Bernadette Siddiqi

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 latest column in this series, we explore the importance of addressing barriers to participation for historically underrepresented and marginalized groups.

Despite growing emphasis on increasing diversity in clinical research, the proportion of underrepresented groups (URGs; defined in this study as women and gender minorities, racial and ethnic minorities, individuals earning below a median household income of $57,000, a high-school education or less, and/or rural residents) in Parkinson’s disease (PD) research remains low, with as many as 91% of participants identifying as non-Hispanic Caucasian in various studies.1–3 Although some studies, such as the MJFF online PD research platform Fox Insight (FI), have been designed to reduce or eliminate research barriers for URGs, equitable representation in PD research remains elusive.4 Without diverse inclusion in these trials, estimates of PD disparities in underrepresented populations, which remain poorly understood, may widen.5–7

Although the barriers to PD clinical research among underrepresented populations have been well identified, it remains unclear whether suggested interventions from the existing literature will improve engagement of traditionally underrepresented populations in PD research. For these reasons, MJFF sponsored the Fostering Inclusivity in Research Engagement for Underrepresented Populations in Parkinson’s Disease (FIRE-UP PD) Study to 1) explore whether it is possible to identify best practices to engage URGs in PD clinical research, 2) to assess knowledge and attitudes toward clinical research designs, and 3) to increase participation of URGs to FI.

A request for proposals (RFP) was released for academic medical centers within the Parkinson Study Group research network to participate in FIRE-UP PD. Sites were instructed to identify a specific URG or geographical region to focus on, a specific barrier to PD research participation experienced by this group as categorized by the Picillo PD research barrier framework8, and a specified intervention as categorized by the Picillo et al. framework. Eight participating sites were selected, and were paired based on their proposed interventions and randomly assigned to either intervention or control conditions. Sites in Chicago, Boston, Denver, and Southern Florida were assigned to the intervention condition and were given $45,500 to execute their proposed design, whereas a second site in Chicago, the rural northern Midwest, the greater Seattle metropolitan area, and San Francisco were given $10,000 to serve as passive controls, maintaining their current recruitment workflow. Interventions included developing educational tools and surveys to engage community health centers in PD diagnosis (Boston), partnerships with local PD support groups to discuss PD research (Southern Florida), developing multi-stakeholder alliances and focus groups to create community-specific educational toolkits (Chicago), and recruiting community stakeholders to reimagine medical and research information for the community through a collaborative method called Boot Camp Translation (Denver).

The study was divided into three temporal phases for all sites: pre-intervention, to establish a recruitment baseline; intervention, to deliver a specified intervention or in the case of control sites, to continue passive recruitment activities, and post-intervention, to determine change from baseline. In addition to recruitment measures to FI, the FIRE-UP PD study was designed to collect survey responses from participants with regard to awareness and trust of PD research. Sites collected the Trust in Medical Research Scale (TIMRS), the Patient Engagement in Research Scale (PEIRS) and PD Research Participation Surveys, which assessed specific PD research designs and their impact on participation willingness. All sites also collected barriers to PD research participation, capturing reasons why URG individuals, who would otherwise participate in FIRE-UP PD, could not do so. All sites displayed FI recruitment materials as designed by MJFF and had a dedicated tablet device for FIRE-UP PD surveys and FI registration.

The FIRE-UP PD study enrolled 488 individuals across the eight sites (intervention n=295), while 230 individuals (intervention barrier n=101) faced insurmountable barriers to participation, outlined in 

Changes in trust, measured via TIMRS did not significantly improve for intervention sites relative to control sites, although a trend towards improvement emerged, t(382)=1.80, p=.073.There was no disproportionate change in patient engagement or in overall research participation willingness for intervention relative to control, all ts < 1. However, participant characteristics indicated that intervention site participants were significantly more diverse at both pre- and post-intervention with respect to race, ethnicity, income, and educational attainment.

Diverse accrual to FI (n=181) improved across all sites over the study period relative to sites’ own baselines, although intervention sites significantly improved diversity with respect to race, ethnicity, income, and educational attainment, while control sites improved race and ethnic diversity alone, as seen in 

The FIRE-UP PD study was designed to measure barriers, attitudes, and FI accrual for URG populations accessing PD clinical research. The study suggests that URG recruitment could have increased by as much as 50% if common participation barriers such as language, time, and the digital divide were addressed. Although sampling and selection factors obscured trends in the attitudinal surveys, intervention sites recruited a broadly diverse sample of participants to complete surveys as well as enroll in FI, despite intervention sites’ focus on a single URG. Notably, although control sites were instructed to continue their baseline recruitment activities, nevertheless these sites yielded increased racial and ethnic diversity in FI. This suggests that while targeted interventions may yield substantial benefits to improved diversity of PD research participation, merely orienting to the problem of lack of study representativeness may alter even passive recruitment practices in subtle ways to promote more inclusive research participant cohorts. Developing detailed recruitment protocols that focus on particular URG populations as well as barriers faced by these groups may be a promising addition to PD research, although future studies will need to better understand specific mechanisms of efficacy and comparative effectiveness given similar site and study characteristics.

Schneider MG, Swearingen CJ, Shulman LM, Ye J, Baumgarten M, Tilley BC. Minority enrollment in Parkinson’s disease clinical trials. 

. 2009;15(4):258-262. doi:10.1016/j.parkreldis.2008.06.005

Mainous AG, Smith DW, Geesey ME, Tilley BC. Factors influencing physician referrals of patients to clinical trials. 

. 2008;100(11):1298-1303. doi:10.1016/S0027-9684(15)31508-X

Eskandar EN, Flaherty A, Cosgrove GR, Shinobu LA, Barker FG. Surgery for Parkinson disease in the United States, 1996 to 2000: practice patterns, short-term outcomes, and hospital charges in a nationwide sample. 

. 2003;99(5):863-871. doi:10.3171/jns.2003.99.5.0863

Jang M, Vorderstrasse A. Socioeconomic status and racial or ethnic differences in participation:web-based survey. 

Svenson LW. Regional disparities in the annual prevalence rates of Parkinson’s disease in Canada. 

. 1991;10(4):205-210. doi:10.1159/000110271

Winter AC, Rist PM, Buring JE, Kurth T. Prospective comorbidity-matched study of Parkinson’s disease and risk of mortality among women. 

. 2016;6(9). doi:10.1136/bmjopen-2016-011888

Chan AK, McGovern RA, Brown LT, et al. Disparities in Access to Deep Brain Stimulation Surgery for Parkinson Disease.

. 2014;71(3):291. doi:10.1001/jamaneurol.2013.5798

Picillo M, Kou N, Barone P, Fasano A. Recruitment strategies and patient selection in clinical trials for Parkinson’s disease: Going viral and keeping science and ethics at the highest standards. 

 2015;21:1041-1048. doi:10.1016/j.parkreldis.2015.07.018

, all with CARE Research Center-Massachusetts General Hospital; and 

MJFF and Dr. Jackson would like to acknowledge the following individuals for their contribution to the research presented in this case study: Dr. Michael Schwarzchild (Co-I), Dr. Angie Sanchez (Research Fellow), Ms. Helen Hemley (Project Manager), and the site principal investigators: Dr. Mitra Afshari, Dr. Pinky Agarwal, Dr. Michael Aminoff, Dr. Meagan Bailey, Dr. Katelyn Bird, Dr. Stephanie Bissonnette, Dr. Michelle Fullard, Dr. Tarannum Khan, Dr. Danielle Larson, Catherine Wielinski, MPH, and Karen Williams, MS.

The MJFF Research Engagement Team includes 

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

The Systemic Synuclein Sampling Study (S4) was a multicenter, cross-sectional, observational study sponsored by MJFF. The primary objective of this 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.

In January 2017, MJFF launched a survey to assess the need for transportation infrastructure at clinical trial sites. 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.

Patient retention is an important element of the Parkinson’s Progression Markers Initiative (PPMI), a landmark, longitudinal, observational study sponsored by MJFF. PPMI aims to find reliable and consistent biomarkers for PD progression by studying cohorts of Parkinson’s patients, populations at risk for PD, and controls without PD.

Building a Physician Referral Network: A Case Study

General practitioners often are not involved in the recruitment strategy for clinical trials. Historical barriers have made engagement with physicians challenging. They may fear losing care of patients to clinical trial site providers, be unfamiliar with the trial and principal investigator (PI), or have concerns about jeopardizing the doctor-patient relationship. One approach to building trust and overcoming these obstacles is for research institutions and PIs to actively engage with community physicians.

Articles

Eliminating barriers to engage underrepresented populations.

Importance of Diversity in Parkinson’s Research

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

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.” 

, 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.

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

The Importance of Site Selection

’ 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 fourth column in this series, we explore retention strategies used in a landmark longitudinal Parkinson’s disease (PD) study.

	To complete a study, it is critical to retain study participants. Participant attrition has the potential to interfere with the scientific validity of a study and distort data designed to measure drug efficacy and safety. According to Forte Research:

		Eighty-five percent of clinical trials fail to retain enough participants.

		The average dropout rate across all clinical trials is 30%.

Patient retention is an important element of the Parkinson’s Progression Markers Initiative (PPMI), a landmark, longitudinal, observational study sponsored by The Michael J. Fox Foundation. PPMI (ppmi-info.org) aims to find reliable and consistent biomarkers for PD progression by studying cohorts of Parkinson’s patients (de novo idiopathic PD and PD-manifesting genetic mutation carriers), populations at risk for PD (non-manifesting genetic mutation carriers and subjects at risk due to REM sleep behavior disorder or hyposmia), and controls without PD.

	Participants in PPMI commit to long-term participation, providing biospecimens (e.g., blood, urine, spinal fluid), and undergoing multiple neuroimaging, clinical and behavioral procedures, and assessments over a period of at least five years.

	The study launched in 2010, and since then, approximately 1,500 individuals have enrolled. PPMI’s retention rate has consistently held strong, year after year, at about 86%.

	To ensure steady participation and to prevent attrition, PPMI weaves together four key tenets of retention, cultivated and refined since study launch: 1) facilitate participation; 2) communicate study progress; 3) express appreciation; and 4) inform participants of study results.

Facilitate participation through travel concierge services, reimbursement, and remote visits. 

PPMI study leadership prioritized and simplified long-term participation in large part because individuals carrying specific PD-linked genetic mutations live across a wide geographical area. To facilitate volunteers’ continued participation, PPMI cultivated a boutique experience for them and their care partners. Prospective and enrolled PPMI participants are given the option for complimentary roundtrip transportation between their home and appointments at two “super sites” that have the capacity to handle a high volume of study volunteers.

	A third-party vendor manages all logistical planning, including participants’ accommodations, meals, and travel to and from study visits. This door-to-door service reflects the value PPMI study leadership puts on participation and participants. For participants who choose not to travel to a super site, travel and hotel expenses are reimbursed through Greenphire/ClinCard. PPMI leadership is always looking for ways to reduce participant burden and is currently exploring the possibility of remote (video and enhanced phone) and home visits.

Communicate study progress through newsletters, update calls, and a centralized webpage. 

Reminding participants of the bigger picture is a meaningful way to engage them in the collective success of a study. According to a 2017 report by The Center for Information and Study on Clinical Research Participation,

 the number one reason individuals choose to participate in clinical research is to help advance science or the treatment of a disease or condition. Given this initial motivation, updates on study progress and contributions to the field will facilitate continued engagement. In PPMI, study progress is communicated in several ways:

		PPMI newsletters provide high-level updates on the study (e.g., study enrollment progress, how the data and samples collected are being used for research) as well as interviews or profiles of study participants and/or study staff.

		PPMI update calls, which are scheduled throughout the year, feature presentations and Q&A sessions with study researchers and study team members.

		A PPMI participant webpage allows centralized access to digital versions of the participant newsletters and recordings of study update calls.

		PPMI blog provides regular news about the study, including recent findings that have emerged from the data.

Express appreciation through a thank-you booklet. 

Letters from members of the Parkinson’s community, researchers, MJFF staff, statisticians, and study coordinators were published in a print and digital booklet to thank and honor volunteers for their participation. Collecting the personal reflections of the many individuals involved in or impacted by PPMI is a meaningful way to empower participants and remind them of the larger cause they are tied to.

Inform participants of study results through newsletters, update calls, and a webpage. 

volunteers (90%) want to receive results from the clinical trial in which they participated.

 Because there is ongoing analysis of PPMI data and continued follow up of participants, study results are shared on a rolling basis. Using familiar channels to communicate study progress is a great way to close the loop with study participants.

	PPMI staff and study leadership also show their commitment to the study’s success, and their appreciation for participants, by hosting annual study update luncheons and dinners that incorporate all the tenets of retention. Having an in-person get together gives participants the chance to meet other volunteers and share experiences of living with PD and taking part in PPMI. During these events, local site staff present study progress and provide relevant results from ongoing data analysis. Michael J. Fox Foundation staff also attend and, together, all study stakeholders thank participants for their time and commitment.

Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (

). For up-to-date information on the study, visit 

PPMI-a public-private partnership-is funded by The Michael J. Fox Foundation for Parkinson’s Research and funding partners, including AbbVie, Allergan, Avid Radiopharmaceuticals, Biogen, BioLegend, Bristol-Myers Squibb, Celgene, Denali, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck & Co., Meso Scale Discovery, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, and Voyager Therapeutics.

		Lopienski, Kristina. “Retention in Clinical Trials – Keeping Patients on Protocols.” Forte Research. June 1, 2015. https://forteresearch.com/news/infographic/infographic-retention-in-clinical-trials-keeping-patients-on-protocols	

		The Center for Information and Study on Clinical Research Participation (CISCRP). “2017 Perceptions & Insights Study: Public and Patient Perceptions of Clinical Research.” https://www.ciscrp.org/wp-content/uploads/2019/06/2017-CISCRP-Perceptions-and-Insights-Study-Participation-Experience.pdf	

		Getz, Kenneth. “Events That Have Shaped Study Participant Protection.” The Gift of Participation: a Guide to Making Informed Decisions about Volunteering for a Clinical Trial, 2nd ed., CISCRP, Center for Information & Study On Clinical Research Participation, 2014, pp. 158–158.

, MA, Associate Director; both with The Michael J. Fox Foundation in New York, NY. To contact the MJFF Recruitment and Retention Team, email: 

MJFF would like to acknowledge the following individuals for their contribution to the research presented in this case study: Vanessa Arnedo, MPH, Sarah Berk, MPH, Sohini Chowdhury, MA, Tara Hastings, MA, Catherine M. Kopil, PhD, and Alyssa Reimer.

A case study of the Parkinson’s Progression Markers Initiative.

Retention Strategies for Keeping Participants Engaged

Physicians play a critical role in facilitating patient participation in clinical research.

 In fact, a poll by Research!America found that 72% of respondents would participate in a trial if their doctor recommended it.

 However, general practitioners often are not involved in the recruitment strategy for clinical trials. Historical barriers have made engagement with physicians challenging. They may fear losing care of patients to clinical trial site providers, be unfamiliar with the trial and principal investigator (PI), or have concerns about jeopardizing the doctor-patient relationship.

 One approach to building trust and overcoming these obstacles is for research institutions and PIs to actively engage with community physicians. Reaching out to local physicians to increase knowledge about trials and generate confidence can facilitate referrals. We explore this theme in our third column in 

	The Institute for Neurodegenerative Disorders (IND) serves as a prime example of how research institutions can better engage with community physicians to build referral networks. Founded in New Haven, Conn., in 2001, IND develops diagnostic tools and treatments for individuals with neurodegenerative disorders. Its founders, Kenneth Marek, MD, and John Seibyl, MD, bucked the traditional research institution model. Foregoing regular clinic hours, they focused instead entirely on clinical research studies. This novel approach meant that trials conducted at IND had to rely heavily on patient referrals from community clinicians.

	Through several years of dedicated outreach to clinicians in the community, IND built a referral network of neurologists located across Connecticut. As a result, the top two referral sources for trials at IND are: 1) new patient referrals from community clinicians, and 2) a database of patients referred to past IND studies. This resource of patient referrals has made IND a top recruiting site for Parkinson’s disease (PD) studies, including the 

Parkinson’s Progression Marker Initiative

, a longitudinal observational study sponsored by The Michael J. Fox Foundation. IND may seem uniquely positioned for success in the development of a physician referral network, but Director of Clinical Research David S. Russell, MD, PhD, believes that traditional research institutions can easily replicate these efforts. Dr. Russell outlines a three-tiered strategy to facilitate engagement and long-term relationship building among community physicians:

Learn about the practices in your community

	To maximize your time and effort, do online research about local practices. Begin with clinics that are most likely to see individuals with the condition you seek. For IND, neurologists historically have provided the most referrals for their neurodegenerative disease studies. Consider connecting with primary care physicians and allied healthcare professionals, but prioritize specialty physicians as they may more frequently engage with your target population.

Understand the needs of community clinicians

	Ask physicians about challenges they may be facing in their practices. For example, a community neurologist may be having difficulties diagnosing a patient. Offer to provide an expert second opinion and send your recommendations. Point out research studies that include procedures and assessments that physicians may find useful to treat their patients. For instance, Dr. Russell has found that community physicians often seek DaTscans for their PD patients. In addition, explain the various patient wellness programs available at your site, such as support groups, education events, and fitness/wellness classes. Patients can learn about recruiting trials at your study site through these programs.

	In addition to sharing the latest in PD research and recruiting trials, remind community physicians that these studies are necessary for the discovery of biomarkers and new and improved treatments. Physicians want the best care for their patients. Reminding them of the importance of clinical research in this process may motivate them to provide referrals. Explain that clinical trials give patients treatment options and access to certain procedures, such as a imaging, at no cost.

	Developing a partnership with community physicians cannot be done overnight. It took years for IND to forge the relationships it has today. At the outset of building a referral network, remember it will take time and effort to be successful.

	When trying to engage with community clinicians, there is no substitute for a face-to-face meeting. Begin by calling the practices you have identified. Introduce yourself, provide them with background on your research, and let them know that you are trying to generate awareness about research studies at your institution. Invite the clinician(s) to your office for a discussion with other medical providers from the community about the latest advances in research and any trials that are currently recruiting. Maximize your time and the number of physicians you can connect with by hosting the meeting in your office or another location that can accommodate a bigger group. If a physician rejects the invitation, be persistent and ask for times that you can drop by their office.

	Make the process of referring patients as simple as possible. Give local practices study flyers and brochures for patients to read in the waiting room and discuss with their doctor. Provide physicians with pocket cards listing high-level eligibility criteria to quickly reference when examining patients. Avoid presenting community clinicians with eligibility criteria not usually gathered through standard clinical care, such as scales and questionnaires used in clinical trials. Physicians may rule out patients if they are unfamiliar with some eligibility criteria. Supply practices with a fax referral form to easily send contact information and a note about interested patients. Obtain patients’ contact information, with their permission; this is faster and more efficient than waiting for patients to call the research site.

	Assure community clinicians that your intention is to expand awareness about research opportunities and help interested patients find a study that is right for them. To alleviate fears that they may lose patients to healthcare providers at your institution, consider the following language: “We will provide only the care necessary to conduct the trial and to ensure patient safety. We will refer the patient back to you for any clinical issues.”

	Update referring clinicians about their patients on a regular basis. If a patient is not eligible for any recruiting studies at the site, send the referring physician a note expressing your gratitude for the referral and explain why the individual was ineligible. If a referred patient is a study candidate, inform their doctor and make yourself available to answer questions. Upon enrolling a referred patient into a study, send their physician an email or letter explaining any medical precautions or exclusionary medications. After a patient is enrolled, provide the referring physicians with updates around milestones, such as a patient’s test results and study withdrawal and/or completion. Consider organizing a group meeting or webinar to explain study results to all referring physicians.

Reinvigorate your physician referral network

	Building a referral network is an ongoing process. Physicians leave practices and new ones are added. It is important to develop new partnerships and maintain existing relationships. IND invites community clinicians from across Connecticut to dinner twice a year to discuss advances in Parkinson’s research and new treatments or challenges in the field. A biannual webinar also can serve as an alternative to an in-person meeting. Remember to express gratitude to physicians in your network for their continued commitment to advancing research.

	While there is no denying that building a physician referral network takes time and dedication, expanding research awareness to more clinicians and ultimately more patients can help accelerate recruitment for clinical trials.

For more information on the Institute for Neurodegenerative Disorders and its work, visit 

		Getz, Kenneth A. “Enabling Healthcare Providers as Facilitators of Patient Engagement.”

http://www.appliedclinicaltrialsonline.com/print/343713?page=full

		Staff Reports, Research!America. “Poll: Majority of Americans Would Participate in Clinical Trials if Recommended by Doctor.” Elsevier. July 31, 2013, 

https://www.elsevier.com/connect/poll-majority-of-americans-would-participate-in-clinical-trials-if-recommended-by-doctor

		Ramirez, Amelie G. et al. “Early Phase Clinical Trials: Referral Barriers and Promoters among Physicians.” 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782313/

		Michaels, Margo, et al. “Impact of Primary Care Provider Knowledge, Attitudes, and Beliefs about Cancer Clinical Trials: Implications for Referral, Education and Advocacy.” 

, MA, Associate Director; both with The Michael J. Fox Foundation in New York, NY. To contact the MJFF Recruitment and Retention Team, email: 

MJFF would like to acknowledge the following individuals for their contribution to the research presented in this case study: David S. Russell, MD, PhD; Sarah Berk, MPH; and Catherine M. Kopil, PhD.

Exploring the Institute for Neurodegenerative Disorders’ non-traditional approach to engaging community physicians.

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 second column in the series, we explore how one study team implemented a multimodal recruitment strategy to meet their target enrollment six months ahead of schedule.

	STEADY-PD III was a 36-month, double-blind, randomized, placebo-controlled study of isradipine, a repurposed antihypertensive drug, in people with early Parkinson’s disease (PD). The projected recruitment period was 18 months at 57 academic research sites across North America.

	STEADY-PD III aimed to enroll 336 men and women with early-stage idiopathic PD. Participants had to be older than 30 at the time of diagnosis, diagnosed less than three years prior, and not receiving PD symptomatic therapy (e.g., levodopa, dopamine agonist or MAO-B inhibitor) or projected to require symptomatic therapy for at least three months from baseline visit. To participate in the study, eligible participants agreed to be followed for up to 36 months and complete 12 in-person visits and four telephone visits. The projected recruitment period of 18 months was based on previously completed studies that targeted a similar PD population.

	Early in the planning process, the STEADY-PD III team identified and engaged key stakeholders from across the recruitment landscape to provide input on constituent motivations, knowledge gaps, and outreach methods. This group, the recruitment committee, consisted of:

		Site representatives (investigator and/or coordinator)

		A representative from The Michael J. Fox Foundation (MJFF)

		A representative from the National Institute of Neurological Disorders and Stroke (NINDS)

	
	The recruitment committee consulted with other national PD organizations, including the National Parkinson Foundation (NPF) and the Parkinson Disease Foundation (PDF), which have since merged to form the Parkinson’s Foundation.

	With this guidance, the committee developed a multi-modal recruitment strategy aimed at educating individuals in the PD community about STEADY-PD III and increasing awareness of resources related to the trial. This strategy was implemented through 1) in-person meetings and events with community groups, physician networks, and support groups; and 2) development of a heightened online presence using mixed media outlets. MJFF’s 

Recruitment and Retention Toolkit materials

, such as a “Physician Referral Letter” and a “Patient-Facing Slide Deck,” facilitated outreach efforts, as did grassroots patient engagement through patient organizations.

	A greater online presence was cultivated through 1) creation of a study-specific website (

); 2) press releases (templates were provided to sites) posted to websites such as NINDS; 3) use of Fox Trial Finder-MJFF’s online trial matching service that enables the Parkinson’s community to connect with trial teams (

); and 4) webinars and podcasts hosted by the STEADY-PD III study principal investigators and broadcast to the networks of patient organizations. Throughout the enrollment period, the recruitment committee met monthly to review recruitment strategies, monitor enrollment at the study and site level, and identify challenges and solutions to any recruitment issues.

	A study enrollment report (see Figure 1 above), generated after all participants had been recruited, shows a steeper slope of actual vs. anticipated enrollment, reflecting a recruitment period accelerated by six months. In addition, the pre-specified goal of 10% minority recruitment was met. Analysis of MJFF communications that took place prior to and throughout the recruitment period provides insight into the role of mixed media in generating awareness of the trial and directing individuals to resources for learning more about participation. In March 2014, MJFF, with study leadership, released a podcast that reported isradipine was moving to Phase III testing, and recruitment would begin later that same year. The podcast was downloaded by 2,043 iTunes listeners. This was 

followed by an uptick in traffic to the STEADY-PD III website that began in May 2014 and peaked in July 2014 (see Figure 2; click to enlarge). One of the steepest peaks occurred in January 2015, after a December 2014 MJFF webinar that focused on therapies with the potential to slow or stop Parkinson’s progression and highlighted the STEADY-PD III trial. A third peak took place in November 2015, after an October 2015 MJFF webinar and podcast on studies to slow or stop PD.

	A multitude of subject referral sources bolstered STEADY-PD III recruitment success (see Figure 3; click to enlarge). 

Referral sources were recorded at the time of screening and logged into case report forms. These data indicate the top four referral sources were site personnel (53%); neurologists (24%); Fox Trial Finder (10.2%); and MJFF communications (3.9%).

	By having a comprehensive recruitment plan and involving key stakeholders early in the planning phase of the clinical trial, STEADY-PD III was able to successfully recruit its full target population six months ahead of schedule. They identified study- and site-level barriers that had the potential to negatively impact recruitment, and were able to develop a strategy to mitigate them. One important component of that strategy was implementation of a comprehensive outreach and awareness campaign. Patient engagement via advocacy organizations; local events including the Brain and Health Fair and the annual Parkinson’s Unity Walk; the power of digital media through webinars and press releases; technology such as Fox Trial Finder to connect volunteers to trial teams; and increased participation of historically underrepresented minority populations with community engagement, translation of materials, and outreach through local publications such as the “Southwestern Parkinson’s Newsletter.” The use of local grassroots events and digital media activities, combined with a proactive approach to recruitment, helped to engage and make aware a broader population than would have been possible for clinical trial sites alone. This approach also enabled study teams to connect with a more diverse population of patients who obtained their information from a variety of media and news sources. While the impact of these efforts is somewhat challenged by self-reported referral source data (see Figure 3), we posit that this is less about the efficacy of these efforts and more about challenges stemming from memory recall bias in referral source attribution. Greater efforts such as interviewer training, better referral source definition, and alternative means of data collection should be considered for future recruitment campaigns to improve the accuracy of attribution.¹

	1. E Hassan. “Recall Bias can be a Threat to Retrospective and Prospective Research Designs.” 

, MA, is an Associate Director on the Recruitment and Retention team at The Michael J. Fox Foundation for Parkinson’s Research. To contact the MJFF Recruitment and Retention Team, email: trialsupport@michaeljfox.org.

MJFF would like to acknowledge the following individuals for their contribution to the research presented in this case study: Sarah Berk, MPH; Kevin Biglan, MD, MPH; Brittany L. Greco; Robert G. Holloway, MD, MPH; Catherine M. Kopil, PhD; Claire Meunier, MBA; and Tanya Simuni, MD