to determine what is and isn’t working. So you have to balance between those things,” she cautioned.

First-in-humans trials always present more uncertainty than later phase studies because going from preclinical to clinical trials is a big step, King said, adding that animal models often are either not available at all or are imperfect.

The potential for benefit should be thought about in exactly the same way: “It’s not enough to simply say: ‘You may or may not benefit if you participate in this study.’ There needs to be more thinking about what the ‘benefit’ actually means.”

Using terms like cell therapy, regenerative medicine and gene therapy inherently blurs the line between research and treatment, she said. Likewise, the wording in some consent forms, ‘You qualify to participate in this research because you failed all standard treatments,’ sounds like ‘Nothing else has worked, so this is the thing that’s going to work.’

“So the way we talk about this is important,” she said. “It’s okay to hope for benefit as long as you don’t expect it.

“It’s difficult to negotiate between what you hope for and what you expect and what’s realistic for investigators,” King maintained. “Good communication is vital and over-optimism, hope and wishful thinking affects not only patients, subjects, their families and the press, but it affects researchers, providers, oversight bodies and funders too. So mistaking or confusing research as treatment … has a lot of potential sources in regenerative medicine research because you’re using patients as research subjects.”

Recently, after traditional treatments failed, a toddler in the U.K. with lymphocytic leukemia received an experimental treatment that combined gene editing with a transplant of T cells. “The baby has been pronounced cured by the press. But this was a wing and a prayer,” King said. “Nobody knows if it’s really a cure: It was definitely not enrolling this baby in a research study. The rationale was: ‘Nothing else has worked, so therefore why don’t we try this?’ — which is not the same as ‘This is somebody who is likely to benefit.’”

Reversibility

The question of reversibility comes up in regenerative medicine, even though it’s not a new question, King said. “Everybody has worried about reversibility for a long time but it may be especially acute in regenerative medicine interventions: If something doesn’t work the way you expect it to, can you undo it?”

A new normal?

As much as it may sound like science fiction, regenerative medicine might redefine what’s normal when it comes to organ function.

If a periodic injection of healthy cells can boost kidney function, staving off the need for dialysis or an organ transplant, are we moving toward a time where people simply can get a booster shot to improve their kidney, heart, pancreas or lung function?

“Regenerative medicine puts those possibilities on the table,” King said.

And might the love of technology drive out other fixes? “Should we quit worrying about climate change if we can make people more tolerant of heat and drought?” King asked rhetorically. It’s tempting if developing new technology seems more doable than tackling complex public health or public policy problems.

The advances new biotechnologies make possible are promising, and there are enormous pressures to move faster, she said. “Innovation exploits patients by promising speed that really is not possible,” King said.

“Right now, really effective replenishing, regrowing, replacing — like regenerative medicine is supposed to do — is pretty much blue-sky for most patient subjects. But the knowledge gains are enormous.”

Her conclusion in light of the rapid changes at play in regenerative medicine: “Slow and steady wins the race. And really good communication with everybody is going to be helpful, both to inform the public better and to get investigators more used to talking about what justifies their work in a very productive way with people who fund it and oversee it,” she said.

“All of this is changing so fast it’s hard to keep up with, so we all just need to just keep talking together about it.”

—Kimberly K. Barlow