... Crossing the Chasm: Lessons Learned Across Medical Technologies...

... The U.S. Food and Drug Administration has several programs intended to help innovative technologies through the regulatory process, including the Total Product Life ...

... compared with the number of people who could benefit from them due to several barriers, including regulatory issues, reimbursement challenges, and some resistance within the Deaf community. (Mann Woods)...

... Responsive neurostimulation has faced challenges in adoption due to relative complexity of programming and high patient burden compared to devices with similar outcomes—emphasizing the advantages of collecting long-term seizure data could be key to ...

... Multiple barriers, including regulatory, referral, and reimbursement, have prevented deep brain stimulation from becoming widely adopted for the treatment of obsessive-compulsive disorder. (Greenberg)...

... 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 ...

... Helen Mayberg, the director of the Nash Family Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai, opened the workshop by saying, “We are actually not talking about science today,” but rather about what is necessary ...

... In treating patients with implantable brain stimulation, Mayberg said, five categories of questions must be answered:...

... Why is it needed? What are the specific symptoms and side effects?...

... What should happen? Should a circuit be activated or blocked? Should the stimulation be delivered continuously or intermittently? How will things change over time?...

... How should the stimulation be implemented? What are the parameters? Should it be integrated with other treatments? What should rehab involve?...

... how to scale up the intervention in such a way that it has the biggest impact on the most people. This involves determining patient eligibility and the best way to implement the therapy on a large scale....

... Denison first provided some background, noting that in Europe alone brain diseases affect tens of millions of people a year and have a total cost of hundreds of millions of euros per year (DiLuca and Olesen, 2014). He then discussed where implantable brain technologies are in ... process of moving from research into practice. To illustrate this process, he showed an adoption curve (adapted from Moore, 2016) and indicated where different technologies fell on that curve....

... Deep brain stimulation (DBS) is still in the realm of pilot research, being carried out by early adopters and visionaries but not adopted in mainstream clinical practice in the way that cardiac pacemakers and cochlear implants have been. In this model of ... , a chasm exists in the adoption curve between pilot research and mainstream clinical practice, for which a path is needed for uses proven to be safe and effective to cross that chasm to move from early demonstrations of the technology’s effectiveness to widespread adoption, said Denison. The chasm, ... explained, represents the transition from thinking about a technology as advanced care to standard care....

... Brian Litt, Perelman Professor of Neurology and director of the Center for Neuroengineering and Therapeutics at the University of Pennsylvania, set the stage for the workshop with a look at a possible future for implantable brain stimulation and ...

... with brain stimulation: patients with new onset idiopathic Parkinson’s disease, focal seizures, familial depression, congenital hearing loss, and blindness from macular degeneration. Today, he said, all of the devices used to treat these patients are therapies of last resort. “In 2040,” he ... may be poorly classified so that they work in some but not in others, while in this future scenario clinicians will be much better at individualizing and targeting therapies. Neuromodulation treatments are now carried out at specialty centers, but in 15 years they may have moved into the mainstream. ...

... Litt identified six factors that may impact the adoption of neuromodulation technologies into the standard of care: effectiveness; acceptance by patients and clinicians; risk, morbidity, and measurable outcomes; complexity; regulatory issues; and total ...

..., he said. The theory of heart pacing was first sketched out in 1889, but it was not until 1958 that the first wearable external pacemaker appeared, and 1960 for the first implantable pacemaker—a latency period of about 70 years from theory to practical devices (Aquilina, 2006). In the ensuing six ... the devices have become increasingly simple and more effective. By 1996, the MADIT trial showed that implantable defibrillators increased survival, with a relative risk reduction of 59 percent ... with standard therapy (Kedia and Saeed, 2012). Today, Litt continued, pacemakers prolong life by 8.5–20 years, depending on the study. Their risk is low, the operation to implant ... pacemaker is simple, and they are accepted almost universally, said Litt. The regulatory pathways governing them require clear evidence of safety for these complex systems ... failure could be life threatening. This means, Litt continued, that each component of these devices (software, hardware, patient and caregiver interfacing systems, charging, long-term performance) must be carefully reviewed and approved. However, companies that regularly build and ... approval for these devices have a comprehensive understanding of these pathways and requirements and they may also seek the advice of regulatory consultants who can provide...

... additional guidance, he added. A pacemaker’s total value is high in terms of decreased hospitalizations, decreased cost of medications, and of lives saved. This could be best exemplified by the indication for both pacemakers and defibrillators which is primary prevention, Litt said....

... Litt summarized several lessons and observations from the pacemaker story: multiple factors drive adoption, the development cycle is shortening, knowledge of the biological circuits is ... , double-blind, controlled trials that provide class I evidence supporting the therapy are necessary, and development takes time and money....

... LESSONS LEARNED ACROSS THERAPEUTIC AREAS...

... lessons learned from the use of different technologies for various disorders that might be applied to implantable brain stimulation: U.S. Food and Drug Administration (FDA)-approved neuromodulation therapies,1 cochlear and retinal implants, responsive neurostimulation for epilepsy, and DBS for ... -compulsive disorder (OCD). Each speaker provided an overview of the therapy and the patient need that was being addressed and shared insights into why that particular therapy has or has not been adopted into clinical care....

... Vivek Pinto, the director of the Division of Neuromodulation and Physical Medicine Devices at the Center for Devices and Radiological Health (CDRH) at the FDA offered an overview of approved neuromodulation therapies....

... The FDA has approved several neuromodulation devices under its premarket approval (Parkinson’s disease, essential tremor, and epilepsy) or humanitarian device exemption (dystonia and OCD) programs. On the “crossing the chasm” curve that Denison displayed, Pinto said that ... ’ stage, which means that for most of them, significant work needs to be done before they can be adopted more widely. It is important to understand what barriers stand in the way of this broader diffusion of the technologies, he said....

... Beyond that, CDRH would like the United States to be a world leader in regulatory science and device innovation and help facilitate device approval or clearance, and to ensure that consumers, patients, and their caregivers and providers have access to ... science-based information about medical devices and that they use this information to make health care decisions. He emphasized the steps the CDRH and FDA are taking to be proactive, saying “when we see things getting in the way, we want to look at policies, procedures, structures so we can do ...

... Showing an organizational chart of the Office of Neurological and Physical Medicine Devices, which contains his division, Pinto said that the Division of Neuromodulation and Physical Medicine Devices (DHT5B) had ... , DBS was being tested as a treatment in a growing number of disorders. The new organization includes teams that focus on specific clinical areas and examine any treatments that are used in their area of responsibility. For example, Pinto’s division has four teams: (1) neurostimulation— ... , (2) neuromodulation—psychiatry, (3) physical medicine—acute injury, and (4) physical medicine—neurodegeneration. The neurostimulation–neurology team is responsible for DBS and noninvasive devices used to treat ... ’s disease, epilepsy, headache, and movement disorders. The office reorganization is only one part of the solution, he said, but “we want to adopt to things we see going on in the ...

... Pinto said that while DBS is recognized as having the potential to alleviate symptoms and improve the quality of life for patients with debilitating conditions, CDRH is experiencing some “short-term struggles” related to the technology. ... For instance, there are different risk-benefit profiles for different specific populations and subpopulations. There are also concerns about which are the most clinically meaningful assessment tools and outcomes. Importantly, Pinto emphasized ...

... CDRH is looking for ways to accelerate the realization of its vision, Pinto said, and he listed three programs intended to help with that: collaborative communities,2 the Breakthrough Devices Program,3 and the Total Product Life Cycle ...

... 2 For more information on the collaborative communities program, see https://www.fda.gov/about-fda/cdrh-strategic-priorities-and-updates/collaborative-communities-addressing-health-care-challenges-together (accessed November 26, 2023)....

... 3 For more information on the Breakthrough Devices Program, see https://www.fda.gov/medical-devices/how-study-and-market-your-device/breakthrough-devices-program (accessed November 26, 2023)....

... 4 For more information on the Total Product Life-Cycle Advisory Program, see https://www.fda.gov/medical-devices/how-study-and-market-your-device/total-product-life-cycle-advisory-program-tap (accessed November 26, 2023)....

... will have access to it. One challenge for the FDA, Pinto continued, is that the agency does not get enough information on the patients’ preferences and the level of risk they are willing to take. Additional patient information and having their voices be heard will be needed to help in the FDA’s ... making, said Pinto. Overall, he concluded, the FDA is dedicating effort and resources to hear from many different perspectives to inform its programming and strategic planning....

... Cochlear Implants and Retinal Implants...

... Carla Mann Woods, the chief executive officer of Mann Healthcare, and a member of the board of counselors at USC Viterbi School of Engineering, spoke about the adoption of cochlear implants and retinal implants to gain insight and lessons that might apply to the adoption of ...

..., and to answer that, she began by looking at the barriers that influenced that adoption. The first barrier was the regulatory system, which gradually expanded the population that could be fitted with cochlear implants, beginning with adults with profound bilateral hearing loss in 1984. Since then, the ...

... A second major barrier in the adoption of cochlear implants is insurance and cost, Mann Woods said. With 21 percent of U.S. adults and 36 percent of U.S. children on Medicaid, she explained, lack of coverage has had a huge limiting effect in cochlear access. “To this day, 40 ...

... 2-1 Chronology of regulatory approval for cochlear implants. (A) Time-line of regulatory approvals of cochlear implants. (B) The population of candidates who are approved to receive cochlear implants has increased with each regulatory approval but remain a smaller proportion of the total ...

... SOURCES: Adapted from figure presented by Carla Mann Woods on October 31, 2023. Data from Goman and Lin (2016)....

... Another 18 percent of the U.S. population is on Medicare, and while the FDA approved cochlear implants for adults with moderate hearing loss in 2002, it was not until 2022 that Medicare allowed payment for ... implants for those patients. That was a huge number of people who would have been suitable candidates, Mann Woods said, which means that Medicare’s refusal to pay for them had a huge impact....

... other cochlear implant services (e.g., postoperative care) as well, she added. Private insurance covers costs adequately, but it is up to employers and plans as to whether to include coverage....

... All of this serves as a disincentive to providers, Mann Woods said. It is expensive to run a cochlear implant program, and, due to the reimbursement limits, the pool of patients who can afford the implants is limited. Furthermore, postoperative care, rehabilitation, and ... support. Yet another issue is that many people with hearing loss end up at hearing aid dispensaries, where the workers are not trained, do not understand who a candidate for a cochlear implant is, and work on commission, resulting in minimal referrals for cochlear implants. As a result, there are fewer ...

... A fourth barrier is the fact that the general population and even the medical community have low awareness of cochlear implants and who is an appropriate candidate....

... Mann Woods explained the result of all these barriers is that there has been profoundly low penetration of the technology—less than 10 percent of candidates who would benefit from cochlear implants ever get one. So, she said, while many people think of cochlear implants as a success, and while it ... is an accepted technology and a covered technology, it has not seen nearly the success that it could have. Only 200,000 Americans have received cochlear implants since 1985, ... with many millions who could have benefited and Mann Woods continued, even today, just 50 percent of candidate children receive an implant, and less than 5 percent of candidate adults do (Nassiri et al., 2022)....

... Mann Woods then spoke briefly about retinal implants, which were developed by Second Sight, a company that was founded in 1998 and filed for approval for its Argus-II retinal prosthesis in 2009–2010. It is mainly a regulatory story, she said. After the company completed its ... , the FDA changed the endpoints for approval and required that Second Sight conduct new trials designed around those new endpoints. The FDA then instructed the company to validate the new endpoints ... going to new trials. This technology was novel, Mann Woods said, and there were no previously established endpoints to define the benefit in this patient population. Ultimately, the submission was withdrawn, new trials ... done and submitted in 2011, and the FDA granted approval in 2013. But the after-the-fact change of approval endpoints may have depleted Second Sight of necessary resources and ... , in 2020, the company became unable to move forward. The company is still in existence under another name and owned by another company, but it is unlikely to recover, she added....

... to those at the end stage of their diseases. Carrying out clinical trials will help establish the benefit of these devices early in the paradigm and, Mann Woods continued, “as soon as possible will help open up the market in these applications.”...

... whose mission is industry-patient advocacy. In the case of cochlear implants, she said, “some of the recent advances in opening up the Medicare candidacy coverage to meet the FDA candidacy labeling that was 20 years after the fact were driven by new, dedicated organization for cochlear implants.” ... Furthermore, it is important to carry out cost-benefit trials early and in parallel with the regulatory trials. Developers will often see getting regulatory approval as the main milestone goal, she said, but it can take ...

... Mann Woods said it will also be valuable to establish referral pathways and providers. “It is very important to understand how those pathways go,” she said, and to understand the incentives or disincentives....

..., Mann Woods said, capital is crucial. “If you are spending too much redoing trials or unable to get reimbursement pay, then you lose capital.” And without enough capital, companies will lose the ability to deliver and support their products, to educate people about them, and to conduct ongoing ...

... the seizure onset zone, which typically involves sophisticated neuroimaging techniques. The device records the patient’s electroencephalogram (EEG) and uploads it to the cloud, where it can be reviewed by the patient’s doctor. The patient’s doctor will then program the device to detect the ... ’s seizures, and the patient will have a series of visits to optimize the delivery of stimulation when the seizure activity is detected....

... for RNS are implanted, Ganguly said. A total of 3.4 million Americans has epilepsy,5 of whom about 1 million have medically refractory epilepsy, and 575,000 have medically refractory focal epilepsy, making them candidates for RNS.6 Yet of those, only 5,000 patients have been implanted with RNS, ...

... 5 See, for example, Zack and Kobau (2017)....

... A major barrier to RNS is that simpler equivalents exist, Ganguly said. In many cases, surgical resection is the standard of care. And if a patient is not a candidate for surgical resection, neuromodulatory options such as vagal nerve stimulation, DBS, and responsive neurostimulation ...

...’ effectiveness is very similar. In controlled trials, both have a responder rate of about 75 percent (i.e., three out of four patients respond, and both have a 75 percent median reduction in the rate of seizures). DBS does not require an invasive presurgical workup, while RNS does. In real-world ... to perform better than DBS, Ganguly said. RNS uploads data to the cloud, while DBS does not. RNS has better a side-effect profile in terms of sleep and mood. But perhaps the biggest difference between them, Ganguly said, is that RNS records long-term EEG recordings, as long as the patient reliably ... tracking are often known to be unreliable, but this data also requires time from a clinician to interpret—time that the clinician may not have and that may not be properly reimbursed....

... RNS’s complexity is a barrier to scaling for a variety of reasons, Ganguly said. First, it demands a provider learning curve, and providers may not wish to invest the time. The complexity also implies that clinicians are at least initially dependent on highly trained clinical ... the amount of time it takes to review this data.” Furthermore, the device is implanted only at level 4 epilepsy centers in the United States.7 And, finally, patient compliance is often poor, and clinicians rely on patients to upload their data....

... based on the number of seizures is short-sighted,” she said. “We know that long-term EEG can inform better surgical plans, elucidate cycles, and inform medication response, yet we give more weight to patient complexity and cost and patient burden.” Given the growing value of EEG data ...

... the use of the device, the titration of medications, and the understanding of epilepsy as a disease could reshape clinicians’ conceptions of RNS....

... available will require, for instance, implementing support systems using artificial intelligence or other technologies to review all the brain data and identify important information, “so we are not drowning in data.” That in turn will require “a lot of intersectionality from programmers and ...

... Deep Brain Stimulation for Obsessive-Compulsive Disorder...

... Benjamin Greenberg, a professor of psychiatry and human behavior at Brown University who also directs the COBRE Center for Neuromodulation at Butler Hospital, offered some thoughts about the use of ...

... care providers for DBS are the norm for OCD, Greenberg said. Referrals from clinicians are relatively rare even if a patient’s case is intractable and quality of life is poor....

... The attitudes of clinician groups vary, he continued. Psychologists and psychiatrists vary in the degree to which they see OCD as a brain problem. In particular, he said, even some behavior-therapy-intensive programs— ... his group refers patients to before surgery and after surgery—are not open to including neurosurgery of any sort in their treatment plans....

... On the regulatory side, Greenberg said, it is useful to think about the different barriers that dystonia and OCD encounter despite both having FDA approval under the humanitarian device exemption.8 He explained the barriers for referral and reimbursement are ...

... Multiple access and workforce issues affect OCD care, even conventional care, he said. “You can’t find an OCD expert psychiatrist.” Even in large medical centers, ... in the next generation of workforce coming in,” he said. Clinicians who also conduct research face increasing difficulties in both clinical life and regulatory burden. “That makes life difficult, if you want to try to do this,” Greenberg said....

... In terms of needs for the future, Greenberg pointed to combined centers that perform neuromodulation and other procedures, such as laser interstitial thermal therapy (LITT) for lesions. “Maybe if there is alignment across fields, one could have ... said. “We also desperately need long-term follow-up data to assess effectiveness, burdens, access to care, cost benefits, effects on functioning, and, what seems to be most important to patients, does this procedure, does this device in the case of DBS, help me to reach my life goals?”...

... In terms of advocacy, he pointed to the Focused Ultrasound Foundation as an “interesting model.” It is aggressive, well organized, and well funded in its advocacy for using ultrasound in various ways, he said....

... devices, which are currently difficult to objectively measure. He wondered whether technology such as mobile phones or smart watches would become standard for monitoring symptoms and prognosis though there would have to be efficient, cost-effective ways to analyze and utilize these large data streams....

... is promising,” although questions remain about how activity is going to be monitored. Also, he continued, in addition to patient self-reports and reports from clinical observers, additional information is needed from “informants”—that is, people who know a patient well and can offer ... about their symptoms and limitations. “I think we can do better than we do now,” he said....

... Funding Opportunities for Deep Brain Stimulation Procedures...

... Litt opened the discussion session by offering a question about funding to the panel: “If we are successful and there’s increased uptake for these devices, how are we going to pay for it?”...

... from Medicare, in his experience. “There is going to have to be a payment regime where the long-term benefit to a patient is key,” he said, “and we don’t have such a thing.”...

... Current Barriers to the Adoption of Implantable Brain Stimulation...

... to provide short answers to another question: “What is the single biggest barrier to uptake of implanted neuro-devices?” “Lack of knowledge and fear,” Greenberg said. “Lack of integration into standard of care,” Ganguly said, with which Mann Woods agreed, and added, insurance coverage ... awareness. Finally, Pinto spoke about patient acceptance of the procedures. Why are some patients more accepting of the technology, and what underlies the fear of the technology that some have? Litt raised the issue of effectiveness, suggesting that there may be a threshold that, once ... of other factors. Litt concluded that including participants in the conversations about implantable brain stimulation will also be important and this sentiment was reflected in the workshop’s ensuing discussions with individuals with lived and living experience....