Deep Brain Stimulation as an Exclusion Criterion in Parkinson's Disease Studies: Time to Rethink?

Deep brain stimulation (DBS) has been part of the Parkinson's Disease (PD) toolkit for more than 20 years.1 Since then, an increasing number of patients have received DBS for management of PD motor fluctuations, parkinsonian tremor, and dyskinesias.2 As clinical experience with DBS for PD has deepened and more results such as the 2013 publication of the EARLYSTIM trial have supported earlier use of DBS, patients who develop motor complications have been referred for DBS at earlier stages of PD.3 Despite the growing number, DBS patients are underrepresented in PD research. Strong evidence supports the positive effects of DBS on cardinal signs of PD and motor complications; notwithstanding, several gaps remain to be filled in the understanding and management of PD, particularly concerning axial and non-motor symptoms, as well as disease modification.4 Clinical trials addressing these and other PD issues are essential, but will the findings be applicable to patients with DBS if this population is not represented in studies?5 We have some concerns with the lack of clarity on eligibility of patients with DBS in PD research. Patients with DBS generally are considered more complex than those without DBS. It is possible that by excluding these patients, clinical studies are incurring a selection bias, in which only candidates with greater potential for favorable outcomes are eligible.6 In addition, PD patients may feel discouraged from undergoing DBS if they have an interest in participating in PD research. Finally, Parkinson's clinical trials have difficulty meeting enrollment goals and so exclusion criteria should be carefully evaluated.5 The Parkinson Study Group (PSG) Functional Neurosurgery Working Group explored this issue. We reviewed the clinical trials registered on clinicaltrials.gov to investigate the eligibility of DBS patients. We also surveyed PSG members on their views of the enrollment of DBS patients in PD research and how these individuals might be managed in the setting of a non-DBS clinical trial. This viewpoint discusses our findings and the potential challenges and solutions for improving access to PD research for DBS patients. DBS neurologists are often asked the following questions by patients: Will I be able to participate in clinical trials after DBS? Or, in other cases: I have DBS, can I participate in research? The answers to these questions can be challenging and are rarely supported by evidence to help in the decision-making process. Using the search criteria detailed in Table 1, we identified PD studies completed between 2016 and 2020. A total of 251 were identified, of which 28 were DBS studies. Among the 223 non-DBS studies, 60 (26.9%), including 11 observational and 49 interventional studies, specified DBS as an exclusion criterion (Fig. 1). In most studies, the rationale for excluding DBS patients was not provided. From 92 drug trials, 28 (30.4%) expressed the exclusion of subjects with previous DBS surgery, ablation surgery, or prior intracranial procedures. Considering all types of non-DBS studies, in the majority (n = 147, 65.9%) of the studies the eligibility of subjects with DBS was not defined in the inclusion and exclusion criteria available on clinicaltrials.gov. It is concerning that more than half of recent PD studies do not mention the eligibility of patients with DBS. It is even more concerning that only 8 (3.6%) studies specifically mentioned that patients with DBS were eligible for participation. We conducted a web-based survey with quantitative and qualitative questions among all PSG members. The survey contained questions about participants' roles in PD clinical trials and in clinical care of DBS patients, and asked whether, in the respondent's opinion, DBS patients should be excluded from different types of PD research. Additional questions exploring their opinion regarding the most appropriate time interval between DBS implantation and trial enrollment, as well as stability of DBS settings prior to enrollment were included. Respondents could support their responses with comments. Individual responses were extracted to a database for analysis and the results are presented below to support our viewpoints. From a total of 115 respondents, 11 were excluded for not being involved in PD research. Among the 104 respondents included in the analysis, 59 (56.7%) were neurologists, 2 (1.9%) neurosurgeons, 29 (27.9%) research coordinators, and 14 (13.4%) clinical and research personnel, such as neuropsychologists, patient advocates, and PD research funders. Of this group, 75 (72.1%) respondents reported that they are directly involved in the clinical care of individuals with DBS. Only 8 (7.7%) of the included respondents suggested that patients with DBS should be categorically excluded from clinical research, whereas the vast majority, 96 (92.3%) did not agree with the systematic exclusion of DBS patients from clinical studies. Most respondents provided a rationale, which in general involved the following themes: (1) the increasing proportion of PD patients who have DBS, (2) the need to consider the possible synergism or interaction between the investigational product or intervention and DBS, and (3) the outcomes and safety in relation to DBS. In addition, participants suggested that a rationale for exclusion of DBS patients should be clearly stated when researchers anticipate that the inclusion of this population would affect the statistical analyses, outcomes, and interpretation of research findings. Another concern cited related to prescribing approved medications to DBS patients based on study results in which they were not represented. Would these patients experience similar benefits? Would safety and tolerability be affected? Considering the complexities of both PD and DBS care, the inference that a potential therapy will also benefit the DBS population becomes a conjecture.7 For instance, an intervention for gait may show a positive treatment effect in a carefully selected clinical trial population, and result in null or negative effects in patients with DBS. Clinical studies in PD encompass a broad spectrum of design, interventions, and endpoints. We acknowledge that enrolling participants with DBS would not be appropriate for certain studies. We, therefore, asked survey respondents what types of trials DBS patients should be allowed to participate in. A large majority (n = 88, 81.25%) suggested that patients with DBS could be included in observational PD studies. When considering eligibility for drug trials, opinions varied according to study objectives and types of interventions. For instance, 82 (85.4%), 73 (76%), and 66 (68.7%) stated that participants with DBS could be considered for clinical trials addressing non-motor symptoms, motor symptoms, and disease modification, respectively. When considering the types of interventions, 85 (88.5%) respondents indicated that studies evaluating exercise-based interventions should consider inclusion of individuals with DBS, while only 53 (55%) and 56 (58%) suggested inclusion of DBS patients in gene therapy/stem cell and non-DBS device studies (e.g., peripheral stimulators or pump or infusion therapies), respectively. There is more complexity to any given study when a more heterogeneous population is considered for inclusion8; therefore, investigators may need to carefully examine the frequency of DBS in the population of interest before considering eligibility. In some circumstances, such as disease-modification trials enrolling 'de novo' participants, people with DBS would not meet eligibility criteria.9 However, in many types of randomized trials addressing motor and non-motor features, randomization will control for treatment factors including the presence of DBS. In studies assessing the impact of interventions on focused non-motor symptoms, such as autonomic dysfunction, the risk of DBS affecting the outcomes of the study may be low enough to allow for consideration of this population.10 It may be challenging to predict a priori the enrollment of patients with DBS that will allow for a well-powered analysis and assessment of outcomes in this specific group of patients. This emphasizes the need for feasibility studies in the DBS population, or the need for planned subgroup analysis in this participant population. One important concern is the potential for changes to stimulation settings during the study, which may influence related study outcomes. However, most DBS patients use stable settings once the best combination of parameters has been found. In our survey, most of the respondents indicated that 3 to 6 months of stable DBS settings would be appropriate prior to enrollment in a clinical trial, with no significant differences between targets, when considering subthalamic nucleus (STN) (70.8%), globus pallidus internus (GPi) (73.9%), and ventral intermediate nucleus (VIM) (69.8%) stimulation. We also inquired about the timing between implant of DBS electrodes and enrollment. Overall, 43.7% of those surveyed indicated that 1 year should be the minimum interval between implantation and enrollment, followed by 28.1% who stated that 6 months would be the minimum interval. Concerns with stability of concomitant PD treatments is not new in PD clinical trials, since changes in PD medications and dose adjustments during clinical trials could affect disease symptoms and study results. Regulatory agencies, such as the European Medicines Agency (EMA), recommend that concomitant medication doses are stable for 4 weeks prior to study entry and that dosing is maintained throughout the study whenever possible.11 Unfortunately, it is not always possible to keep medication stable in PD studies, particularly for longer studies with years of follow-up. In those cases, the study protocol needs to prespecify how concomitant medications will be handled, and the analysis plan needs to address how the effect of the study intervention will be differentiated from adjustment in concomitant medications. We asked survey respondents whether stimulation should be considered similar to medication in PD studies and 74% responded yes, indicating that, in their opinion, stimulation changes should be handled similarly to medication adjustments in PD studies. There are many challenges related to enrollment of patients with DBS in PD research. However, considering the growing proportion of patients receiving DBS, it is essential to initiate a discussion on how to reduce the disparities in access to PD research. Despite the literature discussing methodological issues in PD research, and advising innovative approaches for future research,12 to our knowledge there are no formal guidelines recommending best practices in PD clinical trials design. To date, researchers have been left with no guidance regarding the inclusion of patients with DBS in clinical trials, and the appropriate methodology to reduce the impact of population heterogeneity and potential influence of DBS on study outcomes. Based on our review of the current trials landscape and the informed opinions of PD researchers and DBS clinicians, our viewpoint is that it is definitely time to rethink our current practices. Without the inclusion of DBS patients in research, it is incredibly difficult to derive guidance from the literature about best care practices in this population. One example is the guideline for physical therapy in PD, which failed to identify literature evidence to recommend physical therapy to PD patients with DBS due to lack of studies in this population.13 We would like to encourage the PD community and investigators to consider whether their ongoing and upcoming research projects could consider the inclusion of participants with DBS. None of the authors reports financial support or other financial conflict of interest related to the manuscript. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. C.A.: 1A, 1C, 2C, 3A. L.L.: 1C, 2A, 2B, 3B. P.A.: 1A, 1B, 2C, 3C. K.G.: 1C, 2B, 3A. J.M.R.: 1C, 2A, 2B, 3B. D.M.C.: 1A, 1C, 2A, 3A, 3B. S.M.: 1A, 2A, 2C, 3B. J.J.-S.: 1A, 1B, 1C, 2A, 2B, 3A, 3B. C.A.: none. L.L.: consultant for Mitsubishi Tanabe Pharma America, Inc.; grant funding from Parkinson's Foundation's Advancing Parkinson's Treatments Innovations Grant and an unrestricted grant from Sunovion Pharmaceuticals, Inc. to the Parkinson Study Group, Inc. P.A.: grant funding from The Michael J. Fox Foundation; consultant for AbbVie, Acadia, Accorda, Amneal, Kyowa Kirin, Regenexbio, NQ Medical, Supernus; speaker for AbbVie, Acadia, Accorda, Amneal, CAla Health, Kyowa Kirin, Supernus. K.G.: none. J.M.R.: consulting contracts with Boston Scientific, Monteris, Stryker, and AIM medical robotics. D.M.C.: stock ownership in Medtronic; consultancies with the University of Illinois of Chicago and with Council for Jewish Elderly Senior Life; employed by Northwestern University; honoraria received from the Movement Disorder Society, 2021 Shanghai International Symposium on Medicine in the 21st Century, American College of Sports Medicine, Marianjoy Rehabilitation Hospital, MDS-PAS; recipient of grant funding through the following grants: R01HD075777, U01NS113851, R01NS092950, R01HD091492, R01DK110669, R25HD074546, R01DC017718. S.M.: none. J.J.S.: research grants from Annovis Bio, Sage Therapeutics, Amneal Pharmaceuticals, and The Michael J. Fox Foundation; consulting fees from Medtronic, AbbVie, AlphaOmega, Teva, Nuvelution, and Signant Health; service on data safety monitoring board for BlueRock Therapuetics; advisory board for PhotoPharmics. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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