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Potential Next Steps to Move the Field Forward
HIGHLIGHTS
- Many patients who could benefit from deep brain stimulation must fight stigma and a system that is not always set up to direct them to the proper providers. (Ellis)
- Socioeconomic and demographic disparities in the use of implantable brain stimulation will need to be addressed if the technology is to become fully adopted into the standard of care. (Pulliam)
- It will be vital to educate the various stakeholders, including not only patients but also clinicians, researchers, and engineers, to have a more accurate and complete understanding of the technology and the barriers it faces. (Hammer)
- How an innovation gets through the regulatory system is vital to its success, and innovators should be working with regulators from early in the innovation cycle to smooth the new technology’s path to market. (Kelly, Lisanby)
- Reimbursement issues should be handled in parallel with regulatory issues. (Kelly, Lisanby)
- There is a need for more objective outcome measures, such as with biomarkers, in both the research and the regulatory arena. (Lisanby)
- Through collaboration, innovation, and optimism, the system can be changed. (Mahoney)
NOTE: This list is the rapporteurs’ summary of points made by the individual speakers identified, and the statements have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They are not intended to reflect a consensus among workshop participants.
Mayberg and Denison asked participants to reflect on the core themes and takeaways from the workshop and explore creative approaches or collaborations needed to move the field forwards toward the adoption of implantable brain stimulation into the standard of care across central nervous system disorders. Workshop participants also discussed the implications of comorbidities and opportunities to develop technologies and treatments to holistically treat patients.
A PATIENT PERSPECTIVE
Brandy Ellis, a neuromodulation patient advocate who has a deep brain stimulation (DBS) implant, shared her journey to treatment and perspectives on what’s needed to move the field forward. Before she received the implant as part of a clinical trial, she said, she had had 4 years of treatment-resistant depression. “I had tried 25 different medications, not including different dosages, different combinations.” She had also had 24 electroconvulsive therapy treatments, and she had been dropped as a patient by a half dozen psychiatrists.
“For me in the trial it was very much not flipping a switch,” she said, unlike the experience that Jon Nelson had described in Chapter 4. “I became a responder, which meant my depression rating scale had been reduced by 50 percent at 6 months.” By 21 months she was in full remission. She added that she agreed with Widge’s comment about the treatment not being curative but rather rehabilitative (Chapter 4). She has to work to maintain her mental health every day.
“I will say that the one side effect I did not expect was a nearly pathological desire to talk to anybody about patient advocacy, mental health, and DBS,” Ellis said. “I am now a fully functioning, healthy, happy, mood-appropriate, functional adult who supports herself and has good relationships, and has a full-time job. This is my bonus life, and I went from absolutely terminal treatment-resistant depression to this life that I have now.”
AN ENGINEER’S PERSPECTIVE
Chris Pulliam, an assistant professor of biomedical engineering at Case Western Reserve University, offered a few thoughts about increasing the use of DBS. First, he said, it will be important to address the presence of socioeconomic and demographic disparities in the use of invasive neurologic systems. “I don’t think there is a path toward broad adoption if we don’t wrestle with that topic,” he said.
Referring to Garrido-Revilla’s remarks (Chapter 3), he said that her observations about sex differences in DBS treatment are true. “That is something we understand is an issue, where women are maybe 20 percent or 30 percent less likely to receive DBS after they have been screened as good candidates,” he said. “And as a Black American, I’m much less likely to be a DBS recipient.” Geographical disparities also exist, with people from rural areas much less likely to receive these treatments than those living in major urban areas, particularly those with major medical centers such as Cleveland or Boston or Houston. “Grappling with [these] topics is something we have to take seriously,” he said.
Finally, as an engineer, Pulliam said he believes it is important to advance technological capabilities in a way that lines up with user need. New technological capabilities will make it possible to do many things that were not previously possible, such as data from sensors offering unique insights into physiology, but the emphasis should always be on improving care for patients.
A REGULATORY PERSPECTIVE
Doug Kelly, deputy director of the Center for Devices and Radiological Health of the U.S. Food and Drug Administration (FDA), began by describing his background, which included being a venture capitalist in Silicon Valley, starting several companies himself, and working as a physician and in a laboratory.
One thing about the workshop that struck him, he said, is how much it paralleled his own experience. “I know from a lot of therapy that I’m primarily driven by fear and anger,” he said. “When I hear Jon [Nelson]’s story, it makes me angry that he has to fight for his own care. It’s dehumanizing to do that. That drives a lot of my motivation to change a lot of things at the Food and Drug Administration.”
Then Kelly spoke about the FDA’s Total Product Life Cycle Advisory Program, or TAP. The idea behind it, he said, is to bring together different sectors from the beginning to provide early opportunities to collect input and feedback. He based the TAP program on lessons he had learned starting his own companies, he said, particularly the importance of answering
significant questions about a product and how it will make a profit early in the development process. He described TAP as “a consultancy inside the FDA” that helps innovators maximize their chances of bringing a useful and valuable product to market. For instance, he said, “Often the fastest way through the FDA may not be the best to get you the evidence you need. The evidence you generate is your biggest strategic advantage, your biggest competitive advantage. It may take a little more time to generate that, but you will suffer so much less failure and so much less time in unprofitability. You can’t have a product that makes it out to patients unless it is profitable, and people make money doing it.” The goal of TAP, he said, is to “figure out those things up front and figure out the most efficient path forward.”
A FUNDER’S PERSPECTIVE
When reflecting on the workshop discussions, Sarah Hollingsworth Lisanby, the director of the Noninvasive Neuromodulation Unit and the Division of Translational Research at the National Institutes of Mental Health, organized the themes into the four R’s: research, regulation, reimbursement, and real world. “When we think about the idealized pathway,” she explained, “you start with research, [then] get regulatory approval, reimbursement approval, and achieve real-world impact.” But the various opportunities and gaps discussed at the workshop complicate that simple picture, she said. “We need to redraw arrows. They are not just linear. Some have feedback loops.”
She then offered some of important things she had heard at the workshop relating to each of the four R’s. In the research arena, she said there is a need for better targets and objective outcome measures, perhaps with biomarkers (Alagapan et al., 2023; Deng et al., 2020). Concerning regulation, she emphasized how the FDA has programs such as TAP that accelerate the development of new technologies. “At the level of reimbursement,” she continued, “we have learned that it really should be done and thought about in parallel with regulatory approval,” noting that there are programs for parallel review at FDA and the Centers for Medicare & Medicaid Services. Another regulatory issue, she said, is the importance of looking at functional improvement, not just symptoms.
And at the level of real-world impact, she said, “I thought of the three Cs: clinicians, communities, and care disparities.” Clinicians need training and support, biomarkers that are scalable and reliable for guiding their decisions, and interdisciplinary collaboration. Concerning communities, she continued, “we have heard about lived experience and how that should really be centered in all of our thinking in this regard.” It is also
important to think about whether a device meets the needs of a community and as was seen in the example of the Deaf community’s response to cochlear implants, whether it is culturally sensitive. Concerning care disparities, she said, “we learned there are disparities in access, diagnosis, and treatment along lines of gender, race, and ethnicity.” Mental health or other health conditions can also impact a patient’s access to treatment, she said. “When we think about how that real-world impact should be informing the research that we do,” she said, “we should begin with the end in mind, so we end up with something that does have real-world impact.”
A CLINICAL RESEARCHER’S PERSPECTIVE
Hammer named three things she had identified as important during the workshop. The first was a “focus on broad education and communication among all the stakeholders here.” Certainly, the public needs to have a better understanding of what brain stimulation is and to realize that it is not “mad science” but something that has been around for decades, she said. In particular, patients need better education so that they can advocate for themselves and recognize when a procedure might be appropriate. Clinicians need to be better educated about how to integrate this technology into their own practice, added Hammer.
Second, she said, engineers need to work on making things simpler, not just for today’s technologies but for those in the future. As it exists today, DBS technology is not scalable. Making things more efficient is not always the most exciting thing to work on, said Hammer, “but it is something I think is really important for us to be focusing on.”
The third topic she identified was economic considerations. Overcoming the financial hurdles facing the technologies will require various approaches, including creating various incentives and making the devices more efficient, noted Hammer.
A HEALTH SYSTEM PERSPECTIVE
Mahoney agreed with Morrell’s comments that people in the field should be optimistic (Chapter 5). “We created this system, we can fix this system,” he said. “But it means we all have to . . . look across the aisle and not just maximize our position but [that of] all the stakeholders involved.”
A major hurdle to more widespread use of DBS is inertia, he said. “We are used to the way things are,” he continued. “I think if we change—we, the health system at large—I think we can bring more advances quicker and faster to the globe.”
DISCUSSION
Exploring the Importance of Patient Inclusion
Kelly highlighted that many people who work in health care do so to help their communities, which is why he participated in the workshop—because communication and putting the patient first are important. “One of the first things they teach in medical school,” he said, “is if you do tests and at the end of the day still don’t know what is wrong with the patient, ask. They will almost always tell you. It is a matter of listening.” That lesson applies to the development of implantable brain stimulation and other technologies as well. “People do not ask the patient enough, ‘What does this mean to you? Is this okay for you? Is this good for you?’”
Ellis responded to a question about what can be done to support giving a voice to patients and their groups. Patients absolutely can provide information about health care–related issues that is important to hear, she said. “There are some hard truths here,” she said. “The truth is that a lot of the burdens that are preventing adoption of DBS [from becoming] more widespread are because those burdens are put on the patients. The stigma of DBS is one of those things that is put on the patients. . . . We currently have to prove to our providers all the time that we really are sick. You know, they don’t believe us. We do have to jump through a lot of hurdles. When our symptoms don’t perfectly align, we are told we are wrong. . . . I have yet to meet a person with depression who has not been told they were malingering . . . that they just don’t want to get well.” Furthermore, she said, there is no incentive among providers to not just write prescriptions for the drugs that are pushed by pharmaceutical representatives. “I could not get a provider to write me a [prescription for] transdermal MAOI [monoamine oxidase inhibitor],1 which has been around for decades.” But if she went to too many providers, she was assumed to be provider-shopping or drug-seeking. “I was getting fired by my psychiatrists when everything they tried didn’t work. I was not referred for additional treatments for new technologies.” She was literally told that nothing was going to work for her.
Ellis also said that she found very few support options. People in her situation tend to get referred to the National Alliance on Mental Illness2
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1 MAOIs are a class of effective and well-studied drugs that include the first antidepressants developed. They work by inhibiting the action of monoamine oxidases, enzymes that remove dopamine, serotonin, and norepinephrine from the brain; thus, MAOIs act to increase the levels of dopamine, serotonin, and norepinephrine in the brain.
2 For more information on the National Alliance on Mental Illness, see https://www.nami.org (accessed January 18, 2024).
or the Depression and Bipolar Support Alliance,3 she said, but those organizations “don’t have resources for the atypical people.” They also cannot provide a list of providers who will provide acute care. “Try finding a psychiatrist right now who will take your call when you are in crisis,” she said; they will direct you to call 911. “As someone who watches the news, I’m not real confident in the 911 response to a mental health emergency.”
Even once she was enrolled in a clinical trial, Ellis said, she faced many obstacles. “My parents had to be willing to sign a payer agreement for over $75,000 for me to be admitted in case my insurance didn’t cover my inpatient stay.” Furthermore, her parents paid for her to move to Atlanta and supported her while she was out of work because clinical trial participants are not compensated. “So how do you get people who can’t work because they have to go to three doctor appointments a week?” she asked. “The assumption that we’ll be on disability is not accurate. The ability to get disability is a nightmare.” While acknowledging that she got incredible care and that she is “so thankful for this bonus life that I have,” Ellis noted that she had to agree to be experimented on and be awake during brain surgery to get that quality of care. “I got no quality of care before then,” she concluded. “That is what is preventing people from getting to DBS; [it’s] because we are killing them before they can.”
Kelly followed Ellis’s comments with a statement that it is important to make sure that patient advocacy is as effective as it can be. “Oftentimes patient advocacy is not very effective in changing the course of what therapies get adopted, how they are adopted,” he said. “Part of it is the way a lot of patient advocacy groups are founded. There’s some on one end of the spectrum that are hypercompetent and really good at getting message out, in Parkinson’s disease and diseases like that. There are others where the voice is much weaker. Part of the goal with TAP program as well is make sure we help those patient advocacy groups become better at having a big impact on what technologies get developed and how they develop.”
In response to Ellis’s comments, Mayberg spoke about the things researchers can learn from people who take part in clinical trials. “I see patients as collaborators,” she said. “I’m doing something to you, and you are giving something to me.” She also said that every patient in a clinical trial should get rehab to learn how to live with the implant. “Nobody gets a heart pacemaker and doesn’t get cardiac rehab,” she said. “Nobody gets their knee replaced or hip replaced or gets an insulin pump and doesn’t learn how to control their diet, learn how to exercise, get a physical therapist.” The same is true for implantable brain stimulation.
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3 For more information on the Depression and Bipolar Support Alliance, see https://www.dbsalliance.org (accessed January 18, 2024).
Reflecting on Opportunities to Move the Field Forward
A workshop participant asked what each panelist is planning to do as a result of participating in this workshop and how the workshop changed their perspective on what the field needs to do going forward.
Lisanby answered first and spoke about the need for objective biomarkers. In psychiatry, she said, when researchers doing clinical trials rely exclusively on subjective symptom-based diagnosis and outcome measures, it often leads to a significant amount of heterogeneity within diagnoses and comorbidity across diagnoses and fails to map well onto brain circuitry. Objective biomarkers can be used to reduce that heterogeneity and inform treatment decisions. She mentioned a paper published by researchers at Mount Sinai who identified an electrophysiological fingerprint associated with recovery from depression after DBS (Alagapan et al., 2023). That fingerprint was used to inform dosing so that the clinicians were no longer reliant exclusively upon subjective reports.
Kelly answered next and spoke about speeding up the approval process at the FDA and other regulators. “There’s lots of functions that happen serially that dramatically increase the time to get patient access to devices,” he said. “If we can integrate some of those things into FDA studies early on, . . . it is our responsibility to do that. Our public mission at FDA is timely patient access to safe and effective medical devices. We really need to redouble our efforts on that timely patient access. It is not okay when you have a process that takes 20 years from product ideation to accessibility.” The question, he said, is how to reduce those 20 years to ideally under 10 years, making the process similar in length to what venture capitalists are used to and thus making it more attractive to invest in this area. “Today really makes me want to redouble my effort and really dig into those relationships,” he said.
Hammer said that hearing some of the patients’ stories made her want to find ways to ease their burden. “I’m just starting my career and seeing patients, trying to build a research program,” she said. “I have always thought of community education as something that I will get to later.” Now, she continued, hearing about the importance of first-line providers such as general neurologists and psychiatrists being knowledgeable about these technologies, “I personally will probably change in terms of what I view as a priority.”
Pulliam said that the workshop discussions convinced him that the adoption of implantable brain stimulation or any other new intervention into the standard of care is not just about the research, but it is also influenced by factors beyond research, such as the health care system and the payer system. “What I would do differently, then, is to increase communication with our fellow agencies,” he said. “It is going to take all of us to
cooperate. No one of us can solve this.” He added that he would also be looking for ways to integrate the patient into all levels of the field, including the research level.
“I’m going to continue to cheer every single one of you on,” Ellis said. “I’m going to also continue to talk to anybody who will listen about . . . bioethics, post-clinical-trial responsibility, mental health care, patient advocacy.” She ended by saying, “I want all of you to continue to do the work you are doing because this is absolutely meaningful treatment that absolutely is critical for people to survive and enjoy life.”
Mahoney closed out the discussion period. “I’m inspired by opportunities and want to keep pushing forward,” he said. “I will do a better job with my colleagues across the country pushing them toward total value of care and little less [toward] fee for service. What I heard was, rather than following the scientific evidence, people like me follow the reimbursement evidence, so [I’ll be] trying to lead more on that.” Finally, he said, “Recognizing the importance of the patient is one of my biggest takeaways from today.”
CONCLUDING REMARKS
In her concluding remarks, Mayberg said, “My takeaway bullet point is angry but optimistic.” “Anger is a representation of impatience with things that are obvious and that you have the data, and nobody is listening. That is what makes people angry.” However, she said, seeing the individuals with lived and living experiences at the forefront of these conversations gives her optimism. While the path ahead may not be straightforward, she said, “we need to figure out how to capitalize [on the optimism].”
A second takeaway, she said, is the importance of getting all the clinicians, researchers, and engineers working together—psychologists, neurologists, physiologists, engineers, and so forth. “I’m inspired by Kevin [Mahoney] that there is a mechanism to set up pilot programs in this space,” she said. “That is my advocacy now—to do the science but to figure out how to actually get this into practice.”
Denison then offered his own takeaway. “The analogy floating around in my head for the day is, we have a jazz band where we have all the members of the band on the stage, but we are not yet playing the tune together. That requires us to do a lot more listening. Like a good jazz band, you are listening and building and going with the flow with your companions and accentuating but also giving up the stage as well and giving that notion of a band as being an ecosystem and being mindful. That is my takeaway, making sure I’m listening and not trying to have my trombone overpower the ensemble.”
Denison closed the workshop by acknowledging the patients who make his work and that of other researchers and clinicians possible. “The real
pioneers . . . are actually those first research subjects who volunteer to be the very, very first,” he said. “I think it is appropriate to close out the workshop to recognize them. They are the true pioneers supporting this entire ecosystem.”
