Catherine M. Kopil

A case study focused on the quest for a potential Parkinson’s biomarker highlights the opportunities and challenges in site selection

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) aims to speed clinical research by removing obstacles that stand in the way of drug development. In pursuit of this mission, the Foundation gathers insights from a wide range of stakeholders and uses these perspectives to enhance clinical trial processes from start to finish. In 

Eye on Patient Advocacy series, we will share best practices and lessons learned from the field of Parkinson’s research that can be applied to clinical trials across disease states. In our sixth column in this series, we explore the importance of site selection for study success.	 

	The Systemic Synuclein Sampling Study (S4) was a multicenter, cross-sectional, observational study sponsored by The Michael J. Fox Foundation for Parkinson’s Research. The primary objective of the study was to better understand the progression of Parkinson’s disease (PD) by identifying the optimal biofluids and tissues for measuring the protein alpha-synuclein outside of the brain as a potential biomarker in individuals with PD. The secondary objective of the study was to create standard operating procedures for the collection and assessment of multiple tissues and biofluids to better understand alpha-synuclein’s potential as a biomarker for PD.

	S4 sought to enroll 80 participants meeting the following characteristics (with target enrollment of 20 participants in each category) :

		Individuals with early PD not requiring dopamine replacement therapy.

		Individuals with moderate PD on dopamine replacement therapy without motor fluctuations

		Individuals with advanced PD with motor fluctuations.

	The following section provides a condensed overview of the procedures that study participants underwent as part of S4. For additional information on the procedures and scientific rationale used in the study, please refer to the S4 peer-reviewed publications listed at the end of this article.

		Study staff informed and consented study participants for participation (i.e., study purpose, procedures, potential risks, and benefits were explained, and consent to participate was obtained). Their medical and family histories and any medications were reviewed. Participants’ vital signs were taken, and a general physical and neurological exam were performed. All participants completed MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Hoehn and Yahr scale (H&Y), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson’s Disease.

		Autonomic Dysfunction (SCOPA-AUT) and University of Pennsylvania Smell Identification Test (UPSIT). Individuals with PD received Modified Schwab & England Activities of Daily Living Scale and PD stage assignment.

Biofluid collection and skin biopsy visit

		Whole blood, serum, and plasma were collected through routine venipuncture.

		Cerebrospinal fluid was collected through lumbar puncture under local anesthesia.

		Saliva was collected through 20-minute active drool collection.

		Approximately four samples of thigh and upper back/shoulder skin were biopsied using skin punch under local anesthesia.

		Approximately eight samples of colonic tissue were biopsied from study participants using routine clinical procedures.

		Approximately five samples of submandibular (type of salivary) gland tissue were biopsied using a 16-gauge needle inserted through the neck under local anesthesia.

	The number and type of procedures, as well as the variation in recruitment target population, made the S4 research protocol highly complex. The S4 Steering Committee was aware that this was a potential barrier to successful study implementation and determined that careful selection of sites would help to mitigate this issue. To enhance the site-selection process, the S4 Steering Committee: 1) identified and prioritized site-level characteristics necessary for study implementation; 2) developed a checklist to evaluate sites in person; and 3) conducted in-person site visits.

Identified and prioritized site-level characteristics

	The characteristics identified by the S4 team as most critical to study implementation were:

		Site personnel experience in implementing clinical studies that involve collecting biospecimens.

		Access to the population(s) of interest.

	Each of these characteristics addressed an area of complexity in the research protocol. Experienced site personnel provided additional confidence around the ability to conduct study procedures that were both precise and invasive. Strong site infrastructure ensured that samples were collected in a standardized manner and mitigated concerns around data quality. Access to the population(s) of interest ensured greater success in recruitment and reduced trial delays. This information was assessed by asking invited clinical sites to complete a site interest form. The forms were then evaluated and prioritized by the S4 Steering Committee.

	The S4 Steering Committee created a checklist that was broken out by the three priority characteristics (experience, site-level infrastructure, and access to the population of interest). Within these categories, specific criteria were listed that provided a measure of how well the site ranked on that characteristic (level of experience, type of equipment, access to storage, etc.).

	S4 Steering Committee members visited each of the sites under consideration based on their responses to the site interest form and, using the checklist, evaluated them on the priority characteristics. Sites were selected to participate in the S4 study if they adequately met the criteria for participation, including documented experience collecting biospecimens from a PD population, site infrastructure requirements (such as collaborations with gastroenterologists and ear nose and throat specialists), and recruitment plans for the population of interest.

	S4 was able to recruit its full target population in a timely manner: 82 individuals were recruited to participate in S4 within 21 months (see Table 1). Although recruitment for the trial took three months longer than originally projected, the S4 Steering Committee considered this to be successful, particularly taking into account the harder-to-reach target population and complex protocol.

	While a comprehensive site-selection process may require a significant investment of time and resources at the outset, the benefits may outweigh the long-term risks (e.g., study delays, additional financial resources, high attrition rates, inability to meet enrollment goals).

 Developing a checklist such as the one used by the S4 Steering Committee can facilitate the site-selection process and lead to more open lines of communication between study sponsors and sites. Sites have an opportunity to share their interest, background, and experience, and sponsors can dig deeper into questions they may have about the ways which the protocol and operating objectives align.

To learn more about the S4 study, see the following peer-reviewed publications:

Chahine LM, Beach TG, Seedorff N, et al. Feasibility and Safety of Multicenter Tissue and Biofluid Sampling for a-Synuclein in Parkinson’s Disease: The Systemic Synuclein Sampling Study (S4). Journal of Parkinson’s Disease, in press. 2018

Beach TG, Serrano GE, Kremer T, et al. Systemic Synuclein Sampling Study (S4). Immunohistochemical Method and Histopathology Judging for the Systemic Synuclein Sampling Study (S4). J Neuropathol Exp Neurol. 2018 Aug 13. doi: 10.1093/jnen/nly056.

Visanji NP, Mollenhauer B, Beach TG, et al. Systemic Synuclein Sampling Study (S4). The Systemic Synuclein Sampling Study: toward a biomarker for Parkinson’s disease. Biomarkers in Medicine. 2017;11(4):359-368.

		Beth Harper and David Zuckerman. “Critical Success Factors for Planning for Site Selection and Patient Recruitment Planning.” 

The MJFF Research Engagement Team includes 

, Research Partnerships Officer; all at The Michael J. Fox Foundation in New York, NY. To contact the MJFF Research Engagement Team, email: 

MJFF would like to acknowledge the following individuals for their contribution to the research presented in this case study: Lana Chahine, MD (Co-PI), Sherri Mosovsky, Brit Mollenhauer, MD, PhD (Co-PI), Danna Jennings, MD (ex oficio), John Seibyl, MD, Vanessa Arnedo, Lindsey Riley, Kuldip Dave, PhD,Tatiana Foroud, PhD, Thomas Beach, MD, Charles Adler, MD, PhD, Chris Coffey, PhD, Dixie Ecklund, RN and the Systemic Synuclein Sampling Study (S4); and Sarah Berk, MPH.

Articles

Case study focused on quest for potential Parkinson’s biomarker highlights opportunities and challenges in site selection.

The Importance of Site Selection

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) aims to speed clinical research by removing obstacles that stand in the way of drug development. In pursuit of this mission, the Foundation gathers insights from a wide range of stakeholders and uses these perspectives to enhance clinical trial processes from start to finish. In

’ Eye on Patient Advocacy series, we will share best practices and lessons learned from the field of Parkinson’s research that can be applied to clinical trials across disease states. In our fifth column in this series, we explore the use of a ride-sharing service to reduce transportation barriers for research participation.

	In January 2017, The Michael J. Fox Foundation launched a survey to assess the need for transportation infrastructure at clinical trial sites. Using Fox Trial Finder, MJFF’s online clinical trial matching tool, 843 clinical trial sites in the U.S. were contacted to understand how transportation access impacts participant recruitment, and what kind of transportation participants would find most helpful. Of the 49 sites that responded, 95% reported that transportation infrastructure would improve recruitment efforts, and 63% felt it would ensure all studies recruited on time. Eighty-four percent of respondents reported that a taxi, livery, or ride-sharing service partnership would be the preferred transportation infrastructure.

	Data from the survey was used to inform the design of a transportation intervention that was tested via the Parkinson’s Disease Trial Recruitment Innovation (PD-TRI) project, an MJFF-funded pilot study aimed at reducing barriers and enhancing facilitators to clinical trial recruitment.

	To participate in PD-TRI, project sites had to be based in the U.S., be geographically diverse, and have large clinical research portfolios. One of the three selected sites, Beth Israel Deaconess Medical Center (BIDMC) in Boston, MA, elected to implement a partnership with a ride-sharing service. The study principal investigators, Samuel Frank, MD, and David K. Simon, MD, PhD, felt that providing round-trip transportation to research appointments would alleviate stress and logistical challenges for study participants (e.g., finding parking, relying on a care partner for transportation, transportation costs).

	BIDMC used a template to collect data on the cost of the service and the coordinator time required to arrange it, and assess the impact of the transportation service on recruitment. BIDMC also used a study satisfaction survey to gather insights on participants’ experience in the study and use of the transportation service. (To view and download an example of a study satisfaction survey, visit 

	To partner with a ride-sharing service, BIDMC signed a terms-of-service agreement and implemented a payment system. To use the service, coordinators worked with each study participant to determine a pickup location. The coordinator then arranged the ride in advance using a simple web portal. This removed the need for study participants to have a smartphone or online connection. After completing the ride, the ride service could either charge an institutional credit card or send a monthly invoice to the clinical trial site, thereby removing the stress or logistics of reimbursement from the study participant.

	To protect patient privacy, the ride service allows sites to provide an alias or only the patient’s first name when requesting rides. If a site happens to provide a person’s full name, the driver receives only the first name and last initial. Moreover, passenger information disappears from the driver’s phone once the ride is complete. To ensure the ride-sharing service was ethical and compliant with patient privacy regulations, BIDMC developed a protocol describing the service that was approved by its institutional review board (IRB).

	After a preliminary phone screening to determine study eligibility, individuals were offered rides via the ride service. Data on individual acceptance of transportation, cost and timeliness of rides, and coordinator time spent arranging rides were collected via the template. Participants filled out a study satisfaction survey at their baseline visit to assess the impact of transportation on their decision to enroll in the study.

	Data from the BIDMC and ride-sharing partnership are provided in Table 1 and Figure 1. Data from only one BIDMC study are provided, as recruitment for other studies was limited during the PD-TRI study.

	Results provide insights into the impact of providing transportation on clinical trial recruitment efforts:

		Individuals who live farther from the clinical trial site seem more likely to accept rides, indicating that transportation infrastructure may help clinical trial sites engage with harder to reach populations and broaden their recruitment networks.

		While providing transportation may seem expensive, the average round trip cost (two rides) is $96.37. This figure is quite small in comparison to the average total costs of a Phase III clinical trial (between US $11.5 million [dermatology] and US $52.9 million [pain and anesthesia]).

		Coordinators spend a minimal amount of time and effort to coordinate rides, and from the patient satisfaction surveys, this service appears to provide a great amount of benefit to study participants. Providing this service may help mitigate study attrition.

		Although study participants indicated that they likely would have participated in the current clinical study even without being offered transportation, they responded very positively to the service, with all participants reporting that the rides made it easier for them to attend appointments. This suggests that the provision of transportation could improve participant retention in a study. Also, 90% of respondents agreed or strongly agreed that they would be more likely to participate in another study in the future if transportation were provided. This indicates that providing transportation not only helps recruitment, but also is an asset for long-term community engagement.

		Third-party ride services can be used in a manner that protects participant confidentiality.

Key considerations for sites contemplating transportation partnerships

		Clinical sites seeking to establish a partnership with a transportation service should request contractual materials from the potential partner, share these with internal grants administrators for review, and seek IRB approval.

		Factor in additional time prior to study start-up for contract negotiations and testing any software or processes associated with the partnership. An institution-wide contract with a ride-sharing service may take significantly longer to implement than one for a single study.

		Develop detailed protocols that determine when and how often individuals will be offered rides, and whether they will be offered transportation for visits throughout the full duration of the study.

		Create systems to evaluate your transportation service and determine how it impacts recruitment at your site.

	To learn more about this transportation pilot, read the “Transportation Innovation to Aid Parkinson’s Disease Trial Recruitment” publication in 

Contemporary Clinical Trials Communications

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804741/

		Sertkaya, A, et al. “Key cost drivers of pharmaceutical clinical trials in the United States.” 

. 2016 Apr;13(2):117-26. doi: 10.1177/1740774515625964. Epub Feb 8, 2016.

		Frank, S, et al. “Transportation innovation to aid Parkinson disease trial recruitment.” 

. 2019 Sep 10;16:100449. doi: 10.1016/j.conctc.2019.100449. eCollection Dec 2019.

MJFF would like to acknowledge the following individuals for their contribution to the research presented in this case study: Samuel Frank, MD, David K. Simon, MD, PhD, Laura Hernandez, Holly Shill, MD, Penelope Hogarth, MD, and Sarah Berk, MPH.

Recruitment study tests the use of a ride-sharing service.

Catherine M. Kopil

Articles

The Importance of Site Selection

Overcoming Transportation Barriers to Trial Participation